Deformable liposomes containing alkylcarbonates of γ-cyclodextrins for dermal applications

Liposomes made with hydrogenated soya lecithin (HPC) mixed with dodecylcarbonate γ-cyclodextrin (C12CD) at 20:1, 10:1 and 5:1 w/w ratios were prepared by the solvent evaporation method. C12CD had emulsifying properties and the possibility of producing deformable liposomes, as topical delivery system of progesterone (PG), was evaluated. Liposome size, deformability and drug entrapment were determined and the interaction between C12CD and HPC was investigated using differential scanning calorimetry (DSC). The size and the amount of PG loaded in the liposomes depended on the lipid:C12CD ratio: the smallest liposomes were obtained using 20:1 ratio and the maximum drug entrapment at 5:1 ratio. DSC analysis suggested that C12CD interacted with liposomes disrupting and fluidizing the lipid bilayer. PG transepidermal permeation through intact pig skin and PG skin uptake from deformable liposomes were assessed and compared to the values obtained from aqueous suspension and conventional liposomes. The PG permeations were negligible for all systems, while skin uptake increased for liposomes containing C12CD. This was attributed to the deformability and to the increase in the drug entrapment efficiency of these liposomes. The use of C12CD in liposome formulations can improve PG topical therapy.     

Mechanisms of Penetration Enhancement and Transport Utilizing Skin Keratine Liposomes for the Topical Delivery of Licochalcone A

Keratin liposomes have emerged as a useful topical drug delivery system given theirenhanced ability to penetrate the skin, making them ideal as topical drug vehicles. However, the mechanisms of the drug penetration enhancement of keratin liposomes have not been clearly elucidated. Therefore, licochalcone A(LA)-loaded skin keratin liposomes (LALs) were prepared to investigate their mechanisms of penetration enhancement on the skin and inB16F10 cells. Skin deposition studies, differential scanning calorimetry (DSC), attenuated total reflection-Fourier Transform Infrared Spectroscopy (ATR-FTIR), and skin distribution and intracellular distribution studies were carried out to demonstrate the drug enhancement mechanisms of LALs. We found that the optimal application of LALs enhanced drug permeation via alterations in the components, structure, and thermodynamic properties of the stratum corneum (SC), that is, by enhancing the lipid fluidization, altering the skin keratin, and changing the thermodynamic properties of the SC. Moreover, hair follicles were the main penetration pathways for the LA delivery, which occurred in a time-dependent manner. In the B16F10 cells, the skin keratin liposomes effectively delivered LA into the cytoplasm without cytotoxicity. Thus, LAL nanoparticles are promising topical drug delivery systems for pharmaceutical and cosmetic applications.     

Nonionic Surfactant Vesicles as a Carrier for Transdermal Delivery of Frusemide

The aim of the present study was to formulate and evaluate the nonionic surfactant vesicles of frusemide in order to enhance its skin permeation. The process variables which could affect the preparation and properties of the niosome formulation studied included type of spans, ratio of span and cholesterol, ratio of cholesterol and dicetylphosphate (DCP), concentration of drug, type of solvent, hydration media and time of hydration. The formulated niosomes thus were characterized for various parameters such as surface morphology, size, entrapment efficiency, skin permeation, etc. Stability of the niosomes in terms of drug holding capacity was assessed for a period of 30 days on storage under defined conditions. The maximum entrapment efficiency of 77.73±2.36% was obtained with niosomes formulated from Span 60∶Cholesterol∶DCP (47.5∶47.5∶5) using chloroform:methanol (4∶1) as the solvent system at the hydration time of 1 hr. A direct relationship was observed between the percentage leaching of the drug out of the vesicles and temperature. Higher transdermal flux was obtained with niosomal gel (9.2±0.5 μg/cm²/hour) in comparison to conventional gel (6.4±0.3 μg/cm²/hour).     

Characterization and Bioavailability of Vitamin C Nanoliposomes Prepared by Film Evaporation-Dynamic High Pressure Microfluidization

Vitamin C nanoliposomes were prepared by combining a conventional method (film evaporation) with dynamic high pressure microfluidization. Their physicochemical characterizations (antioxidant activity, particle size, entrapment efficiency, morphology, in vitro drug release, and storage stability) and skin permeation behavior were investigated. The results showed that vitamin C nanoliposomes, having equivalent DPPH (2, 2-diphenyl-1-picrylhydrazyl) free radical scavenging capacity of pure vitamin C solution without loss of their biological activity, exhibited better storage stability at 37°C for 24 hours and at 4°C for 60 days, a more excellent sustained drug release as well as higher skin penetration rate than vitamin C liposomes.     

Niosomes from alpha,omega-trioxyethylene-bis(sodium 2-dodecyloxy-propylenesulfonate): preparation and characterization

The synthesis and characterisation of new surfactants with peculiar physical-chemical properties are amongst the most promising and expanding issues in pharmacological colloid science. The most used vesicular carriers are liposomes prepared from a wide variety of natural and synthetic phospholipids, but several ionic and non-ionic amphiphiles have been used to form multilamellar and/or unilamellar vesicles. In the present study the synthesis of alpha,omega-trioxyethylene-bis(sodium 2-dodecyloxy-propylenesulfonate), an anionic Gemini surfactant, and its ability to form niosomes are elucidated. The compound forms vesicles with and without added cholesterol. The vesicular systems were characterized by size, shape and drug entrapment efficiency. The compounds to be incorporated are beta-carotene and ferulic acid, as antioxidants, acetyl salicylic acid, as FANS, and the antineoplastic 5-flurouracil, widely used in dermatological disorders. The results of this study show that alpha,omega-trioxyethylene-bis(sodium 2-dodecyloxy-propylenesulfonate) can be used for the preparation of niosomes entrapping lypophilic, amphiphilic or hydrophilic substances. These niosomes may be promising candidates as percutaneous carriers for the aforementioned drugs.     

Influence of Liposome Type and Skin Model on Skin Permeation and Accumulation Properties of Genistein

This article investigates the impact of elastic liposomes on enhancing the skin delivery of genistein and the influences of skin tissues with or without hair follicles on permeation and accumulation properties of genistein from liposomal suspensions. The greater permeation rate and deposition values of genistein were observed from the elastic liposomes than conventional liposomes in haired skin. When measured with hairless skin, the flux and skin deposition values of genistein in elastic liposomes were significantly decreased compared to conventional liposomes, indicating that the percutaneous delivery of elastic liposomes was considerably influenced by existence of hair follicles in the skin tissue.     

Evaluation of compatibility of itraconazole with excipients used to develop vesicular colloidal carriers

Liposomes and niosomes are known to be efficient vehicles for localized and systemic delivery of particularly lipophilic drugs resulting in their improved bioavailability, targeted delivery, and fewer side effects. These systems consist of bilayered membrane structures comprising amphiphilic molecules like phosphatidylcholine (liposomes) and nonionic surfactants (niosomes). Itraconazole (ITZ) is a widely used insoluble antifungal agent, which is known to be poorly absorbed from available marketed dosage forms. For countering the bioavailability related problem of oral ITZ products, vesicular systems like liposomes and niosomes could provide a rational approach. Drug–excipient interaction is being considered as an essential first step in development of any drug delivery system nowadays. Therefore, the present work describes the evaluation of drug–excipient interactions of ITZ with selected excipients used for development of liposomes and niosomes. Analytical techniques like differential scanning calorimetry, Fourier transform infrared spectroscopy, optical microcopy, and X-ray powder diffraction analysis were utilized for assessing the drug–excipient interactions. Isothermal stress testing was also performed to quantitatively measure the percent change in initial drug content from ITZ–excipient blends kept under stress conditions. The excipients included phospholipids (Phospholipon 90G^®, Phospholipon 90H^®), surfactants (Span 40 and Span 60), vesicular membrane stabilizer (cholesterol), and a solubilizer (3-hydroxypropyl-betacyclodextrin).     

Preparation of curcumin-loaded liposomes and evaluation of their skin permeation and pharmacodynamics

This study aimed to investigate the in vitro skin permeation and in vivo antineoplastic effect of curcumin by using liposomes as the transdermal drug-delivery system. Soybean phospholipids (SPC), egg yolk phospholipids (EPC), and hydrogenated soybean phospholipids (HSPC) were selected for the preparation of different kinds of phospholipids composed of curcumin-loaded liposomes: C-SPC-L (curcumin-loaded SPC liposomes), C-EPC-L (curcumin-loaded EPC liposomes), and C-HSPC-L (curcumin-loaded HSPC liposomes). The physical properties of different lipsomes were investigated as follows: photon correlation spectroscopy revealed that the average particle sizes of the three types of curcumin-loaded liposomes were 82.37 ± 2.19 nm (C-SPC-L), 83.13 ± 4.89 nm (C-EPC-L), and 92.42 ± 4.56 nm (C-HSPC-L), respectively. The encapsulation efficiency values were found to be 82.32 ± 3.91%, 81.59 ± 2.38%, and 80.77 ± 4.12%, respectively. An in vitro skin penetration study indicated that C-SPC-L most significantly promoted drug permeation and deposition followed by C-EPC-L, C-HSPC-L, and curcumin solution. Moreover, C-SPC-L displayed the greatest ability of all loaded liposomes to inhibit the growth of B16BL6 melanoma cells. Therefore, the C-SPC-L were chosen for further pharmacodynamic evaluation. A significant effect on antimelanoma activity was observed with C-SPC-L, as compared to treatment with curcumin solution in vivo. These results suggest that C-SPC-L would be a promising transdermal carrier for curcumin in cancer treatment.     

Release studies on niosomes containing fatty alcohols as bilayer stabilizers instead of cholesterol

Monomers of some amphiphiles organize into bilayers to form liposomes and niosomes. Such bilayers are unstable or leaky and hence cholesterol is a common ingredient included to stabilize them. Cholesterol stabilizes bilayers, prevents leakiness, and retards permeation of solutes enclosed in the aqueous core of these vesicles. Other than cholesterol a material with good bilayer-stabilizing properties is yet to be identified. We have substituted cholesterol with fatty alcohols in niosomes containing polyglyceryl-3-di-isostearate (PGDS) and polysorbate-80 (PS-80) to explore their membrane-stabilizing property via permeation studies. Niosomes of polyglyceryl-3-di-isostearate, fatty alcohol/cholesterol, and polysorbate were prepared by ether injection method. Aqueous solution of ketorolac tromethamine (KT) was entrapped in them. The effects of alkyl chain length of fatty alcohols (C(12), C(14), C(16), C(18), and C(16+18)), of acyl chain length of polyoxyethylene sorbitan monoester surfactants, and of the molar ratio of lipid mixture on the release rate of ketorolac from niosomes were assessed by employing modified dissolution-dialysis method. Niosomes with cholesterol or fatty alcohols have exhibited a common release pattern. Niosomes containing fatty alcohol showed a considerably slower release rate of KT than those containing cholesterol. Based on the release rate, fatty alcohols can be ranked as stearyl相似文献   

Hyaluronic Acid Derivative Effect on Niosomal Coating and Interaction with Cellular Mimetic Membranes

Hyaluronic acid (HA) is one of the most used biopolymers in the development of drug delivery systems, due to its biocompatibility, biodegradability, non-immunogenicity and intrinsic-targeting properties. HA specifically binds to CD44; this property combined to the EPR effect could provide an option for reinforced active tumor targeting by nanocarriers, improving drug uptake by the cancer cells via the HA-CD44 receptor-mediated endocytosis pathway. Moreover, HA can be easily chemically modified to tailor its physico-chemical properties in view of specific applications. The derivatization with cholesterol confers to HA an amphiphilic character, and then the ability of anchoring to niosomes. HA-Chol was then used to coat Span^® or Tween^® niosomes providing them with an intrinsic targeting shell. The nanocarrier physico-chemical properties were analyzed in terms of hydrodynamic diameter, ζ-potential, and bilayer structural features to evaluate the difference between naked and HA-coated niosomes. Niosomes stability was evaluated over time and in bovine serum. Moreover, interaction properties of HA-coated nanovesicles with model membranes, namely liposomes, were studied, to obtain insights on their interaction behavior with biological membranes in future experiments. The obtained coated systems showed good chemical physical features and represent a good opportunity to carry out active targeting strategies.     

Fabrication and Evaluation of Voriconazole Loaded Transethosomal Gel for Enhanced Antifungal and Antileishmanial Activity

Voriconazole (VRC) is a broad-spectrum antifungal agent belonging to BCS class II (biopharmaceutical classification system). Despite many efforts to enhance its solubility, this primary issue still remains challenging for formulation scientists. Transethosomes (TELs) are one of the potential innovative nano-carriers for improving the solubility and permeation of poorly soluble and permeable drugs. We herein report voriconazole-loaded transethosomes (VRCT) fabricated by the cold method and followed by their incorporation into carbopol 940 as a gel. The prepared VRCT were evaluated for % yield, % entrapment efficiency (EE), surface morphology, possible chemical interaction, particle size, zeta potential, and polydispersity index (PDI). The optimized formulation had a particle size of 228.2 nm, a zeta potential of −26.5 mV, and a PDI of 0.45 with enhanced % EE. Rheology, spreadability, extrudability, in vitro release, skin permeation, molecular docking, antifungal, and antileishmanial activity were also assessed for VRCT and VRC loaded transethosomal gel (VTEG). Ex-vivo permeation using rat skin depicted a transdermal flux of 22.8 µg/cm²/h with enhanced efficiency up to 4-fold. A two-fold reduction in inhibitory as well as fungicidal concentration was observed against various fungal strains by VRCT and VTEG besides similar results against L-donovani. The development of transethosomal formulation can serve as an efficient drug delivery system through a topical route with enhanced efficacy and better patient compliance.     

Quantitative investigation, stability and in vitro release studies of anti-TB drugs in Triton niosomes

The highly stable innocuous niosomes composed of four components (Triton X 100, polyethylene glycol 2000, water, Span 80) have been prepared successfully and characterized using particle size analyzer, transmission and scanning electron microscopy. The mean size has been found to be in the range 200-300 nm. The optimization of niosomes has been carried out using fluorescence spectroscopy. An attempt has been made to incorporate anti-tuberculosis drugs (ATD's) in the prepared niosomes. The stability and encapsulation efficiency of these drugs in the niosome have also been assessed and high encapsulation efficiency is observed. Such high encapsulation efficiency will serve as an advantage to solve the problem of multi-drug resistance in case of tuberculosis. Release studies and kinetics have been carried out to investigate the release behavior of drugs from the prepared niosomes. Fickian or diffusional release has been observed for rifampicin and isoniazid and a non-Fickian release mechanism for pyrazinamide. Fluorescence probe quenching technique has been used to determine the location and distribution coefficient of the ATD's in niosome/water system.     

Formulation and Characterization of Chitosan-Decorated Multiple Nanoemulsion for Topical Delivery In Vitro and Ex Vivo

In the present study, chitosan-decorated multiple nanoemulsion (MNE) was formulated using a two-step emulsification process. The formulated multiple nanoemuslion was evaluated physiochemically for its size and zeta potential, surface morphology, creaming and cracking, viscosity and pH. A Franz diffusion cell apparatus was used to carry out in vitro drug-release and permeation studies. The formulated nanoemulsion showed uniform droplet size and zeta potential. The pH and viscosity of the formulated emulsion were in the range of and suitable for topical delivery. The drug contents of the simple nanoemulsion (SNE), the chitosan-decorated nanoemulsion (CNE) and the MNE were 71 ± 2%, 82 ± 2% and 90 ± 2%, respectively. The formulated MNE showed controlled release of itraconazole as compared with that of the SNE and CNE. This was attributed to the chitosan decoration as well as to formulating multiple emulsions. The significant permeation and skin drug retention profile of the MNE were attributed to using the surfactants tween 80 and span 20 and the co-surfactant PEG 400. ATR-FTIR analysis confirmed that the MNE mainly affects the lipids and proteins of the skin, particularly the stratum corneum, which results in significantly higher permeation and retention of the drug. It was concluded that the proposed MNE formulation delivers drug to the target site of the skin and can be therapeutically used for various cutaneous fungal infections.     

Improved skin delivery and validation of novel stability-indicating HPLC method for ketoprofen nanoemulsion

Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) widely used to treat rheumatoid arthritis and other inflammatory diseases. Normally used by oral route, this drug presents numerous side effects related to this administration route, such as nausea, dyspepsia, diarrhea, constipation and even renal complications. To avoid that, topical administration of ketoprofen represents a good alternative, since this drug has both partition coefficient and aqueous solubility suitable for skin application, compared to other NSAIDs. In this study, we describe the production of a nanoemulsion containing ketoprofen, its skin permeation and in vitro release study and a novel validation method to analyze this drug in the permeation samples and a forced degradation study using skin and nanoemulsion samples. The new HPLC method was validated, with all specifications in accordance with validation parameters and with an easy chromatographic condition. Forced degradation study revealed that ketoprofen is sensitive to acid and basic hydrolysis, developing degradation peaks after exposure to these factors. Concerning in vitro release from the nanoemulsion, release curves presented first order profile and were not similar to each other. After 8 h, 85% of ketoprofen was release from the nanoemulsion matrix while 49% was release from control group. In skin permeation study, nanoemulsion enabled ketoprofen to pass through the skin and enhanced retention in the epidermis and stratum corneum, layer on which the formulation presented statistically different values compared to the control group.     

Submicron Size Formulation of Linseed Oil Containing Omega-3 Fatty Acid for Topical Delivery

The aim of the present study was to design and develop topical submicron size gel formulation of linseed oil with enhanced permeation through the skin for the management of psoriasis. Linseed oil contains significant amount of α-linolenic acid (ALA) an omega-3 fatty acid, which is responsible for its pharmacological actions. In order to enhance permeation through skin, microemulsion based gel formulation was prepared and characterized. Microemulsions were prepared by aqueous phase titration method, using linseed oil, Unitop 100, PEG 400, and distilled water as the oil phase, surfactant, cosurfactant and aqueous phase, respectively. Selected formulations were subjected to physical stability studies and consequently in vitro skin permeation studies. Surface morphology studies of optimized formulation were done by transmission electron microscopy (TEM). The droplet size of microemulsions ranged from 70 to 500 nm with average particle size 186 nm. The optimized microemulsion was converted into hydrogel using carbopol 971 which had a viscosity of 498 ± 0.04 cps. During in vitro permeation study the flux of microemulsion formulation and gel was found to be 19.05 and 10.2 µg/cm²/hr, respectively, which indicated better penetration of linseed oil through the skin. These result indicated that the developed ME formulation may be a good approach for topical therapy for the management of psoriasis.     

Formulation of Piperine–Chitosan-Coated Liposomes: Characterization and In Vitro Cytotoxic Evaluation

The present research work is designed to prepare and evaluate piperine liposomes and piperine–chitosan-coated liposomes for oral delivery. Piperine (PPN) is a water-insoluble bioactive compound used for different diseases. The prepared formulations were evaluated for physicochemical study, mucoadhesive study, permeation study and in vitro cytotoxic study using the MCF7 breast cancer cell line. Piperine-loaded liposomes (PLF) were prepared by the thin-film evaporation method. The selected liposomes were coated with chitosan (PLFC) by electrostatic deposition to enhance the mucoadhesive property and in vitro therapeutic efficacy. Based on the findings of the study, the prepared PPN liposomes (PLF3) and chitosan coated PPN liposomes (PLF3C1) showed a nanometric size range of 165.7 ± 7.4 to 243.4 ± 7.5, a narrow polydispersity index (>0.3) and zeta potential (−7.1 to 29.8 mV). The average encapsulation efficiency was found to be between 60 and 80% for all prepared formulations. The drug release and permeation study profile showed biphasic release behavior and enhanced PPN permeation. The in vitro antioxidant study results showed a comparable antioxidant activity with pure PPN. The anticancer study depicted that the cell viability assay of tested PLF3C2 has significantly (p < 0.001)) reduced the IC₅₀ when compared with pure PPN. The study revealed that oral chitosan-coated liposomes are a promising delivery system for the PPN and can increase the therapeutic efficacy against the breast cancer cell line.     

Formulation and molecular docking simulation study of luliconazole nanosuspension–based nanogel for transdermal drug delivery using modified polymer

The purpose of study was to formulate nanosuspension-based nanogel of luliconazole (LLZ) for transdermal delivery to enhance its skin retention and effectiveness using modified starch ester. Nanosuspensions show promising results with size of 369.1–745.4 nm having PDI 0.193–0.344 and zeta potential 22–45 mV. These nanosuspensions form micelles and hydrophobic core of it provides the reservoir for LLZ with better drug loading and binding interaction. Drug loading was confirmed by percent drug entrapment efficiency (PDEE) and PDI. Molecular docking simulation (MDS) provides detail insight of LLZ polymer complexation at hydrophobic cavity of micelles and revealed that there was binding between drug and polymer in aqueous milieu having interaction energy ranges from ?7.1 to ?6.0 kcal/mol. Nanosuspensions so made were incorporated into gel by using Carbopol 934 ® and tested for % drug content, spreadability, pH, and viscosity with ranges of 101.62–97.71, 28.94–34.38 (gcm/s), 6.91–7.21, and 4802.62–9461.83 (cp), respectively. Nanogel also evaluated for stability and skin permeation study using human cadaver skin (HCS). In vitro skin permeation study indicated that the amount of LLZ permeated through skin from nanogel (71.042–83.818 μgcm ?2) was higher than standard cream (70.085 μgcm ?2). Nanogel increased the accumulation of LLZ in HCS ~3 times than standard cream. The transdermal flux was greater for standard cream (123.79 μgcm ?2), whereas smaller for nanogel (50.394–82.743 μgcm ?2) due to skin retention. Nanosuspension-based gel are able to especially favor LLZ accumulation into skin, provide better drug loading, improve stability, and efficacy. Thus, targeting older antibiotics such as LLZ and formulating into nanosystem utilized to expand its usefulness to physicians to treat illnesses caused by resistant fungal strains.     

Preparation of a highly stable niosome and its hydrotrope-solubilization action to drugs

Highly stable niosomes are prepared and investigated in Tween80/PEG6000/Span80/H2O system. The mean radius of the niosomes is 0.15-0.2 microm. The contents of PEG6000 and Span80 and the system temperature affect the size and the stability of the niosome. A certain Span80 can remarkably improve the stability. The niosome is provided distinctly with the hydrotrope-solubilization action to the hydrophilic drug and hydrophobic drug, which affects the niosome membrane. The mechanism of the effects of PEG6000 and Span80 on the niosome is discussed in this paper.     

Uptake of amitriptyline and nortriptyline with liposomes, proteins, and serum: implications for drug detoxification

Liposomes composed of DOPG and DMPC were studied for their ability to sequester amitriptyline and nortriptyline under physiological conditions. The liposomes reduced the free drug concentration in protein mixtures and in human serum, but the drug uptake efficiency of liposomes was reduced in the presence of plasma proteins, perhaps due to adsorption of proteins on the liposomes. The reduction was significantly more for the pure DOPG liposomes. The 50:50 DMPC:DOPG liposomes (0.72 mg lipid/mL) reduced the free amitriptyline concentration by 50-60% in the presence of 7% proteins (4% albumin (w/w), 2% fibrinogen (w/w), 1% globulins (w/w)). In human serum, the free drug reduction was 35-70% with the same 50:50 liposomes (0.72 mg lipid/mL). The liposomal systems were equally efficient at sequestering nortriptyline, which is a major metabolite of amitriptyline. The drug binding to liposomes in the presence of serum proteins is also quick and reversible and the likely mechanism of drug sequestration is adsorption of drug on the surface of liposomes. Accordingly, the drug uptake increases with increased charge and lipid loading. Even though the serum proteins reduced the effectiveness of the liposomes at sequestering the drug, the 50:50 DMPC:DOPG liposomes may be effective at treating amitriptyline overdose patients.