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Pharmaceutical and Pharmacological Evaluation of the Effect of Nano-Formulated Spironolactone and Progesterone on Inflammation and Hormonal Levels for Managing Hirsutism Experimentally Induced in Rats
Reham I. Amer, Ghada E. Yassin, Reem A. Mohamed & Ahmed M. Fayez
doi : 10.1208/s12249-021-02003-z
22, Article number: 204 (2021)
Hirsutism is a dermatological condition that refers to the excessive growth of hair in androgen-sensitive areas in women. Recently, the enhancement of the visible signs of a hairy female has taken special concern that affected the quality of life. The present study was developed to compare the follicular targeting effect of topical spironolactone (SP) or progesterone (PG)-loaded nanostructured lipid carrier (NLC) on the management of hirsutism. Four NLC formulations were prepared using cold homogenization techniques and pharmaceutically evaluated. SP-NLC and PG-NLC topical hydrogels were prepared to explore their pharmacological effect on letrozole induced polycystic ovarian syndrome (PCOS) in rats. Inflammatory mediators, antioxidant, and hormonal parameters were assayed. Additionally, histopathological examination was carried out to confirm the successful induction of PCOS. Results confirmed that all NLC formulations have a spherical shape with particle size ranged from 225.92 ± 0.41 to 447.80 ± 0.66 nm, entrapment efficiency > 75%, and zeta potential (? 31.4 to ? 36.5 mV). F1 and F3 NLCs were considered as selected formulations for SP and PG, respectively. Female Wistar rats treated with F1 formulation for 3 weeks displayed better outcomes as manifested by the measured parameters as compared to the other tested groups. A significant reduction in hair follicle diameter and density was observed after topical application of SP or PG nano-gels. Finally, the outcomes pose a strong argument that the development of topically administered SP-NLC can be explored as a promising carrier over PG-NLC for more effectual improvement in the visible sign of hirsutism.
Capsanthin, a Plant-Derived Xanthophyll: a Review of Pharmacology and Delivery Strategies
Leenet Edward Kennedy, Annie Abraham, Gunjan Kulkarni, Navya Shettigar, Tanika Dave & Madhur Kulkarni
doi : 10.1208/s12249-021-02065-z
22, Article number: 203 (2021)
Capsanthin, a brightly orange-red–coloured pigment responsible for the peculiar red colour of paprika fruits (Capsicum annuum), belongs to xanthophylls, a class of oxygen-containing carotenoids. The characteristic chemical structure of capsanthin containing a keto group in conjunction with a long chain of 11 conjugated dienes is responsible for its strong radical scavenging and singlet oxygen quenching ability. Chemopreventive, antitumour, skin photo-protective, anti-inflammatory, and antidiabetic activities demonstrated by capsanthin are a consequence of its potent antioxidant action. Anti-obesity, anti-adipogenic, and antihyperlipidaemic activities are some of the more important features of capsanthin. With natural origin, bright red colour, and array of health benefits, capsanthin has a potential to be translated into a commercial cosmeceutical, nutraceutical, and/or pharmaceutical. However, the very low aqueous solubility of capsanthin is responsible for its highly variable and poor oral bioavailability. Moreover, its susceptibility to degradation due to heat, light, oxygen, and moisture poses challenges in the development of stable formulations for this otherwise meritorious compound. The current review presents various pharmacological activities of capsanthin and their underlying mechanisms. The review further discusses hitherto explored formulation strategies to improve solubility and stability of capsanthin.
Nebulization of Risedronate Sodium Microspheres for Potential Attenuation of Pulmonary Emphysema: a Promising New Insight of Alveolar Macrophage Apoptosis
Omar A. Elkady, Layla M. Saleh, Mina Ibrahim Tadros & Hanan M. El-laithy
doi : 10.1208/s12249-021-02078-8
22, Article number: 202 (2021)
Risedronate sodium (RS) is a potent nitrogen-containing bisphosphonate which is known to induce osteoclast apoptosis. As a drug repurposing approach, the current work explored the potential of nebulizable RS-chitosan (CS) microspheres to induce alveolar macrophage apoptosis. RS-CS microspheres were assessed for lung deposition, cytotoxicity, and cellular uptake percentage in Calu-3 cells. The potential of nebulizable microspheres for treating elastase-induced emphysema in rats was investigated, compared to RS marketed oral tablets®, with respect to histopathological, immunohistochemical, and flow cytometric studies. The in vitro lung deposition pattern suggested deep alveolar deposition of RS microspheres, with respect to high FPF% and suitable MMAD (66% and 1.506 ?m, respectively, at a flow rate of 28.3 L min?1). No apparent cytotoxicity was observed, with a cell viability > 90%. The inhalation of RS-CS microspheres was suggested to inhibit airspace enlargement and lung rarefaction after elastase instillation and reduce the macrophage accumulation in alveolar parenchyma. Immunohistochemical and cytometric analyses revealed significant low expression levels of CD68 and CD11b surface markers, respectively, with significantly (P < 0.05) lower detected numbers of intact alveolar macrophages following inhalation of RS-CS microspheres. The nebulization of RS-CS microspheres could induce apoptosis in alveolar macrophages and be promisingly adopted for attenuation of pulmonary emphysema.
Preparation and Characterization of Co-Processed Mannitol and Sorbitol Using NanoCrySP Technology
Srilaxmi G. Rao, Prashantkumar K. Parmar, Katangur Vishruth Reddy & Arvind K. Bansal
doi : 10.1208/s12249-021-02071-1
22, Article number: 201 (2021)
Particle engineering of excipients, at sub-particulate level using co-processing, can provide high functionality excipients. NanoCrySP technology has been recently explored as a novel approach for the generation of nanocrystalline solid dispersion of poorly soluble drugs, using spray drying process. The purpose of the present study was to generate co-processed mannitol and sorbitol (SD-CSM) using NanoCrySP technology having similar composition to commercial co-processed excipient (Compressol® SM, CP). The characterization of excipients was performed to evaluate their various physicomechanical properties. The sub-micron crystallite size of sorbitol in the matrix of mannitol was determined using the Williamson-Hall equation and Halder-Wagner equation. The reduction in crystallite size of sorbitol and mannitol, lower melting point, and lower heat of fusion of SD-CSM could be responsible for excellent compactibility, better tabletability, and comparable compressibility with respect to CP. This was confirmed by the compressibility-tabletability-compactibility (CTC) profile and Heckel plot analysis. Overall, SD-CSM generated using NanoCrySP technology improved functionalities of excipients over CP and would be useful for direct compression application.
Oral Administration of Melatonin or Succinyl Melatonin Niosome Gel Benefits 5-FU-Induced Small Intestinal Mucositis Treatment in Mice
Prangtip Uthaiwat, Aroonsri Priprem, Sirinart Chio-Srichan, Chatri Settasatian, Yao-Chang Lee, Pramote Mahakunakorn, Patcharee Boonsiri, Chanvit Leelayuwat, Patcharaporn Tippayawat, Ploenthip Puthongking & Jureerut Daduang
doi : 10.1208/s12249-021-01941-y
22, Article number: 200 (2021)
Mucositis is one of the most adverse effects of 5-fluorouracil (5-FU) and had no standard drug for treatment. Melatonin is a neurohormone, and can ameliorate radiotherapy-induced small intestinal mucositis. Melatonin encapsulated in niosomes improved its poor bioavailability. Succinyl melatonin, a melatonin derivative, showed prolonged release compared with melatonin. This study investigated the efficacy of melatonin niosome gel (MNG) and succinyl melatonin niosome gel (SNG) in 5-FU-induced small intestinal mucositis treatment in mice. MNG and SNG with particle sizes of 293 and 270 nm were shown to have mucoadhesive potentials. The effect of a daily oral application of MNG, SNG, or fluocinolone acetonide gel (FAG, positive control) was compared to that of the normal group. The body weight, food consumption, histology, Fourier transform infrared (FTIR) spectroscopy, inflammatory cytokines (tumor necrosis factor (TNF)-? and interleukin (IL)-1?), and malondialdehyde (MDA) in the small intestine were monitored. The results showed decreased %body weight and food consumption in all 5-FU-injected groups compared with the normal group. The MNG and SNG treatments maintained the food consumption and the normal integrity of the small intestines, as evidenced by villus length and crypt depth, similar to the observations in the normal groups. The FTIR spectra showed no change in lipids of the MNG and SNG groups compared with the normal group. Moreover, SNG could reduce IL-1? content to a level that was not different from the level in the normal groups. Therefore, the oral application of MNG and SNG could protect against 5-FU-induced small intestinal mucositis in mice.
Solid-in-Oil-in-Water Emulsion: An Innovative Paradigm to Improve Drug Stability and Biological Activity
Anali Sawant, Seema Kamath, Hemanth KG & Girish Pai Kulyadi
doi : 10.1208/s12249-021-02074-y
22, Article number: 199 (2021)
An emulsion is a biphasic dosage form comprising of dispersed phase containing droplets that are uniformly distributed into a surrounding liquid which forms the continuous phase. An emulsifier is added at the interface of two immiscible liquids to stabilize the thermodynamically unstable emulsion. Various types of emulsions such as water-in-oil (w-o), oil-in-water (o-w), microemulsions, and multiple emulsions are used for delivering certain drugs in the body. Water (aqueous) phase is commonly used for encapsulating proteins and several other drugs in water-in-oil-in-water (w-o-w) emulsion technique. But this method has posed certain problems such as decreased stability, burst release, and low entrapment efficiency. Thus, a novel “solid-in-oil-in-water” (s-o-w) emulsion system was developed for formulating certain drugs, probiotics, proteins, antibodies, and tannins to overcome these issues. In this method, the active ingredient is encapsulated as a solid and added to an oil phase, which formed a solid-oil dispersion. This dispersion was then mixed with water to form a continuous phase for enhancing the drug absorption. This article focuses on the various studies done to investigate the effectiveness of formulations prepared as solid-oil-water emulsions in comparison to conventional water-oil-water emulsions. A summary of the results obtained in each study is presented in this article. The s-o-w emulsion technique may become beneficial in near future as it has shown to improve the stability and efficacy of the entrapped active ingredient.
Effect of Chemical Penetration Enhancer-Adhesive Interaction on Drug Release from Transdermal Patch: Mechanism Study Based on FT-IR Spectroscopy, 13C NMR Spectroscopy, and Molecular Simulation
Zheng Luo, Chao Liu, Peng Quan, Yimeng Zhang & Liang Fang
doi : 10.1208/s12249-021-02055-1
22, Article number: 198 (2021)
Chemical penetration enhancers (CPEs) are commonly added into transdermal patches to impart improved skin permeation of drug. However, significant unexplained variability in drug release kinetics in transdermal patches is possible as a result of the addition of CPEs; investigations into the underlying mechanisms are still limited. In the present study, a diverse set of CPEs was employed to draw broad conclusions. Solubility parameters of CPEs and acrylate pressure-sensitive adhesive were calculated by molecular dynamics simulation and Fedors group contribution method to evaluate drug-adhesive miscibility. CPE-adhesive interaction was characterized by FT-IR study, 13C NMR spectroscopy, and molecular docking simulation. Results showed that release enhancement ratio (ERR) of CPEs for zolmitriptan was rank ordered as isopropyl myristate > azone > Plurol Oleique® CC497 > Span® 80 > N-methylpyrrolidone > Transcutol® P. It was found that solubility parameter difference (??) between CPE and adhesive was negatively related with ERR. It was proved that hydrogen bonding between CPE and adhesive would increase drug release rate, but only if the CPE showed good miscibility with adhesive. CPE like isopropyl myristate, which had good miscibility with adhesive, could decrease drug-adhesive interaction leading to the release of drug from adhesive.
Design and Optimization of 3D-Printed Gastroretentive Floating Devices by Central Composite Design
Thapakorn Charoenying, Prasopchai Patrojanasophon, Tanasait Ngawhirunpat, Theerasak Rojanarata, Prasert Akkaramongkolporn & Praneet Opanasopit
doi : 10.1208/s12249-021-02053-3
22, Article number: 197 (2021)
This study aimed to optimize the size of capsule-shaped 3D-printed devices (CPD) using an experimental design by the response surface methodology to provide a gastroretentive drug delivery system (GRDDS) with optimal floating time. The CPD was fabricated using a fused deposition modeling (FDM) 3D printer. The central composite design was employed for the optimization of the devices. The morphology of the CPD was observed using a digital microscope and scanning electron microscope (SEM). The in vitro floating time and drug release were evaluated using a USP dissolution apparatus II. Appropriate total floating time (TFT) of the devices (more than 3 h) was obtained with the device’s body, cap, and bottom thickness of 1.2, 1.8, and 2.9 mm, respectively. The release kinetics of the drug from the devices fitted well with zero-order kinetics. In conclusion, the optimization of CPD for GRDDS using the experimental design provided the devices with desirable floating time and ideal drug release characteristics.
Influence of Plasdone™ S630 Ultra—an Improved Copovidone on the Processability and Oxidative Degradation of Quetiapine Fumarate Amorphous Solid Dispersions Prepared via Hot-Melt Extrusion Technique
Arun Butreddy, Sandeep Sarabu, Suresh Bandari, Amol Batra, Kamaru Lawal, Nick Ningyi Chen, Vivian Bi, Thomas Durig & Michael A. Repka
doi : 10.1208/s12249-021-02069-9
22, Article number: 196 (2021)
In a formulation, traces of peroxides in copovidone can impact the stability of drug substances that are prone to oxidation. The present study aimed to investigate the impact of peroxides in novel Plasdone™ S630 Ultra and compare it with regular Plasdone™ S630 on the oxidative degradation of quetiapine fumarate amorphous solid dispersions prepared via hot-melt extrusion technique. The miscibility of copovidones with drug was determined using the Hansen solubility parameter, and the results indicated a miscible drug–polymer system. Melt viscosity as a function of temperature was determined for the drug–polymer physical mixture to identify the suitable hot-melt extrusion processing temperature. The binary drug and polymer (30:70 weight ratio) amorphous solid dispersions were prepared at a processing temperature of 160°C. Differential scanning calorimetry and Fourier transform infrared spectroscopy studies of amorphous solid dispersions revealed the formation of a single-phase amorphous system with intermolecular hydrogen bonding between the drug and polymer. The milled extrudates were compressed into tablets by using extragranular components and evaluated for tabletability. Stability studies of the milled extrudates and tablet formulations were performed to monitor the oxidative degradation impurity (N-oxide). The N-oxide impurity levels in the quetiapine fumarate - Plasdone™ S630 Ultra milled extrudates and tablet formulations were reduced by 2- and 3-folds, respectively, compared to those in quetiapine fumarate - Plasdone™ S630. The reduced oxidative degradation and improved hot-melt extrusion processability of Plasdone™ S630 Ultra make it a better choice for oxidation-labile drugs over Plasdone™ S630 copovidone.
Cationic Polyelectrolyte Nanocapsules of Moxifloxacin for Microbial Keratitis Therapy: Development, Characterization, and Pharmacodynamic Study
Parasuraman Mohan & Karthikeyan Kesavan
doi : 10.1208/s12249-021-02039-1
22, Article number: 195 (2021)
Microbial keratitis (MK) is a vision-threatening disease and the fourth leading cause of blindness worldwide. In this work, we aim to develop moxifloxacin (MXN)-loaded chitosan-based cationic mucoadhesive polyelectrolyte nanocapsules (PENs) for the effective treatment of MK. PENs were formulated by polyelectrolyte complex coacervation method and characterized for their particle size, surface charge, morphology, mucoadhesive property, in-vitro and ex-vivo release, ocular tolerance, and antimicrobial efficacy studies. The pharmacodynamic study was conducted on rabbit eye model of induced keratitis and it is compared with marketed formulation (MF). Developed PENs showed the size range from 230.7 ± 0.64 to 249.0 ± 0.49 nm and positive surface charge, spherical shape along with appropriate physico-chemical parameters. Both in-vitro and ex-vivo examination concludes that PENs having more efficiency in sustained release of MXN compared to MF. Ocular irritation studies demonstrated that no corneal damage or ocular irritation. The in-vivo study proved that the anti-bacterial efficacy of PENs was improved when compared with MF. These results suggested that PENs are a feasible choice for MK therapy because of their ability to enhance ocular retention of loaded MXN through interaction with the corneal surface of the mucous membrane.
Experimental Solubility of Ketoconazole, Validation Models, and In vivo Prediction in Human Based on GastroPlus
Afzal Hussain, Mohammad A. Altamimi, Sultan Alshehri, Syed Sarim Imam, Usamah Abdulrahman Alnemer & Md. Wasimul Haque
doi : 10.1208/s12249-021-02075-x
22, Article number: 194 (2021)
The study aimed to identify a suitable cosolvent + water mixture for subcutaneous (sub-Q) delivery of ketoconazole (KETO). The solubility was assessed for several dimethyl acetamide (DMA) + water mixtures at T = 293.2 to 318.2 K and pressure P = 0.1 MPa. The experimental solubility (xe) was validated using the Van ?t Hoff and Yalkowsky models and functional thermodynamic parameters (enthalpy ?solH°, entropy ?solS°, and Gibbs free energy ?solG°). The in vitro drug release study was performed at physiological pH, and the data served as the input to GastroPlus, which predicted the in vivo performance of KETO dissolved in a DMA + water cosolvent mixture for sub-Q delivery in human. The maximum solubility (mole fraction) of KETO (9.81 × 10?1) was obtained for neat DMA at 318.2 K whereas the lowest value (1.7 × 10?5) was for pure water at 293.2 K. An apparent thermodynamic analysis based on xe gave positive values for the functional parameters. KETO dissolution requires energy, as evidenced by the high positive values of ?solH° and ?solG°. Interestingly, ?solG° progressively decreased with increasing concentration of DMA in the DMA + water mixture, suggesting that the DMA-based molecular interaction improved the solubilization. Positive values of ?solG° and ?solS° for each DMA + water cosolvent mixture corroborated the endothermic and entropy-driven dissolution. GastroPlus predicted better absorption of KETO through sub-Q delivery than oral delivery. Hence, the DMA + water mixture may be a promising system for sub-Q delivery of KETO to control topical and systemic fungal infections.
Development of Spray-Dried Cyclodextrin-Based Pediatric Anti-HIV Formulations
Ryan Ivone, Ashvin Fernando, Brenton DeBoef, Samantha A. Meenach & Jie Shen
doi : 10.1208/s12249-021-02068-w
22, Article number: 193 (2021)
The human immunodeficiency virus (HIV) impacts up to 37 million people globally, of which 1.8 million are children. To date, there is no cure for HIV, although treatment options such as antiretroviral therapy (ART) are available. ART, which involves a patient taking a combination of antiretrovirals, is being used to treat HIV clinically. Despite the effectiveness of ART, there is currently no palatable pediatric formulation to treat HIV in children, which has hindered patient compliance and overall treatment efficacy. In addition, anti-HIV therapeutics are often poorly water-soluble, and hence have poor bioavailability. In the present study, we developed a pediatric-friendly formulation for anti-HIV therapeutics with improved dissolution characteristics of the therapeutic agents. Lopinavir (LPV) and ritonavir (RTV), available as FDA-approved fixed-dose combination products, were chosen as model ART drugs, and the formulation and processing parameters of spray-dried cyclodextrin (CD)-based LPV and RTV complexes were studied. Results showed that the spray-dried complexes exhibited enhanced dissolution profiles in comparison to pure drugs, particularly spray-dried ?-CD complexes, which showed the most favorable dissolution profiles. This current formulation with enhanced dissolution and taste-masking ability through the use of cyclodextrin has the potential to address the unmet need for the development of suitable pediatric formulations.
Development of Imatinib Mesylate-Loaded Liposomes for Nose to Brain Delivery: In Vitro and In Vivo Evaluation
Raju Saka, Naveen Chella & Wahid Khan
doi : 10.1208/s12249-021-02072-0
22, Article number: 192 (2021)
Neurodegenerative diseases like Alzheimer’s disease require treatment where it is essential for drug to reach brain. Nose to brain delivery of drugs enables direct transport to brain bypassing blood brain barrier. Imatinib mesylate, an anti-cancer agent, was found to have potential anti-Alzheimer’s activity and thus repurposed for the same. However, the drug has severe side effects, poor brain bioavailability which may hinder effective treatment of Alzheimer’s disease. In the current work, imatinib mesylate-loaded liposomes were prepared with particle size below 150 nm with sustained drug release up to 96 h. The liposomal drug formulation was compared with plain drug solution for cytotoxicity on N2a cells and did not show any kind of toxicity at concentrations up to 25 ?g/mL. The nanocarrier formulation was then evaluated for brain deposition by nose to brain administration in comparison with drug solution in rats. The liposomes effectively improved the brain deposition of drug in brain from formulation compared to pure drug solution as indicated by AUC from in vivo experiments. These results indicate that the nose to brain delivery of liposomal imatinib mesylate improved the drug deposition and residence time in brain compared to drug solution administered through oral and intranasal routes.
Formulation and In Vitro Characterization of PLGA/PLGA-PEG Nanoparticles Loaded with Murine Granulocyte-Macrophage Colony-Stimulating Factor
Nicole E. Mihalik, Sijin Wen, Benoit Driesschaert & Timothy D. Eubank
doi : 10.1208/s12249-021-02049-z
22, Article number: 191 (2021)
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has demonstrated notable clinical activity in cancer immunotherapy, but it is limited by systemic toxicities, poor bioavailability, rapid clearance, and instability in vivo. Nanoparticles (NPs) may overcome these limitations and provide a mechanism for passive targeting of tumors. This study aimed to develop GM-CSF-loaded PLGA/PLGA-PEG NPs and evaluate them in vitro as a potential candidate for in vivo administration. NPs were created by a phase-separation technique that did not require toxic/protein-denaturing solvents or harsh agitation techniques and encapsulated GM-CSF in a more stable precipitated form. NP sizes were within 200 nm for enhanced permeability and retention (EPR) effect with negative zeta potentials, spherical morphology, and high entrapment efficiencies. The optimal formulation was identified by sustained release of approximately 70% of loaded GM-CSF over 24 h, alongside an average size of 143 ± 35 nm and entrapment efficiency of 84 ± 5%. These NPs were successfully freeze-dried in 5% (w/v) hydroxypropyl-?-cyclodextrin for long-term storage and further characterized. Bioactivity of released GM-CSF was determined by observing GM-CSF receptor activation on murine monocytes and remained fully intact. NPs were not cytotoxic to murine bone marrow-derived macrophages (BMDMs) at concentrations up to 1 mg/mL as determined by MTT and trypan blue exclusion assays. Lastly, NP components generated no significant transcription of inflammation-regulating genes from BMDMs compared to IFN?+LPS “M1” controls. This report lays the preliminary groundwork to validate in vivo studies with GM-CSF-loaded PLGA/PEG-PLGA NPs for tumor immunomodulation. Overall, these data suggest that in vivo delivery will be well tolerated.
Streamlining of the Powder Mixing Process based on a Segregation Test
Simona R?merov?, Ond?ej Dammer & Petr Z?mostn?
doi : 10.1208/s12249-021-02073-z
22, Article number: 190 (2021)
In direct compression of tablets, it is crucial to maintain content uniformity within acceptable margins, especially in formulations with low drug loading. To assure it, complex and multistep mixing processes are utilized in the industry. In this study, we suggest the use of a simple segregation test to evaluate mixing process performance and mixture segregation to produce tablets having satisfying content uniformity while keeping the process as simple and low cost as possible. Eventually, the formulation propensity to segregation can be evaluated using process analytical technology (PAT) to adjust the mixing process parameters to changing source drug properties. In this study, that approach was examined on a model drug with a broad batch-to-batch variability in particle size and shape. Excipients were chosen so that the resulting blend composition mimicked some marketed formulations. For each drug batch, two formulation blends were prepared through different preparation processes (one simple and one complex) and subsequently subjected to segregation tests. From those, segregation coefficients were obtained to compare segregation tendencies and homogeneity robustness between the drug batches and the blend preparation methods. The inter-particulate interactions were substantially influenced by the drug particle morphology and size and resulted in different segregation behavior. Based on these findings, a simple segregation test proved to be a useful tool for determining the suitability of different batches of the model drug to be used in a certain formulation. Moreover, for a particular batch A, the test revealed a potential for mixing process simplification and therefore process intensification and cost reduction.
Combination of Phospholipid Complex and Matrix Dispersion
Ravi Kumar Chakravarti, Shamandeep Kaur, Sanjaya K. Samal, Mahesh C. Kashyap & Abhay T. Sangamwar
doi : 10.1208/s12249-021-02067-x
22, Article number: 189 (2021)
Phospholipid complexation, despite being a successful, versatile, and burgeoning strategy, stickiness of phospholipids leads to suboptimal dissolution rate of drugs. This work was undertaken to fabricate simvastatin-phospholipid complex (SIM-PLC)–loaded matrix dispersion (SIM-PLC-MD) using Soluplus® as carrier material, to augment dispersibility and dissolution of SIM-PLC without altering complexation between simvastatin (SIM) and phospholipid. SIM-PLC and SIM-PLC-MD were prepared using solvent evaporation and discontinuous solvent evaporation techniques, respectively. The successful complexation was substantiated by FTIR method. Besides, PXRD and SEM studies disclosed the absence of crystallinity of SIM in both SIM-PLC and SIM-PLC-MD. The TEM analysis monitored the self-assembly of SIM-PLC and SIM-PLC-MD into colloidal structures, which could be correlated with redispersion in GIT fluids upon oral administration. The considerable increase in hydrophilicity of SIM-PLC-MD and SIM-PLC as evident from partition coefficient experiment can further be correlated with their remarkably improved solubility profiles in the following pattern: SIM-PLC-MD?SIM-PLC?SIM. Correspondingly, improved dispersibility of SIM-PLC-MD in comparison to SIM-PLC can be accountable for accelerated dissolution rate by 2.53-fold and 1.5-fold in pH 1.2 and 6.8 conditions, respectively. The oral pharmacokinetic evaluation in Sprague Dawley (SD) rats revealed 3.19-fold enhancement in oral bioavailability of SIM through SIM-PLC-MD when compared with plain SIM, whereas 1.83-fold increment was observed in the case of SIM-PLC. Finally, the efficacy experimentation in SD rats revealed that SIM-PLC-MD significantly reduced triglycerides and cholesterol levels in comparison to SIM and SIM-PLC. These outcomes suggest that a matrix dispersion strategy improves oral bioavailability and hypolipidemic activity of SIM.
Effect of Elevated pH on the Commercial Enteric-Coated Omeprazole Pellets Resistance: Patent Review and Multisource Generics Comparison
Valentyn Mohylyuk, Anna Yerkhova, Marina Katynska, Vitaliy Sirko & Kavil Patel
doi : 10.1208/s12249-021-02038-2
22, Article number: 188 (2021)
Omeprazole is a widely used over-the-counter (20 mg) proton pump inhibitor, usually supplied as oral enteric-coated pellets intended to release at pH 5.5 and higher; however, it is sensitive to acidic pH. The likelihood of elevated gastric pH in practice is very high for patients; thus, the aim of this study was to investigate the effect of elevated pH on the performance of commercial omeprazole pellets. Commercial enteric-coated delayed-release pellets were tested with water uptake-weight loss (WU-WL) test at pH range between 1.2 and 4.5 in addition to “gastric” (pH 1.2 or 4.5) and “intestinal” (pH 7.4) phase dissolution tests. The range of physical characteristics of pellets was determined with a single pellet size and sedimentation time measurement, followed by the application of modified Stokes’ Law equation. The coefficient of variation of pellet size and density, and volume-density determination coefficient (R2) as descriptors of coating thickness and microstructure variability, degree of ionisation of enteric polymers, aqueous solubility and molecular weight of plasticisers have been found useful to explain commercial delayed-release pellets behaviour during WU-WL and dissolution test. Investigated commercial delayed-release pellets demonstrated pH-dependent WU-WL results. “Gastric phase” dissolution testing of pellets at pH 4.5 showed the highest omeprazole degradation (48.1%) for Nosch Labs, intermediate values of dose loss (23.4% and 17.1%) for Teva and UQUIFA delayed-release pellets, respectively. Lab Liconsa pellets have been found as the least susceptible (3.2% of dose loss). Additionally, “gastric phase” dissolution test at pH 4.5 significantly influenced omeprazole release during the “intestinal phase”. The risk of inadequate therapy associated with intake of investigated enteric-coated delayed-release pellets at elevated gastric pH has been found as minimal for Lab Liconsa and has increased from UQUIFA and Teva to Nosh Labs pellets.
Process Optimization for the Continuous Production of a Gastroretentive Dosage Form Based on Melt Foaming
?d?m Haimhoffer, G?bor Vasv?ri, Gy?rgy Trencsényi, Monika Béresov?, Istv?n Budai, Zsuzsa Czomba, ?gnes Ruszny?k, Judit V?radi, Ildik? B?cskay, Zolt?n Ujhelyi, P?lma Fehér, Mikl?s Vecsernyés & Ferenc Fenyvesi
doi : 10.1208/s12249-021-02066-y
22, Article number: 187 (2021)
Several drugs have poor oral bioavailability due to low or incomplete absorption which is affected by various effects as pH, motility of GI, and enzyme activity. The gastroretentive drug delivery systems are able to deal with these problems by prolonging the gastric residence time, while increasing the therapeutic efficacy of drugs. Previously, we developed a novel technology to foam hot and molten dispersions on atmospheric pressure by a batch-type in-house apparatus. Our aim was to upgrade this technology by a new continuous lab-scale apparatus and confirm that our formulations are gastroretentive. At first, we designed and built the apparatus and continuous production was optimized using a Box–Behnken experimental design. Then, we formulated barium sulfate-loaded samples with the optimal production parameters, which was suitable for in vivo imaging analysis. In vitro study proved the low density, namely 507 mg/cm3, and the microCT record showed high porosity with 40 ?m average size of bubbles in the molten suspension. The BaSO4-loaded samples showed hard structure at room temperature and during the wetting test, the complete wetting was detected after 120 min. During the in vivo study, the X-ray taken showed the retention of the formulation in the rat stomach after 2 h. We can conclude that with our device low-density floating formulations were prepared with prolonged gastric residence time. This study provides a promising platform for marketed active ingredients with low bioavailability.
Effect of Packaging Materials and the Leached Iron on the Stability of Butorphanol Tartrate Injection
Zijun Dai, Chunmei Zhu, Chunfeng Liu, Jinyuan Lyu, Jiajian Xu, Haoxiang Wu & Fuli Zhang
doi : 10.1208/s12249-021-02060-4
22, Article number: 186 (2021)
The aim of this study was to investigate the effect of various parameters on the stability of butorphanol tartrate injection and to screen the optimal packaging material. The effect of the headspace oxygen levels, ampoule color, manufacturer, and size on the stability of butorphanol tartrate formulation were evaluated. The headspace oxygen levels controlled by nitrogen purging were found to be particularly effective in improving stability of the butorphanol formulation, especially below 2%. Although it is a photolabile drug, butorphanol tartrate was getting degraded at much higher extent in amber color ampoules in comparison to clear ampoules. The degradation by oxidation was found to be a free radical-mediated process catalyzed by the presence of iron ions leached from the amber ampoules. The ampoule manufacturers also had a significant effect on the stability of butorphanol. Two-milliliter ampoules provided a better stability of the butorphanol tartrate injection than 1mL ampoules as 2-mL ampoules had the lower headspace oxygen level at the same level of oxygen content. The oxidation mechanism of the butorphanol tartrate injection was investigated under various conditions, which include iron powder spiking, removal of excipients, exposure to oxygen/nitrogen, exposure to stainless steel and at different pH. Iron powder spiking, presence of citric acid, exposure to oxygen, exposure to stainless steel, and high pH accelerated the oxidative degradation. The effect of oxygen, iron ion and citric acid is in agreement with a metal-catalyzed oxidation mechanism called Udenfriend reaction. Based on the formulation test results, limiting headspace oxygen level, ampoule color, manufacturer, size, controlling iron ion contamination, and pH are recommended for formulation development. In conclusion, it can be suggested that this study can lead to a better understanding of the degradation mechanism of butorphanol tartrate; hence, it would contribute to the development of butorphanol tartrate injection with improved stability.
Spray-Dried Inhalable Powder Formulations of Therapeutic Proteins and Peptides
Basanth Babu Eedara, Wafaa Alabsi, David Encinas-Basurto, Robin Polt & Heidi M. Mansour
doi : 10.1208/s12249-021-02043-5
22, Article number: 185 (2021)
Respiratory diseases are among the leading causes of morbidity and mortality worldwide. Innovations in biochemical engineering and understanding of the pathophysiology of respiratory diseases resulted in the development of many therapeutic proteins and peptide drugs with high specificity and potency. Currently, protein and peptide drugs are mostly administered by injections due to their large molecular size, poor oral absorption, and labile physicochemical properties. However, parenteral administration has several limitations such as frequent dosing due to the short half-life of protein and peptide in blood, pain on administration, sterility requirement, and poor patient compliance. Among various noninvasive routes of administrations, the pulmonary route has received a great deal of attention and is a better alternative to deliver protein and peptide drugs for treating respiratory diseases and systemic diseases. Among the various aerosol dosage forms, dry powder inhaler (DPI) systems appear to be promising for inhalation delivery of proteins and peptides due to their improved stability in solid state. This review focuses on the development of DPI formulations of protein and peptide drugs using advanced spray drying. An overview of the challenges in maintaining protein stability during the drying process and stabilizing excipients used in spray drying of proteins and peptide drugs is discussed. Finally, a summary of spray-dried DPI formulations of protein and peptide drugs, their characterization, various DPI devices used to deliver protein and peptide drugs, and current clinical status are discussed.
Hot-Melt Extrusion: a Roadmap for Product Development
Marta F. Sim?es, Rui M. A. Pinto & Sérgio Sim?es
doi : 10.1208/s12249-021-02017-7
22, Article number: 184 (2021)
Hot-melt extrusion has found extensive application as a feasible pharmaceutical technological option over recent years. HME applications include solubility enhancement, taste masking, and sustained drug release. As bioavailability enhancement is a hot topic of today’s science, one of the main applications of HME is centered on amorphous solid dispersions. This review describes the most significant aspects of HME technology and its use to prepare solid dispersions as a drug formulation strategy to enhance the solubility of poorly soluble drugs. It also addresses molecular and thermodynamic features critical for the physicochemical properties of these systems, mainly in what concerns miscibility and physical stability. Moreover, the importance of applying the Quality by Design philosophy in drug development is also discussed, as well as process analytical technologies in pharmaceutical HME monitoring, under the current standards of product development and regulatory guidance.
Immediate-Release Formulations Produced via Twin-Screw Melt Granulation: Systematic Evaluation of the Addition of Disintegrants
Kristina E. Steffens & Karl G. Wagner
doi : 10.1208/s12249-021-02056-0
22, Article number: 183 (2021)
The current study evaluated the effect of location and amount of various superdisintegrants on the properties of tablets made by twin-screw melt granulation (TSMG). Sodium-croscarmellose (CCS), crospovidone (CPV), and sodium starch glycolate (SSG) were used in various proportions intra- and extra-granular. Tabletability, compactibility, compressibility as well as friability, disintegration, and dissolution performance were assessed. The extra-granular addition resulted in the fasted disintegration and dissolution. CPV performed superior to CCS and SSG. Even if the solid fraction (SF) of the granules was lower for CPV, only a minor decrease in tabletability was observed, due to the high plastic deformation of the melt granules. The intra-granular addition of CPV resulted in a more prolonged dissolution profile, which could be correlated to a loss in porosity during tableting. The 100% intra-granular addition of the CPV resulted in a distinct decrease of the disintegration efficiency, whereas the performance of SSG was unaffected by the granulation process. CCS was not suitable to be used for the production of an immediate-release formulation, when added in total proportion into the granulation phase, but its efficiency was less impaired compared to CPV. Shortest disintegration (78 s) and dissolution (Q80: 4.2 min) was achieved with CPV extra-granular. Using CPV and CCS intra-granular resulted in increased disintegration time and Q80. However, at a higher level of appx. 500 s and appx. 15 min, only SSG showed a process and location independent disintegration and dissolution performance.
Development of Gelucire® 48/16 and TPGS Mixed Micelles and Its Pellet Formulation by Extrusion Spheronization Technique for Dissolution Rate Enhancement of Curcumin
Umesh K. Shinde, Dilipkumar G. Suryawanshi & Purnima D. Amin
doi : 10.1208/s12249-021-02032-8
22, Article number: 182 (2021)
The oral bioavailability of curcumin is limited, attributed to its low solubility or dissolution and poor absorption. Herein, the study describes formulation of curcumin-loaded mixed micelles of Gelucire® 48/16 and TPGS for its dissolution rate enhancement. Curcumin was dispersed in these molten lipidic surfactants which was then adsorbed on carrier and formulated as pellets by extrusion spheronization. Critical micelle concentration (CMC) of binary mixture of Gelucire® 48/16 and TPGS was lower than their individual CMC demonstrating the synergistic behavior of mixture. Thermodynamic parameters like partition coefficient and Gibbs free energy of solubilization indicated that mixed micelles were more efficient than micelles of its individual components in curcumin solubilization. Dynamic light scattering (DLS) suggested slight increase in micellar size of mixed micelles than its components suggesting curcumin loading in mixed micelles. Fourier transform infrared spectroscopy (FTIR) revealed that phenolic hydroxyl group interacts with lipids which contribute to its enhanced solubility. Furthermore, the differential scanning calorimetry (DSC) and X-ray diffraction (XRD) study indicated the conversion of crystalline curcumin into amorphous form. In the pellet formulation, Gelucire® 48/16 acted as a binder and eliminated the requirement of additional binder. Microcrystalline cellulose (MCC) forms wet mass and retards the release of curcumin from pellets. Increase in concentration of water-soluble diluent increased drug release. The optimized formulation released more than 90% drug and maintains supersaturation level of curcumin for 2 h. Thus, mixed micellar system was effective delivery system for curcumin while pellet formulation is an interesting formulation strategy consisting semi-solid lipids.
Bi-polymeric Spongy Matrices Through Cross-linking Polymerization: Synthesized and Evaluated for Solubility Enhancement of Acyclovir
Saima Asghar, Naveed Akhtar, Muhammad Usman Minhas & Kifayat Ullah Khan
doi : 10.1208/s12249-021-02054-2
22, Article number: 181 (2021)
In this study, two hydrophilic polymers hydroxypropyl methyl cellulose and beta-cyclodextrin (?-CD) are used to synthesize highly responsive and spongy polymeric matrices. Porous and stimulus-responsive polymeric network was developed to improve the solubility of acyclovir (ACV) at significant level. Grafting was successfully carried out by free radical polymerization technique. Spongy matrices were characterized by percentage entrapment efficiency, drug loading, solubility studies, FTIR, powder X-ray diffraction, TGA, DSC, XRD, SEM, swelling studies, and in vitro studies. Acute oral toxicity studies were conducted to determine the safety of oral administration of prepared HPMC-?CD-g-poly(AMPS) formulation. Porous and spongy structures were depicted in SEM images. Complex formation and thermal stability of constituents and drug (ACV) were analyzed by FTIR, TGA, and DSC spectra. XRD analysis revealed reduction in acyclovir crystallinity in spongy matrices. Particle size of optimized formulation was found in the range of 197 ± 2.55 nm. The momentous difference with reference product committed that drug solubility and release characteristics were markedly enhanced by the developed spongy matrices. Toxicity studies endorsed that developed spongy matrices were non-toxic and compatible to biological system. The efficient method of preparation, enhanced solubility, excellent physico-chemical characteristics, high dissolution, and non-toxic HPMC-?CD-g-poly(AMPS) spongy matrices may be a promising approach for oral delivery of poorly soluble drugs.
Fabrication and Evaluation of Celecoxib Oral Oleogel to Reduce the Inflammation of Ulcerative Colitis
Nermin M. Sheta & Sylvia A. Boshra
doi : 10.1208/s12249-021-02042-6
22, Article number: 180 (2021)
Oleogel consists of hydrophobic solvent and an oleogelator. In this study, attempts were made to study the influence of Celecoxib solubility, concentration and dispersability on its release, absorption, and biological performance. Oleogels were prepared to study the formulation variables on its stability and release. Castor oil was selected as the oil and the oleogelator concentration was 4.5% w/w. F3 revealed the highest release and stability compared to other formulae. The percent permeated across the rat intestine showed a 7.5-fold increase over free Celecoxib, and its lifetime was found to be greater than 18 months. The efficacy of free Celecoxib and oleogel formulae to treat rats with ulcerative colitis was done via the induction of ulcerative colitis (UC) through administration of 5% dextran sodium sulphate (DSS). Celecoxib besides its formulae significantly reduced the release of Leucine rich 2 glycoprotein (LRG), Myeloperoxidase (MPO), Tumor necrosis factor–? (TNF-?), proinflammatory cytokine expression, High mobility group box 1 (HMGB1), Nuclear factor kappa B (NF-?B), Trefoil Factor 3 (TFF3), Metalloproteinase-3 (MMP3), and miRNA31. Moreover, F3 significantly increased the colonic cAMP in DSS treated rats and reduced the intestinal inflammation beside healing of mucosa and restitution of the epithelium of the gastrointestinal tract.
Nanocrystals for Improving Oral Bioavailability of Drugs: Intestinal Transport Mechanisms and Influencing Factors
Zonghua Tian, Yaping Mai, Tingting Meng, Shijie Ma, Guojing Gou & Jianhong Yang
doi : 10.1208/s12249-021-02041-7
22, Article number: 179 (2021)
With the limitation of solubility and dissolution rate of insoluble drugs, following oral administration, they would rifely prove poor and volatile bioavailability, which may fail to realize its therapeutic value. The drug nanocrystals are perceived as effective tactic for oral administration of insoluble drugs attributes to possess many prominent properties such as elevating dissolution rate and saturation solubility, high drug loading capacity, and improving oral bioavailability. Based on these advantages, the application of nanocrystals in oral drug delivery has acquired significant achievement, and so far more than 20 products of drug nanocrystals have been confirmed in the market. However, the oral absorption of drug nanocrystals is still facing huge challenges due to the limitation of many factors. Intrinsic properties of the drugs and complex physiological environment of the intestinal tract are the two most important factors affecting the oral bioavailability of drugs. In addition, the research on the multi-aspect mechanisms of nanocrystals promoting gastrointestinal absorption and bioavailability has been gradually deepened. In this review, we summarized recent advances of the nanocrystals delivered orally, and provided an overview to the research progress for crossing the intestinal tract transport mechanisms of the nanocrystals by some new research techniques. Meanwhile, the factors relevant to the transport of drug nanocrystals were also elaborated in detail.
Predictive Approach to Understand and Eliminate Tablet Breakage During Film Coating
William R. Ketterhagen, Jeffery Larson, Kevin Spence & Jared A. Baird
doi : 10.1208/s12249-021-02061-3
22, Article number: 178 (2021)
Pharmaceutical tablets can be susceptible to damage such as edge chipping or erosion of the core during the tablet coating process. The intersection of certain process parameters, equipment design, and tablet properties may induce more significant tablet damage such as complete tablet fracture. In this work, a hybrid predictive approach was developed using discrete element method (DEM) modeling and lab-based tablet impact experiments to identify conditions that may lead to tablet breakage events. The approach was extended to examine potential modifications to the coating equipment and process conditions in silico to mitigate the likelihood of tablet breakage during future batches. The approach is shown to enhance process understanding, identify optimal process conditions within development constraints, and de-risk the manufacture of future tablet coating batches.
Fluvastatin-Loaded Emulsomes Exhibit Improved Cytotoxic and Apoptosis in Prostate Cancer Cells
Nabil A. Alhakamy, Shaimaa M. Badr-Eldin, Hibah M. Aldawsari, Anas Alfarsi, Thikryat Neamatallah, Solomon Z. Okbazghi, Usama A. Fahmy, Osama A.A. Ahmad, Basma G. Eid, Wael Ali Mahdi, Adel F. Alghaith, Sultan Alshehri & Shadab Md
doi : 10.1208/s12249-021-02021-x
22, Article number: 177 (2021)
Fluvastatin (FLV) is known to inhibit the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), which is over-expressed in various cancers. FLV has been reported to decrease cancer development and metastasis. However, because of low bioavailability, extensive first-pass metabolism and short half-life of FLV (1.2 h), it is not appropriate for clinical application. Therefore, FLV-loaded emulsomes were formulated and optimized using Box–Behnken experimental design to achieve higher efficiency of formulation. Antitumor activity of optimized FLV-loaded emulsomes was evaluated in prostate cancer cells using cell cytotoxicity, apoptotic activity, cell cycle analysis, and enzyme-linked immunosorbent assay. The FLV-loaded emulsomes exhibited a monodispersed size distribution with a mean particle size less than 100 nm as measured by zetasizer. The entrapment efficiency was found to be 93.74% with controlled drug release profile. FLV-EMLs showed a significant inhibitory effect on the viability of PC3 cells when compared to the free FLV (P < 0.0025). Furthermore, FLV-EMLs showed significant arrest in G2/M and increase in percentage of apoptotic cells as compared to free FLV. FLV-EMLs were more effective than free FLV in reducing mitochondrial membrane potential and increase in caspase-3 activity. These results suggesting that FLV-EMLs caused cell cycle arrest which clarifies its significant antiproliferative effect compared to the free drug. Therefore, optimized FLV-EMLs may be an effective carrier for FLV in prostate cancer treatment.
Correction to: Development of Apremilast Solid Dispersion Using TPGS and PVPVA with Enhanced Solubility and Bioavailability
Liuhong Yang, Penghui Wu, Jinchao Xu, Dihuan Xie, Zhongqing Wang, Qian Wang, Yong Chen, Chuan Hua Li, Jiaxin Zhang, Hangping Chen & Guilan Quan
doi : 10.1208/s12249-021-02046-2
22, Article number: 176 (2021)
Formulation Approach that Enables the Coating of a Stable Influenza Vaccine on a Transdermal Microneedle Patch
Mahmoud Ameri, Yi Ao & Hayley Lewis
doi : 10.1208/s12249-021-02044-4
22, Article number: 175 (2021)
A trivalent influenza split vaccine was formulated at high concentration for coating on the transdermal microneedle system. Monovalent vaccine bulks of three influenza strains, two influenza A strains, and one B strain were diafiltrated, concentrated, and lyophilized. The lyophilized powder of each vaccine strain was separately reconstituted and subsequently combined into a coating formulation of high concentration trivalent vaccine. The formulation process converted the monovalent vaccine bulks with low hemagglutinin (HA) concentrations 0.1 mg/mL into a viscous, emulsion containing HA at ~50 mg/mL. This physically stable emulsion demonstrated viscosity 1 poise and 30° contact angle for effective, homogeneous coating on each microneedle. Evaluation of the vaccine antigen HA by SRID and SDS-PAGE/Western blot showed that HA remained stable throughout the vaccine transdermal microneedle system manufacturing process and 1-year ambient storage (25°C). Anti-influenza antibody responses were evaluated by ELISA and hemagglutination inhibition (HAI) assay after primary and booster immunization with the vaccine-coated transdermal microneedle systems at either 25-?g or 40-?g total HA. The results showed the induction of serum anti-influenza IgG and anti-HA neutralizing antibodies after primary immunization and significant titer rises after booster immunization for both doses, indicating the dry-coated trivalent vaccine delivered by transdermal microneedle system elicited both primary and recall antibody responses against all three antigen strains. The study demonstrates that the transdermal microneedle system provides an attractive alternative for influenza vaccine delivery with key advantages such as preservative-free and room-temperature storage.
Design and In Vitro Evaluation of a Slow-Release Intraocular Implant of Betamethasone
Zohreh Sadat Rastegar Ramsheh, Zahra Mohtashami, Neda Kargar, Hamid Akbari Javar, Morteza Rafiee Tehrani & Farid Abedin Dorkoosh
doi : 10.1208/s12249-021-02048-0
22, Article number: 174 (2021)
Posterior eye diseases are a common cause of vision problems in developing countries, which have encouraged the development of new treatment models for these degenerative diseases. Intraocular implants are one of the drug delivery systems to the posterior region of the eye. Using these implants, the blood-eye barrier can be bypassed; the complications caused by repeated in vitro administrations can be eliminated, and smaller amounts of the drug would be used during the treatment process. Meanwhile, biodegradable implants have received more attention due to their biodegradable structure and the lack of need for re-surgery to remove the rest of the system from the eye. The aim of this study is to employ biodegradable implants composed of polyethylene glycol (PEG) and 3-hydroxybutyrate-co-3-hydroxyvalerat (PHBV) to deliver betamethasone to the back of the eye in the treatment of retinopathy. PHBV polymer has been selected as the main polymer with a certain ratio of drug to polymer for fabrication of enamel and different amounts of PEG with three molecular weights used as pore generators to control drug release over a period of time. Based on the analysis of the results of differential scanning calorimetry (DSC) and FTIR spectroscopy, none of the polymers were degraded in the temperature range of the manufacturing process, and among betamethasone derivatives, the best option for implant preparation is the use of its basic form. Drug release studies over a period of three months showed that implants containing PHBV HV2% and PEG 6000 had a more appropriate release profile.
Middle East Respiratory Syndrome (MERS) Virus—Pathophysiological Axis and the Current Treatment Strategies
Abdullah M Alnuqaydan, Abdulmajeed G Almutary, Arulmalar Sukamaran, Brian Tay Wei Yang, Xiao Ting Lee, Wei Xuan Lim, Yee Min Ng, Rania Ibrahim, Thiviya Darmarajan, Satheeshkumar Nanjappan, Jestin Chellian, Mayuren Candasamy, Thiagarajan Madheswaran, Ankur Sharma, Harish Dureja, Parteek Prasher, Nitin Verma, Deepak Kumar, Kishneth Palaniveloo, Dheeraj Bisht, Gaurav Gupta, Jyotsana R. Madan, Sachin Kumar Singh, Niraj Kumar Jha, Kamal Dua & Dinesh Kumar Chellappan
doi : 10.1208/s12249-021-02062-2
22, Article number: 173 (2021)
Middle East respiratory syndrome (MERS) is a lethal respiratory disease with its first case reported back in 2012 (Jeddah, Saudi Arabia). It is a novel, single-stranded, positive-sense RNA beta coronavirus (MERS-CoV) that was isolated from a patient who died from a severe respiratory illness. Later, it was found that this patient was infected with MERS. MERS is endemic to countries in the Middle East regions, such as Saudi Arabia, Jordan, Qatar, Oman, Kuwait and the United Arab Emirates. It has been reported that the MERS virus originated from bats and dromedary camels, the natural hosts of MERS-CoV. The transmission of the virus to humans has been thought to be either direct or indirect. Few camel-to-human transmissions were reported earlier. However, the mode of transmission of how the virus affects humans remains unanswered. Moreover, outbreaks in either family-based or hospital-based settings were observed with high mortality rates, especially in individuals who did not receive proper management or those with underlying comorbidities, such as diabetes and renal failure. Since then, there have been numerous reports hypothesising complications in fatal cases of MERS. Over the years, various diagnostic methods, treatment strategies and preventive measures have been strategised in containing the MERS infection. Evidence from multiple sources implicated that no treatment options and vaccines have been developed in specific, for the direct management of MERS-CoV infection. Nevertheless, there are supportive measures outlined in response to symptom-related management. Health authorities should stress more on infection and prevention control measures, to ensure that MERS remains as a low-level threat to public health.
Tozinameran (BNT162b2) Vaccine: The Journey from Preclinical Research to Clinical Trials and Authorization
Nimrat Khehra, Inderbir Padda, Urooj Jaferi, Harshan Atwal, Shreya Narain & Mayur S. Parmar
doi : 10.1208/s12249-021-02058-y
22, Article number: 172 (2021)
Vaccination development and production was an essential question for the prevention and global control of COVID-19. The strong support from governing authorities such as Operation Warp Speed and robust funding has led to the development and authorization of the tozinameran (BNT162b2) vaccine. The BNT162b2 vaccine is a lipid nanoparticle-encapsulated mRNA that encodes for SARS-CoV-2 spike protein, the main site for neutralizing antibodies. Once it binds with the host cells, the lipid nanoparticles enable the transfer of the RNA, causing S antigens’ expression of the SARS-CoV-2, conferring immunity. The vaccine is administered as a 2-dose regime 21 days apart for individuals 16 years and older. Pfizer-BioNTech’s BNT162b2 vaccine was the first candidate to receive FDA-Emergency Use Authorization (EUA) on December 11, 2020. During phase 2/3 clinical trials, 95% efficacy was reported among 37,706 participants over the age of 16 who received the BNT162b2 vaccination; additionally, 52% efficacy was noted 12 days following the administration of the first dose of BNT162b2, reflecting early protection of COVID-19. The BNT162b2 vaccine has exhibited 100% efficacy in clinical trials of adolescents between the ages of 12 and 15. Clinical trials in pregnant women and children under the age of 12 are expected to also exhibit promising results. This review article encompasses tozinameran (BNT162b2) vaccine journey, summarizing the BNT162b1 and BNT162b2 vaccines from preclinical studies, clinical trial phases, dosages, immune response, adverse effects, and FDA-EUA.
Layer-by-Layer Assembled Nanostructured Lipid Carriers for CD-44 Receptor–Based Targeting in HIV-Infected Macrophages for Efficient HIV-1 Inhibition
Ketan Mahajan, Satish Rojekar, Dipen Desai, Smita Kulkarni, Gandhali Bapat, Smita Zinjarde & Pradeep Vavia
doi : 10.1208/s12249-021-01981-4
22, Article number: 171 (2021)
Macrophages act as a cellular reservoir in HIV infection. Elimination of HIV from macrophages has been an unfulfilled dream due to the failure of drugs to reach them. To address this, we developed CD44 receptor–targeted, novel hyaluronic acid (HA)-coated nanostructured lipid carriers (NLCs) of efavirenz via washless layer-by-layer (LbL) assembly of HA and polyallylamine hydrochloride (PAH). NLCs were subjected to TEM analysis, size and zeta potential, in vitro release and encapsulation efficiency studies. The uptake of NLCs in THP-1 cells was studied using fluorescence microscopy and flow cytometry. The anti-HIV efficacy was evaluated using p24 antigen inhibition assay. NLCs were found to be spherical in shape with anionic zeta potential (?23.66 ± 0.87 mV) and 241.83 ± 5.38 nm particle size. NLCs exhibited prolonged release of efavirenz during in vitro drug release studies. Flow cytometry revealed 1.73-fold higher uptake of HA-coated NLCs in THP-1 cells. Cytotoxicity studies showed no significant change in cell viability in presence of NLCs as compared with the control. HA-coated NLCs distributed throughout the cell including cytoplasm, plasma membrane and nucleus, as observed during fluorescence microscopy. HA-coated NLCs demonstrated consistent and significantly higher inhibition (81.26 ± 1.70%) of p24 antigen which was 2.08-fold higher than plain NLCs. The obtained results suggested preferential uptake of HA-coated NLCs via CD44-mediated uptake. The present finding demonstrates that HA-based CD44 receptor targeting in HIV infection is an attractive strategy for maximising the drug delivery to macrophages and achieve effective viral inhibition.
Polyvinyl Alcohol/Chitosan Single-Layered and Polyvinyl Alcohol/Chitosan/Eudragit RL100 Multi-layered Electrospun Nanofibers as an Ocular Matrix for the Controlled Release of Ofloxacin: an In Vitro and In Vivo Evaluation
Shahla Mirzaeei, Shiva Taghe, Kofi Asare-Addo & Ali Nokhodchi
doi : 10.1208/s12249-021-02051-5
22, Article number: 170 (2021)
A novel nanofiber insert was prepared with a modified electrospinning method to enhance the ocular residence time of ofloxacin (OFX) and to provide a sustained release pattern by covering hydrophilic polymers, chitosan/polyvinyl alcohol (CS/PVA) nanofibers, with a hydrophobic polymer, Eudragit RL100 in layers, and by glutaraldehyde (GA) cross-linking of CS-PVA nanofibers for the treatment of infectious conjunctivitis. The morphology of the prepared nanofibers was studied using scanning electron microscopy (SEM). The average fiber diameter was found to be 123 ± 23 nm for the single electrospun nanofiber with no cross-linking (OFX-O). The single nanofibers, cross-linked for 10 h with GA (OFX-OG), had an average fiber diameter of 159 ± 30 nm. The amount of OFX released from the nanofibers was measured in vitro and in vivo using UV spectroscopy and microbial assay methods against Staphylococcus aureus, respectively. The antimicrobial efficiency of OFX formulated in cross-linked and non-cross-linked nanofibers was affirmed by observing the inhibition zones of Staphylococcus aureus and Escherichia coli. In vivo studies using the OFX nanofibrous inserts on a rabbit eye confirmed a sustained release pattern for up to 96 h. It was found that the cross-linking of the nanofibers by GA vapor could reduce the burst release of OFX from OFX-loaded CS/PVA in one layer and multi-layered nanofibers. In vivo results showed that the AUC0–96 for the nanofibers was 9–20-folds higher compared to the OFX solution. This study thus demonstrates the potential of the nanofiber technology is being utilized to sustained drug release in ocular drug delivery systems.
Preparation and Characterization of a Lutein Solid Dispersion to Improve Its Solubility and Stability
Chaemin Lim, Jin Kook Kang, Chan Eun Jung, Taehoon Sim, Jaewon Her, Kioh Kang, Eun Seong Lee, Yu Seok Youn, Han-Gon Choi & Kyung Taek Oh
doi : 10.1208/s12249-021-02036-4
22, Article number: 169 (2021)
Lutein has been used as a dietary supplement for the treatment of eye diseases, especially age-related macular degeneration. For oral formulations, we investigated lutein stability in artificial set-ups mimicking different physiological conditions and found that lutein was degraded over time under acidic conditions. To enhance the stability of lutein upon oral intake, we developed enteric-coated lutein solid dispersions (SD) by applying a polymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF), through a solvent-controlled precipitation method. The SD were characterized in crystallinity, morphology, and drug entrapment. In the dissolution profile of lutein SD, a F80 formulation showed resistance toward the acidic environment under simulated gastric conditions while exhibiting a bursting drug release under simulated intestinal conditions. Our results highlight the potential use of HPMCAS-LF as an effective matrix to enhance lutein bioavailability during oral delivery and to provide novel insights into the eye-care supplement industry, with direct benefits for the health of patients.
From Lab Formulation Development to CTM Manufacturing of KO-947 Injectable Drug Products: a Case Study and Lessons Learned
Xiaohu Deng, Pingda Ren, Wanping Mai, Yi Wang, Yuanyang Zhang, Hongbing Wu, Yinwei Xie & Huazhen Chen
doi : 10.1208/s12249-021-02059-x
22, Article number: 168 (2021)
Formulation development of KO-947-K mesylate injectable drug products was described. Solution formulations were initially attempted, and key parameters such as drug concentration, buffer, pH, complexing agent, and tonicity modifying agent were carefully evaluated in the lab setting, mainly focusing on solubility and chemical stability. A lead solution formulation was advanced to a scaleup campaign. An unexpected stability issue was encountered, and the root cause was attributed to the heterogeneous liquid freezing process of the formulated solution at ?20°C, which had not been captured in the lab setting. A lyophilized product was then designed to overcome the issue and supplied to the phase I clinical trial.
Evaluation of Microwave-Assisted Extraction Method for Preparation and Assessment of Thai Herbal Medicine Oral Tablets With Enriched Phytochemical Compounds
Patcharawalai Jaisamut, Subhaphorn Wanna, Atcharaporn Thanakoon, Supanit Saejew, Nutkawan Saowapark, Waramporn Suchato, Preyanuch Chumvong, Tanpisit Kosawiwat, Phonsinee Momaklua & Sasitorn Chusri
doi : 10.1208/s12249-021-02052-4
22, Article number: 167 (2021)
In developing countries, populations have employed herbal medicines for primary health care because they are believed to be more appropriate to the human body and have less side effects than chemically synthesized drugs. The present study aimed to develop and evaluate herbal tablets incorporated with a Thai traditional medicinal extract, U-pa-ri-waat (URW), using microwave-assisted extraction (MAE). The extraction efficiency for URW using MAE and traditional solvent extraction was compared based on the percent yield after spray drying. URW tablets were prepared using the dry granulation method. The optimized products were assessed using standard characterization methods based on the United States and British Pharmacopeias. DPPH and ABTS radical scavenging assays were performed to analyze the antioxidant capacity of the microwave-assisted extracts. The results revealed that the flowability of the dry granule with added maltodextrin was improved compared to a granule without additives, as indicated by an angle of repose of 33.69 ± 2.0°, a compressibility index of 15.38 ± 0.66, and a Hausner’s ratio of 1.18 ± 0.06. The resulting formulation produced flat tablets with uniform weight variation, hardness, thickness, friability, and optimum disintegration time. The URW extracts showed antioxidant activity and MAE with maltodextrin carrier displayed the strongest DPPH and ABTS radical activities with IC50 values of 1.60 ± 0.02 ?g/mL and 4.02 ± 0.24 ?g/mL, respectively. The URW tablet formulation passed the quality control tests. Storage of the formulation tablets for 90 days under accelerated conditions had minimal effects on tablet characteristics.
Correction to: Coating Lacticaseibacillus rhamnosus GG in Alginate Systems: an Emerging Strategy Towards Improved Viability in Orange Juice
Angela Bonaccorso, Nunziatina Russo, Alessia Romeo, Claudia Carbone, Maria Aurora Grimaudo, Carmen Alvarez-Lorenzo, Cinzia Randazzo, Teresa Musumeci & Cinzia Caggia
doi : 10.1208/s12249-021-02023-9
22, Article number: 166 (2021)
Novel Gellan Gum-Based In Situ Nanovesicle Formulation of Docetaxel for Its Localized Delivery Using Depot Formation
Amrinder Singh, Shubham Thakur, Narpinder Singh, Satwinderjeet Kaur & Subheet Kumar Jain
doi : 10.1208/s12249-021-02033-7
22, Article number: 165 (2021)
In the present study, different in situ hydrogel formulations of docetaxel (DTX) based on biocompatible polymers such as Hyaluronic Acid (HA), poloxamer-407, chitosan and gellan gum were formulated to increase its therapeutic efficacy and reduce toxicity. DTX was loaded in nanovesicles (20 mg/mL equivalent to commercial strength) and further incorporated into the hydrogel bases to possess a dual rationale of protection against burst release and enhanced solubility of the drug. The optimized hydrogel formulation (NV-TPGS-3-GG-4) showed ideal rheological behavior and in situ characteristics at 37±0.5°C with sustained release of more than 144 h. The optimized formulation had instant in vitro gelation (2.8±0.3 min) with good injectability in comparison to the conventional commercial DTX injectable formulation having instant release (<2 h). Additionally, developed formulation exhibited an improved biodisponibility (25.1±0.2 h) in comparison to the commercially available formulation (1.7±0.1 h). The Solid Tumor Carcinoma model in Swiss albino mice revealed that the optimized formulation (based on gellan gum) showed better tumor reduction (85.7±1.2%) and lower toxicity as compared to the commercial formulation (77.3±1.3%). Pharmacokinetic and biodistribution studies demonstrated 3 to 4 times higher localization of drug in tumors. Our findings suggested that injectable gellan gum-based in situ hydrogel formulation can be an effective delivery system for DTX with enhanced solubility, reduced toxicity, and better targeting to the tumors for improved therapeutics.
Recent Advancement in Topical Nanocarriers for the Treatment of Psoriasis
Prativa Biswasroy, Deepak Pradhan, Biswakanth Kar, Goutam Ghosh & Goutam Rath
doi : 10.1208/s12249-021-02057-z
22, Article number: 164 (2021)
Psoriasis is a life-threatening autoimmune inflammatory skin disease, triggered by T lymphocyte. Recently, the drugs most commonly used for the treatment of psoriasis include methotrexate (MTX), cyclosporine (CsA), acitretin, dexamethasone, and salicylic acid. However, conventional formulations due to poor absorptive capacity, inconsistent drug release characteristics, poor capability of selective targeting, poor retention of drug molecules in target tissue, and unintended skin reactions restrict the clinical efficacy of drugs. Advances in topical nanocarriers allow the development of prominent drug delivery platforms can be employed to address the critical issues associated with conventional formulations. Advances in nanocarriers design, nano-dimensional configuration, and surface functionalization allow formulation scientists to develop formulations for a more effective treatment of psoriasis. Moreover, interventions in the size distribution, shape, agglomeration/aggregation potential, and surface chemistry are the significant aspects need to be critically evaluated for better therapeutic results. This review attempted to explore the opportunities and challenges of current revelations in the nano carrier-based topical drug delivery approach used for the treatment of psoriasis.
Nanoemulgel for Improved Topical Delivery of Desonide: Formulation Design and Characterization
Qiuyan Ma, Jing Zhang, Bohong Lu, Huaqing Lin, Rajib Sarkar, Tao Wu & Xuee Li
doi : 10.1208/s12249-021-02035-5
22, Article number: 163 (2021)
This research aimed to develop a novel drug delivery system to improve treatment of skin disorders. The system is comprised of a Carbopol 980-based nanoemulgel (NE-gel) containing a desonide (DES; 0.05%, w/w) nanoemulsion (NE), which has a small particle size, high encapsulation efficiency, good thermodynamic stability, good permeation ability, and high skin retention. DES-loaded NE (DES-NE) was prepared by high-pressure homogenization. The developed formulation was characterized by differential scanning calorimetry (DSC), X-ray diffraction, drug release, skin permeation, and drug retention. DES in vitro release and skin permeation studies with different formulations of artificial membrane and rat abdominal skin were performed with the Franz diffusion cell system. Confocal laser scanning microscopy (CLSM) was used to detect the localization and permeation pathways of drugs in the skin. Compared with commercially available gel (CA-gel) and NE, the NE-gel release process conformed to the Higuchi release model (R2 = 0.9813). NE-gel prolonged the drug release time and allowed for reduced administration dose and frequency. The unit cumulative permeation of NE and NE-gel through the skin for 12 h was 63.13 ± 2.78 and 42.53 ± 2.06 ?g/cm2, respectively, values significantly higher (p < 0.01) than that of the CA-gel (30.65 ± 1.25 ?g/cm2) and CA-cream (15.21 ± 0.97 ?g/cm2). The DES-NE and DES NE-gel skin drug retention was significantly higher than commercially available formulations (p < 0.01). Hence, the prepared NE-gel is a potential vehicle for improved topical DES delivery for better treatment of skin disorders.
Formulation, Evaluation, and Clinical Assessment of Novel Solid Lipid Microparticles of Tetracycline Hydrochloride for the Treatment of Periodontitis
Rajkiran Narkhede, Rajani Athawale, Nikita Patil & MalaDixit Baburaj
doi : 10.1208/s12249-021-02037-3
22, Article number: 162 (2021)
The novel solvent-free process to formulate long-acting microparticles of tetracycline hydrochloride (TH) using hot melt extrusion granulation process coupled with size reduction using comil for the treatment of periodontitis was investigated using hydrogenated castor oil (HCO) as hydrophobic matrix former. The microparticles were characterized for micromeritics, drug diffusion, SEM studies, and stability analysis by DSC, FTIR, and proton NMR. Xanthan gum gel was used as delivery vehicles to administer microparticles inside periodontal pockets. The microparticles were sterilized using gamma radiation; delivery vehicle was sterilized using gamma radiation and autoclave process. Microparticles were evaluated for microbial load as per compendial guidelines. Optimized composition was evaluated for clinical parameters such as plaque index, gingival index, probing pocket depth, and clinical attachment level. Based on the statistical analysis of the data, the micromeritic properties and drug diffusion profiles vary based on the concentration of HCO in the formulation. SEM images reflect the surface properties prior and post drug diffusion studies, which indicates that release takes place predominantly by diffusion of TH through HCO matrix. DSC studies indicate no change in the respective spectra of initial and stability samples. FTIR studies indicate possibility of hydrogen bonding. Proton NMR data suggests characteristic peaks of TH being retained in the stability samples, indicating stable composition. Gamma radiation has led to significant reduction in viscosity of xanthan gum solution over autoclave. Clinical studies indicated statistical improvements in the formulation compared to baseline results, indicating the efficacy of the formulation in the treatment of periodontitis.
Formulation of Gelucire®-Based Solid Dispersions of Atorvastatin Calcium: In Vitro Dissolution and In Vivo Bioavailability Study
Basmah N. Aldosari, Alanood S. Almurshedi, Iman M. Alfagih, Bushra T. AlQuadeib, Mohammad A. Altamimi, Syed Sarim Imam, Afzal Hussain, Faleh Alqahtani, Ehab Alzait & Sultan Alshehri
doi : 10.1208/s12249-021-02019-5
22, Article number: 161 (2021)
Atorvastatin (ATV) is a poorly water-soluble drug that exhibits poor oral bioavailability. Therefore, present research was designed to develop ATV solid dispersions (SDs) to enhance the solubility, drug release, and oral bioavailability. Various SDs of ATV were formulated by conventional and microwave-induced melting methods using Gelucire®48/16 as a carrier. The formulated SDs were characterized for different physicochemical characterizations, drug release, and oral bioavailability studies. The results obtained from the different physicochemical characterization indicate the molecular dispersion of ATV within various SDs. The drug polymer interaction results showed no interaction between ATV and used carrier. There was marked enhancement in the solubility (1.95–9.32 folds) was observed for ATV in prepared SDs as compare to pure ATV. The drug content was found to be in the range of 96.19% ± 2.14% to 98.34% ± 1.32%. The drug release results revealed significant enhancement in ATV release from prepared SDs compared to the pure drug and the marketed tablets. The formulation F8 showed high dissolution performance (% DE30 value of 80.65 ± 3.05) among the other formulations. Optimized Gelucire®48/16–based SDs formulation suggested improved oral absorption of atorvastatin as evidenced with improved pharmacokinetic parameters (Cmax 2864.33 ± 573.86 ng/ml; AUC0-t 5594.95 ± 623.3 ng/h ml) as compared to ATV suspension (Cmax 317.82 ± 63.56 ng/ml; AUC0-t 573.94 ± 398.9 ng/h ml) and marketed tablets (Cmax 852.72 ± 42.63 ng/ml; 4837.4 ± 174.7 ng/h ml). Conclusively, solid dispersion-based oral formulation of atorvastatin could be a promising approach for enhanced drug solubilization, dissolution, and subsequently improved absorption.
Ocular Distribution of Papaverine Using Non-aqueous Vehicles
Priyanka Agarwal, Sairam Behera & Ilva Dana Rupenthal
doi : 10.1208/s12249-021-02050-6
22, Article number: 160 (2021)
Papaverine, a poorly soluble opium alkaloid, has recently been shown to reduce retinal inflammation due to which it may have therapeutic application in the management of Leber’s hereditary optic neuropathy. In this study, papaverine eyedrops based on medium chain triglycerides were prepared and the effect of diethyl glycol monoethyl ether (DGME) on their ocular distribution was evaluated using an ex vivo porcine eye model. The route of drug penetration was also studied by orienting the eye to expose either only the cornea or the sclera to the formulation. Furthermore, in vivo studies were performed to confirm ocular tolerability and evaluate ocular drug distribution. Our results showed increased papaverine concentrations in the cornea and sclera in the presence of DGME but with a slight reduction in the retina-choroid (RC) drug concentration when administered via the corneal route, suggesting that DGME enhances drug accumulation in the anterior ocular tissues but with little effect on posterior drug delivery. In vivo, the papaverine eyedrop with DGME showed good ocular tolerability with the highest drug concentration being observed in the cornea (1.53 ± 0.28 ?g/g of tissue), followed by the conjunctiva (0.74 ± 0.18 ?g/g) and sclera (0.25 ± 0.06 ?g/g), respectively. However, no drug was detected in the RC, vitreous humor or plasma. Overall, this study highlighted that DGME influences ocular distribution and accumulation of papaverine. Moreover, results suggest that for hydrophobic drugs dissolved in hydrophobic non-aqueous vehicles, transcorneal penetration via the transuveal pathway may be the predominant route for drug penetration to posterior ocular tissues.
Lipid Coating of Chitosan Nanogels for Improved Colloidal Stability and In Vitro Biocompatibility
Victor Passos Gibson, Julia Balestrero Braga Nunes, Deborah Quintanilha Falcao, V. Gaëlle Roullin & Jeanne Leblond Chain
doi : 10.1208/s12249-021-02027-5
22, Article number: 159 (2021)
Chitosan-based carriers have coined their position as delivery agents. When assembled with polyanions into nanogels (NG), these vectors have enabled the delivery of drugs, genes, and proteins to a myriad of applications. However, the chemical and colloidal instability of chitosan nanoformulations in physiologically compatible media prejudices in vitro biocompatibility and, thus, scale-up applications. To overcome this issue, we envisaged the coating of chitosan nanogel with phospholipids. In this investigation, we report a two-stage synthesis of hybrid lipid-coated chitosan nanogels, named nanolipogels (NLG), to improve colloidal stability and in vitro biocompatibility over chitosan NG. Practically, we employed a mixing platform to first prepare chitosan NG by ionic gelation, dilute the suspension, and, in a second stage, coat the NG with lipids. We demonstrate that lipid coating increased particle size and reversed the ?-potential to negative values, suggesting the successful formation of NLG, while maintaining a homogeneous size distribution (PDI < 0.25). Furthermore, multiple light scattering analysis confirmed NLG improved colloidal stability in phosphate buffer saline and cell culture medium, with respect to NG. Finally, lipid coating completely abrogated the cytotoxicity of NG when incubated at 50 ?g·mL?1 with HeLa, U87, or b.End3 cell lines and significantly improved the biocompatibility at 100 and 150 ?g·mL?1. Future investigations will explore how the lipid coating affects drug loading, release profile, and the ability of NLG to deliver drugs and genes in vitro.
Triphenylphosphonium functionalized Ficus religiosa L. extract loaded nanoparticles improve the mitochondrial function in oxidative stress induced diabetes
Priyanka Karunanidhi, Nitin Verma, Dulla Naveen Kumar, Ashish Kumar Agrawal & Sanjay Singh
doi : 10.1208/s12249-021-02016-8
22, Article number: 158 (2021)
The present study was aimed to enhance the mitochondrial function in oxidative stress-induced diabetes. To achieve this, Ficus religiosa L. extract loaded solid lipid nanoparticles (ETNPs) were prepared and functionalized by using triphenylphosphonium. Developed nanoparticles demonstrated desired quality attributes with sustained release for up to 24 h and excellent storage stability for up to 180 days at 40 ± 2°C and 75 ± 5% relative humidity. In vitro cytotoxicity assessment showed no toxicity of ETNPs. Interestingly, oral administration of ETNPs to diabetic rats demonstrated improved mitochondrial function by normalizing the mitochondrial morphology, intracellular calcium ion concentration, complexes I, II, IV, and V activity, mitochondrial membrane potential, and antioxidant levels. Further, reduction in apoptotic markers viz. cytochrome-C, caspase-3, and caspase-9 was observed following the ETNP treatment. Moreover, significant reduction in blood glucose and glycosylated hemoglobin while significant improvement in plasma insulin was observed as compared to the diabetic group following the treatment with developed formulation. Furthermore, histopathology studies confirmed the safety of the developed formulation and thus, data in hand collectively suggest that proposed strategy can be effectively used to improve the mitochondrial function in oxidative stress-induced diabetes along with better control over blood glucose and glycosylated hemoglobin.
[10]-Gingerol-Loaded Nanoemulsion and its Biological Effects on Triple-Negative Breast Cancer Cells
Ideli Zanesco-Fontes, Ana Carolina Lopes Silva, Patr?cia Bento da Silva, Jonatas Lobato Duarte, Leonardo Delello Di Filippo, Marlus Chorilli, Marcia Regina Cominetti & Ana Carolina Baptista Moreno Martin
doi : 10.1208/s12249-021-02006-w
22, Article number: 157 (2021)
The apoptotic, cytotoxic, and cytostatic activities for [10]-gingerol in triple-negative breast cancer cells (TNBCs) were already reported. However, despite these important antitumor activities, the compound has the disadvantage to have a hydrophobic characteristic, hindering in vivo administration. To surpass this issue, in this study we have created a [10]-gingerol-loaded nanoemulsion (10GNE) in order to increase the stability and solubility of the compound. The nanoemulsion was characterized and tested for its cytotoxic, cytostatic, and apoptotic effects on a panel of murine and human TNBC cell lines, as well as non-tumor cells, and compared with a [10]-gingerol-free nanoemulsion (NE) and with [10]-gingerol itself. Except for the murine 4T1.13 cell line, the IC50 of the free 10G molecule, after 72 h of incubation, was higher in all cell lines tested, both murine and human, demonstrating therefore the efficacy of the 10GNE regarding cytotoxicity. In murine tumor cells, 60 ?M 10GNE was able to arrest cell cycle at sub-G0 phase and induce apoptosis, leading to 48% and 78% of total cell death in 4T1.13 and 4T1Br4 murine tumor cells, respectively. This represents an improvement compared to 10G-free molecule that only induced 74% of total apoptosis at 100 ?M in 4T1Br4 cells. Taken together, our results show that nanoformulation preserved the [10]-gingerol cytotoxic and cytostatic properties and improved its apoptotic function on murine TNBC cell lines. These data open new perspectives to a more suitable drug-delivery approach for [10]-gingerol for TNBC treatment that should be further demonstrated using in vivo assays.
Insights on the Critical Parameters Affecting the Probiotic Viability During Stabilization Process and Formulation Development
Sharda Gurram, Durgesh K. Jha, Devanshi S. Shah, Madhuri M. Kshirsagar & Purnima D. Amin
doi : 10.1208/s12249-021-02024-8
22, Article number: 156 (2021)
Probiotics have gained a lot of interest in recent years as an alternative as well as adjuvant therapy for several conditions owing to their health benefits. These live microorganisms have proven efficacy for treating gut disorders, inflammation, bacterial vaginosis, hepatic and depressive disorders, and many more. There are conventional as well as non-conventional formulations available for the delivery of probiotics with the latter having fewer regulatory guidelines. The conventional formulations include the pharmaceutical formulations specifically designed to deliver an efficacious number of viable microorganisms. Studies have indicated 108–109 CFU/g as an ideal dose of probiotics for achieving health benefits, and hence, all the formulations must at least contain the said number of viable bacteria to show a therapeutic effect. The most crucial feature of probiotic formulations is that the bacteria are prone to several environmental and processing factors which all together reduce the viability of the bacteria in the final formulation. These factors include processing parameters like temperature, humidity, pressure, and storage conditions. Thus, the present review primarily focuses on the critical process parameters affecting the probiotic viability during stabilization process and formulation development. Understanding these factors prior to processing helps in delivering probiotics in the required therapeutic numbers at the target site.
