Nanostructured cochleates: a multi-layered platform for cellular transportation of therapeutics.

Among lipid-based nanocarriers, multi-layered cochleates emerge as a novel delivery system because of prevention of oxidation of hydrophobic and hydrophilic drugs, enhancement in permeability, and reduction in dose of drugs. It also improves oral bioavailability and increases the safety of a drug by targeting at a specific site with less side effects. Nanostructured cochleates are used as a carrier for the delivery of water-insoluble or hydrophobic drugs of anticancer, antiviral and anti-inflammatory action. This review article focuses on different methods for preparation of cochleates, mechanism of formation of cochleates, mechanism of action like cochleate undergoes macrophagic endocytosis and release the drug into the systemic circulation by acting on membrane proteins, phospholipids, and receptors. Advanced methods such as calcium-substituted and ß-cyclodextrin-based cochleates, novel techniques include microfluidic and modified trapping method. Cochleates showed enhancement in oral bioavailability of amphotericin B, delivery of factor VII, oral mucosal vaccine adjuvant-delivery system, and delivery of volatile oil. In near future, cochleate will be one of the interesting delivery systems to overcome the stability and encapsulation efficiency issues associated with liposomes. The current limiting factors for commercial preparation of cochleates involve high cost of manufacturing, lack of standardization, and specialized equipments.

Development and Characterization of Microstructured, Spray-Dried Co-Amorphous Mixture of Antidiabetic Agents Stabilized by Silicate.

In the present work, co-amorphous mixture (COAM) of poorly soluble nateglinide (NT) and highly soluble Metformin hydrochloride (MT) was prepared by spray drying method to improve the dissolution rate of NT and the processability of COAM. Binary spray-dried COAM of NT and MT (120 mg: 500 mg) was prepared in its clinical dose ratio whereas 20% Neusilin®US2 (NS) was added to prepare non-sticky, free flowing ternary COAM. Solubility studies of binary and ternary COAM exhibited sevenfold and tenfold rise in the solubility of NT. Complete amorphization of NT was revealed in XRPD and DSC studies of both COAM and hydrogen-bonding interactions were reflected in FTIR-spectra. SEM microphotographs illustrated round-shaped microparticles in ternary COAM against the irregular particles in binary COAM. In vitro dissolution of NT was significantly improved in ternary COAM > binary COAM > NT irrespective of dissolution medium. On contrary, MT has partially transformed to the amorphous form in COAM without altering the solubility. In accelerated stability studies, NT and MT devitrification was not observed in XRPD of ternary COAM in contrast to binary COAM. Therefore, enhanced dissolution of NT, stabilization of spray-dried dispersion, and its improved processability can be achieved by preparing ternary COAM of NT:MT:NS.

Pharmacokinetics and pharmacodynamics of intranasally administered selegiline nanoparticles with improved brain delivery in Parkinson's disease.

Selegiline, a well-known anti-Parkinson agent, is reported to be associated with poor oral bioavailability and safety. Therefore, we formulated selegiline as chitosan nanoparticles and evaluated its pharmacokinetics and pharmacodynamics after intranasal administration to rats relative to those after oral administration. The optimized formulation exhibited spherical nanoparticles with more than 90% drug loading and steady in vitro and ex vivo drug release. Selegiline concentrations in the brain and plasma were 20- and 12-fold higher, respectively, after intranasal administration than after oral administration. Treatment with intranasal nanoparticles was also associated with better performance in locomotor activity, catalepsy, and stride length tests and significantly increased dopamine, catalase activity, and glutathione content in the brain. Therefore, intranasally administered selegiline nanoparticles holds superior therapeutic value compared to oral administration and can be a promising approach for the treatment of Parkinson's disease.

Co-Amorphous Combination of Nateglinide-Metformin Hydrochloride for Dissolution Enhancement.

The aim of the present work was to prepare a co-amorphous mixture (COAM) of Nateglinide and Metformin hydrochloride to enhance the dissolution rate of poorly soluble Nateglinide. Nateglinide (120 mg) and Metformin hydrochloride (500 mg) COAM, as a dose ratio, were prepared by ball-milling technique. COAMs were characterized for saturation solubility, amorphism and physicochemical interactions (X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR)), SEM, in vitro dissolution, and stability studies. Solubility studies revealed a sevenfold rise in solubility of Nateglinide from 0.061 to 0.423 mg/ml in dose ratio of COAM. Solid-state characterization of COAM suggested amorphization of Nateglinide after 6 h of ball milling. XRPD and DSC studies confirmed amorphism in Nateglinide, whereas FTIR elucidated hydrogen interactions (proton exchange between Nateglinide and Metformin hydrochloride). Interestingly, due to low energy of fusion, Nateglinide was completely amorphized and stabilized by Metformin hydrochloride. Consequently, in vitro drug release showed significant increase in dissolution of Nateglinide in COAM, irrespective of dissolution medium. However, little change was observed in the solubility and dissolution profile of Metformin hydrochloride, revealing small change in its crystallinity. Stability data indicated no traces of devitrification in XRPD of stability sample of COAM, and % drug release remained unaffected at accelerated storage conditions. Amorphism of Nateglinide, proton exchange with Metformin hydrochloride, and stabilization of its amorphous form have been noted in ball-milled COAM of Nateglinide-Metformin hydrochloride, revealing enhanced dissolution of Nateglinide. Thus, COAM of Nateglinide-Metformin hydrochloride system is a promising approach for combination therapy in diabetic patients.

Formulation and comparative characterization of chitosan, gelatin, and chitosan-gelatin-coated liposomes of CPT-11-HCl.

Liposomes containing phosphatidylcholine and cholesterol (uncoated) and coated by chitosan, gelatin, and combination of chitosan and gelatin were prepared by the modified ethanol injection method. The aim of this work was to formulate and characterize liposomes of camptothecin (CPT)-11-HCl (Irinotecan HCl) containing chitosan, gelatin, and both polymers as coating materials; and also to increase its circulation longevity when compared with the free drug while maintaining the agent in its active lactone form. Size, shape, zeta potential, encapsulation efficiency, stability study, in vitro, and in vivo release study were used for characterization of liposomes. The size of liposomes was in the order of uncoated < chitosan coated < gelatin coated < combination of chitosan and gelatin coated. The zeta potential of liposomes was in the order of combination of chitosan and gelatin coated > chitosan coated > gelatin coated > uncoated. The formulations showed the long-term stability. The encapsulation efficiency of liposomes was in order of combination of chitosan and gelatin coated > gelatin coated > chitosan coated > uncoated. The in vitro and in vivo release of drug was observed in the order of combination chitosan and gelatin coated > gelatin coated > chitosan coated > uncoated.

Evaluation of Nanocarrier-Based Dry Powder Formulations for Inhalation with Special Reference to Anti-Tuberculosis Drugs.

Pulmonary tuberculosis (TB) is a leading cause of death worldwide and is caused by the pathogen Mycobacterium tuberculosis (MTb). As treatment for TB, dry powders for inhalation (DPIs) are considered stable compared with nebulizers and metered dose inhalers and are suitable for high-dose formulations. Although extensive research has been done over the last two to three decades on nanocarrier-based DPIs for targeting MTb infection, none of the anti-TB DPI formulations have reached the market. Challenges in the proper assessment of nanocarrier-based DPIs due to the complexity of lungs is one of the reasons. In this review, the details of in vitro evaluation parameters of nanocarriers and nanocarrier-based DPIs along with their need and basic principles are discussed. Further, the thorough in vitro, ex vivo, and in vivo pharmacological evaluations, together with their procedures wherever required, are covered. The different evaluation parameters during process development, release specifications, and stability studies suggested by U.S. Food and Drug Administration Center for Drug Evaluation and Research to apply for new drug applications and abbreviated new drug applications of DPIs are also discussed. Lastly, the evaluation parameters for DPIs provided in European, United States, British, and Indian pharmacopeias are summarized.

Pramipexole dihydrochloride loaded chitosan nanoparticles for nose to brain delivery: Development, characterization and in vivo anti-Parkinson activity.

In the current study, Pramipexole dihydrochloride loaded chitosan nanoparticles (P-CNs) were prepared for Parkinson's disease via nose to brain pathway by ionic gelation method. Optimized P-CNs with chitosan and sodium tripolyphosphate (6:1 v/v) exhibited particle size and entrapment efficiency of 292.5 nm ±â€¯8.80 and 91.25% ±â€¯0.95 respectively and its diffusion across the artificial membrane and goat nasal mucosa was found to be 93.32% ±â€¯2.56 and 83.03% ±â€¯3.48 correspondingly after 24 h. Transmission electron microscopy displayed the spherical nature of the P-CNs particles and rough surface morphology was observed in scanning electron microphotographs. In pharmacodynamic studies, the comparative results of behavioral testing revealed improved score of photoactometer and reduced motor deficit in the form of catalepsy in P-CN treatment group as compare to its nasal solution or oral marketed tablets. Similarly, P-CNs enhanced antioxidant status in the form of increased superoxide dismutase and catalase activities, along with increased dopamine level in the brain significantly. Therefore, it can be concluded that intranasal delivery of Pramipexole loaded chitosan nanoparticles exhibited essential in vitro characteristics and superior in vivo activity than other formulations for brain targeted delivery in Parkinson disease.

Brain targeted delivery of mucoadhesive thermosensitive nasal gel of selegiline hydrochloride for treatment of Parkinson's disease.

Selegiline hydrochloride (SL), is an anti-Parkinson's agent, has low-oral bioavailability due to its high first pass metabolism and scarce oral absorption. In the present study, SL mucoadhesive nasal thermosensitive gel (SNT-gel) was prepared to enhance the bioavailability and subsequently, its concentration in the brain. The SNT-gel was prepared using Poloxamer 407-Chitosan combination and optimised formulation was further evaluated for physicochemical parameters. The comparative pharmacodynamic studies including behavioural studies, biochemical testing and histopathology of the brain was carried out in rats for SNT-gel, SL-nasal solution and SL Marketed Tablets. The optimised SNT-gel formulation (SNT-V) revealed sol-gel transition at 33-34°C. In-vitro diffusion study of SNT-V showed 102.37 ± 2.1% diffusion at 12 h which reduced to 89.64 ± 1.2% in Ex-vivo diffusion. Comparative results of behavioural studies indicated an improved score of photoactometer and reduced motor deficit (catalepsy score) in SNT-gel treatment group as compared with other groups. Similarly, a significant increase in brain dopamine, reduction in monoamine oxidase B level, increase in catalase activity and level of reduced glutathione upon treatment with SNT-gel indicated its effectiveness which was also supported by histopathology results. Therefore, nasal thermosensitive gel holds better potential for brain targeting in Parkinson's disease over the conventional nasal or oral formulations.

A technology roadmap of smart biosensors from conventional glucose monitoring systems.

The objective of this review article is to focus on technology roadmap of smart biosensors from a conventional glucose monitoring system. The estimation of glucose with commercially available devices involves analysis of blood samples that are obtained by pricking finger or extracting blood from the forearm. Since pain and discomfort are associated with invasive methods, the non-invasive measurement techniques have been investigated. The non-invasive methods show advantages like non-exposure to sharp objects such as needles and syringes, due to which there is an increase in testing frequency, improved control of glucose concentration and absence of pain and biohazard materials. This review study is aimed to describe recent invasive techniques and major noninvasive techniques, viz. biosensors, optical techniques and sensor-embedded contact lenses for glucose estimation.

Enhanced dissolution and bioavailability of Nateglinide by microenvironmental pH-regulated ternary solid dispersion: in-vitro and in-vivo evaluation.

OBJECTIVES: Nateglinide, an Antidiabetic drug (BCS II), shows pH-dependent solubility and variable bioavailability. The purpose of study was to increase dissolution and bioavailability of Nateglinide by development of its microenvironmental pH-regulated ternary solid dispersion (MeSD). METHODS: MeSD formulation of Nateglinide, poloxamer-188 and Na2 CO3 was prepared by melt dispersion in 1 : 2 : 0.2 w/w ratio and further characterised for solubility, In-vitro dissolution, microenvironmental pH, crystallinity/amorphism, physicochemical interactions, bioavailability in Wistar rats. KEY FINDINGS: Solubility of Nateglinide was increased notably in MeSD, and its in-vitro dissolution study showed fourfold increase in the dissolution, particularly in 1.2 pH buffer. Prominent reduction in the peak intensity of X-ray powder diffraction (XRPD) and absence of endotherm in DSC thermogram confirmed the amorphism of Nateglinide in MeSD. Attenuated total reflectance Fourier transform infrared spectra revealed the hydrogen bond interactions between Nateglinide and poloxamer-188. In-vivo study indicated that MeSD exhibited fourfold increase in area under curve over Nateglinide. Tmax of MeSD was observed at 0.25 h, which is beneficial for efficient management of postprandial sugar. Instead of mere transformation of the Nateglinide to its amorphous form as evidenced by DSC and XRPD, formation of a soluble carboxylate compound of Nateglinide in MeSD was predominantly responsible for dissolution and bioavailability enhancement. CONCLUSIONS: The study demonstrates the utility of MeSD in achieving pH-independent dissolution, reduced Tmax and enhanced bioavailability of Nateglinide.

Engineering of microcomplex of artemether and lumefantrine for effective drug treatment in malaria.

The objective of the present work was to engineer and characterize stable citric acid cross-linked microcomplex of the inclusion complexes of artemether with ß-cyclodextrin and Kollidon VA 64® with lumefantrine to release the drugs in controlled manner for effective combinational drug treatment in malaria. The microcomplex had a hydrodynamic diameter of 1047 ± 147 nm with surface charge of -19.7 ± 0.5 mV. The microcomplex showed high encapsulation efficiencies 85.6 ± 1.78% for artemether and 91.16 ± 2.21% for lumefantrine due to the lipophilic nature of drugs. In-vitro and in-vivo drug release studies showed the controlled release of artemether and lumefantrine for a period of 24 h.

Multi-particulate Systems: Cutting-edge Technology for Controlled Drug Delivery.

BACKGROUND: In the last two decades, multi-particulate dosage forms have caught the attention of formulation scientists due to their tremendous potential as a drug delivery system with a broad range of applications. METHODS: Recent patented technologies are focused on designing multi-particulate systems that can enhance therapeutic efficacy and oral bioavailability with minimum systemic toxicity. The technologies offer opportunities to the manufacturers for increasing their market share, especially for competitive generics, and also establishing intellectual property positions. RESULTS: The present paper provides an overview of advanced technologies and patents, based on different principles, for designing multi-particulate dosage forms. The review covers basic characteristics of the current technologies, the mechanisms by which they overcome the limitations of conventional oral dosage forms, and their applications. CONCLUSION: Comprehensive knowledge of these technologies will expedite further development and platform technologies for multi-particulate controlled drug delivery systems.

In Vitro CYP2D Inhibitory Effect and Influence on Pharmacokinetics and Pharmacodynamic Parameters of Metoprolol Succinate by Terminalia arjuna in Rats.

BACKGROUND: Terminalia arjuna Wight & Arn. (Combretaceae) is a tree having an extensive medicinal potential in cardiovascular disorders. T. arjuna bark extract has been reported to play a significant role as a cardiac stimulant for its beneficial effects in angina. Herb - drug interactions (HDI) are one of the most important clinical concerns in the concomitant consumption of herbs and prescription drugs. Our study was to investigate the in vitro CYP2D inhibition potential of Terminalia arjuna (T. arjuna) extracts in rat liver microsomes and to study the influence of aqueous bark extract of T. arjuna on the oral pharmacokinetics and pharmacodynamics of metoprolol succinate in rats. METHODS: The CYP2D inhibition potential of herbal extracts of T. arjuna was investigated in rat liver microsomes. Pharmacokinetic-pharmacodynamic interaction of aqueous extract of T. arjuna with metoprolol succinate was investigated in rats. RESULTS: The ethyl acetate, alcoholic & aqueous bark extracts of T. arjuna showed potent reversible non-competitive inhibition CYP2D enzyme in rat liver microsomes with IC50 values less than 40 µg/mL. Arjunic acid, arjunetin and arjungenin did not show significant inhibition of CYP2D enzyme in rat liver microsomes. Pharmacokinetic studies showed that aqueous bark extract of T. arjuna led to a significant reduction (P < 0.05) in AUC0-24h and Cmax of metoprolol succinate in rats, when co-administered. Pharmacodynamic studies reveal a significant reduction in therapeutic activity of metoprolol succinate on co-administration with aqueous bark extract of T. arjuna. CONCLUSION: Based on our in vitro and in vivo findings and until further clinical drug interaction experiments are conducted, the co-administration of drugs, especially those primarily cleared via CYP2D catalyzed metabolism, with T. arjuna extracts should be done with caution.

In vitro modulatory effects of Terminalia arjuna, arjunic acid, arjunetin and arjungenin on CYP3A4, CYP2D6 and CYP2C9 enzyme activity in human liver microsomes.

Terminalia arjuna is a tree having an extensive medicinal potential in cardiovascular disorders. Triterpenoids are mainly responsible for cardiovascular properties. Alcoholic and aqueous bark extracts of T. arjuna, arjunic acid, arjunetin and arjungenin were evaluated for their potential to inhibit CYP3A4, CYP2D6 and CYP2C9 enzymes in human liver microsomes. We have demonstrated that alcoholic and aqueous bark extract of T. arjuna showed potent inhibition of all three enzymes in human liver microsomes with IC50 values less than 50 µg/mL. Arjunic acid, arjunetin and arjungenin did not show significant inhibition of CYP enzymes in human liver microsomes. Enzyme kinetics studies suggested that the extracts of arjuna showed reversible non-competitive inhibition of all the three enzymes in human liver microsomes. Our findings suggest strongly that arjuna extracts significantly inhibit the activity of CYP3A4, CYP2D6 and CYP2C9 enzymes, which is likely to cause clinically significant drug-drug interactions mediated via inhibition of the major CYP isozymes.

Reverse docking: a powerful tool for drug repositioning and drug rescue.

Reverse or inverse docking is proving to be a powerful tool for drug repositioning and drug rescue. It involves docking a small-molecule drug/ligand in the potential binding cavities of a set of clinically relevant macromolecular targets. Detailed analyses of the binding characteristics lead to ranking of the targets according to the tightness of binding. This process can potentially identify novel molecular targets for the drug/ligand which may be relevant for its mechanism of action and/or side effect profile. Another potential application of reverse docking is during the lead discovery and optimization stages of the drug-discovery cycle. This review summarizes the state-of-the-art and future prospects of the reverse docking with particular emphasis on computational molecular design.