R. S. R. Murthy

Recent approaches of lipid-based delivery system for lymphatic targeting via oral route

Abstract Lymphatic system is a key target in research field due to its distinctive makeup and huge contributing functions within the body. Intestinal lymphatic drug transport (chylomicron pathway) is intensely described in research field till date because it is considered to be the best for improving oral drug delivery by avoiding first pass metabolism. The lymphatic imaging techniques and potential therapeutic candidates are engaged for evaluating disease states and overcoming these conditions. The novel drug delivery systems such as self-microemulsifying drug delivery system, nanoparticles, liposomes, nano-lipid carriers, solid lipid carriers are employed for delivering drugs through lymphatic system via various routes such as subcutaneous route, intraperitoneal route, pulmonary route, gastric sub-mucosal injection, intrapleural and intradermal. Among these colloidal particles, lipid-based delivery system is considered to be the best for lymphatic delivery. From the last few decades, mesenteric lymph duct cannulation and thoracic lymph duct cannulation are followed to assess lymphatic uptake of drugs. Due to their limitations, chylomicrons inhibitors and in-vitro models are employed, i.e. lipolysis model and permeability model. Currently, research on this topic still continues and drainage system used to deliver the drugs against lymphatic disease as well as targeting other organs by modulating the chylomicron pathway.

The critical role of bisphosphonates to target bone cancer metastasis: an overview

Abstract Cancer becomes the leading cause of deaths worldwide, including breast cancer, prostate cancer and lung cancer that preferentially metastasize to bone and bone marrow. Bisphosphonates (BPs) have been used successfully for many years to reduce the skeletal complications related with the benign and malignant bone diseases that are characterized by enhanced osteoclastic bone resorption. Nitrogen-containing bisphosphonates (N-BPs) have also been demonstrated to exhibit direct anti-tumour effects. BPs binds avidly to the bone matrix, and released from matrix during bone resorption process, BPs are internalized by the osteoclasts where they interfere with biochemical pathways and induce osteoclast apoptosis. BPs also antagonizes the production of osteoclast and promotes the osteoblasts proliferation. Currently, Zoledronic acid is widely used as one of the BP having high bone specificity and potential to inhibit the osteoclast-mediated bone resorption. In addition to inhibition of cell multiplication and initiation of apoptosis in cultured cancer cells, they also interfere with adhesion of cancer cells to the bone matrix and inhibit cell migration and invasion. Pathophysiology and current target therapies like conjugate of BPs with liposomes, nanoparticle used for the treatment of bone cancer is reviewed in this article along with the use of different BPs.

Development, optimization and evaluation of surfactant-based pulmonary nanolipid carrier system of paclitaxel for the management of drug resistance lung cancer using Box-Behnken design.

Abstract In the present study, nanostructured lipid carriers (NLCs) along with various surfactants loaded with paclitaxel (PTX) were prepared by an emulsification technique using a Box-Behnken design. The Box-Behnken design indicated that the most effective factors on the size and PDI were at high surfactant concentration (1.5%), low lipids ratio (6:4) and medium homogenization speed (6000 rpm). Among all the formulations, Tween 20-loaded NLCs show least particle size compared to Tween 80 and Tween 60. Entrapment efficiency of Tween 20, Tween 80 and Tween 60-loaded formulations were 82.40, 85.60 and 79.78%, respectively. Drug release of Tween 80, Tween 20 and Tween 60-loaded NLCs is 64.9, 62.3 and 59.7%, respectively (within 72 h). Maximum cellular uptake was observed with Tween 20 formulation on Caco-2 cell lines. Furthermore, spray drying of resultant NLCs was showed good flow properties and was selected for drug delivery to deeper airways. In-vivo studies demonstrated the better localization of drug within the lungs using different surfactant-based pulmonary delivery systems. From this study, we have concluded that delivering drugs through pulmonary route is advantageous for local action in lungs as maximum amount of drug concentration was observed in lungs. The surfactants could prove to be beneficial in treating drug resistance lung cancer by inhibiting P-gp efflux in the form of nano lipidic carriers.

Surfactant-based drug delivery systems for treating drug-resistant lung cancer

Abstract Among all cancers, lung cancer is the major cause of deaths. Lung cancer can be categorized into two classes for prognostic and treatment purposes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Both categories of cancer are resistant to certain drugs. Various mechanisms behind drug resistance are over-expression of superficial membrane proteins [glycoprotein (P-gp)], lung resistance-associated proteins, aberration of the intracellular enzyme system, enhancement of the cell repair system and deregulation of cell apoptosis. Structure–performance relationships and chemical compatibility are consequently major fundamentals in surfactant-based formulations, with the intention that a great deal investigation is committed to this region. With the purpose to understand the potential of P-gp in transportation of anti-tumor drugs to cancer cells with much effectiveness and specificity, several surfactant-based delivery systems have been developed which may include microspheres, nanosized drug carriers (nanoparticles, nanoemulsions, stealth liposomes, nanogels, polymer–drug conjugates), novel powders, hydrogels and mixed micellar systems intended for systemic and/or localized delivery.

Development, Optimization & Evaluation of Porous Chitosan Scaffold Formulation of Gliclazide for the Treatment of Type-2 Diabetes Mellitus

This article characterizes the activities required to launch a new pharmaceutical molecule into the market, summarizes studies that have attempted to pinpoint the research and development costs incurred per approved new molecule, and analyzes the various critiques levied against published R&D cost estimates. It finds that by any reckoning, R&D costs per approved molecule have risen sharply over time, most likely at a rate of approximately 7 percent per year after stripping out the effects of general economic inflation.A is a newer NSAID, used in treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Aceclofenac has shorter biological half-life around 4 h which makes it suitable for modified release to improve bioavailability and to reduce dosing frequency. Present work was aimed to develop and evaluate aceclofenac modified release (Triple Layer Tablet) TLT following direct compression technique using natural and synthetic polymers. Aceclofenac TLT containing immediate-releaselayer (IM) as first layer, controlled-release-layer (CR) as second layer and ethyl cellulose layer as barrier-layer (BL) were prepared. IM was optimized by D-optimal design where 16 formulations (IM1 – IM16) were developed by using super disintegrating agents like mannitol and SSG. CR was optimized by 32 full factorial design and 9 batches (CN1–CN9 & CS1–CS9) were developed using natural and synthetic polymers like guar gum, xanthan gum and HPMC K100 CR, HPMC K100 LVCR respectively. Drugpolymers compatibility was evaluated by Infrared spectroscopy, where all compositions were found compatible without any interaction. All formulations were evaluated for various post-compression parameters like disintegration time (DT), swelling index, hardness, friability and weight variation etc., and results were found in desirable range. IM and CR formulations were evaluated for drug release behavior in pH 6.8 phosphate buffer and best release compositions among batches were chosen to prepare TLT with BL to modify the release. Among IM formulations least DT was found in IF9 with 90.86% drug release in 10 min 21 sec so, IF9 was claimed as best composition. Among CR formulations the best compositions found were CN3 and CS6 with Time at 47.38 % and 26.42% drug release around 8 h respectively and, were then developed as triple layered tablets with IF9 where drug release was extended up to 24 h.H compounds have received considerable attention owing to their variety of biological activities, especially as inhibitors of PDE5 extracted from human platelets, HIV-1 reverse transcriptase, human EPK2, cyclin-dependent kinas. Also, heterocyclic nitrogen compounds are indispensable structural units for medicinal chemists and used as antibiotics, anthelmintics, antiviral, antidepressant, and anti-inflammatory. In view of these observations we evaluate some new poly hetero cyclic compounds which were previously synthesized according to for their analgesic, anti-inflammatory and anti-microbial activities in comparison to some reference drugs. Pyrimidines present an interesting group of compounds many of which possess wide-spread pharmacological properties such as antidepressant, antimicrobial, anticancer, and anticonvulsant activitiesM drugs combination is a promising strategy in biomedical fields, such as cancer chemotherapy, tissue engineering. The multi-drug system enables to be delivered with multiply targets and exhibits the additive or synergistic effects of drugs. However, the specific distinct drug release kinetics of the multiply drugs are required to meet the clinical needs, especially in the combined therapy of tissue regeneration and tumor chemotherapy. In order to deliver the individual drug at optimal dosages, the release behaviors of each drug in multi-drug systems should be controlled independently. Therefore, two kinds of nanoparicles with core-shell structure (PVP/PLGA and PCL/PLGA) were fabricated by coaxial electrospray in this paper. Each kind of nanoparticles can both encapsulate the hydrophilic rhodamine B and hydrophobic naproxen in one single step efficiently. The monodisperse size distribution as well as the desired core-shell structure was observed. These two multi-drug systems with dual drug loaded exhibited different distinct release profiles, attributing to the distinct core-shell structures of nanoparticles and the difference of two drugs in hydrophilic properties. Meanwhile, the release profiles of encapsulated drugs with different amount were investigated as well. The drug release behaviors were dominated by the following processes: water penetration, surface drug release, outer drug diffusion with shell polymer erosion, inner drug diffusion and nanoparticle collapse. The results suggested that the distinct release kinetics of multiply drugs fabricated by coaxial electrospray can be obtained and tuned to fulfill the clinical requirement in combination therapy.Aspirin suppositories are in commercial use, suffer with side effects such as irritation, burning sensation, rectal hemorrhage. The aim of the present work is to formulate aspirin nanoparticles loaded suppositories and to perform In vitro investigation for the prepared suppositories. Initially aspirin-chitosan nanoparticles were prepared by ionic gelation method and the nanoparticles evaluated for different In vitro evaluation studies; based on results the best formulation was selected and in order to know the diffusion efficiency, different compositions of aspirin glycerogelatin suppositories were prepared and subjected to various In vitro evaluation studies and best composition was selected. From the previously performed evaluation studies best formulation from aspirin nanoparticles incorporated in to selected glycerol gelatin bases and evaluated for In vitro characteristics. The results indicates that formulation Fa9 Aspirin nanoparticles were proved to be best formulation with 88.3±1.1 % of drug release at the end of 24hr, with zero drug release. In vitro characterization performed for aspirin suppositories indicates that Fs2, Fs4, Fs9 and Fa11 was proved to be best composition with highest percentage of drug release at the end of 60 minutes with 98.06±1, 99.3±0.45, 97.6±1.8 and 97±1 drug release and other characteristic studies performed indicates that all formulation are ideal characteristics. Previously selected bases composition used for the loading of nanoparticles based on displacement value results indicates that drug release appears with a lag phase initially and controlled for a period of 24hr.Orally dissolving tablets (ODT) provides a patient compliance solution for patients swallowing difficulties. Foam granulation is a newer technique that promises better distribution of the granulating system and better properties of the produced tablets. Aceclofenac (anti-inflammatory and analgesic) was selected as the model drug. The poor hydrophilicity of the drug results in variable dissolution rate and poor bioavailability. In this study, we tried to prepare aceclofenac ODT using the newer technique and various types of disintegrants, glidants, and lubricants. The resulted tablets were evaluated for hardness, friability, weight variation, in vitro disintegration time, and wetting time. All the formulation showed acceptable disintegration time. It was concluded that the prepared aceclofenac ODT by foam granulation technique using selective range of excipients can provide a dosage form with better patient compliance and effective therapy.

Development, optimization and evaluation of long chain nanolipid carrier for hepatic delivery of silymarin through lymphatic transport pathway.

In the present study, nanostructured lipid carriers (NLCs) with three different lipid combinations (solid lipid:liquid lipid) were prepared through emulsification and ultrasonication using a Box-Behnken design. From the design, the best lipid combination was glyceryl monostearate and oleic acid, which gives particle of smaller size (223.73 ± 43.39nm) with high drug entrapment efficiency (78.65 ± 2.2%). In vitro release studies show that 84.60 ± 5.66% of drug was released in 24h. In vivo studies revealed that drug absorption occurs through lymphatic pathway as only 5.008 ± 0.011μg/ml of peak plasma concentration was achieved in blood plasma in presence of chylomicron inhibitor. The peak plasma concentration (Cmax) for silymarin loaded NLC was found to be 25.565 ± 0.969μg/ml as compared to silymarin suspension whose Cmax was found to be 14.050 ± 0.552 μg/ml, this confirms 2-fold increase in relative bioavailability. In vivo studies revealed that 19.268 ± 1.29μg of drug reaches to liver in 2h whereas negligible drug concentration reported in other organs. It was concluded that drug loaded NLCs was beneficial for targeting liver or other lymphatic disorders through lymphatic transport pathway. Finally, the main purpose of modifying lymphatic transport system was successfully achieved through NLCs.

Efficacy study of vesicular gel containing methotrexate and menthol combination on parakeratotic rat skin model

Methotrexate (MTX) is indicated in the symptomatic control of severe, recalcitrant, and disabling psoriasis. The oral or parenteral route of administration causes systemic toxicity. The topical route of delivery, though, reduces systemic toxicity and has limited applicability due to restricted permeability. Liposomal and niosomal MTX topical formulations have also been investigated with limited success to achieve drug localization in the skin. Menthol has been suggested in conditions of psoriasis, in addition to its skin-penetration–enhancing effect on drugs. The present work aimed at investigating the potential benefits of combining menthol with MTX in a vesicular gel base for not only improving the penetration and dermal availability of MTX, but also to render such a formulation more effective with greater patient acceptability. MTX liposomes were prepared by thin-film hydration, and the vesicles were characterized for drug-entrapment efficiency, size, and morphology. These liposomal vesicles were incorporated in a gel base, and this vesicular gel was evaluated for transdermal drug permeation and extent of drug accumulation in the skin, using a rat skin ex vivo model. Skin histology studies were carried out to investigate any structural changes caused by the permeation enhancers. Antipsoriatic efficacy of the formulations was tested in vivo, using the rat tail model. The results indicated that the vesicular gel containing menthol could cause maximum drug retention in the skin. The skin treated with menthol had a disrupted epidermis and microcavities. The in vivo studies also ascertained the effectiveness of the formulation in inducing a normal pattern of differentiation in the rat tail skin that initially showed parakeratosis, which is also characteristic of psoriatic epidermis. These results show the potential of vesicular gel containing MTX and menthol to improve penetration into the skin and cause drug retention in skin appendages.

Enhancing the bioavailability of mebendazole by integrating the principles solid dispersion and nanocrystal techniques, for safe and effective management of human echinococcosis

The method based on integrating the principles of solid dispersion and nanocrystal techniques was developed to prepare polymer crystals (PCs) of mebendazole (MBZ) and polyethylene glycol (PEG). Powder X-Ray diffraction (PXRD) of the PC crystals shows the required integrated crystalline and amorphous regions. The in vitro solubility studies showed a 32-fold increase in the solubility of the drug. Tests of dissolution of the PCs showed that the crystals have an enhanced dissolution rate in comparison to those in the MF. The results of the pharmacokinetic study showed a 2.12-fold increase in the bioavailability of the drug. Thus, the present study has proved the potential in enhancing solubility, dissolution, and bioavailability of the drug.

Spray-dried particles as pulmonary delivery system of anti-tubercular drugs: design, optimization, in vitro and in vivo evaluation

Abstract Currently, one-third of the world’s population is infected with tuberculosis (TB) mainly spread by inhalation of the tubercle bacilli, Mycobacterium tuberculosis. Patient non-compliance is the major reason for failure of anti-tubercular drugs (ATDs) chemotherapy due to multidrug administration for longer duration of time period. The main aim of current research study was to develop and characterize inhalable spray-dried particles for pulmonary delivery of ATDs, i.e., rifampicin (RIF) and isoniazid (INH). ATDs-loaded alginate particles were prepared by ionotropic gelation technique followed by spray drying and characterized on the basis of various evaluation parameters. Results showed that the optimized spray-dried particles were found to be spherical in shape with excellent flow properties. The drug release showed the biphasic pattern of release, i.e., initial burst (30–40% up to 4 h) followed by a sustained release pattern (90% up to 60 h). Optimized formulations exhibited lower cytotoxicity and excellent lung uptake up to 8 h. Optimized formulation also showed higher rate and extent of drug uptake by lungs due to preferential phagocytosis be macrophage. In future, alginate particles could be a promising carrier for targeted delivery of ATDs to alveolar macrophages for efficient management of TB.

“Fusion and binding inhibition” key target for HIV-1 treatment and pre-exposure prophylaxis: targets, drug delivery and nanotechnology approaches

Abstract More than 35 million people are living with HIV worldwide with approximately 2.3 million new infections per year. Cascade of events (cell entry, virus replication, assembly and release of newly formed virions) is involved in the HIV-1 transmission process. Every single step offers a potential therapeutic strategy to halt this progression and HIV fusion into the human host cell is one such stage. Controlling the initial event of HIV-1 transmission is the best way to control its dissemination especially when prophylaxis is concerned. Action is required either on the HIV’s or host’s cell surface which is logically more rational when compared with other intracellular acting moieties. Aim of this manuscript is to detail the significance and current strategies to halt this initial step, thus blocking the entry of HIV-1 for further infection. Both HIV-1 and the possible host cell’s receptors/co-receptors are under focus while specifying the targets available for inhibiting this fusion. Current and under investigation moieties are categorized based on their versatile mechanisms. Advanced drug delivery and nanotechnology approaches present a key tool to exploit the therapeutic potential in a boosted way. Current drug delivery and the impact of nanotechnology in potentiating this strategy are detailed.