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Celastrol (CL), a bioactive compound isolated from Tripterygium wilfordii, has demonstrated bioactivities against a variety of diseases including cancer and obesity. However, its poor water solubility and rapid in vivo clearance limit its clinical applications. To overcome these limitations, nanotechnology has been employed to improve its pharmacokinetic properties. Nanoparticles made of biological materials offer minimal adverse effects while maintaining the efficacy of encapsulated therapeutics. Silk fibroin (SF) solution was prepared successfully by extraction from the cocoons of silkworms, and a final concentration of 2 mg/mL SF solution was used for the preparation of CL-loaded SF nanoparticles (CL-SFNP) by the desolvation method. A stirring speed of 750 rpm and storage time of 20 h at &minus, 20 &deg, C resulted in optimized product yield. A high-performance liquid chromatography (HPLC) method was developed and validated for the analysis of CL in rat plasma in terms of selectivity, linearity, intra-/inter-day precision and accuracy, and recovery. No interference was observed in rat plasma. Linearity in the concentration range of 0.05&ndash, 5 &micro, g/mL was observed with R2 of 0.999. Precision and accuracy values were below the limit of acceptance criteria, i.e., 15% for quality control (QC) samples and 20% for lower limit of quantification (LLOQ) samples. Rats were given intravenous (IV) administration of 1 mg/kg of pure CL in PEG 300 solution or CL-SFNP. The pharmacokinetic profile was improved with CL-SFNP compared to pure CL. Pure CL resulted in a maximum concentration (Cmax) value of 0.17 &micro, g mL&minus, 1 at 5 min following administration, whereas that for CL-SFNP was 0.87 &micro, 1 and the extrapolated initial concentrations (C0) were 0.25 and 1.09 &micro, 1, respectively, for pure CL and CL-SFNP. A 2.4-fold increase in total area under the curve (AUC0-inf) (&micro, g h mL&minus, 1) was observed with CL-SFNP when compared with pure CL. CL-SFNP demonstrated longer mean residence time (MRT, 0.67 h) than pure CL (0.26 h). In conclusion, the preparation of CL-SFNP was optimized and the formulation demonstrated improved pharmacokinetic properties compared to CL in solution following IV administration.

The objective of the present study was to develop a proliposomal formulation to increase the oral bioavailability of dronedarone hydrochloride (dronedarone HCl) by enhancing solubility, dissolution, and/or intestinal absorption. Proliposomes were prepared by using solvent evaporation method. In this process, different ratios of drug, phospholipids, such as soy phosphatidylcholine (SPC), Phospholipon 90H, hydrogenated egg phosphatidylcholine (HEPC), and dimyristoyl phosphatidylglycerol (DMPG), and cholesterol were used. Physical characterization and in vitro dissolution studies were evaluated for the prepared formulations. In vitro transport across the membrane was carried out using Caco-2 cells. Among all the formulations, the amount of drug released in dissolution was higher with DPF8 formulation (drug:DMPG Na:cholesterol:::1:2:0.2) compared to the pure drug. Also, Caco-2 cell permeability studies resulted in 2.6-fold increase in apparent permeability. Optimized formulation was evaluated in vivo in male Sprague-Dawley rats. After single oral administration of optimized formulation (DPF8), a relative bioavailability of 148.36% was achieved compared to the pure drug. Improved oral bioavailability of dronedarone could be provided by an optimized proliposomal formulation with enhanced solubility, permeability, and oral absorption.

The objective of this study was to develop proliposomal formulation and self micro-emulsifying drug delivery system (SMEDDS) for a poorly bioavailable drug, nisoldipine and to compare their in vivo pharmacokinetics. Proliposomes were prepared by thin film hydration method using different lipids such as Soy phosphatidylcholine (SPC), Hydrogenated Soy phosphatidylcholine (HSPC), Dimyristoylphosphatidylcholine (DMPC) and Dimyristoyl phosphatidylglycerol sodium (DMPG), Distearyl phosphatidylcholine (DSPC), and Cholesterol in various ratios. SMEDDS formulations were prepared using varying concentrations of Capmul MCM, Labrasol, Cremophor EL and Tween 80. Both proliposomes and SMEDDS were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug release was carried out in purified water using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague-Dawley rats. Among the different formulations, proliposomes with drug:DMPC:cholesterol in the ratio of 1:2:0.5 and SMEDDS with Capmul MCM (13.04% w/w), Labrasol (36.96% w/w), Cremophor EL (34.78% w/w) and Tween 80 (15.22% w/w) demonstrated the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes and SMEDDS compared to pure nisoldipine in purified water after 1h. Nisoldipine permeability across PAMPA and everted rat intestinal perfusion models was significantly higher with proliposomes and SMEDDS. Following single oral administration of proliposomes and SMEDDS, a relative bioavailability of 301.11% and 239.87% respectively, was achieved compared to pure nisoldipine suspension.

Lipids have been extensively used in formulations to enhance dissolution and bioavailability of poorly water-soluble as well as water-soluble drug molecules. The digestion of lipid-based formulations, in the presence of bile salts, phospholipids, and cholesterol, changes the lipid composition in vivo, resulting in the formation of different colloidal phases in the intestine. Therefore, in vitro characterization and evaluation of such formulations are critical in developing a successful formulation. This review covers comprehensive discussion on in vitro characterization techniques such as solubility, drug entrapment, thermal characterization, dissolution, and digestion of lipid-based formulations.

The objective of this study was to develop proliposomes and self-nanoemulsifying drug delivery system (SNEDDS) for a poorly bioavailable drug, valsartan, and to compare their in vivo pharmacokinetics. Proliposomes were prepared by thin-film hydration method using different lipids such as soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoyl phosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. SNEDDS formulations were prepared using varying concentrations of capmul MCM, labrafil M 2125, and Tween 80. Both proliposomes and SNEDDS were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water and 0.1 N HCl using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal permeation techniques. Among the formulations, the proliposomes with drug/DMPG/cholesterol in the ratio of 1:1:0.5 and SNEDDS with capmul MCM (16.0% w/w), labrafil M 2125 (64.0% w/w), and Tween 80 (18.0% w/w) showed the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes and SNEDDS as compared to pure valsartan. Valsartan permeability across PAMPA and everted rat intestinal permeation models was significantly higher with proliposomes and SNEDDS. Following single oral administration of proliposomes and SNEDDS, a relative bioavailability of 202.36 and 196.87%, respectively, was achieved compared to pure valsartan suspension. The study results indicated that both proliposomes and SNEDDS formulations are comparable in improving the oral bioavailability of valsartan.

Insoluble drugs often formulated with various excipients to enhance the dissolution. Cyclodextrins (CDs) are widely used excipients to improve dissolution profile of poorly soluble drugs. Drug-CD complexation process is complex and often requires multiple processes to produce solid dosage form. Hence, this study explored commonly used granulation processes for simultaneous complexation and granulation. Poorly soluble drugs ibuprofen and glyburide were selected as experimental drugs. Co-evaporation of drug:CD mixture from a solvent followed by wet granulation with water was considered as standard process for comparison. Spray granulation and fluid bed processing (FBP) using drug:CD solution in ethanol were evaluated as an alternative processes. The dissolution data of glyburide tablets indicated that tablets produced by spray granulation, FBP and co-evaporation-granulation have almost identical dissolution profile in water and 0.1% SLS (>70% in water and >60% in SLS versus 30 and 34%, respectively for plain tablet, in 120 min). Similarly, ibuprofen:CD tablets produced by co-evaporation-granulation and FBP displayed similar dissolution profile in 0.01 M HCl (pH 2.0) and buffer pH 5.5 (>90 and 100% versus 44 and 80% respectively for plain tablets, 120 min). Results of this study demonstrated that spray granulation is simple and cost effective process for low dose poorly soluble drugs to incorporate drug:CD complex into solid dosage form, whereas FBP is suitable for poorly soluble drugs with moderate dose.

The aim of this study was to develop a proliposomal formulation of lipopeptide antibiotic drug daptomycin (DAP) for oral delivery. Thin film hydration was the selected method for preparation of proliposomes. Different phospholipids including soy-phosphatidylcholine (SPC), hydrogenated egg-phosphatidylcholine (HEPC), and distearoyl-phosphatidylcholine (DSPC) were evaluated in combination with cholesterol. The inclusion of surface charge modifiers in the formulation such as dicetyl phosphate (DCP) and stearylamine (SA) to enhance drug encapsulation was also evaluated. Particle size, surface charge, and encapsulation efficiency were performed on daptomycin-hydrated proliposomes as part of physical characterization. USP type II dissolution apparatus with phosphate buffer (pH 6.8) was used for in vitro drug release studies. Optimized formulation was evaluated for in vivo pharmacokinetics after oral administration to Sprague-Dawley rats. Proliposomes composed of SPC exhibited higher entrapment efficiency than those containing HEPC or DSPC. The highest entrapment efficiency was achieved by positively charged SPC-SA proliposomes, showing an encapsulation efficiency of 92% and a zeta potential of + 28 mV. In vitro drug release of optimized formulation demonstrated efficient drug retention totaling for less than 20% drug release within the first 60 min and only 42% drug release after 2 h. Pharmacokinetic parameters after single oral administration of optimized proliposomal formulation indicated a significant increase in oral bioavailability of DAP administered as SPC-SA proliposomes when compared to drug solution. Based on these results, incorporation of charge modifiers into proliposomes may increase drug loading and proliposomes an attractive carrier for oral delivery of daptomycin.

The aim of this study was to develop and characterize phospholipid bearing pellets for a poorly water-soluble drug, nisoldipine. Pellets were prepared using extrusion-spheronization technique containing microcrystalline cellulose, soy phosphatidylcholine (SPC), granulating fluid and lactose. Operational parameters such as extrusion speed, spheronization speed and residence time were evaluated. Optimal extrusion speed was found to be 50 rpm with a spheronization speed of 60 Hz and residence time of 2 min. Pellets were characterized for their size, shape, density, flow properties, friability, moisture content, surface morphology and thermal properties. Pellets were evaluated for their assay and in vitro drug release. Mathematical modeling was used to determine the release patterns of the pellets. Pellets were found to be spherical, 600-850 μm size with0.01% friability and had70% yield. Scanning electron microscopic (SEM) studies showed a smoother external surface and a porous internal matrix. SPC incorporated pellets resulted in improved dissolution of the drug. Pellets with SPC (20 and 30%) released90% of the drug within 24 h. The dissolution profiles of the pellets were best fitted to Korsmeyer-Peppas kinetic model. In this study, we could successfully incorporate a lipid and a water-insoluble drug into a pellet formulation with improved dissolution profile.

We study the influence of phosphorylation on the foamability and stability of Bovine Serum Albumin (BSA), phosphorylated BSA (pBSA) and citrus peel pectin (CPP) mixed foams as a function of BSA – CPP, pBSA – CPP mixing ratios, at a fixed solution pH of 4.5. Our results show that pBSA solutions result in more stable foams as compared to their BSA counterparts. We further show that the addition of CPP leads to BSA – CPP and pBSA – CPP complexation which increases the foamability and stability of foams as compared to protein only foams. Also, foam stability is highest for pBSA – CPP mixed foams with mixing ratio pBSA:CPP = 1:1 due to the combined effect of pBSA – pBSA and pBSA – CPP interactions.

The efficacy of n-lauryl-beta-D-maltopyranoside, (dodecylmaltoside, DDM) as a permeability-enhancer for tiludronate and cromolyn (BCS Class III, water-soluble compounds with oral bioavailability5%) was evaluated in Caco-2 cell monolayers and rat intestinal sacs. In Caco-2 cells samples were collected over a 5-h period and transepithelial resistance (TEER) was measured concurrently. In rat intestinal sacs, samples of the test compounds and marker (Lucifer Yellow) were collected over a 40 min period; accumulation in the serosal fluid and intestinal tissue was measured. At lower concentration DDM had no effect on cromolyn permeability and a marginal increase was observed at higher concentration. Tiludronate permeability in the presence of DDM showed greater enhancement as compared to cromolyn. At higher concentration DDM appeared to cause permanent damage to the cell monolayer (irreversible change in TEER). In the intestinal tissue, DDM caused increased tissue accumulation of test compounds. This indicated that transport was not restricted to the paracellular route and damage to the intestinal tissue could not be ruled out. Based on the results obtained in this study it can be concluded that at concentrations that are non-toxic DDM appears to have a limited use to improve the oral absorption of cromolyn and tiludronate.

The objective of this study was to develop proliposomal formulation for a poorly bioavailable drug, tacrolimus. Proliposomes were prepared by thin film hydration method using different lipids such as hydrogenated soy phosphatidylcholine (HEPC), soy phosphatidylcholine (SPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoylphosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. Proliposomes were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague-Dawley (SD) rats. Among the different formulations, proliposomes with drug/DSPC/cholesterol in the ratio of 1:2:0.5 demonstrated the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes compared to pure tacrolimus in purified water after 1 h. Tacrolimus permeability across PAMPA and everted rat intestinal perfusion models was significantly higher with proliposomes. The optimized formulation of proliposomes indicated a significant improvement in the rate and absorption of tacrolimus. Following a single oral administration, a relative bioavailability of 193.33% was achieved compared to pure tacrolimus suspension.

The objective of our investigational work was to develop a proliposomal formulation to improve the oral bioavailability of valsartan. Proliposomes were formulated by thin film hydration technique using different ratios of phospholipids:drug:cholesterol. The prepared proliposomes were evaluated for vesicle size, encapsulation efficiency, morphological properties, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug-release studies were performed in simulated gastric fluid (pH 1.2) and purified water using dialysis bag method. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA), Caco-2 monolayer and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague Dawley (SD) rats. Among the proliposomal formulations, F-V was found to have the highest encapsulation efficiency of 95.6 ± 2.9% with a vesicle size of 364.1 ± 14.9 nm. The in vitro dissolution studies indicated an improved drug release from proliposomal formulation, F-V in comparison to pure drug suspension in both, purified water and pH 1.2 dissolution media after 12 h. Permeability across PAMPA, Caco-2 cell and everted rat intestinal perfusion studies were higher with F-V formulation as compared to pure drug. Following single oral administration of F-V formulation, a relative bioavailability of 202.36% was achieved as compared to pure valsartan.

The objective of this study was to design an in situ biodegradable polymer implant controlled-release drug delivery system, using novel combinations of co-solvents and a model polypeptide, calcitonin (CT), and to assess the release of drug as a function of these co-solvents. Formulations were prepared by dissolving/ suspending CT polypeptide in poly-(lactic acid) (PLA) polymer solutions/suspensions containing combinations of a hydrophobic (benzyl benzoate, BB) and a hydrophilic (benzyl alcohol, BA) solvent. The CT-PLA mixtures were each injected into test tubes containing phosphate buffered saline solution to form the in situ implant and sampling was conducted over a 28-day period. The samples were analyzed for drug content using a modified Lowry protein assay procedure. Cumulative drug release demonstrated a rank-order correlation depending on the amount of the hydrophobic (BB) and hydrophilic (BA) solvents within each system. Increasing the amounts of the hydrophobic solvent, BB, in formulations demonstrated a 1.2-4.4-fold increase in CT release. Stability studies of all formulations over a 4-month period showed progressive increase in degradation of the CT polypeptide, especially at 37 degrees C, but a slower degradation pattern prevailed at 4 degrees and 20 degrees C. Differential scanning calorimetric studies revealed a homogenous mixture of drug in the polymer matrix. Overall, these studies demonstrated the feasibility of designing controlled release systems capable of releasing a polypeptide drug as a function of influence of different co-solvent combinations.

In this study, we evaluated the ability of a coated, encapsulated formulation to increase the oral bioavailability of (±)-halofantrine (HF) enantiomers, a drug with low and erratic oral bioavailability. After encapsulation of HF in distearoylphosphatidylcholine, the dried particles were coated with cellulose acetate phthalate. A suspension of the product was made using methylcellulose as a dispersion agent, and the product was administered to Sprague-Dawley rats to provide a HF dose of 7 mg kg−1 as the HCl salt. HF HCl powder in 1 % methylcellulose with or without liposomal product excipients was also administered to separate groups of rats, which served as control groups. Serial blood samples were obtained from the rats and plasma was assayed by stereospecific high-performance liquid chromatography. There were no significant differences in the area under the concentration-time curve (AUC) or maximum concentration (Cmax) between the two control groups. Plasma concentrations of both HF enantiomers were significantly higher in the rats given HF as an encapsulated proliposomal formulation compared with the control groups. Compared with methyl-cellulose control, the encapsulation product resulted in increases of 41 to 47% in the AUC of HF enantiomers, and 90 to 100% in Cmax. The ability of an encapsulated proliposomal product to significantly increase the oral absorption of HF was clearly demonstrated.

The objective of this study was to design lipid-based formulation to enhance the absorption of unmetabolized resveratrol (RSV) over adequate time and investigate various factors that contribute to prolonged absorption of RSV.Proliposomal formulations containing distearoyl phosphatidyl choline (DSPC) with or without cholesterol were prepared and evaluated. The liposomes obtained from hydration of proliposomal mixture were evaluated for size, zeta, physical appearance and entrapment. The integrity of liposomes in bile salt solution and solubility of RSV in sodium taurocholate solution in the presence of various concentrations of DSPC were evaluated to assess the stability and in varied gastrointestinal conditions. Finally, oral pharmacokinetic studies of liposomal dispersions in comparison with RSV solution were evaluated.Results revealed that spontaneous formation of liposomes did not occur upon hydration of RSV: DSPC proliposomes rather showed tendency to form loose cotton-like aggregates. Cholesterol aided in the formation of stable liposomes with large negative zeta potential. Release of RSV from liposomes in the presence of taurocholate was dependent on the amount and type of total lipid. Liposomes without cholesterol showed faster release, and release increased as the amount of DSPC in the formulation increased. Solubility studies indicated that DSPC increases the solubility of RSV in the presence of sodium taurocholate, and corroborates that bilayer assembly is disrupted because of interaction between RSV and DSPC. Mixture of RSV:DSPC:Chol at 1:0.25:0.25 formed stable colloidal dispersion with zeta potential -22 and released only 20 - 23% of entrapped RSV when incubated with 20 mM sodium taurocholate. Pharmacokinetic profile revealed that AUC and Cmax were twofold higher than plain RSV.The proliposomal formulation optimized by considering various physicochemical factors and simulated in vitro testing result in significant improvement rate and extent of absorption of unmetabolized RSV.

The objective of this study was to formulate a hydrogel-forming bioadhesive drug delivery system for oral administration of didanosine (ddI). The aim of this tablet dosage form is to improve the oral absorption of ddI by delivering it in small doses over an extended period and localizing it in the intestine by bioadhesion. Compressed tablets of ddI using Polyox WSRN-303, Carbopol 974P-NF, and Methocel K4M as the bioadhesive release rate-controlling polymers were prepared. The effect of polymer concentration on the release profile and in vitro bioadhesion of the matrix tablets was studied. Tablet formulations with Polyox WSRN-303 (10%) and Methocel K4M (30%) showed 93 and 90% drug release, respectively, after 12 h. The drug release was found to be linear when fitted in the Higuchi equation (square-root time equation), suggesting zero-order release. Carbopol 974-P-NF was found to inhibit the complete release of ddI because of drug-polymer interaction; hence, is not suitable for formulation of ddI. Drug diffusion and swelling of the polymer (anomalous Fickian release) was found dominant in ddI release. In general, in vitro bioadhesion increased with an increase in polymer concentration. Tablets containing a single polymer can be designed to form hydrogels serving the dual purpose of bioadhesion and sustained release.

A stability indicating high performance liquid chromatography method has been developed for simultaneous determination of acetaminophen, salicylamide and phenyltoloxamine. The reversed-phase method utilizes UV detection at 220 nm and a C8 column. This paper presents the data to support linearity, precision, specificity, and robustness of the method. The known potential degradation products of acetaminophen, p-aminophenol, p-nitrophenol, precursor impurity p-hydroxyacetophenone, the potential degradation product of salicylamide, salicylic acid, and precursor impurity ethylsalicylate were separated for quantitation simultaneous with parent compounds. Quantification was achieved by peak area and external standard method. This method can be employed in determining stability, assay, content uniformity, and dissolution of the combination in pharmaceutical dosage forms.

The objective of this study is to determine the effect of various neutral liposomes on corneal and conjunctival permeability of didanosine (ddI), an antiviral drug. Multi-lamellar vesicles (MLVs), large unilamellar vesicles (LUVs), and sonicated multi-lamellar vesicles (SMLVs) encapsulating ddI (with trace quantities of 3HddI) were prepared using distearoyl phosphatidylcholine (DSPC), a neutral lipid. The liposomes contained 14C-cholesteryl oleate as a lipid tracer. Liposome formulations containing free and encapsulated drug (f + e) and those containing only encapsulated drug (e) of an equal quantity were compared with free drug in this study. The permeability studies were conducted in the mucosal to serosal direction across excised rabbit cornea and conjunctiva. The percent encapsulation of ddI in MLVs, LUVs, and SMLVs was 25.66 0.30, 26.56 0.57, and 19.41 0.30, respectively. The mean particle size of MLVs, LUVs, and SMLVs containingfree and encapsulated drug was 3058, 774, and 270 nm, respectively. With...

The objective of this study was to examine the encapsulation of stavudine (d4T), an approved drug for AIDS treatment, in liposomes composed of various lipids and the in vitro release characteristics, and to evaluate the stability. The reverse phase evaporation method was used to prepare liposomes and the effect of cholesterol on drug encapsulation was studied by adding different amounts of cholesterol to a constant amount of lipid. The effect of charge of the lipid bilayer on drug encapsulation was also studied. Stearylamine or dicetylphosphate (10 mol%) were used to induce positive or negative charges, respectively. The particle size of the liposomes was measured using dynamiclightscattering. Stabilitystudies were performed by storing formulations at 4, 25, and 37 C for 12 weeks, and then subjecting them to alternate heat-cool cycles and simulated transportation conditions. Encapsulation of stavudine was found to be maximum (48%) in DSPC liposomes containing equimolar amounts of cholesterol. Encapsulatio...

Cytokine restraining agents (CRAs) are a family of compounds having profound anti-inflammatory properties. Among them, HP 228 is a heptapeptide, containing some unnatural amino acids, with the unique ability to restrain the pathological effects of cytokines without interfering with their essential immune functions. A liposomal formulation of HP 228 was developed to protect the drug from proteolytic enzymes and to provide controlled release of the drug. The liposomes were prepared using either dimyristoyl phosphatidylcholine or dipalmitoyl phosphatidylcholine and cholesterol by the thin-film hydration method. Dicetyl phosphate was added to the lipids to provide negative charge to the liposomes. Homogeneous size distribution of multilamellar vesicles (MLVs) was achieved by extruding them through the 800-nm polycarbonate membranes. The size distribution was characterized using a submicrometer particle size analyzer. Encapsulation efficiency of HP 228 was determined by adding protamine to MLVs and sep...

2′,3′-Dideoxyinosine (ddI), an anti–human immunodeficiency virus (HIV) agent, was encapsulated in liposomes. The influence of the phospholipid/cholesterol ratio, concentration of phospholipid (PL), and chain length of PL on the encapsulation of ddI in multilamellar vesicles (MLVs), frozen and thawed multilamellar vesicles (FAT MLVs), and large unilamellar vesicles (LUVs) was studied. An optimum formulation was then selected to prepare long circulating liposomes. Stability studies at 4, 25, and 37°C and under certain stress conditions were performed. Release characteristics in phosphate buffer (pH 7.4) at 37°C were studied. Results show an increase in encapsulation efficiency (EE) with increasing amounts of cholesterol, a decrease in EE and increase in encapsulation yield (EY) with increasing concentrations of PL, and an increase in EE with increases in PL chain length, in both MLVs and LUVs. Freezing and thawing of MLVs had no influence on EE at a PL concentration of 10 mg/mL but increased EE at h...

Iontophoresis is useful for the transdermal delivery of charged drugs. However, nonionized drugs either have a low flux (due to electro-osmosis) or cannot be delivered using this technique. Because ionized or nonionized drugs can be encapsulated in charged liposomes, it was hypothesized that charged liposomes can deliver neutral or nonionized drug efficiently by iontophoresis. Colchicine, a neutral drug, was encapsulated in large unilamellar vesicles (LUVs), prepared with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) along with cholesterol (1:0.5 mole ratio). Multilamellar vesicles (MLVs) were prepared by the thin-film hydration method and LUVs were obtained by extruding MLVs through polycarbonate filters of 200 nm pore size. Positive charge was induced in the liposomes by adding stearylamine and negative charge by adding dicetyl phosphate. Nonencapsulated drug was separated from LUVs by...

Glyburide (GLY) is an oral hypoglycemic agent that is poorly soluble in water. The present study describes the preparation of solid dispersions and lyophilization of the dispersions designed to increase the solubility. Solid dispersions of GLY were prepared using polyethylene glycol 4000 (PEG 4000), PEG 6000 and a mixture of PEG 4000 and PEG 6000 (h1 mixture). The effect of melt and solvent methods of preparation of solid dispersion on dissolution behavior was also investigated. Dissolution studies indicated a significant increase in dissolution of GLY when dispersed in PEGs. Physical mixtures containing PEGs also showed improved dissolution of GLY as compared with that of pure drug, indicating the solubilizing effect of PEGs. Solid dispersions containing GLY/PEG 6000, 1:8, showed a 14-fold increase in dissolution after 60 min (D60) and another dispersion containing GLY/PEG 4000, 1:10, showed an 8-fold increase in the phosphate buffer system. The dispersion containing six parts of the PEG mixture (PEG 4000/PEG 6000, 1:1 mixture) showed a 12-fold increase in D60 as compared with pure drug. When multi-carrier solid dispersion containing six parts of mixture was prepared by the solvent method, the D60 value was about 2-fold that of the same dispersion prepared by the melt method. The dissolution of lyophilized solid dispersions further increased the dissolution of GLY significantly.

rapid high-performance liquid chromatography (HPLC) method for the quantification of vancomycin in mouse plasma samples was developed and validated. Norvancomycin was used as the internal standard. Chromatographic separation was achieved on a Vydac C18 column (4.6×50 mm, 3 μm particle size) and the detection was made at 214 nm. A gradient elution was programmed with the mobile phases of 0.1% v/v trifluoroacetic acid (A) and 95:5 v/v acetonitrile: 0.1% TFA (B) and a flow rate of 1 ml/min. The total run time was 15 min. The calibration curve was linear over the range of 0.1-20 μg/ml, with a correlation coefficient (r) higher than 0.997 and the lower limit of quantitation (LLOQ) of 0.1 μg /ml. The intra-day accuracy values were between 90 and 112% and the inter-day ones ranged from 96 to 104%. Precision values ranged from 1.7 to 9.5% for intra-day and 6.3 to 9.4% for inter-day. Stability studies under normal laboratory conditions without significant loss of the drug. The assay was successfully applied to the pharmacokinetics and bio-distribution study of novel formulations of vancomycin in mice.

Liposomes bearing surface-attached antibody were prepared to study the retention of dideoxyinosine triphosphate (ddITP). Liposomes of various lipid composition were prepared and conjugated with modified mouse monoclonal antibodies. The antibody (H-2-K k ) used in this study is for Fc-mediated targeting. Antibody specificity was measured by studying the binding of antibody-liposome conjugates to antimouse IgG-Sepharose. The binding of antibody-liposome conjugates (L-Ab) was maximum when negatively charged liposomes (DMPC: CHOL: DCP) were employed. Inclusion of cholesterol to DMPC liposomes increased the binding by 4%. The binding was least when the neutral phospholipid compositions were employed (DMPC, DPPC and DMPC: CHOL) to prepare liposomes. The retention of ddITP was measured in plain liposomes and antibody-bearing liposomes stored at 4, 25 and 37°C. The leakage was maximal in DMPC liposomes. Only 20% of ddITP was retained in DMPC liposomes stored at 4°C after a month. However, when samples were stored at 25 and 37°C the retention was 12% and 4% respectively. There was no leakage of ddITP at 4 and 25°C in liposomes prepared using DMPC: CHOL (1:1 mole ratio) and DMPC: CHOL: DCP (7:2:1 mole ratio). The retention of ddITP was significantly increased in DMPC and DPPC liposomes after conjugation with antibodies. The retention of ddITP in DMPC: CHOL and DMPC: CHOL: DCP liposomes conjugated with antibodies was comparable to plain liposomes. These results suggest that the lipid composition used in the preparation of liposomes affect the conjugation of antibodies to liposomes and also the retention of an encapsulated drug.

A novel multilamellar vesicular delivery system was developed for the controlled release application. Multilamellar vesicles were prepared by thin film hydration and converted into proliposomes by freeze-drying. A model drug metoclopramide, a highly hydrophilic drug, was successfully encapsulated into proliposomes. The proliposomes produced were non-sticky, free-flowing powders. The proliposomes were formulated into a unit dosage form by combining with various excipients. The effect of different compositions such as type and concentration of phospholipid or hydrophilic polymer was investigared to optimize the formulation. The formation of multilamellar vesicles was confirmed by observing the process of hydration of proliposomes under an optical microscope. The spherical shape of vesicles was confirmed by transmission electron microscopy (TEM) and mean particle sizes were in the range of 1.3-2.5 microm, as measured by dynamic light scattering technique. Differential scanning calorimetry (DSC) study of formulations was conducted to understand the crystalline nature of drug in the vesicles. The results indicated a molecular level dispersion of drug into proliposomes with encapsulation efficiency up to 43%. Critical formulation parameters were identified to obtain a near zero order in vitro release pattern. Proliposomal formulations produced were suitable as multiparticulate drug delivery systems for the controlled release of a highly hydrophilic molecule.

The concept of using liposomes as carriers for the delivery of drugs is well established, and the liposomal incorporation of various molecules, including peptides and proteins, has been described. In this study, propranolol (PPL) and atenolol (ATL) were used as model drugs to measure the encapsulation efficiency and release characteristics from multilamellar (MLV) and small unilamellar (SUV) liposomes. MLVs were prepared by hydration of thin lipid films and agitation using PPL and ATL solutions in phosphate-buffered saline (pH 7.4). Unilamellar liposomes were prepared by sonicating these MLVs. The non-encapsulated drug was separated either by centrifugation (MLV) or by size exclusion chromatography (SUV). The encapsulation of ATL and PPL was higher in small unilamellar liposomes. The encapsulation of PPL was higher than ATL in multi- as well as in unilamellar liposomes. The rate of drug efflux from liposomes was determined in vitro at 37°C and pH 7.4. The maximum release of both ATL and PPL was found with DSPC MLVs and DMPC: CHOL: DCP SUVs. The liposomal encapsulation and release of drug molecules are governed by the lipophilicity of drug molecules, type of liposomes and lipid composition.

Indomethacin is a nonsteroidal anti-inflammatory agent and has a short half life, and causes gastric irritation. Sustained release beads of indomethacin were prepared and dissolution profiles were investigated. Beads were prepared by allowing drops of a suspension of the drug and excipients in a solution of cellulose acetate phthalate to drop into an acetic acid solution by means of a peristaltic pump. In a previous study1, sulfadiazine was used as a model drug to prepare beads by a similar method and the effects of various viscosity agents on the properties of these beads were assessed. Glycerin, polymers (Methocel and Avicel), and surfactants (Tween 80 and Span 80) were used as excipients. The incorporation of various viscosity agents and polymers into the suspension yielded beads with different disintegration and dissolution values. A high performance liquid chromatography method showed no indication of drug degradation during the preparation. The dissolution studies of the indomethacin prepara...

The aim of the present study was to develop proliposomal formulations to enhance the oral bioavailability of exemestane by improving solubility, dissolution and/or intestinal permeability. Proliposomal powder formulations were prepared using different ratios of drug (exemestane), distearoyl-phosphatidylcholine (DSPC), cholesterol and dimyristoyl-phosphatidylglycerol (DMPG) by solvent evaporation method. The effect of phospholipid composition and drug:lipid ratio on in vitro performance of proliposomes was studied. Proliposomes were characterized for their particle size distribution, thermal characteristics by differential scanning calorimetry (DSC) and dissolution behavior. Further, the formulated proliposomes were subjected to in vitro permeation or transport studies using different models such as rat intestine, parallel artificial membrane permeability assay (PAMPA) and Caco-2 cell line. Proliposomes provided enhanced exemestane dissolution due to incorporation into the phospholipid bilayers and change in the physical state from crystalline to amorphous. The in vitro transport studies in rat intestine, PAMPA and Caco-2 models revealed that the proliposomes were successful in enhancing the permeation of exemestane. These proliposomal formulations of exemestane could provide improved oral bioavailability due to enhanced solubility, permeability and hence absorption.

Proliposomal bead formulations for improved oral delivery of cromolyn (BCS Class III compound) were formulated. Phospholipid (distearylphosphatidylcholine)-cholesterol-surfactant (Tween 80/sodium cholate) systems were spray-coated on beads containing cromolyn sodium and the dosage forms were characterized for vesicle formation and encapsulation efficiency. Delivery of cromolyn sodium from this novel dosage form was evaluated across the Caco-2 and everted rat intestinal sac model. Spontaneous formation of vesicles upon dilution of beads was observed. Enhancement in cromolyn transport was higher with phospholipids-surfactant proliposomal formulations compared to surfactant-free lipid formulations or pure surfactant solutions, most significant enhancement being with formulations with low surfactant concentration. No evidence of cellular damage to Caco-2 monolayers (e.g. significant decrease in the TEER) or change in transport and tissue accumulation of a marker molecule in the intestinal tissue model was observed. This indicated enhancement of transport via transcellular routes and not due to the modulation of the tight junctions or cell disruption. Results suggest that phospholipids-surfactant proliposomal beads offer a good potential for improved oral delivery of cromolyn.

The aim of our study is to assess the release characteristics, in vitro permeation, and stability of an enteric-coated, bioadhesive, sustained-release formulation of didanosine (ddI). Enteric-coated tablets of ddI, containing Polyox WSRN-303 and Methocel K4M, were prepared using hydroxypropylmethylcellulose phthalate (HPMCP 5.5). The enteric-coated formulation was resistant to dissolution in 0.1 N HCl solution but dissolved within 10 min (+/-2 min) in pH 7.4 phosphate buffered saline. The release profiles were linear with square root time. Stability studies indicate that the formulations were stable at 4 degrees C, room temperature, and 40 degrees C upon storage for 6 months. Polyox WSRN-303 tablets exhibited a higher ddI permeation ratio across live intestinal tissue compared with conventional tablets. Enteric-coated, sustained-release, bioadhesive tablets deliver ddI in small doses and at the same time prevent acid-induced degradation and hence hold a potential to improve ddI's oral bioavailability.

The objective of our study was to formulate and evaluate proliposomes in the form of enteric-coated beads using glyburide as a model drug. The beads were enteric coated with Eudragit L-100 by a fluidized bed coating process using triethyl citrate as plasticizer. Content uniformity of glyburide was estimated using HPLC analysis of beads dissolved in methanol. These proliposomal beads formed liposomes on disintegration in phosphate buffered saline (pH 7.4), which was confirmed by transmission electron microscopy. The dissolution study of enteric-coated beads exhibited enhanced dissolution compared with pure drug and a marketed product. Liposomes can be successfully prepared for oral administration in the form of enteric-coated beads that may offer a stable system to produce liposomes for oral administration.

The severe toxicity and low therapeutic index of colchicine limit its therapeutic use. Encapsulation in liposomes might reduce these toxic effects. The objective of this study was to determine the factors influencing encapsulation of colchicine in liposomes and to optimize the encapsulation parameters. Colchicine was encapsulated in multilamellar liposomes and large unilamellar liposomes prepared using various phospholipids. The effects of method of preparation, type of vesicle, charge, and concentration of cholesterol on encapsulation of colchicine in liposomes were investigated. Also, stability of colchicine under stress conditions and at various temperatures, and in-vitro release characteristics were determined. A significant difference in encapsulation of colchicine in multilamellar liposomes was observed when prepared by two different methods. Induction of charge on the liposome surface increased encapsulation of colchicine in multilamellar liposomes, but did not affect large unilamellar liposomes. The liposome preparations could withstand simulated transport conditions and frequent changes in temperature. Particle size and concentration of colchicine did not change significantly during storage at various temperatures for six months. In order to retain encapsulated colchicine in liposomes, storage at or below room temperature was found to be suitable. In-vitro release of colchicine from large unilamellar liposomes was biphasic and was influenced by two rate-limiting barriers, the dialysis membrane and the liposome bi-layers. For optimum encapsulation and stability of colchicine liposomes were prepared from a mixture of 1,2-distearoyl-sn-glycero-3-phosphocholine, cholesterol and either stearylamine or dicetyl phosphate.

The purpose of this study was to compare the various methods available to separate non-encapsulated drug from large unilamellar liposomes (LUV). Multilamellar liposomes (MLV) were prepared by thin film hydration using distearoylphosphatidylcholine:cholesterol (2:1 molar ratio). MLVs were passed through a 0.2-μm polycarbonate membrane using an extruder to prepare LUVs. Particle size of liposome preparations was characterized using a submicron particle-size analyser. The non-encapsulated drug was separated by: filtering through Centrifree tubes; passing through gel (Sepharose-4B and Sephadex G-25M); passing through minicolumn; ficoll density gradient; protamine aggregation; or dialysis. The dialysis method was found to be unsuitable for separation of non-encapsulated drug due to equilibration of encapsulated drug as the free drug was dialyzed. The upper limit for lipid concentration was 5 mg mL−1 using the Centrifree method. Separation using gel chromatography led to dilution of liposome preparation. Minicolumn and density gradient techniques did not lead to sample dilution, however the minicolumn method was tedious. The time required for separation of liposomes by protamine aggregation was longer for neutral liposomes. Thus it was concluded that the Centrifree was the fastest method to estimate encapsulation; the density gradient method was ideal to separate non-encapsulated drug; and protamine aggregation was the least expensive method to estimate encapsulation efficiency.

Transdermal iontophoretic transport of a liposomal formulation of [Leu 5 ]enkephalin, across human cadaver skin, was investigated. Franz (vertical) cells were supplied with 0.5 mA/cm 2 current density via silver/ silver chloride electrodes from a Scepter power supply. Enkephalin spiked with [ 3 H]enkephalin was transported across skin from anode or cathode, depending on the charge on the molecule. Liposomes or their constituents were shown to penetrate into the skin. Enkephalin, when delivered iontophoretically at its isoelectric point, from liposomes carrying positive or negative charge on their surface, resulted in permeation of radioactivity which was same or less than that of the controls when analyzed by liquid scintillation counting. When analyzed by radiochromatograpy detector on HPLC, degradation of enkephalin during transport was observed, with several degradation peaks in the chromatogram. The degradation was less in liposome formulations, as compared to controls. This is the first report of the combined use of liposomes and iontophoresis for transdermal delivery.