The Use of Nanoneedles in Drug Delivery: an Overview of Recent Trends and Applications.

Nanoneedles (NN) are growing rapidly as a means of navigating biological membranes and delivering therapeutics intracellularly. Nanoneedle arrays (NNA) are among the most potential resources to achieve therapeutic effects by administration of drugs through the skin. Although this is based on well-established approaches, its implementations are rapidly developing as an important pharmaceutical and biological research phenomenon. This study intends to provide a broad overview of current NNA research, with an emphasis on existing approaches, applications, and types of compounds released by these systems. A nanoneedle-based delivery device with great spatial and temporal accuracy, minimal interference, and low toxicity could transfer biomolecules into living organisms. Due to its vast potential, NN has been widely used as a capable transportation system of many therapeutic active substances, from cancer therapy, vaccine delivery, cosmetics, and bio-sensing nanocarrier drugs to genes. The use of nanoneedles for drug delivery offers new opportunities for the rapid, targeted, and exact administration of biomolecules into cell membranes for high-resolution research of biological systems, and it can treat a wide range of biological challenges. As a result, the literature has analyzed existing patents to emphasize the status of NNA in biological applications.

A novel RP-HPLC method development and validation for simultaneous quantification of gefitinib and resveratrol in polymeric hybrid lipid nanoparticles and glioma cells.

Resveratrol and Gefitinib are adjunct therapies for various cancers; however, both have been limited by low solubility, low cellular uptake, and bioavailability issues. As a result, this research aimed to develop an accurate, precise, selective, and sensitive reverse-phase high-performance liquid chromatography (RP-HPLC) method to simultaneously determine both compounds in nanoformulation and Glioma cells. The phenomenex luna C8 column, a mobile phase (80: 20 ratios of acetonitrile: 200 mM ammonium acetate) with a flow rate of 1 mL. min-1, 40 ± 0.2 °C as a column temperature, and the injection volume was 20 µl were selected as optimized chromatographic conditions. Retention time (RT) of resveratrol (1.80 min) and gefitinib (2.56 min) were identified using an optimized analytical method and detected at 345 nm (isosbestic point). The approach was proven to be specific for resveratrol and gefitinib analysis in the existence of PHLNPs, precise (RSD 2 %), and accurate (>90 %). The simultaneous analytical method was successfully developed to identify percentage drug entrapment efficiency (% DEE), % drug loading (% DL) of resveratrol and gefitinib in PHLNPs, and secondary estimates of in-vitro drug release profile and percentage cellular uptake studies. The in-vitro results revealed that the developed analytical method could simultaneously detect and quantify these drugs in other nanoformulations and in-vivo studies.

Can manipulation of gut microbiota really be transformed into an intervention strategy for cardiovascular disease management?

Recent advancement in manipulation techniques of gut microbiota either ex vivo or in situ has broadened its plausible applicability for treating various diseases including cardiovascular disease. Several reports suggested that altering gut microbiota composition is an effective way to deal with issues associated with managing cardiovascular diseases. However, actual translation of gut microbiota manipulation-based techniques into cardiovascular-therapeutic approach is still questionable. This review summarized the evidence on challenges, opportunities, recent development, and future prospects of gut microbiota manipulation for targeting cardiovascular diseases. Initially, issues associated with current cardiovascular diseases treatment strategy, association of gut microbiota with cardiovascular disease, and its influence on cardiovascular drugs were discussed, followed by applicability of gut microbiota manipulation as a cardiovascular disease intervention strategy along with its challenges and future prospects. Despite the fact that the gut microbiota is rugged, interventions like probiotics, prebiotics, synbiotics, fecal microbiota transplantation, fecal virome transplantation, antibiotics, diet changes, and exercises could manipulate it. Advanced techniques like administration of engineered bacteriophages and bacteria could also be employed. Intensive exploration revealed that if sufficiently controlled approach and proper monitoring were applied, gut microbiota could provide a compelling answer for cardiovascular therapy.

Current Status of Brain Tumor in the Kingdom of Saudi Arabia and Application of Nanobiotechnology for Its Treatment: A Comprehensive Review.

OBJECTIVE: Brain tumors are the most challenging of all tumors and accounts for about 3% of all cancer allied deaths. The aim of the present review is to examine the brain tumor prevalence and treatment modalities available in the Kingdom of Saudi Arabia. It also provides a comprehensive analysis of the application of various nanotechnology-based products for brain cancer treatments along with their prospective future advancements. METHODS: A literature review was performed to identify and summarize the current status of brain cancer in Saudi Arabia and the scope of nanobiotechnology in its treatment. RESULTS: Depending upon the study population data analysis, gliomas, astrocytoma, meningioma, and metastatic cancer have a higher incidence rate in Saudi Arabia than in other countries, and are mostly treated in accordance with conventional treatment modalities for brain cancer. Due to the poor prognosis of cancer, it has an average survival rate of 2 years. Conventional therapy includes surgery, radiotherapy, chemotherapy, and a combination thereof, but these do not control the disease's recurrence. Among the various nanomaterials discussed, liposomes and polymeric nanoformulations have demonstrated encouraging outcomes for facilitated brain cancer treatment. CONCLUSIONS: Nanomaterials possess the capacity to overcome the shortcomings of conventional therapies. Polymer-based nanomaterials have shown encouraging outcomes against brain cancer when amalgamated with other nano-based therapies. Nonetheless, nanomaterials could be devised that possess minimal toxicity towards normal cells or that specifically target tumor cells. In addition, rigorous clinical investigations are warranted to prepare them as an efficient and safe modality for brain cancer therapy.

Pulmonary Targeting of Inhalable Moxifloxacin Microspheres for Effective Management of Tuberculosis.

In the present study, the objective was to attain a localized lung delivery of an anti-tubercular fluoroquinolone, moxifloxacin (MXF), targeting the alveolar macrophages through a non-invasive pulmonary route using inhalable microspheres as a dry powder inhaler approach. MXF-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres (MXF-PLGA-MSs) were fabricated by solvent evaporation technique and optimized by using a central composite statistical design. The morphology and particle size, as well as the flowability of the optimized microspheres, were characterized. In addition, the aerosolization performance of the optimized formula was inspected using an Andersen cascade impactor. Furthermore, in vivo fate following intrapulmonary administration of the optimized formula was evaluated. The optimized MXF-PLGA-MSs were spherical in shape with a particle size of 3.16 µm, drug loading of 21.98% and entrapment efficiency of 78.0%. The optimized formula showed a mass median aerodynamic diameter (MMAD) of 2.85 ± 1.04 µm with a favorable fine particle fraction of 72.77 ± 1.73%, suggesting that the powders were suitable for inhalation. Most importantly, in vivo studies revealed that optimized MXF-PLGA-MSs preferentially accumulated in lung tissue as manifested by a two-fold increase in the area under the curve AUC0-24h, compared to plain drug. In addition, optimized MXF-PLGA-MS sustained drug residence in the lung for up to 24 h following inhalation, compared to plain drug. In conclusion, inhalable microspheres of MXF could be a promising therapeutic approach that might aid in the effective eradiation of tuberculosis along with improving patient adherence to the treatment.

Design and formulation of polymeric nanosponge tablets with enhanced solubility for combination therapy.

Three drugs namely caffeine, paracetamol, and aceclofenac are commonly used for treating various acute and chronic pain related ailments. These 3 drugs have varied solubility profiles, and formulating them into a single tablet did not have the desired dissolution profile for drug absorption. The objective of the present research was to tailor the drug release profile by altering drug solubility. This was achieved by loading the drug into nanosponges. Here, three-dimensional colloidal nanosponges were prepared using ß-cyclodextrin with dimethyl carbonate as a cross-linker using the hot-melt compression method. The prepared nanosponges were characterized by FTIR, 1H NMR spectroscopy, DSC, XRPD studies and SEM. The FTIR and DSC results obtained indicated polymer-drug compatibility. The 1H NMR spectroscopy results obtained indicated the drug entrapment within nanosponges with the formation of the inclusion complex. XRPD studies showed that the loaded drug had changed crystalline properties altering drug solubility. SEM photographs revealed the porous and spongy texture on the surface of the nanosponge. Box-Behnken experimental design was adopted for the optimization of nanosponge synthesis. Among the synthesized nanosponges containing paracetamol, aceclofenac and caffeine, batch F3-P31, F3-A31 and F3-C31 were considered optimized. Their particle size was 185, 181 and 199 nm with an entrapment efficiency of 81.53, 84.96, and 89.28% respectively. These optimized nanosponges were directly compressed into tablets and were studied for both pre and post-compression properties including in vitro drug release. The prepared tablet showed desired drug dissolution properties compared to the pure drug. The above outcomes indicated the applicability of nanosponges in modulating the drug release with varied solubility for combination therapy.

A Paradigm Shift in the Development of Anti-Candida Drugs.

BACKGROUND: The considerable increase in the incidence of Candida infection in recent times has prompted the use of numerous antifungal agents, which has resulted in the development of resistance towards various antifungal agents. With rising Candida infections, the need for design and development of novel antifungal agents is in great demand. However, new therapeutic approaches are very essential in preventing the mortality rate and improving the patient outcome in those suffering from Candida infections. OBJECTIVE: The present review objective is to describe the burden, types of Candidiasis, mechanism of action of antifungal agents and its resistance and the current novel approaches used to combat candidiasis. METHODS: We have collected and analyzed 135 different peer-reviewed literature studies pertinent to candidiasis. In this review, we have compiled the major findings from these studies. RESULTS AND CONCLUSION: The review describes the concerns related to candidiasis, its current treatment strategy, resistance mechanisms and imminent ways to tackle the problem. The review explored that natural plant extracts and essential oils could act as sources of newer therapeutic agents, however, the focus was on novel strategies, such as combinational therapy, new antibodies, utilization of photodynamic therapy and adaptive transfer primed immune cells with emphasis on the development of effective vaccination.

Development and Efficacy Assessment of an Enteric Coated Porous Tablet Loaded With F4 Fimbriae for Oral Vaccination of Piglets against F4+ Escherichia coli Infections.

Enterotoxigenic Escherichia coli (ETEC) infection is one of the major causes contributing to the development of diarrhoea and mortality in new born, suckling and newly weaned piglets. To date, no preventive/treatment strategy showed promising results, which could be due to the lack of potent vaccines, and/or due to the development of resistance of ETEC to antibiotics. Therefore, in the present investigation, a novel porous sodium alginate (SA) tablet formulation loaded with F4 fimbriae antigen was developed and tested for efficacy against ETEC infections in piglet models. Precompression parameters of the powder mixes and post compression parameters of tablets have been evaluated and results were found to be satisfactory. Loading of F4 fimbrial antigens into the tablets was achieved by inducing pores in the tablets via the sublimation of camphor followed by incubation with purified F4 fimbriae. The loaded tablets have been coated with Eudragit L100 to protect the F4 fimbriae from (a) highly acidic gastric environment; (b) proteolytic cleavage by pepsin; and (c) to promote subsequent release in the intestine. Evaluation of developed F4 fimbrial tablets in a Pig model demonstrated induction of mucosal immunity, and a significant reduction of F4+ E. coli in faeces. Therefore, F4 fimbriae loaded porous tablets could be a novel oral vaccination candidate to induce mucosal and systemic immunity against ETEC infections.

Design of phosphated cross-linked microspheres of bael fruit gum as a biodegradable carrier.

Present work was aimed at designing of phosphated cross-linked microspheres of bael fruit gum (BFG) by emulsification method using sodium-tri-meta phosphate as a cross-linking agent for treatment of colon cancer using 5-fluorouracil as model drug. Stirring speed was found to be 1,000 rpm for about 5 h to be optimal to obtain reproducible microspheres. It was found that there is an increase in particle size as polymer concentration is increased whereas a reduction in particle size was observed as there is increase in stirring speed. Cross-linked BFG microspheres were successfully prepared by emulsification method. Optimum surfactant concentration was found to be 2 % w/w. Scanning electron microscopy studies showed that the drug-loaded microspheres were non-aggregated and in spherical shape. Differential scanning calorimetry and Fourier transform infrared-spectroscopy studies showed that drug and excipients are compatible. Release studies showed that drug release was more profound in cecal medium induced with enzymes causing degradation of the cross linked BFG than that of the release showed in simulated intestinal fluid. Stability studies showed that there were no significant changes in the drug content and physical appearance of microspheres.

Calcipotriol delivery into the skin as emulgel for effective permeation.

The objective of this work is to formulate and evaluate an emulgel containing calcipotriol for treatment of psoriasis. Emulgels have emerged as a promising drug delivery system for the delivery of hydrophobic drugs. Isopropyl alcohol and polyethylene glycol have been employed as permeation enhancers. Formulation chart is made with seven formulations, evaluated for physical parameters, drug content, viscosity, thixotropy, spreadability, extrudability, mucoadhesion, diffusion studies, skin irritation test along with short term stability studies. Carbopolis is reported to have a direct influence on appearance and viscosity of final formulation. The photomicroscopic evaluations showed the presence of spherical globules in size range of 10-15 µm. Rheograms revealed that all the formulations exhibited pseudoplastic flow. Optimized formulation (F6) had shown 86.42 ± 2.0% drug release at the end of 8 h study. The release rate through dialysis membrane and rat skin is higher when compared to commercial calcipotriol ointment. Hence it is concluded that calcipotriol can be delivered topically with enhanced penetration properties when formulated as emulgel.

Preparation and Comparative Bioavailability Studies of Indomethacin-Loaded Cetyl Alcohol Microspheres.

The purpose of the present study was to compare the in vitro release and to find out whether the bioavailability of a 75 mg indomethacin capsule (Microcid SR) was equivalent to optimized formulation (indomethacin-loaded cetyl alcohol microspheres). Indomethacin-loaded cetyl alcohol microspheres were prepared by meltable emulsified cooling-induced technique. Surface morphology of microspheres has been evaluated using scanning electron microscopy. A single dose, randomized, complete cross over study of IM microspheres was carried out on 10 healthy male and female Albino sheep's under fasting conditions. The plasma was separated and the concentrations of the drug were determined by HPLC-UV method. Plasma indomethacin concentrations and other pharmacokinetic parameters obtained were statistically analyzed. The SEM images revealed the spherical shape of fat microspheres, and more than 98.0% of the isolated microspheres were in the size range 12-32 µm. DSC, FTIR spectroscopy and stability studies indicated that the drug after encapsulation with fat microspheres was stable and compatible. Both formulations were found to be bioequivalent as evidenced by in vivo studies. Based on this study, it can be concluded that cetyl alcohol microspheres and Microcid SR capsule are bioequivalent in terms of the rate and extent of absorption.

Development and evaluation of microporous osmotic tablets of diltiazem hydrochloride.

Microporous osmotic tablet of diltiazem hydrochloride was developed for colon targeting. These prepared microporous osmotic pump tablet did not require laser drilling to deliver the drug to the specific site of action. The tablets were prepared by wet granulation method. The prepared tablets were coated with microporous semipermeable membrane and enteric polymer using conventional pan coating process. The incorporation of sodium lauryl sulfate (SLS), a leachable pore-forming agent, could form in situ delivery pores while coming in contact with gastrointestinal medium. The effect of formulation variables was studied by changing the amounts of sodium alginate and NaCMC in the tablet core, osmogen, and that of pore-forming agent (SLS) used in the semipermeable coating. As the amount of hydrophilic polymers increased, drug release rate prolonged. It was found that drug release was increased as the concentration of osmogen and pore-former was increased. Fourier transform infrared spectroscopy and Differential scanning calorimetry results showed that there was no interaction between drug and polymers. Scanning electron microscopic studies showed the formation of pores after predetermined time of coming in contact with dissolution medium. The formation of pores was dependent on the amount of pore former used in the semipermeable membrane. in vitro results showed acid-resistant, timed release at an almost zero order up to 24 hours. The developed osmotic tablets could be effectively used for prolonged delivery of Diltiazem HCl.

Effect of hydrophilic natural gums in formulation of oral-controlled release matrix tablets of propranolol hydrochloride.

In order to develop a controlled delivery of highly water-soluble propranolol hydrochloride (PPHCl) using hydrophilic natural gums (xanthan gum [X] and locust bean gum [LBG]) as cost-effective, nontoxic, easily available. The granules of PPHCl were prepared by wet granulation method using a different ratios drug: gum ratios of X, LBG and XLBG(X and LBG in 1:1 ratios). To increase the flowability and compressibility of the granules, and to prevent its adhesion to punch and die, magnesium stearate and talc were added to the granules in 1:2 ratios before punching. The tablet was analysed to determine hardness, friability, % assay and invitro release study was carried out. The release of PPHCl from a gelatinous swollen mass, which controls the diffusion of drug molecules through the polymeric material into aqueous medium. The XLBG matrice shows precise controlled release than the X and LBG matrice because of burst effect and fast release in case of X and LBG matrice respectively and there was no chemical interaction between drug and polymer in XLBG formulation as confirmed by FTIR studies. First pass effect of PPHCl can be avoided by these formulations. Matrices with XLBG show zero-order release via swelling, diffusion and relaxation mechanism. The XLBG matrice leads to more precise result than X and LBG alone by the utilization of synergistic interaction between two biopolymers and uniformity in the hydration layer in dissolution media. However, according to the similarity factor (f(2)) XLBG3 were the most similar formulations to Lol-SR as the reference standard.

Preparation, evaluation and bioavailability studies of indomethacin-bees wax microspheres.

The present study envisages the preparation of microspheres containing indomethacin (IM) as model drug and bees wax as carrier, and to compare the in vitro release and pharmacokinetics of prepared IM formulation with commercially available oral formulation MicrocidSR. The microsphere formulations were prepared by meltable emulsified dispersion and cooling induced solidification. Surface morphology of microspheres has been evaluated using scanning electron microscopy (SEM). The SEM images revealed the spherical shape of microspheres and more than 98.0% of the isolated microspheres were in the size range 115-855 mum. Differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy studies indicated that the drug after encapsulation with bees wax was stable and compatible. A single dose randomized complete cross over study of IM (75 mg) microspheres was carried out on 8 healthy Albino sheeps. Plasma IM concentrations and other pharmacokinetic parameters obtained were statistically analyzed. The T (max), C (max), AUC(O-24) and T (1/2) values of MicrocidSR and optimized formulation were 3.0 h, 2038 +/- 51.31 ng/ml, 9528 +/- 129.65 ng/ml h(-1), and 2.59 +/- 0.02 h(-1); and 3.2 h, 1940 +/- 22.61 ng/ml, 8751 +/- 41.32 ng/ml h(-1), and 2.68 +/- 0.02 h(-1), respectively. Beeswax microspheres showed controlled release and it can be concluded that both the prepared formulation and MicrocidSR are bioequivalent.