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

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.

Effect of high-pressure homogenization on formulation of TPGS loaded nanoemulsion of rutin - pharmacodynamic and antioxidant studies.

Polyphenolic bioflavonoid, Rutin possesses wide range of pharmacological activities. However, it shows poor bioavailability when administered orally. The aim of this study was to formulate and compare the potential of nanoemulsions for the solubility enhancement of rutin (RU) by using different techniques. RU-loaded nanoemulsions were prepared by spontaneous emulsification method and high-pressure homogenization (HPH) technique using sefsol 218 and tocopheryl polyethylene glycol 1000 succinate (TPGS) (1:1), solutol HS15 andtranscutol P as oil phase, surfactant and co-surfactant, respectively. The prepared formulations were compared for various parameters like droplet size, percentage transmittance, zeta potential, viscosity, refractive index and in vitro release. The HPH nanoemulsions showed smaller droplet size and increased in vitro release when compared to nanoemulsions prepared by spontaneous emulsification method. The optimized formulation showed spherical globules with average globule diameter of 18 nm and zeta potential of -41 mV. Cumulative percentage drug released obtained for RU, PF6 (spontaneous emulsification formulation F6) and HF6 (HPH formulation F6) were 41.5 ± 0.04%, 49.5 ± 0.06% and 94.8 ± 0.03%, respectively, after 6 h. The permeability of RU from HF6 was found to be ≈4.6 times higher than RU suspension during ex vivo everted gut sac studies. Antioxidant activity was determined by using DPPH assay and reducing power assay method. Results showed a high scavenging efficiency toward DPPH radicals by HF6. Anti-inflammatory effect of RU as determined by carrageenan-induced rat paw edema method was found to be higher (75.2 ± 4.8%) when compared to RU suspension (46.56 ± 3.5%). It can be inferred that TPGS-loaded nanoemulsion of RU serve as an effective tool in increasing solubility and permeability of RU.

Bisphosphonates: therapeutics potential and recent advances in drug delivery.

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.

Pharmacoscintigraphic evaluation of potential of lipid nanocarriers for nose-to-brain delivery of antidepressant drug.

Efficacy of antidepressants relies upon their continued presence at the site of action (brain) over a prolonged period of time. The BBB restricts the access of antidepressants to the brain on oral as well as intravenous administration. Direct delivery (by-passing the BBB) of antidepressant drugs can increase the CSF concentration with concomitant reduction in dose and side effects. Intranasal administration of nanostructured lipid carriers (NLC) containing antidepressant drug circumvent the BBB and maintain the prolonged release at the site of action. The aim of the present study was to evaluate the enhancement in brain uptake of NLC containing duloxetine (DLX) after intranasal administration. Duloxetine loaded NLC (DLX-NLC) was evaluated pharmacoscintigraphically for drug targeting potential (DTP), drug targeting efficiency (DTE) and biodistribution studies in different organs including brain. The radiolabeling efficiency of DLX and DLX-NLC was found to be 98.41 ± 0.96 and 98.87 ± 0.82 after 30 min, respectively. The biodistribution studies exhibited higher percentage of radioactivity/g for DLX-NLC formulations in brain as compared with the DLX. The higher DTP (86.80%) and DTE (757.74%) suggested that DLX-NLC formulation has a better brain targeting efficiency than DLX solution (DTP=65.12%; DTE=287.34%) when administered intranasally. Moreover, the intranasal administration exhibited about 8-times higher concentration of DLX in brain when compared with the intravenous administration of DLX solution. The intranasal NLC containing DLX can be employed as an effective method for the treatment of depression.

Resveratrol: review on therapeutic potential and recent advances in drug delivery.

INTRODUCTION: Natural products have seen a wide range of acceptability for the prevention and treatment of diseases throughout history. Resveratrol, a member of the stilbene family, has been found to potentially exhibit anticancer, antiangiogenic, immunomodulatory and cardioprotective activities as well as being an antioxidant. This is in addition to its usefulness in the treatment of neurodegenerative disease, diabetes and cardiac ailments. Currently, various studies have revealed that resveratrol is a potential drug candidate with multi-spectrum therapeutic application. AREAS COVERED: This review aims to describe the various studies supporting the wide range of pharmacological activities of resveratrol. In addition, it includes a section devoted to discussing the challenges associated with the drug and strategies to improve the properties of resveratrol such as solubility, stability and bioavailability. EXPERT OPINION: Resveratrol demonstrated its ability to be a potential drug candidate for the treatment of different ailments due to its potent antioxidant properties. To improve the drug stability, increase the bioavailability and minimize side-effects of resveratrol, novel drug delivery systems have been formulated to bring this potential candidate to the first line of disease treatment.

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 Parkinson's 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 Parkinson's disease.

Insights into direct nose to brain delivery: current status and future perspective.

Now a day's intranasal (i.n) drug delivery is emerging as a reliable method to bypass the blood-brain barrier (BBB) and deliver a wide range of therapeutic agents including both small and large molecules, growth factors, viral vectors and even stem cells to the brain and has shown therapeutic effects in both animals and humans. This route involves the olfactory or trigeminal nerve systems which initiate in the brain and terminate in the nasal cavity at the olfactory neuroepithelium or respiratory epithelium. They are the only externally exposed portions of the central nervous system (CNS) and therefore represent the most direct method of noninvasive entry into the brain. This approach has been primarily used to explore therapeutic avenues for neurological diseases. The potential for treatment possibilities with olfactory transfer of drugs will increase as more effective formulations and delivery devices are developed. Recently, the apomorphine hydrochloride dry powders have been developed for i.n. delivery (Apomorphine nasal, Lyonase technology, Britannia Pharmaceuticals, Surrey, UK). The results of clinical trial Phase III suggested that the prepared formulation had clinical effect equivalent to subcutaneously administered apomorphine. In coming years, intranasal delivery of drugs will demand more complex and automated delivery devices to ensure accurate and repeatable dosing. Thus, new efforts are needed to make this noninvasive route of delivery more efficient and popular, and it is also predicted that in future a range of intranasal products will be used in diagnosis as well as treatment of CNS diseases. This review will embark the existing evidence of nose-to-brain transport. It also provides insights into the most relevant pre-clinical studies of direct nose-brain delivery and delivery devices which will provide relative success of intranasal delivery system. We have, herein, outlined the relevant aspects of CNS drugs given intranasally to direct the brain in treating CNS disorders like Alzheimer's disease, depression, migraine, schizophrenia, etc.

Oral delivery of therapeutic proteins and peptides: a review on recent developments.

Advent of recombinant technology in protein synthesis has given birth to a new range of biopharmaceuticals. These therapeutic peptides and proteins are now emerging as an imperative part of various treatment protocols especially in the cancer therapeutics. Despite extensive research efforts, oral delivery of therapeutic peptide or protein is still a challenge for pharmaceutical industries and researchers. Number of factors including high proteolytic activity and low pH conditions of gastrointestinal tract act as major barriers in the successful delivery of intact protein/peptide to the targeted site. Low permeability of protein/peptide across the intestinal barrier is also a factor adding to the low bioavailability. Therefore, because of the short circulatory half-life exhibited by peptides in vivo, they need to be administered frequently resulting in increased cost of treatment and low patient compliance. Nano-carrier-based delivery presents an appropriate choice of drug carriers owing to their property to protect proteins from degradation by the low pH conditions in stomach or by the proteolytic enzymes in the gastrointestinal tract. This review focuses on recent aspects and patents on oral delivery of therapeutic proteins and peptides with special emphasis on nano-carrier-based approach.

Intranasal infusion of nanostructured lipid carriers (NLC) containing CNS acting drug and estimation in brain and blood.

The present study was aimed to evaluate the nanostrucured lipid carriers (NLC) containing duloxetine (DLX-NLC) for intranasal infusion through the nasal cavity of rat. The in vivo nasal infusion studies were performed using Wistar rats and the amount of DLX permeated and its amount in brain and blood was estimated. The effects on absorption rate and type of drug delivery systems (nanocarriers and drug solution) for nose to brain/blood permeation were assessed. DLX was found to be permeated from the nasal cavity into the body of rat and the permeated amount was found to be more in case of DLX-NLC. Approximately 2.5-times better permeation was exhibited by DLX-NLC than DLX-solution. Appreciable amount of DLX was estimated in blood and brain and the estimated amount was higher in case of DLX-NLC. Thus the administration of NLC containing DLX through intranasal route was found to be potential method for the delivery of DLX for the treatment of depression.

Rutin : therapeutic potential and recent advances in drug delivery.

INTRODUCTION: Natural compounds such as bioflavonoids have found application in health care system due to their wide biological activities, high safety margins and lower cost. Rutin , a polyphenolic bioflavonoid has shown wide range of pharmacological applications due to its significant antioxidant properties. Conventionally, it is used as antimicrobial, antifungal, and antiallergic agent. However, current research has shown its multispectrum pharmacological benefits for the treatment of various chronic diseases such as cancer, diabetes, hypertension and hypercholesterolemia. Its use is advantageous over other flavonoids as it is a nontoxic and nonoxidizable molecule. AREAS COVERED: This review focus on various studies done on rutin explaining its broad spectrum pharmacological activities. In addition, this review will also focus on the challenges associated with the drug and various approaches to improve the oral bioavailability of rutin. EXPERT OPINION: Rutin is a highly potent molecule due to its strong antioxidant properties. In the near future, enhancing its bioavailability using novel drug delivery methods having minimum side effects will bring this promising natural molecule to the forefront of therapy for the treatment of various chronic human diseases.

Exploring targeted pulmonary delivery for treatment of lung cancer.

Lung cancer is the most malignant cancer today. The treatment of lung cancer continues to be a challenge for oncologists. The direct delivery of chemotherapeutic agents to the lungs could represent a novel therapeutic approach for patients with pulmonary metastases. The large alveolar surface area, the low thickness of the epithelial barrier, and an extensive vascularization make the pulmonary route an ideal route for administration of oncolytics. This paper reviews the research performed over the last and current decades on the delivery of various oncolytics for pulmonary delivery for the treatment of lung cancer. Inhaled drug delivery devices in cancer therapy are also discussed in the present manuscript.

Exploring drug delivery systems for treating osteoporosis.

INTRODUCTION: Osteoporosis (OP) is a major disease in elderly people; its complications and prevalence are rapidly increasing worldwide. It is associated with high fragility fracture mainly of hip, wrist and spine. With the rising lifespan worldwide, the number of hip fractures throughout globe will rise from 1.66 million in 1990 to 6.26 million by 2050. So there is a major problem in our society related to the bone diseases which needs to be addressed. AREAS COVERED: This review gives knowledge about OP, its symptoms and problems associated with the existing therapies. It gives idea about various drug delivery systems for bone targeting. This review also gives a comprehensive compilation of the various in vitro and in vivo studies conducted till date and US FDA approved drugs for the treatment of OP. EXPERT OPINION: Various drug delivery systems reduce the adverse effects of drugs and increase the availability of drugs to the target site mainly bones. Active researches are going on to improve the OP treatment, whose high prevalence and considerable functional and socioeconomic impact will raise formidable challenges in the near future. We should work on different targets rather than conventional therapies which will improve the overall treatment strategies.

Bromocriptine loaded chitosan nanoparticles intended for direct nose to brain delivery: pharmacodynamic, pharmacokinetic and scintigraphy study in mice model.

The primary aim of this study was to investigate the potential use of chitosan nanoparticles as a delivery system to enhance the brain targeting efficiency of bromocriptine (BRC) following intranasal (i.n.) administration. The BRC loaded chitosan nanoparticles (CS NPs) were prepared by ionic gelation of CS with tripolyphosphate anions. These NPs had a mean size (161.3 ± 4. 7 nm), zeta potential (+40.3 ± 2.7 mV), loading capacity (37.8% ± 1.8%) and entrapment efficiency (84.2% ± 3.5%). The oral administration of haloperidol (2mg/kg) to mice produced typical Parkinson (PD) symptoms. Catalepsy and akinesia outcomes in animals receiving BRC either in solution or within CS NPs showed a reversal in catalepsy and akinesia behavior when compared to haloperidol treated mice, this reversal being specially pronounced in mice receiving BRC loaded CS NPs. Biodistribution of BRC formulations in the brain and blood of mice following i.n. and intravenous (i.v.) administration was performed using optimized technetium labeled (99mTc-labeled) BRC formulations. The brain/blood ratio of 0.47 ± 0.04, 0.69 ± 0.031, and 0.05 ± 0.01 for BRC solution (i.n.), BRC loaded CS NPs (i.n.) and (i.v.) respectively, at 0.5h are suggestive of direct nose to brain transport bypassing the blood-brain barrier. Gamma scintigraphy imaging of mice brain following i.v. and i.n. administrations were performed to determine the localization of drug in brain. The drug targeting index and direct transport percentage for BRC loaded CS NPs following i.n. route were 6.3 ± 0.8 and 84.2% ± 1.9%. These encouraging results confirmed the development of a novel non-invasive nose to brain delivery system of BRC for the treatment of PD.

Development and validation of stability-indicating assay method by UPLC for a fixed dose combination of atorvastatin and ezetimibe.

A stability-indicating ultra-performance liquid chromatography method was developed and validated for the simultaneous determination of a fixed dose combination of atorvastatin and ezetimibe in bulk drugs. The developed method was successfully applied to the simultaneous quantitative analysis of the combination drugs in tablet. The chromatographic separation was performed on a Kromasil Eternity C18 UHPLC column (2.5 µm, 2.1 × 50 mm) using a gradient elution of acetonitrile and ammonium acetate buffer (pH 6.70; 0.01M) as the mobile phase at a flow rate of 0.2 mL/min with column oven temperature of 40°C. Ultraviolet detection was performed at 245 nm. Total run time was 5 min, within which the primary compounds and their degradation products were separated. The method was validated for accuracy, repeatability, reproducibility and robustness. Linearity, limit of detection and limit of quantitation were established for atorvastatin and ezetimibe.

Intranasal administration of nanostructured lipid carriers containing CNS acting drug: pharmacodynamic studies and estimation in blood and brain.

The present study was aimed to investigate and compare the efficacy of duloxetine (DLX) loaded nanostructured lipid carriers (NLC) with DLX solution pharmacodynamically following intranasal administration. The study was further conducted to estimate DLX concentration in brain and blood. DLX was administered to albino Wistar rats either intranasally or orally in solution form (DLX solution) or encapsulated in NLC (DLX-NLC). These were evaluated in-vivo for pharmacodynamic studies for depression by forced swimming test and locomotor activity test. Intranasal DLX-NLC treatment exhibited improved behavioural analysis results (swimming, climbing, and immobility) than the DLX solution after 24 h of study. Furthermore, DLX-NLC significantly increased the total swimming and climbing time when compared with control and significantly reduced the immobility period. The intranasal DLX-NLC demonstrated improved locomotor activity when compared with DLX solution. Amount of DLX was quantified in blood and brain after the forced swimming test. The intranasal DLX-NLC demonstrated higher concentration in brain compared with DLX solution. Thus, intranasal DLX-NLC was found to be a promising formulation for the treatment of depression.

Nanostructure-based drug delivery systems for brain targeting.

CONTEXT: It is well-known fact that blood brain barrier (BBB) hinders the penetrance and access of many pharmacotherapeutic agents to central nervous system (CNS). Many diseases of the CNS remain undertreated and the inability to treat most CNS disorders is not due to the lack of effective CNS drug discovery, rather, it is due to the ineffective CNS delivery. Therefore, a number of nanostructured drug delivery carriers have been developed and explored over the past couple of years to transport the drugs to brain. OBJECTIVE: The present review will give comprehensive details of extensive research being done in field of nanostructured carriers to transport the drugs through the BBB in a safe and effective manner. METHODS: The method includes both the polymeric- and lipid-based nanocarriers with emphasis on their utility, methodology, advantages, and the drugs which have been worked on using a particular approach to provide a noninvasive method to improve the drug transport through BBB. RESULTS: Polymeric- and lipid-based nanocarriers enter brain capillaries before reaching the surface of the brain microvascular endothelial cells without the disruption of BBB. These systems are further modified with specific ligands vectors and pegylation aiming to target and enhance their binding with surface receptors of the specific tissues inside brain and increase long circulatory time which favors interaction and penetration into brain endothelial cells. CONCLUSION: This review would give an insight to the researchers working on neurodegenerative and non-neurodegenerative diseases of the CNS including brain tumor.

Treatment modalities and evaluation models for periodontitis.

Periodontitis is the most common localized dental inflammatory disease related with several pathological conditions like inflammation of gums (gingivitis), degeneration of periodontal ligament, dental cementum and alveolar bone loss. In this perspective, the various preventive and treatment modalities, including oral hygiene, gingival irrigations, mechanical instrumentation, full mouth disinfection, host modulation and antimicrobial therapy, which are used either as adjunctive treatments or as stand-alone therapies in the non-surgical management of periodontal infections, have been discussed. Intra-pocket, sustained release systems have emerged as a novel paradigm for the future research. In this article, special consideration is given to different locally delivered anti-microbial and anti inflammatory medications which are either commercially available or are currently under consideration for Food and Drug Administration (FDA) approval. The various in vitro dissolution models and microbiological strain investigated to impersonate the infected and inflamed periodontal cavity and to predict the in vivo performance of treatment modalities have also been thrashed out. Animal models that have been employed to explore the pathology at the different stages of periodontitis and to evaluate its treatment modalities are enlightened in this proposed review.

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.

Recent advances and patents in solid dispersion technology.

High lipophilicity and high lattice energy of drugs, which result in poor solubility are major real challenges in the pharmaceutical industry for the successful development and commercialization of suitable dosage forms. Therefore various formulation strategies like complexation, lipid based systems, micronization, nanonization, co-crystals, solid dispersions, solubilization etc. have been investigated to resolve the problems associated with solubility related oral bioavailability of poorly water soluble drugs. This article focuses on solid dispersions which is used as one of the formulation strategies to improve the solubility and bioavailability of BCS class II drugs. The present review discusses the fundamentals of solid dispersions, their formulation techniques including various carriers used, their applications, limitations as well as provide an insight into the various alternative approaches to overcome problems associated with solid dispersions. This review also discusses some important aspects of solid dispersion like phase transition, importance of Tg for solid dispersion, controlled release formulations, IVIVC, and the prospect of innovative solid dispersions. Furthermore, the different patents highlighting the applications of solid dispersions have also been comprehensively discussed in the present review.