Mohammad Fazil

Development and evaluation of rivastigmine loaded chitosan nanoparticles for brain targeting

The rivastigmine (RHT) loaded chitosan nanoparticles (CS-RHT NPs) were prepared by ionic gelation method to improve the bioavailability and enhance the uptake of RHT to the brain via intranasal (i.n.) delivery. CS-RHT NPs were characterized for particles size, particle size distribution (PDI), encapsulation efficiency, zeta potential and in vitro release study. Nose-to-brain delivery of placebo nanoparticles (CS-NPs) was investigated by confocal laser scanning microscopy technique using rhodamine-123 as a marker. The brain/blood ratio of RHT for different formulations were 0.235, 0.790 and 1.712 of RHT (i.v.), RHT (i.n.), and CS-RHT NPs (i.n.) respectively at 30 min are indicative of direct nose to brain transport bypassing the BBB. The brain concentration achieved from i.n. administration of CS-NPs (966 ± 20.66 ng ml(-1); t(max) 60 min) was significantly higher than those achieved after i.v. administration of RHT sol (387 ± 29.51 ngml(-1); t(max) 30 min), and i.n. administration of RHT solution (508.66 ± 22.50 ng ml(-1); t(max) 60 min). The higher drug transport efficiency (355 ± 13.52%) and direct transport percentage (71.80 ± 6.71%) were found with CS-RHT NPs as compared to other formulation. These results suggest that CS-RHT NPs have better brain targeting efficiency and are a promising approach for i.n. delivery of RHT for the treatment and prevention of Alzheimers disease (AD).

Venlafaxine loaded chitosan NPs for brain targeting: Pharmacokinetic and pharmacodynamic evaluation

The purpose of the present investigation was to prepare venlafaxine (VLF) loaded chitosan nanoparticles (NPs) to enhance the uptake of VLF to brain via intranasal (i.n.) delivery. VLF loaded chitosan NPs were prepared and characterized for particle size, size distribution, zeta potential, encapsulation efficiency and in vitro drug release. In order to investigate the localization of chitosan NPs in brain and other organs qualitatively confocal laser scanning microscopy technique was carried out using rhodamine-123 (ROD-123) as marker. The levels of VLF in plasma and brain tissues were also determined, the brain/blood ratios of VLF for VLF (i.v.), VLF (i.n.), VLF chitosan NPs (i.n.) were 0.0293, 0.0700 and 0.1612, respectively, at 0.5h, indicative of better brain uptake of VLF chitosan NPs. The higher drug transport efficiency (508.59) and direct transport percentage (80.34) of VLF chitosan NPs as compared to other formulations suggest its better efficacy in treatment of depression.

Bisphosphonates: therapeutics potential and recent advances in drug delivery

Abstract Context: Bisphosphonates (BPs) are widely used for prevention and treatment of osteoporosis. BPs are known as gold standard for osteoporosis (OP) treatment due to their positive results in clinical studies. But some serious side effects are associated with BPs like gastrointestinal adverse effect i.e. esophagitis and ulcer of esophagus. Oral bioavailability (BA) of BPs ranges from 0.6 to 1% due to poor absorption through gastrointestinal tract (GIT). Objective: The main objective of this review is to explore the role of novel drug delivery systems (DDSs) for the delivering of BPs and minimizing the drawbacks associated with them. Methods: The current review is focusing on classification, mechanism of action, and limitations of BPs, and is also dwelling on the use of novel DDSs like nanoparticles, liposomes, topical, transdermal systems, implants, bisphosphonate osteotropic DDS (BP-ODDS), microspheres, and calcium phosphate cements (CPCs) for BPs. This review also gives a critically reviewed compilation of the various in vitro and in vivo studies conducted till date. Conclusion: On the basis of the exhaustive literature, it has been found that the novel DDS minimizes the side effects associated with BPs and enhances the BA. The advance drug delivery has a greater impact on reducing the undesirable effects and increasing the BA of BPs.

Nanostructured lipid (NLCs) carriers as a bioavailability enhancement tool for oral administration

ABSTRACT Context: Nanostructured lipid carrier (NLCs) is the second generation solid lipid nanoparticles (NPs) made up of physiological, biocompatible, biodegradable, non-sensitizing and non-irritating lipids. Objective: The main objective of this review is to explore the role of NLCs system for delivering drugs by oral route and thus increasing the oral bioavailability. Methods: The present review article highlights the definition and types of NLCs and their importance as colloidal carriers including the production techniques and their formulation. This review article also deals with the fate of lipids used in the NLCs formulation and the NLCs toxicity. Conclusion: On the basis of the literature survey done, it was concluded that the NLCs enhances the oral bioavailability of the drug and may decrease the side effects and toxicity of the lipids used in other polymeric NPs as NLCs uses physiological and biodegradable lipids.

Optimised nanoformulation of bromocriptine for direct nose-to-brain delivery: biodistribution, pharmacokinetic and dopamine estimation by ultra-HPLC/mass spectrometry method

Objective: The present work evaluated whether the prepared nanoparticles (NPs) would be able to target the drug to the brain by a non-invasive nasal route enhancing its bioavailability. Methods: Bromocriptine (BRC) chitosan NPs (CS NPs) were prepared by ionic gelation method. The biodistribution, pharmacokinetic parameters and dopamine concentration was analysed by ultra-HPLC/mass spectrometry method. The histopathological examination in haloperidol-induced Parkinsons disease in mice model following intranasal (i.n.) administration was evaluated. Results: BRC was found stable in all exposed conditions and the percentage accuracy observed for intra-day and inter-day batch samples ranged from 90.5 to 107% and 95.3 to 98.9% for plasma and brain homogenates, respectively. BRC-loaded CS NPs showed greater retention into the nostrils (42 ± 8.5% radioactivity) for about 4 h, whereas the 44 ± 7.5% could be retained up to 1 h for BRC solution. The brain:blood ratios of 0.96 ± 0.05 > 0.73 ± 0.15 > 0.25 ± 0.05 of BRC-loaded CS NPs (i.n.) > BRC solution (i.n.) > BRC-loaded CS NPs (intravenous), respectively, at 0.5 h indicated direct nose-to-brain transport bypassing blood–brain barrier. BRC-loaded CS NPs administered intranasally showed significantly high dopamine concentration (20.65 ± 1.08 ng/ml) as compared to haloperidol-treated mice (10.94 ± 2.16 ng/ml) (p < 0.05). Histopathology of brain sections showed selective degeneration of the dopaminergic neurons in haloperidol-treated mice which was markedly reverted by BRC-loaded CS NPs. Conclusion: Nanoparticulate drug delivery system could be potentially used as a nose-to-brain drug delivery carrier for the treatment of Parkinsons disease.

Brain targeted nanoparticulate drug delivery system of rasagiline via intranasal route.

Abstract The aim of the present study was to prepare and evaluate a rasagiline-loaded chitosan glutamate nanoparticles (RAS-CG-NPs) by ionic gelation of CG with tripolyphosphate anions (TPP). RAS-loaded CG-NPs were characterized for particle size, size distribution, encapsulation efficiency and in vitro drug release. The mean particles size, polydispersity index (PDI) and encapsulation efficiency was found to be 151.1 ± 10.31, 0.380 ± 0.01 and 96.43 ± 4.23, respectively. Biodistribution of RAS formulations in the brain and blood of mice following intranasal (i.n.) and intravenous (i.v.) administration was performed using HPLC analytical method. The drug concentrations in brain following the i.n. of CG-NPs were found to be significantly higher at all the time points compared to both drug (i.n.) and drug CG-NPs (i.v.). The Cmax (999.25 ng/ml) and AUC (2086.60 ng h/ml) of formulation CG-NPs (i.n) were found to be significantly higher than CG-NPs (i.v.) and RAS solution (i.n.). The direct transport percentage (DTP%) values of RAS-loaded CG-NPs (i.n.) as compared to drug solution (i.n.) increased from 66.27 ± 1.8 to 69.27 ± 2.1%. The results showed significant enhancement of bioavailability in brain, after administration of the RAS-loaded CG-NPs which could be a substantial achievement of direct nose to brain targeting in Parkinsons disease therapy.

Nanotherapeutics for Alzheimer’s disease (AD): Past, present and future

Drug delivery to the brain still remains highly challenging for the treatment of Alzheimer’s disease (AD). The development of new practical treatment modalities for the treatment of AD is currently a highly active area of research. Our lack of success in the development of effective therapies for AD is attributed to, but not limited to a number of factors including the complexity of the brain. Besides this, it is recognized that AD is multisystemic in nature and this presents numerous difficulties for the potential treatment of these disorders. Another important reason for the lack of development of effective drugs and drug delivery system for AD is inability to deliver drugs effectively to the brain due to the numerous protective barriers surrounding the CNS i.e. blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB) and circumventricular organs (CVOs). Solutions to these problems require enhanced novel research activities that can address each of these problems. This review article provides a concise movement into the current and future applications of nanoparticulate drug delivery systems for the treatment of AD and explores the application of nanotechnology in clinical neuroscience to develop innovative therapeutic modalities for the AD.

Brain delivery of buspirone hydrochloride chitosan nanoparticles for the treatment of general anxiety disorder

The present work discusses the preparation, characterization and in vivo evaluation of thiolated chitosan nanoparticles (TCS-NPs) of buspirone hydrochloride (BUH) for brain delivery through intranasal route. TCS NPs were prepared by ionic gelation method and characterized for various parameters. The NPs formed were having particle size of 226.7±2.52nm with PDI 0.483±0.031. Drug entrapment efficiency (EE) and loading capacity (LC) were found to be 81.13±2.8 and 49.67±5.5%. The cumulative percentage drug permeation through nasal mucosa was 76.21%. Bioadhesion study carried out on porcine mucin and showed a bioadhesion efficiency of 90.218±0.134%. Nose-to-brain delivery of placebo NPs was investigated by confocal laser scanning microscopy (CLSM) technique using rhodamine-123 as a marker. The brain concentration achieved after intranasal administration of TCS-NPs was 797.46±35.76ng/ml with tmax 120min which was significantly higher than achieved after intravenous administration on BUH solution 384.15±13.42ng/ml and tmax of 120min and intranasal administration of BUH solution 417.77±19.24ng/ml and tmax 60min.

Tacrolimus-loaded nanostructured lipid carriers for oral delivery – Optimization of production and characterization

Tacrolimus (TL), which is currently the mainstay of immunosuppressive therapy faces significant hurdles subsequent to its oral administration attributable to its poor aqueous solubility and extensive intestinal and hepatic first pass metabolism. Therefore, the present study aimed to design the stable nanostructured lipid carrier (NLC) of TL that would be able to overcome such hurdles. Capmul MCMC8 and Compritol 888ATO in 3:2 were selected as binary lipid phase on the basis of solubility study. An exhaustive screening of surfactants is done by aqueous titration to select the surfactant with best emulsifying potential and to optimize the concentration of lipids and surfactants in NLC. Different methods of preparation were explored and compared to optimize NLC which could have the best characteristic properties. TL-NLC was characterized for particle size, drug entrapment efficiency, crystal state, surface morphology and drug release. The obtained particle size, PDI and % drug entrapment efficiency of optimized formulations i.e., NLC-C2 and NLC-N2 were 70±5.42nm, 98±7.52nm; 0.43±0.081, 0.2±0.029 and 87±2.34%, 94±3.18%, respectively. The results of in vitro release studies showed significantly increased (***p<0.001) and sustained release of TL from NLC dispersions as compared to drug suspension (95.73% from NLC-C2, 99.86% from NLC-N2 and 9.27% drug suspension in pH 1.2 in 24h; 93.11% from NLC-C2, 96.65% from NLC-N2 and 10.2% drug suspension in pH 6.8 in 24h). The study demonstrated that proper selection of excipients (by aqueous titration) and modification of method of preparation (by inclusion of cold step) would lead to production of NLC with best characteristic properties.

Nanostructured lipid carrier in photodynamic therapy for the treatment of basal-cell carcinoma.

Abstract Topical photodynamic therapy (PDT) is a promising alternative for malignant skin diseases such as basal-cell carcinoma (BCC), due to its simplicity, enhanced patient compliance, and localization of the residual photosensitivity to the site of application. However, insufficient photosensitizer penetration into the skin is the major issue of concern with topical PDT. Therefore, the aim of the present study was to enable penetration of photosensitizer to the different strata of the skin using a lipid nanocarrier system. We have attempted to develop a nanostructured lipid carrier (NLC) for the topical delivery of second-generation photosensitizer, 5-amino levulinic acid (5-ALA), whose hydrophilicity and charge characteristic limit its percutaneous absorption. The microemulsion technique was used for preparing 5-ALA-loaded NLC. The mean particle size, polydispersity index, and entrapment efficiency of the optimized NLC of 5-ALA were found to be 185.2 ± 1.20, 0.156 ± 0.02, and 76.8 ± 2.58%, respectively. The results of in vitro release and in vitro skin permeation studies showed controlled drug release and enhanced penetration into the skin, respectively. Confocal laser scanning microscopy and cell line studies respectively demonstrated that encapsulation of 5-ALA in NLC enhanced its ability to reach deeper skin layers and consequently, increased cytotoxicity.