Encapsulation Of Drugs In Liposomes Research Articles

Novel Topical Liposomal Gel of Benzoyl Peroxide And Resveratrol For Treatment Of Acne

Liposomal formulations have been used in the treatment of a number of dermatological diseases . Benzoyl peroxide is the drug of choiceused for the treatment of acne but suffers from side effects such as skin redness, irritation, itching, oedema and dryness. In this research work benzoyl peroxide was encapsulated into liposomes, alongwith herbal drug resveratrol for treatment of acne . Liposomes were prepared by thin film hydration technique and evaluated for pH , particle size , zeta potential , FT -IR, XRD and TEM etc. which indicated suitable encapsulation of drugs in liposomes. Liposomal gel was prepared using different polymers and evaluated for colour, pH, drug content, homogeneity and grittiness and in vitro release studies .Suitable penetration enhancers were added to the selected preparation . The final selected formulation was evaluated further for viscosity, spreadibility ,drug release, kinetic study and stability studies .Selected liposomal gel showed prolonged release of both drugs and the product was found to be stable .Ex-vivo diffusion studies and drug deposition studies on animals was performed. Skin irritation studies on animals did not show any irritation,dryness or redness.

Fluorescent Imaging Analysis for Distribution of Fluorescent Dye Labeled- or Encapsulated-Liposome in Monocrotaline-Induced Pulmonary Hypertension Model Rat.

Pulmonary hypertension (PH) is a life-threatening lung disease. Despite the availability of several approved drugs, the development of a new treatment method is needed because of poor prognosis. Tissue selective drug delivery systems can avoid the adverse effects of current therapy and enhance efficacy. We evaluated the possibility of delivering drugs to the lungs of a PH rat model using fluorescence dye-labeled nanosized liposomes. To evaluate the tissue distribution following systemic exposure, fluorescent dye-labeled, 40-180 nm liposomes with and without polyethylene glycol (PEG) were intravenously administered to a monocrotaline-induced PH (MCT) rat model and tissue fluorescence was measured. Fluorescent dye-containing liposomes were intratracheally administered to the MCT model to evaluate the distribution of the liposome-encapsulated compound following local administration to reduce systemic exposure. The lung vascular permeability, plasma concentration of surfactant protein (SP)-D, lung reactive oxygen species (ROS) production, and macrophage marker gene cluster of differentiation (CD68) expression were measured. PEG and 80-nm liposome accumulation in the lung was elevated in the MCT model compared to that in normal rats. The intratracheally administered liposomes were delivered selectively to the lungs of the MCT model. The lung vascular permeability, plasma SP-D concentration, and CD68 expression were significantly elevated in the lungs of the MCT model, and were all significantly and positively correlated to liposome lung accumulation. Liposomes can accumulate in the lungs of an MCT model by enhancing vascular permeability by the inflammatory response. Therefore, drug encapsulation in liposomes could be an effective method of drug delivery in patients with PH.

Evaluation of the physicochemical properties of liposomes as potential carriers of anticancer drugs: spectroscopic study

Vesicle size and composition are a critical parameter for determining the circulation half-life of liposomes. Size influences the degree of drug encapsulation in liposomes. The geometry, size, and properties of liposomes in an aqueous environment have to be described to enable potential applications of liposome systems as drug carriers. The characteristics of multiple thermotropic phase transitions are also an important consideration in liposomes used for analytical and bioanalytical purposes. The aim of this study was to evaluate the physicochemical properties of liposomes which accommodate hydrophilic and amphiphilic drugs used in cancer therapy. The studied liposomes were prepared with the involvement of the modified reverse-phase evaporation method (mREV). The prepared liposomes had a diameter of 70–150 nm. The analyzed compounds were 1-β-d-arabinofuranosylcytosine, cyclophosphamide, and ifosfamide. In literature, there is no information about simultaneous incorporation of cytarabine, ifosfamide, and cyclophosphamide, in spite of the fact that these drugs have been used for more than 30 years. A combination of the examined drugs is used in CODOX-M/IVAC therapy. CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) is one of the currently preferred intensive-dose chemotherapy regimens for Burkitt lymphoma (BL). The present research demonstrates the pioneering studies of incorporation of ifosfamide into liposome vesicles, location of and competition between the analyzed drugs and liposome vesicles. The applied methods were nuclear magnetic resonance (NMR), atomic force microscopy (AFM), differential scanning calorimetry (DSC). .

Impact of multicellular tumor spheroids as an invivo‑like tumor model on anticancer drug response.

The incidence of colorectal cancer is higher in men than in women, amounting to 15% of cancer-related diseases as a whole. As such, undesirable effects, arising from the administration of current chemotherapeutic agents (the FOLFIRI/FOLFOX combinations), which are exerted on the remaining non-cancerous tissues and/or cells, have contributed to the occurrence of resistance to multiple drugs, thus markedly reducing their efficacy. However, the delivery of chemotherapeutic agents may be improved and their action may be more selectively targeted to diseased tissues/cells by means of developing biotechnologies and nano-techniques. Thus, the current focus is on creating biological tissue and related tumor models, by means of three-dimensional (3D) spheres, in an attempt to bridge the gap between results obtained in the pre-clinical phase and promising outcomes obtained in clinical trials. For this purpose, the characterization and use of so-called ‘multicellular tumor spheroids’, may prove to be invaluable. In this study, we focus on describing the efficacy of a model 3D system as compared to the traditional 2D tumor spheres in determining drug response, highlighting a potentially greater effect of the drugs following the encapsulation of respective liposomes. The results obtained demonstrate the successful preparation of a suspension of liposomes loaded with folinic acid, oxaliplatin and 5-fluorouracil (5-FU), and loaded with meso-tetra (4-sulfonatophenyl) porphyrin. Following its use on HT-29 colorectal cancer cells, an important comparative reduction was noted in the viability of the HT-29 cells, demonstrating the efficacy of multicellular tumor spheroids carrying liposomes loaded with therapeutic drugs. These findings indicate that the method of drug encapsulation in liposomes may improve the treatment efficacy of chemotherapeutic agents.

Efficacy of liposomal gentamicin against Rhodococcus equi in a mouse infection model and colocalization with R. equi in equine alveolar macrophages

Rhodococcus equi, a facultative intracellular pathogen and an important cause of pneumonia in foals, is highly susceptible to killing by gentamicin in vitro. However, gentamicin is not effective in vivo, due to its poor cellular penetration. Encapsulation of drugs in liposomes enhances cellular uptake. The objectives of this study were to compare liposomal gentamicin and free gentamicin with respect to their uptake by equine macrophages and intracellular colocalization with R. equi and to compare the efficacies of liposomal gentamicin, free gentamicin and clarithromycin with rifampin for the reduction of R. equi CFU in a mouse model of infection. After ex vivo exposure, a significantly higher mean (±SD) percentage of equine alveolar macrophages contained liposomal gentamicin (91.9±7.6%) as opposed to free gentamicin (16.8±12.5%). Intracellular colocalization of drug and R. equi, as assessed by confocal microscopy, occurred in a significantly higher proportion of cells exposed to liposomal gentamicin (81.2±17.8%) compared to those exposed to free gentamicin (10.4±8.7%). The number of R. equi CFU in the spleen was significantly lower in mice treated with liposomal gentamicin compared to that of mice treated with free gentamicin or to untreated control mice. Treatment with liposomal gentamicin also resulted in a significantly greater reduction in the number of R. equi CFU in the liver compared to treatment with clarithromycin in combination with rifampin. These results support further investigation of liposomal gentamicin as a new treatment for infections caused by R. equi.

Constant Pressure-controlled Extrusion Method for the Preparation of Nano-sized Lipid Vesicles

Liposomes are artificially prepared vesicles consisting of natural and synthetic phospholipids that are widely used as a cell membrane mimicking platform to study protein-protein and protein-lipid interactions, monitor drug delivery, and encapsulation. Phospholipids naturally create curved lipid bilayers, distinguishing itself from a micelle. Liposomes are traditionally classified by size and number of bilayers, i.e. large unilamellar vesicles (LUVs), small unilamellar vesicles (SUVs) and multilamellar vesicles (MLVs). In particular, the preparation of homogeneous liposomes of various sizes is important for studying membrane curvature that plays a vital role in cell signaling, endo- and exocytosis, membrane fusion, and protein trafficking. Several groups analyze how proteins are used to modulate processes that involve membrane curvature and thus prepare liposomes of diameters <100 - 400 nm to study their behavior on cell functions. Others focus on liposome-drug encapsulation, studying liposomes as vehicles to carry and deliver a drug of interest. Drug encapsulation can be achieved as reported during liposome formation. Our extrusion step should not affect the encapsulated drug for two reasons, i.e. (1) drug encapsulation should be achieved prior to this step and liposomes should retain their natural biophysical stability, securely carrying the drug in the aqueous core. These research goals further suggest the need for an optimized method to design stable sub-micron lipid vesicles. Nonetheless, the current liposome preparation technologies (sonication, freeze-and-thaw, sedimentation) do not allow preparation of liposomes with highly curved surface (i.e. diameter <100 nm) with high consistency and efficiency, which limits the biophysical studies of an emerging field of membrane curvature sensing. Herein, we present a robust preparation method for a variety of biologically relevant liposomes. Manual extrusion using gas-tight syringes and polycarbonate membranes, is a common practice but heterogeneity is often observed when using pore sizes <100 nm due to due to variability of manual pressure applied. We employed a constant pressure-controlled extrusion apparatus to prepare synthetic liposomes whose diameters range between 30 and 400 nm. Dynamic light scattering (DLS), electron microscopy and nanoparticle tracking analysis (NTA) were used to quantify the liposome sizes as described in our protocol, with commercial polystyrene (PS) beads used as a calibration standard. A near linear correlation was observed between the employed pore sizes and the experimentally determined liposomes, indicating high fidelity of our pressure-controlled liposome preparation method. Further, we have shown that this lipid vesicle preparation method is generally applicable, independent of various liposome sizes. Lastly, we have also demonstrated in a time course study that these prepared liposomes were stable for up to 16 hours. A representative nano-sized liposome preparation protocol is demonstrated below.

Specific features of drug encapsulation in liposomes (A review)

Liposomes are hollow particles, the internal space of which is bounded by a lipid membrane. Liposomes are promising drug delivery systems for organs and tissues because of their colloidal properties, controlled size, surface characteristics, membrane action, and biocompatibility. Liposomal drugs have found wide use in the diagnosis and chemotherapy of cancer, vaccinology, ophthalmology, pulmonology, and the treatment of other pathologies. This review describes the methods of encapsulation of biologically active compounds with various physicochemical properties in liposomes, which is very important for the production of liposomal drugs.

Design of anti-bacterial drug and anti-mycobacterial drug for drug delivery system.

Liposome-encapsulated drugs often exhibit reduced toxicity and have also been shown to enhance retention of drugs in the tissues. Thus, encapsulation of drugs in liposomes has often resulted in an improved overall therapeutic efficacy. The results of efficacy of liposome-encapsulated ciplofloxacin or azithromycin for therapy of intracellular M. avium infection show enhanced cellular delivery of liposome-encapsulated antibiotics and suggest that efficiency of intracellular targeting is sufficient to mediate enhanced antimycobacterial effects. The antitubercular drugs encapsulated in lung specific stealth liposomes have enhanced efficacies against tuberculosis infection in mice. These results from stealth liposome study indicate that antitubercular drugs encapsulated in liposome may provide therapeutic advantages over the existing chemotherapeutic regimen for tuberculosis. Liposomes with encapsulated amikacin are able to protect collagen almost completely from adherence of bacterial cells of all strains examined and prevent from invading of bacteria.

Topical Liposomal Gel of Tretinoin for the Treatment of Acne: Research and Clinical Implications

An attempt was made to pharmaceutically develop a topical liposomal tretinoin (TRE) gel and clinically evaluate the developed formulation for the treatment of acne in patients. Liposomes of TRE were prepared using the lipid film hydration technique and the entrapment efficiency of TRE in liposomes was optimized to 79.96%. The drug retention in liposomes and in liposomal TRE gel (Carbopol 934 gel base) studied at three storage conditions indicated maximum drug retention at refrigeration temperature. For liposomal TRE gel, reduced drug leakage was observed as compared to that of liposomes at all three storage conditions. Diffusion studies of plain TRE gel and liposomal TRE gel suggested prolongation (3.4 times reduction in flux value) of drug diffusion and almost two- fold increase in skin drug retention after liposomal encapsulation of drug. A comparative double-blind clinical study of the developed liposomal TRE gel, carried out on 30 acne patients over a period of 3 months, demonstrated significant enhancement (about 1.5-fold) in drug efficacy. More remarkable improvement was observed in the treatment of comedones, where the mean percent reduction in lesions increased from 62.36% for plain TRE gel to 94.17% for liposomal TRE gel. Erythema and irritation associated with the use of plain TRE gel was reduced considerably with the use of liposomal TRE gel. The findings of this investigation therefore underscore potential utility of commercialization of liposomal TRE gel in the treatment of acne.

Materials Engineering of Lipid Bilayers for Drug Carrier Performance

The liquid-phase lipid bilayer is a unique engineering material. Biologically, it holds a central position in cellular life, providing the structural basis for the membrane that surrounds every cell on the planet. From a materials perspective, it is essentially a 4-nm-thick, water-insoluble sheet of 2-poise oil. Artificial membranes were “discovered” 35 years ago. It was soon recognized that liposomes could have a range of potential uses, and investigators sought to exploit the obvious capsular and biocompatibility properties of the membrane in applications such as liposome drug delivery. Since 1966, some 18,000 papers on liposomes have appeared in the literature (listed on Medline, and see References 4–7 for reviews), and 260 patents have been issued describing the use of liposomes in the pharmaceutical industry. These patented applications have included the delivery of cancer drugs, intracellular drug delivery, inhalation, topical drugs, gene therapy, proteins, peptides, amino acids, vaccines, targeted liposomes, lipophilic drugs, and liposome production, separation, and analysis. A huge database therefore exists with which to establish boundary conditions for predicting under which circumstances the encapsulation of drugs in liposomes or other carriers may be expected to result in improved therapy. Despite this enormous effort, only a few formulations, principally for amphotericin (an antifungal drug) and anthra-cyclins (anticancer drugs), have been approved and marketed, heralding the promise and potential that these versatile lipid-bilayer materials present. The reasons for this limited success are many, not the least of which is that the cost of developing a new pharmaceutical product can be several hundred million dollars.

Liposomal formulations of ABT-077: In vitro characterization studies

ABT-077 (zileuton) is an active 5-lipoxygenase inhibitor with potential for the treatment of asthma and rheumatoid arthritis. It is rapidly eliminated after local administration to the lungs. Hence, various liposomal formulations of this compound were tested in vitro for potential modulated release in vivo. Fourteen ABT-077 compositions were screened for distribution coefficients ( K) between lipid and aqueous buffer (0.05 M phosphate, pH 6.5). With lipids consisting of 20–50% w/w cholesterol (CHL) in egg phosphatidylcholine (PC), log K of approximately 2.15 and drug loadings of approximately 6 μg/mg were obtained. When the lipid film was washed with aqueous buffer, 60–80% of the originally loaded drug was retained. Thereafter, a 3 3 factorial study was conducted to investigate the effect of lipid composition (9, 35 or 50% w/w CHL in PC), drug level (1, 13 or 25% w/w of total lipid) and extent of dilution (0, 1:25 and 1:100 fold) on drug encapsulation in liposomes. The log K values ranged between 2.2 and 3.2, and drug loadings ranged between 6 and 230 #g/mg lipid. With diluted samples, estimated drug loadings ranged between 1 and 45 μg/mg lipid. Overall, the data suggests that encapsulation of ABT-077 may enable modulated drug release kinetics in vivo.

New Ophthalmic Drug Delivery Systems

AbstractOne of the ways to optimize ocular drug delivery is to prolonge precorneal drug residence time. This review focusses on recent findings on the formulation effects in ocular drug bioavailability, employing polymers for the preparation of hydrogels, bioadhesive dosage forms, in situ gelling systems and colloidal systems including liposomes and nanoparticles. The results observed suggested that mucoadhesion or bioadhesion played a role in the sustained action of drugs more significantly compared to non-mucoadhesive polymers. Encapsulation of drugs in liposomes and nanoparticles was correlated to an increase of the drug concentration in the ocular tissues. However, all the results described suggest that the physico-chemical properties of the encapsulated drug have a significant influence on the effect with the carrier. The results suggest also that the superficial charge, the binding type of the drug onto the nanoparticles and the nature of the polymer were the most important factors regarding the imp...

Inhibition of liver metastases of M 5076 tumor by liposome-entrapped adriamycin.

The toxicity and therapeutic efficacy of free adriamycin (AM) and AM entrapped in standardized liposomes (AM-MLV) were evaluated in normal mice and in mice bearing M 5076 murine tumor, which metastasizes to the liver after i.v. and s.c. transplants of tumor cell suspensions. Acute and chronic toxicity to AM could be reduced by drug encapsulation in liposomes. The data indicated that at approximately equitoxic doses of free AM (10 mg/kg) and AM-MLV (greater than 20 mg/kg), the increase in survival times of mice transplanted i.v. with tumor cells were 25% and 100%, respectively. Furthermore, only in the AM-MLV-treated mice were long-term survivors observed. In contrast AM-MLV were equally effective as free AM in mice transplanted s.c. with tumor cell suspensions. AM-MLV, however, were more effective than free AM against liver metastases in mice bearing s.c. tumor, indicating differential antitumor activities against the same tumor type growing at different locations in the same animals.