Convolutions in the rendition of nose to brain therapeutics from bench to bedside: Feats & fallacies.

Brain, a subtle organ of multifarious nature presents plethora of physiological, metabolic and bio-chemical convolutions that impede the delivery of biomolecules and thereby resulting in truncated therapeutic outcome in pathological conditions of central nervous system (CNS). The absolute bottleneck in the therapeutic management of such devastating CNS ailments is the BBB. Another pitfall is the lack of efficient technological platforms (due to high cost and low approval rates) as well as limited clinical trials (due to failures of neuro­leads in late-stage pipelines) for CNS disorders which has become a literal brain drain with poorest success rates compared to other therapeutic areas, owing to time consuming processes, tremendous convolutions and conceivable adverse effects. With the advent of intranasal delivery (via direct N2B or indirect nose to blood to brain), several novel drug delivery carriers viz. unmodified or surface modified nanoparticle based carriers, lipid based colloidal nanocarriers and drysolid/liquid/semisolid nanoformulations or delivery platforms have been designed as a means to deliver therapeutic agents (small and large molecules, peptides and proteins, genes) to brain, bypassing BBB for disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, schizophrenia and CNS malignancies primarily glioblastomas. Intranasal application offers drug delivery through both direct and indirect pathways for the peripherally administered psychopharmacological agents to CNS. This route could also be exploited for the repurposing of conventional drugs for new therapeutic uses. The limited clinical translation of intranasal formulations has been primarily due to existence of barriers of mucociliary clearance in the nasal cavity, enzyme degradation and low permeability of the nasal epithelium. The present review literature aims to decipher the new paradigms of nano therapeutic systems employed for specific N2B drug delivery of CNS drugs through in silico complexation studies using rationally chosen mucoadhesive polymers (exhibiting unique physicochemical properties of nanocarrier's i.e. surface modification, prolonging retention time in the nasal cavity, improving penetration ability, and promoting brain specific delivery with biorecognitive ligands) via molecular docking simulations. Further, the review intends to delineate the feats and fallacies associated with N2B delivery approaches by understanding the physiological/anatomical considerations via decoding the intranasal drug delivery pathways or critical factors such as rationale and mechanism of excipients, affecting the permeability of CNS drugs through nasal mucosa as well as better efficacy in terms of brain targeting, brain bioavailability and time to reach the brain. Additionally, extensive emphasis has also been laid on the innovative formulations under preclinical investigation along with their assessment by means of in vitro /ex vivo/in vivo N2B models and current characterization techniques predisposing an efficient intranasal delivery of therapeutics. A critical appraisal of novel technologies, intranasal products or medical devices available commercially has also been presented. Finally, it could be warranted that more reminiscent pharmacokinetic/pharmacodynamic relationships or validated computational models are mandated to obtain effective screening of molecular architecture of drug-polymer-mucin complexes for clinical translation of N2B therapeutic systems from bench to bedside.

Engineered Site-specific Vesicular Systems for Colonic Delivery: Trends and Implications.

Steering drug-loaded, site-specific, coated lipid vesicles to the target receptor sites have the potential of plummeting adverse effects and improving the pharmacological response in diverse pathologies of the large bowel, especially the colon. Colonic delivery via oral route has its own challenges, often governed by several glitches such as drug degradation or absorption in the upper GIT, instability of proteins/peptides due to high molecular weight, and peptidase activity in the stomach. Consequently, colon-specific coated liposomal systems (CSLS) offer a potential alternate for not only site-specificity, but protection from proteolytic activity, and prolonged residence time for greater systemic bioavailability. On the other hand, liposomal delivery via the oral route is also cumbersome owing to several barriers such as instability in GIT, difficulty in crossing membranes, and issues related to production at the pilot scale. New advancements in the field of CSLS have successfully improved the stability and permeability of liposomes for oral delivery via modulating the compositions of lipid bilayers, adding polymers or ligands. Despite this ostensible propitiousness, no commercial oral CSLS has advanced from bench to bedside for targeted delivery to the colon as yet. Nevertheless, CSLS has quite fascinated the manufacturers owing to its potential industrial viability, simplistic and low-cost design. Hence, this review aims to decipher the convolutions involved in the engineering process of industrially viable CSLS for colonic delivery.

Bio-Inspired Strategies against Diabetes and Associated Complications: A Review.

Bio-molecules are the most important target to be considered while designing any drug delivery system. The logic lies in using such bio-sensing or bio-mimicking systems in their formulations that can mimic the active site of those receptors to which the drug is going to bind. Polymers mimicking the active site of target enzymes are regarded as bio-inspired polymers and can be used to ameliorate many diseased conditions. Nowadays, this strategy is also being adopted against diabetes and its complications. Under hyperglycemic conditions, many pathways get activated which are responsible for the progression of diabetes-associated secondary complications viz. retinopathy, neuropathy, and nephropathy. The enzymes involved in the progression of these complications can be mimicked for their effective management. For an instance, Aldose Reductase (ALR2), a rate-limiting enzyme of the polyol pathway (downstream pathway) which gets over-activated under hyperglycemic condition is reported to be mimicked by using polymers which are having same functionalities in their structure. This review aims at critically appraising reports in which target mimicking bio-inspired formulations have been envisaged against diabetes and its complications. The information summarized in this review will provide an idea about the bio-sensing approaches utilized to manage blood glucose level and the utility of bio-inspired polymers for the management of diabetic complications (DC). Such type of information may be beneficial to pharmaceutical companies and academia for better development of targeted drug delivery systems with sustained-release property against these diseased conditions.

Optimization of an aqueous tablet-coating process containing carboxymethylated Cassia fistula gum.

The present investigation was aimed at developing and optimizing a simple aqueous tablet-coating formulation and its process. 5-Fluorouracil (5-FU) was used to ascertain the relative lipophilic/hydrophilic behavior of the coating system. Optimization was performed by evaluating the adhesive force strength and cohesive force strength of the tablet coat using a texture analyzer. The in vitro release of 5-FU was found to decrease with an increase in (tablet surface-coat) adhesive force strength. The (tablet-tablet) cohesive force strength was reduced by the addition of magnesium silicate to the coating solution. The addition of magnesium silicate (0.2% w/v) to the carboxymethyl Cassia fistula gum-chitosan (CCG-CH) coating surface significantly inhibited the release of 5-FU possibly due to an increase in the hydrophobic character of the coated tablet surface. This was possible by coating cohesive force strength reduction coating compositions (CCG-CH (70:30) and 0.3% magnesium silicate). Further, the FTIR-ATR and DSC analyses suggested the pivotal role of magnesium silicate in modifying the release of 5-FU from CCG-CH-coated tablets due to hydrogen bonding of its Si-O-Si or Mg-O groups with -OH moieties of CCG-CH.

Immunomodulatory and therapeutic potential of a mycelial lectin from Aspergillus nidulans.

Lectins bind to surface receptors on target cells, and activate a cascade of events, eventually leading to altered immune status of host. The immunomodulatory potential of purified lectin from Aspergillus nidulans was evaluated in Swiss albino mice treated intraperitoneally with seven different doses of purified lectin. Lectin prevented BSA-induced Arthus reaction and systemic anaphylaxis. The enhanced functional ability of macrophages was evident from respiratory burst activity and nitric oxide production in splenocyte cultures. Interferon-gamma and interleukin-6 levels were significantly up-regulated in treated groups. Maximum stimulatory effect was observed at the dose of 1.5 mg/kg body weight. Therapeutic potential of A. nidulans lectin was assessed against trinitrobenzene sulfonic acid-induced ulcerative colitis in male Wistar rats. Rats pre-treated with 80 mg/kg body weight of purified lectin intraperitoneally prior to colitis induction showed lesser disease severity and recovery within 7 days, while rats post-treated with the same dose showed recovery in 11 days. The results demonstrate immunomodulatory effects of A. nidulans lectin in Swiss albino mice, resulting in improved immune status of the animals and unfold its curative effect against ulcerative colitis in rat model. This is the first report on immunomodulatory and therapeutic potential of a lectin from microfungi.

Cross-linked chitosan films: effect of cross-linking density on swelling parameters.

Equilibrium water content (EWC), equilibrium swelling ratio (ESR) and mass gain ratio are the swelling parameters that are useful for correlating drug release characteristics from polymeric films, barriers etc. These parameters can be judiciously used in predicting and modifying drug release from dosage forms. Further, drug release is known to be influenced by cross-linking density. Therefore, the present investigation was conducted to study the influence of cross-linking density on swelling parameters. For this purpose, chitosan (CH) films were prepared by cross-linking with various concentrations of sodium tripolyphosphate (NaTPP) or sodium citrate (NaCit) solutions. The swelling parameters and in vitro permeation of model polar drug (5-FU) and nonpolar drug (INDO) cross-linked CH films were determined. The swelling characteristics revealed that cross-linking with 5% w/v NaTPP or 10% w/v NaCit solution of films containing 4% w/v CH as well as with 1% w/v NaTPP or 5% w/v NaCit solution of films containing 2.5% w/v CH exhibited minimum ESR and EWC. The in vitro permeation of both 5-FU and INDO across these films was lowest. However, these films showed maximum mass gain ratio. Further, lowest ΔH of the endothermic transition characteristics of water uptake in films suggested the role of cross-linking density in water uptake by these films. IR analysis showed two terminal -PO(3)- moieties of NaTPP or -COO- moieties of NaCit to be linked with two -NH(3)+ (OOCH(3)-) moieties of CH monomers one on each side. Overall, the results indicate role of swelling parameters in predicting cross-linking density in polymeric films.

Preparation and in vitro, in vivo characterization of elastic liposomes encapsulating cyclodextrin-colchicine complexes for topical delivery of colchicine.

In the present study, an attempt was made to develop a cyclodextrin-colchicine complex and to study its effect on skin permeation and deposition of colchicine. Colchicine beta cyclodextrin (BCD) complex was prepared by freeze-drying method and complex formation was confirmed by NMR and in vitro drug release study. Formulation containing cyclodextrin-drug complex showed 6-fold increase in transdermal flux in comparison with drug solution. Skin retention studies were carried out with the objective of determining the depot effect of elastic liposomes in skin. The amount of drug deposited was 12.4-fold higher in case of elastic liposomes of colchicine-cyclodextrin complex (567+/-1.5 microg) than drug solution (46+/-1.1 microg). The biological evaluation of various vesicular formulations and drug solution was carried out using monosodium urate-induced air pouch model. The results of anti-gout activity in rats showed better and sustained biological effects over 24 h measured in terms of exudate volume, reduction in leukocyte count, decrease in inflammatory cell accumulation, and collagen deposition with colchicine-BCD elastic liposomal formulation than drug solution. Hence the present study reveals that colchicine-cyclodextrin-elastic liposomes approach possesses good potential to enhance skin accumulation, prolong drug release, and improve the site-specificity of colchicine.

Elastic liposomal formulation for sustained delivery of colchicine: in vitro characterization and in vivo evaluation of anti-gout activity.

Colchicine, an alkaloid found in extracts of the plants Colchicum autumnale and Gloriosa superb, is effective in the treatment of acute gout and dermatological conditions like leuko-cytoclastic vasculitis, psoriasis, and Sweet's syndrome. Oral administration of colchicine is associated with gastrointestinal side effects and its accumulation in the body leads to bone marrow suppression. In the present study, an attempt has been made for development and in vitro and in vivo evaluation of elastic liposomal formulation for topical delivery of colchicine. The in vitro skin permeation study across rat skin found transdermal flux for different elastic liposomal formulations to range between 32.8 +/- 1.2 and 44.4 +/- 1.9 microg h(-1) cm(-2), which was approximately seven to 11 times higher than obtained using drug solution (4.3 +/- 0.6 microg h(-1) cm(-2)). The results of skin deposition study showed that elastic liposomal formulation provide 12.5-fold higher skin deposition as compared to drug solution of colchicine. Confocal laser scanning microscopy also revealed better accumulation and deeper penetration (up to 200 microm) of elastic liposomes than drug solution (up to 12 microm). The biological evaluation of various vesicular formulations and drug solution was carried out using monosodium urate-induced air pouch model. The results of anti-gout activity in rats showed better and sustained biological effects in 24 h measured in terms of exudate volume (63.1 +/- 5.7% and 9.6 +/- 0.5% reduction with elastic liposomes and drug solution, respectively), reduction in leukocyte count (74.2 +/- 6.0% and 4.1 +/- 0.3% reduction with elastic liposomes and drug solution, respectively), decrease in inflammatory cells accumulation, and collagen deposition with elastic liposomal formulation than drug solution. Hence, the present study reveals that elastic liposomal formulation of colchicine possesses greater potential to enhance skin accumulation, prolong drug release, and improve the site-specificity of colchicine.

Screening of Aspergillus species for occurrence of lectins and their characterization.

Ten species of Aspergillus were screened for occurrence of lectins. Each of the species was investigated for the occurrence of extracellular, surface-bound and intracellular lectin activities. As many as four species namely, Aspergillus niger, Aspergillus versicolor, Aspergillus rugulosus and Aspergillus nidulans, were found to possess intracellular lectin activities, while none of the species showed extracellular or surface-bound lectin activities. Each of the lectin was characterized with respect to blood group and carbohydrate specificities. All the lectins were found to agglutinate human erythrocytes, irrespective of their blood group and pig erythrocytes. However, they did not show agglutination with sheep or goat erythrocytes. Of the various carbohydrates tested, all lectins were found to be specific for inulin, mucin, asialofetuin, N-acetyl galactosamine, melibiose, D-ribose, L-fucose, D-arabinose, D-sucrose and D-mannitol. The minimum inhibitory concentration of each of the specific sugars was also determined. The lectins were partially purified using ammonium sulfate precipitation technique. Each of the lectin was found to be precipitated at 40-50% saturation of ammonium sulfate, yielding about 80% of lectin activity.

Spermicidal activity of sulfonylureas and meglitinide analogues: role of intrasperm Ca2+ elevation.

Intrasperm calcium concentration ([Ca2+]is) is known to play a vital role in regulating motility and viability of ejaculated spermatozoa. K ATP channel blockers are reported to block K ATP channels, leading to depolarization of the cell membrane. This activates the voltage-gated calcium channels, resulting in enhanced Ca2+ influx, which eventually elevates the intracellular [Ca2+] level. Hence, it can be hypothesized that drugs acting on K ATP channels could possess the ability to elevate [Ca2+]is. Sulfonylureas such as glibenclamide or gliclazide, as well as meglitinide analogues such as repaglinide, produced a dose- and time-dependent decrease in viability, each requiring 7.5 mM, 10 mM and 6.5 mM, respectively, to produce death of all sperm cells immediately upon addition to ejaculated human semen samples. The reduction in sperm viability was accompanied by an elevation of [Ca2+]is and was affected by removal of extracellular Ca2+. Significantly (P < 0.05) less time was required to elevate [Ca2+](is) and produce complete loss of sperm viability when any of these drugs were added to sperm cells simultaneously with selected agents affecting Ca2+ homeostasis. Thus, the spermicidal activity of these drugs attributed to elevation of [Ca2+]is and their synergism can be potentially exploited for developing contact spermicidal formulations.

Thermotropic and spectroscopic behavior of skin: relationship with percutaneous permeation enhancement.

Stratum corneum (SC) is comprised of lipids, protein and low molecular weight water-soluble components. Changes in these skin micro constituents can be understood by instrumental methods like differential scanning calorimetry (DSC) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. The former provides information about changes in thermotropic behavior of SC lipids and proteins, whereas the latter provides data about alterations at molecular and conformational level. Most of the DSC thermograms of intact mammalian SC show two reversible and two irreversible transitions in the temperature range of 25-125 degrees C. The reversible endotherms are ascribed to lipid melting transitions, whereas the irreversible endotherms are ascribed to protein denaturation. Similarly, the FTIR spectral bands of SC occurring between 2920-2850 cm-1 and between 1650-1550 cm-1 have been suggested to arise from lipid and protein molecular vibrations, respectively. Treatment of skin with solvents or permeation enhancers alters the composition of lipids or their molecular arrangement in the skin microenvironment, which leads to changes in permeability of drug molecules. Furthermore, inhibition of lipid synthesis in epidermis with concomitant decrease in enthalpy of lipid endothermic transitions and reduction in height and area of asymmetric and symmetric C-H stretching peaks have been found to be directly correlated with enhanced permeation of drugs. In addition, method of skin preparation, type of skin, types of enhancer etc. also influence both the nature and intensity of responses recorded in spectrographs and thermograms. Therefore, the modification in spectrographs and thermograms of skin samples treated with various enhancers, vehicles etc. are expected to provide better insight into their mechanism of action on the skin. This review article shall critically evaluate the thermotropic and infrared spectroscopic data of SC/epidermis after various treatments.

Skin lipid synthesis inhibition: a possible means for enhancing percutaneous delivery of levodopa.

Skin perturbation with ethanol followed by application of beta-chloroalanine (beta-CA) or atorvastatin (AVN) was employed for delaying the recovery of sphingosine (a precursor of ceramide) and cholesterol, respectively in epidermis of rats. Dose optimization studies revealed 600 microg of beta-CA and 750 microg of AVN significantly (p<0.05) inhibited the synthesis of sphingosine and cholesterol, respectively and prevented their replenishment to normal levels till 48 hr in viable rat skin. Co-application of calcium chloride (0.1 mM) inhibited the synthesis of both micro constituents of epidermis to a greater magnitude, whereas verapamil reduced this effect. The in vitro permeation of levodopa across treated skin portions was directly correlated with percentage of sphingosine and cholesterol inhibited by the treatments. The in vitro permeation of levodopa across skin excised after treatment with beta-CA or AVN was enhanced 3-fold. Effective plasma concentration (1.58 microg/ml) of levodopa in rats was achieved within 2 hr and maintained till 12 hr after AVN treatment, and increased to 36 hr with the co-application of calcium chloride. However, when the skin was treated with beta-CA, Ceff was achieved after 4 hr and was maintained till 36 hr. The inclusion of calcium chloride maintained Ceff for 48 hr. Hence, synthesis inhibition of skin lipids seems to offer a feasible means to enhance the systemic delivery of polar drugs like levodopa.