Nanogels as Drug Delivery Carrier: A Narrative Review on Formulation Techniques, Characterization, Applications, and Patents.

Under the umbrella of targeted drug delivery systems, several techniques are unleashed in the market that allow a drug or other pharmacologically active material to be delivered to the target cell to treat a condition or health problem. The improvement of the pharmaceutical delivery systems' effectiveness, safety, and stability is accomplished through the Formulation of the nano-gel-based delivery system. Nanogels are aqueous dispersions of submicronsized, three-dimensional, strongly cross-linked networks of hydrophilic polymers that are inflated by water. Through a variety of delivery routes, such as oral, pulmonary, nasal, parenteral, and intraocular, an active pharmaceutical agent or therapeutic agent with a high or low molecular weight can be easily encapsulated into nanogels. Nanogels have been researched as drug delivery systems due to their beneficial qualities, such as biocompatibility, high stability, flexible particle size, drug loading capacity, and potential surface modification for active targeting by attaching ligands that recognize cognate receptors on target cells or tissues. By responding to internal or external stimuli, including pH, temperature, light, and redox, nano gels can be made to be stimulus-responsive, allowing for regulated drug release. Thus, in the fact of said characteristics' of nano gels, this review manuscript aims to provide an overview of characterization, evaluation, formulation technique, recent applications, and patents of nano gels.

Formulation and Optimization of Solid Lipid Nanoparticle-based Gel for Dermal Delivery of Linezolid Using Taguchi Design.

BACKGROUND: Linezolid (LNZ) is a synthetic oxazolidinone antibiotic approved for the treatment of uncomplicated and complicated skin and soft tissue infections caused by gram-positive bacteria. Typically, LNZ is administered orally or intravenously in most cases. However, prolonged therapy is associated with various side effects and life threatening complications. Cutaneous application of LNZ will assist in reducing the dose, hence minimizing the unwanted side/adverse effects associated with oral administration. Dermal delivery provides an alternative route of administration, facilitating a local and sustained concentration of the antimicrobial at the site of infection. OBJECTIVE: The current research work aimed to formulate solid lipid nanoparticles (SLNs) based gel for dermal delivery of LNZ in the management of uncomplicated skin and soft tissue infections to maximise its benefits and minimise the side effects. METHODS: SLNs were prepared by high-shear homogenisation and ultrasound method using Dynasan 114 as solid lipid and Pluronic F-68 as surfactant. The effect of surfactant concentration, drug-to-lipid ratio, and sonication time was investigated on particle size, zeta potential, and entrapment efficiency using the Taguchi design. The main effect plot of means and signal-to-noise ratio were generated to determine the optimized formulation. The optimized batch was formulated into a gel, and ex-vivo permeation study, in-vitro and in-vivo antibacterial activity were conducted. RESULTS: The optimised process parameters to achieve results were 2% surfactant concentration, a drug-to-lipid ratio of 1:2, and 360 s of sonication time. The optimized batch was 206.3± 0.17nm in size with a surface charge of -24.4± 4.67mV and entrapment efficiency of 80.90 ± 0.45%. SLN-based gel demonstrated anomalous transport with an 85.43% in vitro drug release. The gel showed a 5 cm zone of inhibition while evaluated for in vitro antibacterial activity against Staphylococcus aureus. Ex-vivo skin permeation studies demonstrated 20.308% drug permeation and 54.96% cutaneous deposition. In-vivo results showed a significant reduction in colony-forming units in the group treated with LNZ SLN-based gel. CONCLUSION: Ex-vivo studies ascertain the presence of the drug at the desired site and improve therapy. In-vivo results demonstrated the ability of SLN-based gel to significantly reduce the number of bacteria in the stripped infection model. The utilization of SLN as an LNZ carrier holds significant promise in dermal delivery.

A Comprehensive Review on Molecular Mechanism Involved in Arsenic Trioxide Mediated Cerebral Neurodegenerative and Infectious Diseases.

Arsenic is an environmental toxicant and its toxicity is a global health problem affecting millions of people. Arsenic exposure occurs from natural geological sources leaching into aquifers, contaminating drinking water and may also occur from mining and other industrial processes. Both cancerous, noncancerous and immunological complications are possible after arsenic exposure. The many other target organs like lungs, thymus, spleen, liver, heart, kidney, and brain. Arsenic-mediated neuro, as well as immunotoxicity, is the main concern of this review. Long-term arsenic exposure can lead to various neurological dysfunctions, which may cause neurobehavioral defects and biochemical impairment in the brain, this might negatively affect one's quality of life in later stages. Arsenic also alters the levels of various neurotransmitters such as serotonin, dopamine and norepinephrine in the brain which produces neurotoxic effects and immunological deficiency. So, it is crucial to understand the neurotoxic mechanism of arsenic trioxide-mediated cerebro neurodegenerative and immunerelated alterations. One of the major mechanisms by which it exerts its toxic effect is through an impairment of cellular respiration by inhibition of various mitochondrial enzymes, and the uncoupling of oxidative phosphorylation. This review focuses on the various toxic mechanisms responsible for arsenic-mediated neurobehavioral and immune-related changes. Therefore, this review provides a critical analysis of mitochondrial dysfunctions, oxidative stress, glutamate excitatory, inflammatory and apoptosis-related mechanistic aspects in arsenic-mediated immunotoxicity, neurotoxicity, and neurodegenerative changes.

Niosomes gel of apigenin to improve the topical delivery: development, optimization, ex vivo permeation, antioxidant study, and in vivo evaluation.

Niosomes (NS) are the promising and novel carrier of the drug for effective transdermal delivery. Apigenin (AN) is a natural bioactive compound and has various pharmacological activities. AN is poorly water soluble which directly affects therapeutic efficacy. The aim of this research work was to develop the AN-NS gel to improve transdermal delivery. The thin-film hydration method was used for the development of AN-NS. The optimized AN-NS (AN-NS2) has a vesicle size of 272.56 ± 12.49 nm, PDI is 0.249, zeta potential is -38.7 mV, and entrapment efficiency of 86.19 ± 1.51%. The FTIR spectra of the AN-NS2 depicted that AN encapsulated in the NS matrix. AN-NS2 formulation was successfully incorporated into chitosan gel and evaluated. The optimized AN-NS2 gel (AN-NS2G4) has 2110 ± 14cps of viscosity, 10.40 ± 0.21g.cm/sec of spreadability, and 99.65 ± 0.53% of drug content. AN-NS2G4 displayed significantly (p < 0.05) higher AN released (67.64 ± 3.03%) than pure AN-gel (37.31 ± 2.87%). AN-NS2G4 showed the Korsmeyer Peppas release model. AN-NS2G4 displayed significantly (p < 0.05) higher antioxidant activity (90.72%) than pure AN (64.53%) at 300 µg/ml. AN-NS2G4 displayed significantly (p < 0.05) higher % inhibition of swelling than pane AN-gel in carrageenin-induced paw oedema in rats. The finding concluded that niosomes-laden gel is a good carrier of drugs to improve transdermal delivery and therapeutic efficacy.

Ameliorative Effect of Ethanolic Extract of Moringa oleifera Leaves in Combination with Curcumin against PTZ-Induced Kindled Epilepsy in Rats: In Vivo and In Silico.

The ameliorative effect of ethanolic extract of M. oleifera (MOEE) leaves in combination with curcumin against seizures, cognitive impairment, and oxidative stress in the molecular docking of PTZ-induced kindled rats was performed to predict the potential phytochemical effects of MOEE and curcumin against epilepsy. The effect of pretreatment with leaves of M. oleifera ethanolic extracts (MOEE) (250 mg/kg and 500 mg/kg, orally), curcumin (200 mg/kg and 300 mg/kg, orally), valproic acid used as a standard (100 mg/kg), and the combined effect of MOEE (250 mg/kg) and curcumin (200 mg/kg) at a low dose on Pentylenetetrazole was used for (PTZ)-induced kindling For the development of kindling, individual Wistar rats (male) were injected with pentyletetrazole (40 mg/kg, i.p.) on every alternate day. Molecular docking was performed by the Auto Dock 4.2 tool to merge the ligand orientations in the binding cavity. From the RCSB website, the crystal structure of human glutathione reductase (PDB ID: 3DK9) was obtained. Curcumin and M. oleifera ethanolic extracts (MOEE) showed dose-dependent effects. The combined effects of MOEE and curcumin leaves significantly improved the seizure score and decreased the number of myoclonic jerks compared with a standard dose of valproic acid. PTZ kindling induced significant oxidative stress and cognitive impairment, which was reversed by pretreatment with MOEE and curcumin. Glutathione reductase (GR) is an enzyme that plays a key role in the cellular control of reactive oxygen species (ROS). Therefore, activating GR can uplift antioxidant properties, which leads to the inhibition of ROS-induced cell death in the brain. The combination of the ethanolic extract of M. oleifera (MOEE) leaves and curcumin has shown better results than any other combination for antiepileptic effects by virtue of antioxidant effects. As per the docking study, chlorogenic acid and quercetin treated with acombination of curcumin have much more potential.

Neuroprotective Effect of Morinda citrifolia on Behavioural and Biochemical Deficits in PTZ-induced Kindled Mice.

INTRODUCTION: Epilepsy is a group of chronic neurological disorders characterized by seizures. Kindling, a chronic epileptic mouse model, was used to explore the epileptogenic mechanism and seek new anti-epileptics. In kindling, sub-convulsive (chemical/ electrical) stimuli were delivered repeatedly and erratically, eventually causing massive convulsions. Moreover, Morinda citrifolia (Noni) extracts are used as a remedy in ayurvedic preparations for many ailments. Noni has recently been shown to protect mice from amyloid beta-induced memory loss. OBJECTIVE: This study was used to investigate the neuroprotective potential of Morinda citrifolia in mice over pentylenetetrazol (PTZ)-induced kindling seizure. METHODS: Kindling was provoked by subsequent (one-day-gap) injections of PTZ (subconvulsive; 35 mg/kg; s.c.) for 29 days in mice. Following PTZ injection, convulsive behaviours were noted for 30 minutes. Open-field-test (locomotor activity), forced swimming test (depressive behaviors), elevated plus-maze, and passive avoidance tests were employed to evaluate cognition. Brain homogenate was used to estimate oxidative stress (glutathione, superoxide-dismutase, lipid-peroxidation) and acetylcholinesterase activity. RESULTS: PTZ-provoked kindled mice displayed depressive behaviors, impaired locomotion, cognitive dysfunctions and various biochemical changes. However, treatment with Morinda citrifolia extract (500 and 1000 mg/kg, p.o) and valproic acid (200 mg/kg, p.o) before 60 min of each PTZ injection diminished kindling scores and restored behavioural, and biochemical changes. CONCLUSION: Our findings suggest Morinda citrifolia offered neuroprotective effects against PTZinduced kindling seizures in mice, which were established by behavioural and biochemical paradigms.

A Review on Autism Spectrum Disorder: Pathogenesis, Biomarkers, Pharmacological and Non-Pharmacological Interventions.

Autistic spectrum disorder (ASD) is a complicated developmental disease characterized by persistent difficulties in social interaction, speech and nonverbal communication, and restricted/ repetitive activities. Our goal is to deliver a step ahead awareness on neurodevelopment in ASD through early behavioral screenings, genetic testing, and detection of various environmental triggers. This would significantly reduce the tally of people with autistic characteristics. As of now, much work is to be done in understanding and treating ASD. Firstly, awareness campaigns must be organized and maintained so that ASD children can be identified and treated feasibly. Secondly, prenatal and prepregnancy environmental risk awareness, including advice against consanguineous marriages, information on optimum mother nutrition, and minimizing pollutants exposure, can be focused. Finally, the extension of genetic screening along with early postnatal monitoring of newborn feeding, nutrition, and eye contact will help in early therapy. People with ASD have strict dietary habits, but they are also more prone to gastrointestinal problems, including diarrhoea, constipation, and sometimes irritable bowel syndrome. Despite significant studies on the symptoms and possible causes of ASD, GI dysfunction is becoming a hot issue of discussion. Dietary strategies can partially help to alleviate both GI and behavioural issues due to the link between gut-microbiota and brain activity. Dietary treatments may be less expensive, easier to administer and have fewer adverse effects than pharmacological interventions. Hence, there is an increasing interest in autistic children's customized diets and supplements. Future studies should look at whether these diets are applicable to diverse people and whether they are practical in various circumstances (areas with fewer resources, lower socioeconomic areas, countries with different dietary restrictions, etc.). The dietary phytochemicals, including curcumin, resveratrol, naringenin, and sulforaphane, have a substantial role as neurotherapeutic agents. These agents can act as an antioxidant, immunomodulator, gut microbiota modulator and Nrf2 activator to provide benefits to ASD patients. Hence an urgent need is to create brain-targeted delivery methods for these dietary phytochemicals and to investigate their therapeutic value in ASD.

Evaluation of Ameliorative Effect of Quercetin and Candesartan in Doxorubicin-Induced Cardiotoxicity.

Background: Several mechanisms have been explored for the anthracycline myocardial toxicity. These are free-radical generation, myocyte apoptosis, lipid peroxidation, mitochondrial deterioration, and direct repression of muscle-specific gene expression. Adriamycin (Doxorubicin) is a potent anti-cancer agent. Adriamycin in prolonged use is fatal and generates free radicals that lead to dose-dependent cardiac toxicity. Objective: The intent of the study was to explore the protective activity of candesartan and quercetin in cardiomyopathy induced by doxorubicin in rats. Methods: To induce cardiac toxicity, rats were intraperitoneally treated with doxorubicin (06 equivalent injections of 2.5 mg/kg, i. p. at 48 hour interval for 02 consecutive weeks to achieve a cumulative dose of 15 mg/kg). Individual and combined oral treatment of candesartan (5 mg/kg/day) and quercetin (10 mg/kg/day) was administered for four weeks. Results: Following cardiomyopathy, heart/body weight ratio (3.526 × 10-3), serum creatine kinase (352.4±16.99 IU/L), lactate dehydrogenase (661.7±20.45 IU/L) levels were elevated in addition to altered lipid profile (TC - 118.4±4.25 mg/dL, TG - 263.3±9.99 mg/dL, VLDL - 52.66±1.99 mg/dL, LDL - 52.99±5.80 mg/dL and HDL - 12.78±0.36 mg/dL). The pre-cotreatment of candesartan and quercetin significantly restored the values to normal. The increased level of lipid peroxides (33.12±1.63 µmol/mg protein), serum troponin-T (1.82 ± 0.11 pg/mL) and nitric oxide (13.33±0.73 nmol/mg protein) level along with attenuating antioxidant profile, ie catalase, glutathione and superoxide dismutase (1.43±0.12 nmol/mg protein, 8.48±0.42 nmol/mg protein and 2.09±0.031 U/mg protein) were reversed to normal. Morphometry and histopathologic changes represented a beneficial effect of single and combination pre-cotreatment of drugs which significantly decreases adriamycin cardiac toxicity. Conclusion: The overall result depicts more beneficial and cardioprotective effect of quercetin and candesartan combination as compared to their individual effects in doxorubicin treated animals. Therefore, this combination might be a suitable option to treat the cardiotoxic effect of doxorubicin.

Formulation of intranasal surface engineered nanostructured lipid carriers of rotigotine: Full factorial design optimization, in vitro characterization, and pharmacokinetic evaluation.

The objective of the present research was to develop, optimize, and evaluate rotigotine (RT)-loaded chitosan (CH) coated nanostructured lipid carriers (RT-CH-NLCs) for nose-to-brain delivery. The NLCs were prepared by homogenization and sonication technique as well as optimized by using three factors at three-level Box-Behnken design. The prepared NLCs were evaluated for particle size, zeta potential, entrapment efficiency, drug release, and ex vivo permeation. The pharmacokinetic study was conducted on albino Wistar rats to evaluate the bioavailability and neuropharmacokinetic parameters after intranasal administration of the optimized formulation (RT-CH-NLCs-OPT). The optimized formulation showed the particle size (170.48 ± 8.37 nm), PDI (0.19 ± 0.03), zeta potential (+26.73 mV), and entrapment efficiency (82.37 ± 2.48 %). In vitro drug release study displayed a sustained drug release pattern from RT-CH-NLCs-OPT (86.73 ± 8.58 % in 24 h) in comparison to RT-Dis (98.61 ± 7.24 % in 16 h). The permeability coefficient (PC) was found to be 11.39 ± 1.08 × 10-4 cm.h-1 and 2.34 folds higher than RT-Dis (4.85 ± 1.53 × 10-4 cm.h-1). The relative bioavailability of RT from RT-CH-NLCs-OPT was 3.2-fold greater as compared to RT-Dis. The absolute bioavailability of RT after intranasal administration of RT-CH-NLCs-OPT was 2.1-fold higher than RT-CH-NLCs-OPT administered intravenously. The brain targeting and targeting potential was displayed by DTE (422.03 %) and DTP (76.03 %) after intranasal administration of RT-CH-NLCs-OPT as compared to RT-Dis (DTE 173.91 % and DTP 59.97 %). Furthermore, confocal laser scanning microscopy results confirmed better brain targeting for RT-CH-NLCs-OPT as compared to RT-Dis. From these findings, it could be concluded that RT-CH-NLCs could serve as a promising strategy for targeting RT through the intranasal route.

Letter to the Editor: Integrating the Roles of Pharmacy Practice and Drug Delivery in Mitigating COVID-19.

No Abstract Available.

Investigation on protective effect of Terminalia bellirica (Roxb.) against drugs induced cardiotoxicity in wistar albino rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Various traditional texts like Ayurveda and Materia Medica profoundly mentioned the ethnopharmacological use of Terminalia bellirica fruit for its protective effect on heart and various other vital organs. Hence the present research was focussed to scientifically prove the effect of T. bellirica in support of its traditionally claimed use as cardioprotective agent. AIM THE STUDY: The aim and objective of the present study was to investigate the protective effect of T. bellirica (Roxb.) against drugs viz. Doxorubicin (DOX) and Isoproterenol (ISO) induced cardiotoxicity in wistar albino rats. MATERIAL AND METHODS: Cardiotoxicity was induced using DOX (15 mg/kg, i.p.) and ISO (85 mg/kg s.c.) models. Methanolic extract of T. bellirica (METB) was subjected to rats in two different doses (low dose of 250 mg/kg p.o.; and high dose of 500 mg/kg p.o.) for the purpose of investigation of various biochemical markers present in cardiac tissue as well as in blood serum, in order to assess the improvement in drugs induced cardiotoxicity. Also, the histopathological study was carried out in terms of ultrastructural changes occurred in the myocardium during drugs induced cardiomyopathy, to ensure the proposed cardioprotective effect of METB. RESULT: Biochemical investigation of cardiac tissue using METB showed significant decrease in CK-MB (creatine kinase-muscle/brain) activity and MDA (malondialdehyde) levels and increase in GSH (reduced glutathione) levels. It also increased the activity of SOD (superoxide dismutase) and CAT (catalase). In serum, METB increased the levels of oxidative stress markers like ALP (alkaline phosphatase), UA (uric acid), ALT (alanine transferase), and AST (aspartate transaminase) near to their normal values as in control group. The use of METB also decreased the levels of total cholesterol and TGs (triglycerides) in serum and significantly increased HDL (high density lipoprotein) levels. Treatment with METB also proved a considerable restoration in histopathological findings of myocardium. CONCLUSION: In the present study it was concluded that T. bellirica fruit has profound potential for the treatment of drugs induced cardiotoxicity suggesting the consumption of T. bellirica for cardiac benefits during routine treatment of cardiotoxicity.

Silk fibroin protein modified acellular dermal matrix for tissue repairing and regeneration.

Worldwide the demand of skin-graft has been increasing day by day, for these different biomaterials and techniques have been used. In the present study, we have fabricated Silk Fibroin (SF) modified hybrid acellular goat-dermal matrix (SF-AGDM) by modifying the AGDM in different concentration SF- 5, 10, 15%, for enhancing the wound healing process. The grafts (AGDM and SF-AGDM) were evaluated for skin tissue regeneration by subjecting it through physical, chemical and biological characterization. SLS analysis showed the molecular weight of SF was 10,000 Da. Here, we found that SF-AGDM modified with low concentration of SF showed good porosity 78.56 ±â€¯14.30% and pore size 74.69 ±â€¯28.66 µm as similar to the AGDM. FTIR analysis showed the shifting of NH stretching (3400-3600 cm-1), amide I band at 3427 cm-1 and 1641 cm-1 and disappearance of the peaks of CH asymmetrical stretching (3000-2800 cm-1), amide II and amide III band, which indicate formation of amide linkage or other interaction between the SF protein and AGDM. In vitro cell culture studies by seeding 3 T3 mouse fibroblast cells on the scaffold revealed excellent cell viability, proliferation rate and adhesion in the scaffold. Pre-clinical study done in albino mice model showed within 14 days, all the wounds were completely cured, full thickness skin was regenerated without any significant inflammatory response. SF-ADGM results better healing as compared to the unmodified AGDM, which indicates the synergetic effect of SF coupled with acellular ECM based matrix. Thus, SF-AGDM is biocompatible, cost-effective material that can be potentially applied for tissue engineering application.

Erythromycin-induced genotoxicity and hepatotoxicity in mice pups treated during prenatal and postnatal period.

The main aim of this study was to investigate the oxidative stress, genotoxicity and cytotoxicity of erythromycin (EMC) in pups of treated dams in gestation as well as the lactation period (LP). The two doses of EMC were compared using intraperitoneal (i.p.) route in two different periods, that is, in gestation period and in the LP. The rationale behind selection of i.p. route is because of the fact that EMC gets degrades in acidic pH of the stomach. The doses of EMC used were clinically equivalent dose (CED; EMC 14.2 mg/kg, i.p.) and a lower dose (EMC 10 mg/kg, i.p.) than CED. EMC toxicities in mice pups were evaluated using various parameters such as micronucleus (MN) test in peripheral blood and bone marrow, malondialdehyde (MDA) assay, glutathione (GSH reduced) assay and histopathological assessment in liver tissue. The CED of EMC led to a significant increase in MDA and decreased in GSH concentration in pups' liver tissue in both gestation and LPs and also to a significant increase in MN frequency in both peripheral blood and bone marrow cells of pups. There were no significant toxicities at a lower dose than CED. There were also some chronic findings with liver histopathological examination at CED. It is thus concluded that EMC accentuates the oxidative stress, cytotoxicity and DNA damage in pups of their postnatal life; hence, EMC should be avoided in the pregnancy and also in the LP.

Platelet-activating factor (PAF)-antagonists of natural origin.

Presently herbal medicines are being used by about 80% of the world population for primary health care as they stood the test of time for their safety, efficacy, cultural acceptability and lesser side effects. The discovery of platelet activating factor antagonists (PAF antagonists) during these decades are going on with different framework, but the researchers led their efficiency in studying in vitro test models. Since it is assumed that PAF play a central role in etiology of many diseases in humans such as asthma, neuronal damage, migraine, cardiac diseases, inflammatory, headache etc. Present days instinctively occurring PAF antagonist exists as a specific grade of therapeutic agents for the humans against these and different diseases either laid hold of immunological or non-immunological types. Ginkgolide, cedrol and many other natural PAF antagonists such as andrographolide, α-bulnesene, cinchonine, piperine, kadsurenone, different Piper species' natural products and marine origin plants extracts or even crude drugs having PAF antagonist properties are being used currently against different inflammatory pathologies. This review is an attempt to summarize the data on PAF and action of natural PAF antagonists on it, which were evaluated by in vivo and in vitro assays.