Liposomes: Advancements and innovation in the manufacturing process.

Liposomes are well recognised as effective drug delivery systems, with a range of products approved, including follow on generic products. Current manufacturing processes used to produce liposomes are generally complex multi-batch processes. Furthermore, liposome preparation processes adopted in the laboratory setting do not offer easy translation to large scale production, which may delay the development and adoption of new liposomal systems. To promote advancement and innovation in liposome manufacturing processes, this review considers the range of manufacturing processes available for liposomes, from laboratory scale and scale up, through to large-scale manufacture and evaluates their advantages and limitations. The regulatory considerations associated with the manufacture of liposomes is also discussed. New innovations that support leaner scalable technologies for liposome fabrication are outlined including self-assembling liposome systems and microfluidic production. The critical process attributes that impact on the liposome product attributes are outlined to support potential wider adoption of these innovations.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron.

Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver. Ondansetron, a 5HT3 receptor antagonist, is used at doses ranging from 4 mg to 24 mg in the management of nausea and vomiting associated with chemotherapy, radiotherapy, and postoperative treatment. It is a weak base and thus exhibits pH-dependent solubility. However, it is able to meet the criteria of "high solubility" as well as "high permeability" and can therefore be classified as a BCS class I drug. Furthermore, ondansetron hydrochloride 8 mg IR tablets (Zofran® 8 mg) and multiples thereof (16 mg = Zofran® 8 mg × 2 tablets and 24 mg = Zofran® 8 mg × 3 tablets) meet the criteria of "rapidly dissolving" in dissolution testing. Ondansetron hydrochloride has a wide therapeutic window and is well-tolerated after oral administration. Based on its favorable physicochemical properties, pharmacokinetic data and the minimal risks associated with an incorrect bioequivalence decision, the BCS-based biowaiver procedure can be recommended for ondansetron hydrochloride dihydrate IR tablets.

Inhalable Levofloxacin Liposomes Complemented with Lysozyme for Treatment of Pulmonary Infection in Rats: Effective Antimicrobial and Antibiofilm Strategy.

Treatment of bacterial infections becomes increasingly complicated due to increasing bacterial resistance and difficulty in developing new antimicrobial agents. Emphasis should be laid on improvising the existing treatment modalities. We studied the improved antimicrobial and antibiofilm activity of levofloxacin (LFX) and lysozyme (LYS) in microbiological studies. LFX at sub-minimum inhibitory concentration with LYS eradicated > 85% of preformed biofilm. LFX was actively loaded into the liposomes using pH gradient method and was spray-dried with LYS solution. Percent entrapment of LFX in liposome was > 80% and prolonged cumulative release of 85% LFX at the end of 12 h. In vitro lung deposition study and solid-state characterization for spray dried LFX liposome in combination with LYS (LFX liposome-LYS) was performed. Co-spray dried product had mass median aerodynamic diameter ranging < 5 µm. In pharmacodynamic study, Staphylococcus aureus infected rats were treated with LFX liposome-LYS. Lungs, bronchoalveolar lavage fluid (BALF), and nasal fluid were evaluated for microbial burden. Expression of cytokine levels in BALF and serum were also studied by ELISA. In addition, mRNA expression for lung inflammatory mediators and lung myeloperoxidase activity were carried out. Further, lungs and histological changes were observed grossly. Untreated infected rat lungs demonstrated higher mRNA expression for inflammatory markers, cytokine levels, and microbial load compared to vehicle control. Conversely, LFX liposome-LYS significantly abated these adverse repercussions. Histology findings were also in agreement of above. Acute toxicity study revealed safeness of LFX liposome-LYS. Our findings confirm LFX liposome-LYS exhibited prolonged, improved antibiofilm and antimicrobial efficacy in treating S. aureus infection.

Catanionic systems in nanotherapeutics - Biophysical aspects and novel trends in drug delivery applications.

Mixtures of surfactants can result in formation of various structures like micelles, vesicles and inverted micelles. Catanionic vesicular systems are preferred on account of their ease of formation and thermodynamic stability. Furthermore, their charge and surfactant properties render them as useful vehicles for DNA delivery and cytotoxic compounds. They suffer from disadvantages of being leaky and yielding low encapsulation efficiencies which are averse to drug delivery purposes. Extensive efforts are being undertaken to overcome these barriers and render these vesicles amenable to spatial placement and temporal delivery of drugs. This manuscript addresses diverse aspects of catanionic vesicles including their formation, fabrication and stability. The manuscript focuses further on applications of catanionic vesicles in nanodrug delivery. Novel trends in the field of catanionics with respect to bio-compatibility and novel technologies developed using these systems have also been reviewed. An attempt has been made to compile catanionic systems reported in literature detailing surfactants and therapeutic agents employed to aid understanding and yield information of various facets that drive fabrication and potential utility of these systems in therapeutics.

Pulmonary delivery of synergistic combination of fluoroquinolone antibiotic complemented with proteolytic enzyme: A novel antimicrobial and antibiofilm strategy.

Bacterial resistance remains a major hindrance in treatment with antimicrobial agents. Therefore, we assessed the improved antimicrobial and antibiofilm activity of Levofloxacin (LFX) and Serratiopeptidase (SRP) combinations in in vitro microbiological studies. Further, pharmacodynamic and pharmacokinetic studies of liposomal LFX in combination with SRP (LFX liposome-SRP) were performed in S. aureus infected rats. LFX at sub-MIC with SRP eradicated >90% of the preformed biofilm. The entrapment efficiency of LFX in liposome was >80% and the co-spray dried product had MMAD <5 µm. We observed high LFX concentration in the lung (3.39 µg/ml over 3 h) and AUC/MIC ≥100. In a pharmacodynamic study, untreated infected rat lungs demonstrated higher mRNA expression for inflammatory markers, cytokine levels and microbial load compared to control. Conversely, LFX liposome-SRP significantly abated these adverse repercussions. Histological findings were also in agreement with these observations. Furthermore, our findings corroborate exhibited improved antibiofilm and antimicrobial efficacy of LFX liposome-SRP in treating S. aureus infection.

Surface-Modified Liposomal Formulation of Amphotericin B: In vitro Evaluation of Potential Against Visceral Leishmaniasis.

Surface modification of liposomes with targeting ligands is known to improve the efficacy with reduced untoward effects in treating infective diseases like visceral leishmaniasis (VL). In the present study, modified ligand (ML), designed by modifying polysaccharide with a long chain lipid was incorporated in liposomes with the objective to target amphotericin B (Amp B) to reticuloendothelial system and macrophages. Conventional liposomes (CL) and surface modified liposomes (SML) were characterized for size, shape, and entrapment efficiency (E.E.). Amp B SML with 3% w/w of ML retained the vesicular nature with particle size of ∼205 nm, E.E. of ∼95% and good stability. SML showed increased cellular uptake in RAW 264.7 cells which could be attributed to receptor-mediated endocytosis. Compared to Amp B solution, Amp B liposomes exhibited tenfold increased safety in vitro in RAW 264.7 and J774A.1 cell lines. Pharmacokinetics and biodistribution studies revealed high t 1/2, area under the curve (AUC)0-24, reduced clearance and prolonged retention in liver and spleen with Amp B SML compared to other formulations. In promastigote and amastigote models, Amp B SML showed enhanced performance with low 50% inhibitory concentration (IC50) compared to Amp B solution and Amp B CL. Thus, due to the targeting ability of ML, SML has the potential to achieve enhanced efficacy in treating VL.

Lecithin and PLGA-based self-assembled nanocomposite, Lecithmer: preparation, characterization, and pharmacokinetic/pharmacodynamic evaluation.

The present study investigates the drug delivery potential of polymer lipid hybrid nanocomposites (Lecithmer®) composed of poly(D,L-lactide-co-glycolide (PLGA) and soya lecithin. Core-shell structure of Lecithmer was evident from cryo-TEM images. Daunorubicin (DNR) and lornoxicam (LNX)-incorporated Lecithmer nanocomposites were evaluated for anticancer and anti-inflammatory activity. DNR- and LNX-loaded Lecithmer had mean particle size of ∼335 and ∼282.7 nm, respectively. Lecithmer formulated with different cationic lipids resulted in lower particle size (∼120 nm) and positive zeta potential. Entrapment efficiency of DNR and LNX was 93.16 and 88.59 %, respectively. In vitro release of DNR from Lecithmer was slower compared to PLGA nanoparticles. DNR release from Lecithmer was significantly higher at pH 5.5 (80.96 %) as compared to pH 7.4 (55.95 %), providing advantage for selective tumor therapy. Similarly, sustained release of LNX (30 % in 10 h) was observed at pH 7.4. DNR in Lecithmer showed superior cytotoxicity on human erythroleukemic K562 cells. Pharmacokinetic study in Wistar rats with i.v. administered DNR-loaded Lecithmer showed higher volume of distribution, lower elimination rate constant, and longer half-life (81.68 L, 0.3535 h(-1), 1.96 h) as compared to DNR solution (57.46 L, 0.4237 h(-1), 1.635 h). Pharmacodynamic evaluation of orally administered LNX-loaded Lecithmer showed superior anti-inflammatory activity with maximum inhibition of 81.2 % vis-à-vis 53.57 % in case of LNX suspension. In light of these results, Lecithmer can be envisaged as a promising nanosystem for parenteral as well as oral drug delivery.

Characterization of pioglitazone cyclodextrin complexes: Molecular modeling to in vivo evaluation.

AIMS: The objective of present study was to study the influence of different ß-cyclodextrin derivatives and different methods of complexation on aqueous solubility and consequent translation in in vivo performance of Pioglitazone (PE). MATERIAL AND METHODS: Three cyclodextrins: ß-cyclodextrin (BCD), hydroxypropyl-ß-cyclodextrin (HPBCD) and Sulfobutylether-7-ß-cyclodextrin (SBEBCD) were employed in preparation of 1:1 Pioglitazone complexes by three methods viz. co-grinding, kneading and co-evaporation. Complexation was confirmed by phase solubility, proton NMR, Fourier Transform Infrared spectroscopy, Differential Scanning Calorimetry (DSC) and X-Ray diffraction (XRD). Mode of complexation was investigated by molecular dynamic studies. Pharmacodynamic study of blood glucose lowering activity of PE complexes was performed in Alloxan induced diabetic rat model. RESULTS: Aqueous solubility of PE was significantly improved in presence of cyclodextrin. Apparent solubility constants were observed to be 254.33 M(-1) for BCD-PE, 737.48 M(-1) for HPBCD-PE and 5959.06 M(-1) for SBEBCD-PE. The in silico predictions of mode of inclusion were in close agreement with the experimental proton NMR observation. DSC and XRD demonstrated complete amorphization of crystalline PE upon inclusion. All complexes exhibited >95% dissolution within 10 min compared to drug powder that showed <40% at the same time. Marked lowering of blood glucose was recorded for all complexes. CONCLUSION: Complexation of PE with different BCD significantly influenced its aqueous solubility, improved in vitro dissolution and consequently translated into enhanced pharmacodynamic activity in rats.

In Vitro and Ex Vivo Evaluations of Lipid Anti-Cancer Nanoformulations: Insights and Assessment of Bioavailability Enhancement.

Lipid-based nanoformulations have been extensively investigated for improving oral efficacy of plethora of drugs. Chemotherapeutic agents remain a preferred option for effective management of cancer; however, most chemotherapeutic agents suffer from limitation of poor oral bioavailability that is associated with their physicochemical properties. Drug delivery via lipid-based nanosystems possesses strong rational and potential for improving oral bioavailability of such anti-cancer molecules through various mechanisms, viz. improving their gut solubilisation owing to micellization, improving mucosal permeation, improving lymphatic uptake, inhibiting intestinal metabolism and/or inhibiting P-glycoprotein efflux of molecules in the gastrointestinal tract. Various in vitro characterization techniques have been reported in literature that aid in getting insights into mechanisms of lipid-based nanodevices in improving oral efficacy of anti-cancer drugs. The review focuses on different characterization techniques that can be employed for evaluation of lipid-based nanosystems and their role in effective anti-cancer drug delivery.

Docetaxel in cationic lipid nanocapsules for enhanced in vivo activity.

The usefulness of Docetaxel (DT) as an anti-cancer agent is limited to parenteral route owing to its very poor oral bioavailability. Thus, to improve its oral efficacy, DT was loaded in novel cationic lipid nanocapsules (DT CLNC). The DT CLNC possessed size of 130-150 nm, zeta potential of +72mV, adequate DT loading and over 95% encapsulation efficiency. TEM revealed capsular structure of DT CLNC. Lipolysis study indicated improved solubilization of DT by nanocapsules in comparison to DT solution. DT CLNC exhibited significantly higher release of DT in comparison to DT solution during in vitro permeation studies employing non-reverted rat-intestinal sac. Superior uptake of DT in zebra fishes exposed to DT CLNC resulted in greater apoptosis-based cell death as compared to those exposed to DT solution. This correlated well with the significantly superior (p < 0.05) anti-angiogenic activity of DT CLNC system over DT solution, in zebra fish model. DT CLNC also inhibited tumor growth in melanoma cell line induced tumors in C57BL/6 mice significantly, as compared to DT solution (p < 0.05). The DT CLNC system demonstrated adequate stability, with tremendous potential to improve oral efficacy of DT and can serve as an alternative to existing DT formulations available commercially for parenteral use.

LeciPlex, invasomes, and liposomes: A skin penetration study.

The present study compares three vesicular systems, cationic LeciPlex, invasomes, and conventional liposomes for their ability to deliver drugs deep into the skin. Skin penetration ability of the three vesicular systems was studied for two drugs namely idebenone (antioxidant/anticancer) and azelaic acid (antiacne). All systems showed sizes in nanometer range with small polydispersity indices. Vesicular systems were characterized by CryoTEM studies to understand the differences in morphology of the vesicular systems. Ex vivo human skin penetration studies suggested a pattern in penetration of drugs in different layers of the skin: LeciPlex showed higher penetration for idebenone whereas invasomes showed higher penetration of azelaic acid. Ex vivo study using a fluorescent dye (DiI) was performed to understand the differences in the penetration behavior of the three vesicular systems on excised human skin. In vitro cytotoxicity studies on B16F10 melanoma cell lines revealed, when loaded with idebenone, LeciPlex formulations had the superior activity followed by invasomes and liposomes. In vitro antimicrobial study of azelaic acid loaded systems on Propionibacterium acne revealed high antimicrobial activity for DDAB leciplex followed by almost equal activity for invasomes and CTAB LeciPlex followed by liposomes. Whereas antiacne efficacy study in rats for azelaic acid loaded systems, invasomes exhibited the best antiacne efficacy followed by liposomes and LeciPlex.

Influence of Formulation Factors and Compression Force on Release Profile of Sustained Release Metoprolol Tablets using Compritol(®) 888ATO as Lipid Excipient.

Tablets containing metoprolol succinate and Compritol(®) 888ATO in the ratio of 1:2 yielded the desired sustained release profile in phosphate buffer pH 6.8 when evaluated using USP type II paddle apparatus and was selected as the optimized formulation. Robustness of optimized formulation was assessed by studying the effect of factors like varying source of metoprolol succinate and Compritol(®) 888ATO, compression force and hydroalcoholic dissolution medium on the release profile. No significant difference (P>0.05) in release profile was observed when metoprolol succinate from three different sources and Compritol(®) 888ATO from two different batches were used. Release profile of sustained release tablets of metoprolol succinate in media containing various concentrations of ethanol was comparable with media devoid of ethanol as evaluated by f2 test. This indicated that release profile of sustained release tablets of metoprolol succinate was reliable with no significant change due to variation in source of active pharmaceutical ingredient, particularly due to particle size distribution. Sustained release tablets of metoprolol succinate yielded release pattern within specifications irrespective of presence or absence of ethanol in the medium indicating that release properties of Compritol(®) 888ATO matrix are not affected by ethanol. Tablets compressed at compression force of <100 kg/cm(2) exhibited low hardness with total porosity of 15.39% and significantly increased (P<0.05) metoprolol succinate release as compared to tablets compressed at 2000 kg/cm(2) with 6.90% of total porosity revealing influence of compression force. Compritol(®) 888ATO holds great potential in providing reliable and controlled release profile of highly water soluble metoprolol succinate.

Liposomes for targeting hepatocellular carcinoma: use of conjugated arabinogalactan as targeting ligand.

Present study investigates the potential of chemically modified (Shah et al., 2013) palmitoylated arabinogalactan (PAG) in guiding liposomal delivery system and targeting asialoglycoprotein receptors (ASGPR) which are expressed in hepatocellular carcinoma (HCC). PAG was incorporated in liposomes during preparation and doxorubicin hydrochloride was actively loaded in preformed liposomes with and without PAG. The liposomal systems with or without PAG were evaluated for in vitro release, in vitro cytotoxicity, in vitro cell uptake on ASGPR(+) cells, in vivo pharmacokinetic study, in vivo biodistribution study, and in vivo efficacy study in immunocompromised mice. The particle size for all the liposomal systems was below 200 nm with a negative zeta potential. Doxorubicin loaded PAG liposomes released significantly higher amount of doxorubicin at pH 5.5 as compared to pH 7.4, providing advantage for targeted tumor therapy. Doxorubicin in PAG liposomes showed superior cytotoxicity on ASGPR(+) HepG2 cells as compared to ASGPR(-), MCF7, A549, and HT29 cells. Superior uptake of doxorubicin loaded PAG liposomes as compared to doxorubicin loaded conventional liposomes was evident in confocal microscopy studies. Higher AUC in pharmacokinetic study and higher deposition in liver was observed for PAG liposomes compared to conventional liposomes. Significantly higher tumor suppression was noted in immunocompromised mice for mice treated with PAG liposomes as compared to the conventional liposomes. Targeting ability and superior activity of PAG liposomes is established pre-clinically suggesting potential of targeted delivery system for improved treatment of HCC.

Apoptosis induction and anti-cancer activity of LeciPlex formulations.

PURPOSE: Cationic agents have been reported to possess anti-neoplastic properties against various cancer cell types. However, their complexes with lipids appear to interact differently with different cancer cells. The purpose of this study was to (i) design and generate novel cationic lecithin nanoparticles, (ii) assess and understand the mechanism underlying their putative cytotoxicity and (iii) test their effect on cell cycle progression in various cancer-derived cell lines. In addition, we aimed to evaluate the in vivo potential of these newly developed nanoparticles in oral anti-cancer delivery. METHODS: Cationic lecithin nanoparticles were generated using a single step nanoprecipitation method and they were characterized for particle size, zeta potential, stability and in vitro release. Their cytotoxic potential was assessed using a sulforhodamine B assay, and their effect on cell cycle progression was evaluated using flow cytometry. The nanoparticle systems were also tested in vivo for their anti-tumorigenic potential. RESULTS: In contrast to cationic agents alone, the newly developed nanoformulations showed a specific toxicity against cancer cells. The mechanism of toxic cell death included apoptosis, S and G2/M cell cycle phase arrest, depending on the type of cationic agent and the cancer-derived cell line used. Both blank and drug-loaded systems exhibited significant anti-cancer activity, suggesting a synergistic anti-tumorigenic effect of the drug and its delivery system. CONCLUSIONS: Both in vitro and in vivo data indicate that cationic agents themselves exhibit broad anti-neoplastic activities. Complex formation of the cationic agents with phospholipids was found to provide specificity to the anti-cancer activity. These formulations thus possess potential for the design of effective anti-cancer delivery systems.

Preclinical formulations: insight, strategies, and practical considerations.

A lot of resources and efforts have been directed to synthesizing potentially useful new chemical entities (NCEs) by pharmaceutical scientists globally. Detailed physicochemical characterization of NCEs in an industrial setup begins almost simultaneously with preclinical testing. Most NCEs possess poor water solubility posing bioavailability issues during initial preclinical screening, sometimes resulting in dropping out of an NCE with promising therapeutic activity. Selection of right formulation approach for an NCE, based on its physicochemical properties, can aid in improving its solubility-related absorption and bioavailability issues. The review focuses on preclinical formulations stressing upon different preclinical formulation strategies and deciphers the understanding of formulation approaches that could be employed. It also provides detailed information related to a vast pool of excipients available today, which is of immense help in designing preclinical formulations. Few examples mentioned, throw light on key aspects of preclinical formulation development. The review will serve as an important guide for selecting the right strategy to improve bioavailability of NCEs for academic as well as industrial formulation scientists.

Tamoxifen guided liposomes for targeting encapsulated anticancer agent to estrogen receptor positive breast cancer cells: in vitro and in vivo evaluation.

Tamoxifen (TMX), an estrogen receptor (ER) antagonist, incorporated at surface of liposomes loaded with Doxorubicin (DOX), was hypothesized to serve as ligand for targeting overexpressed ERs on surface and cytosol of breast cancer cells, in addition to its synergism with DOX in killing MCF-7 cells. The TMX-DOX liposomes demonstrated mean size of 188.8±2.2nm and positive potential of+47mV, both suitable for better cellular interaction. TMX-DOX liposomes sustained DOX release in vitro (25.9%) in pH 7.4 at 48h, in comparison with 64.5% DOX release at pH 5.5. In vitro cell line studies demonstrated that TMX-DOX liposomes were more cytotoxic to ER+ve MCF-7 cells as compared to DOX liposomes, DOX solution and TMX-DOX solution (P<0.05). However, there was no statistical difference in cyto-toxicity of TMX-DOX liposomes and DOX liposomes towards ER-ve MDA-MB-231 cells. Flow cytometry and confocal studies in MCF-7 cells revealed greater cell and nuclear uptake of DOX, with TMX guided liposomes as compared to DOX liposomes and DOX solution. TMX-DOX liposomes demonstrated significantly increased inhibition of MCF-7 cell based tumor growth in nude mice (P<0.05) in comparison to DOX solution and DOX liposomes, indicative of target specificity and higher DOX accumulation at tumor site.

Bolaamphiphiles: a pharmaceutical review.

The field of drug discovery is ever growing and excipients play a major role in it. A novel class of amphiphiles has been discussed in the review. The review focuses on natural as well as synthetic bolaamphiphiles, their chemical structures and importantly, their ability to self assemble rendering them of great use to pharmaceutical industry. Recent reports on their ability to be used in fabrication of suitable nanosized carriers for drug as well as genes to target site, has been discussed substantially to understand the potential of bolaamphiphiles in field of drug delivery.

Lipid colloidal carriers for improvement of anticancer activity of orally delivered quercetin: formulation, characterization and establishing in vitro-in vivo advantage.

Novel lipid nanocarriers, GeluPearl (GP) comprising of Precirol ATO 5 lipid nanoparticles with (GPNLC) or without oil (GPSLN), loaded with Quercetin (QR), were successfully fabricated to improve therapeutic efficacy. QR loaded GP nanoparticles were optimized to yield adequate colloidal stability, mean particle size in range of 350-380 nm and entrapment efficiency of more than 90%. GPSLN and GPNLC were characterized for morphological evaluation by virtue of cryo-TEM, surface charge, protection offered to QR against alkali mediated degradation and fluorescence studies to evaluate QR-lipid interaction. DSC analysis was performed to get insight into physical state of QR loaded in nanosystems. The in vitro release studies demonstrated sustained drug release potential of QR loaded GP. In vitro lipolysis studies confirmed that lipidic nanocarriers can improve QR solubilization. QR loaded GP nanosystems significantly (P < 0.05) reduced flank tumor volumes in C57BL/6 mice over a 22 day study period compared to QR suspension. GPSLN significantly reduced lung colonization and enhanced antimetastatic activity (P < 0.05) of drug against B16F10 melanoma cells in C57BL/6 mice as compared to QR suspension. QR loaded GPSLN and GPNLC could be effectively lyophilized without much change in particle size and drug content using 15% w/v mannitol as cryoprotectant.

Compritol®888 ATO a lipid excipient for sustained release of highly water soluble active: formulation, scale-up and IVIVC study.

The potential of Compritol(®)888 ATO as a release modifier to retard the release of highly water soluble drug, metoprolol succinate (MPL) was exploited. Different ratios of Compritol(®)888 ATO versus MPL were utilized and the effect of various formulation methods was evaluated to sustain the release of MPL. MPL: Compritol(®)888 ATO in 1:2 ratio could successfully retard the release of MPL. Melt granulation method "as hot process" was found to be effective when compared to direct compression and wet granulation. The in vitro release characteristics of tablets were studied in pH 6.8 phosphate buffer at 50 rpm using USP Type II apparatus. Formulation F7 retarded MPL release with ~90% release after 20 h. Stability studies showed no significant difference (f2>50) in MPL release profile after three months of storage period at 25 ± 2°C/60 ± 5% RH and 40 ± 2°C/75 ± 5% RH. The bioavailability of sustained release tablets, F7 was compared with commercially available tablets, MetXL50 in 12 healthy human volunteers in a crossover design. Plasma concentration of MPL was determined using HPLC with fluorescence detector. IVIVC correlation was obtained by deconvoluting the plasma concentration-time curve using a model independent Wagner-Nelson method. Correlations of fraction of drug dissolved in vitro and fraction of drug absorbed in vivo displayed a significant linear relationship for sustained release tablets of MPL.

Synthesis, characterization, and in vitro evaluation of palmitoylated arabinogalactan with potential for liver targeting.

Arabinogalactan (AG), a water soluble polysaccharide with more than 80 mol% galactose units, was hydrophobized by covalent attachment of palmitoyl chains using a base-catalyzed esterification reaction with the objective of effective amalgamation of arabinogalactan in liposomes for targeting asialoglycoprotein receptors (ASGPR) on liver parenchymal cells. Palmitoylated AG (PAG) was characterized by physico-chemical parameters, IR, (1)H NMR, and (13)C NMR and molecular weight determination by gel permeation chromatography. PAG was incorporated in liposomes and the liposomes were characterized by dynamic light scattering, optical microscopy, zeta potential, and transmission electron microscopic (TEM) techniques. The liposomal system was evaluated for acute toxicity in swiss albino mice and was found to be safe. Targeting ability of PAG was confirmed by in vitro binding affinity to Ricinus communis agglutinin (RCA(120)), a lectin specific for galactose. The liposomal system with PAG was evaluated for cytotoxicity on HepG2, MCF7, and A549 cancer cell lines. Cytotoxicity study revealed enhanced activity on ASGPR-expressive HepG2 cells as compared to MCF7.