Vesicular Phospholipid Gels Research Articles

Vesicular phospholipid gels: A new strategy to improve topical antimicrobial dermatotherapy

Therapeutically effective and biocompatible dermal formulations that can ensure localization of a high level of antimicrobial drug at the site of action for an appropriate duration, while at the same time providing intrinsic reepithelization properties, are of particular importance for the treatment of infected and injured skin. The current research aimed to explore the potentials of using vesicular phospholipid gels (VPGs), semisolid formulations consisting of tightly packed liposomes (100–––200 nm), as innovative local depot drug vehicles for advanced topical dermatotherapy. Ciprofloxacin hydrocholoride (CPX) was selected as a model hydrophilic antibacterial drug and was loaded into several VPGs, differing in their composition. Various CPX-loaded VPGs (CPX-VPGs) were evaluated in vitro for the rheological and physicochemical characteristics, drug release profile, stability under in vivo mimicked conditions and during storage, skin permeability, biocompatibility with the epidermal cells, antibacterial efficacy and wound healing assay, to determine the optimal CPX-VPG for topical dermatotherapy. Viscosity and bilayers fluidity of VPGs affected the release of CPX from CPX-VPGs and its skin localization, limiting CPX percutaneous absorption. All CPX-VPGs exhibited even a 2-fold increase in anti-biofilm activity against both Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) clinical isolate compared to the free drug, while showing no toxic effects on human keratinocytes in vitro. Based on the pronounced proliferative effects on keratinocytes, superior in vitro wound healing effect and drug localization on/inside the skin, CPX-VPGs containing chitosan and hydrogenated phospholipid proved to be the most promising for topical dermatotherapy. These findings, along with increased bioadhesiveness and the slow drug release, with CPX concentrations significantly above the minimum biofilm inhibitory concentrations for bacteria typical in infected wounds, would contribute not only to the improvement of the antimicrobial dermatotherapy, but also to reduction of the frequency of the drug administration.

A new long-acting analgesic formulation for postoperative pain management

Local anesthetics (LA), as part of multimodal analgesia, have garnered significant interest for their role in delaying the initiation of opioid therapy, reducing postoperative opioid usage, and mitigating both hospitalization duration and related expenses. Despite numerous endeavors to extend the duration of local anesthetic effects, achieving truly satisfactory long-acting analgesia remains elusive. Drawing upon prior investigations, vesicular phospholipid gels (VPGs) emerge as promising candidates for extended-release modalities in small-molecule drug delivery systems. Therefore, we tried to use the amphiphilicity of phospholipids to co-encapsulate levobupivacaine hydrochloride and meloxicam, two drugs with different hydrophilicity, to obtain a long-term synergistic analgesic effect. Initially, the physicochemical attributes of the formulation were characterized, followed by an examination of its in vitro release kinetics, substantiating the viability of extending the release duration of the dual drugs. Sequentially, in vivo investigations encompassing pharmacokinetic profiling and assessment of analgesic efficacy were undertaken, revealing a prolonged release duration of up to 120 h and attainment of optimal postoperative analgesia. Subsequently, inquiries into the mechanism underlying synergistic analgesic effects and safety evaluations pertinent to the delivery strategy were pursued. In summation, we successfully developed a promising formulation to achieve long-acting analgesia.

Functionalized and Theranostic Lipidic and Tocosomal Drug Delivery Systems: Potentials and Limitations in Cancer Photodynamic Therapy.

Photodynamic therapy (PDT) is a multidisciplinary area, which involves photophysics and photochemical sciences and plays an important role in cancer diagnosis and treatment. PDT involves a photo-activable drug called photosensitizer (PS), a specific wavelength of light and cellular compounds to produce toxic oxygen species in a much-localized way to destroy malignant tumors. Despite the various benefits of PDT, some PS-related limitations hinder its use as an ideal treatment option for cancer. To address these limitations (e.g., poor bioavailability, weak permeability, hydrophobicity, and aggregation), lipid-based and vesicular drug delivery systems have been employed. These carrier systems possess the ability to enhance the bioavailability, permeability, and solubility of the drug. Furthermore, they tend to load hydrophobic and lipophilic compounds and can be employed for an efficient and targeted drug delivery. The purpose of this review is to highlight the precise idea of PDT, the limitations of PDT related to PS, and the application of lipidic and tocosomal carriers in PDT for the treatment of various types of cancers. Liposomes, nanoliposomes, solid lipid nanoparticles, vesicular phospholipid gels, exosomes, transferosomes, and tocosomes are presented as commonly-employed vesicular drug carriers. Moreover, the amalgamation of cell-based drug delivery systems (CBDDS) with PDT holds considerable potential as an encouraging avenue in cancer treatment, especially in the context of immunotherapy.

In vitro antimicrobial testing of ciprofloxacin-loaded vesicular phospholipid gels

In vitro antimicrobial testing of ciprofloxacin-loaded vesicular phospholipid gels

Vesicular phospholipid gels as topical ocular delivery system for treatment of anterior uveitis

In this paper, we developed a vesicular phospholipid gels (VPGs) for topical ocular delivery of flurbiprofen (FLB) to treat anterior uveitis. FLB loaded VPGs (FLB VPGs), composed of FLB and egg yolk lecithin, were prepared by high-pressure homogenization technique. The effects of egg yolk lecithin content and homogenization pressure on properties of FLB VPGs, including size, encapsulation efficiency, yield and in vitro release profile were investigated. The resultant FLB VPGs were characterized by the transmission electron microscopy, differential scanning calorimetry, X-ray diffraction, fourier transform infrared spectroscopy, rheological behavior, and storage stability. Corneal permeation experiments revealed that VPGs could improve the transcorneal delivery of FLB under ex vivo conditions. VPGs were nonirritant toward to the rabbit eye, as indicated by slit lamp observation and histological observation. The results of tear pharmacokinetics and in vivo fluorescence imaging showed that VPGs could significantly prolong the precorneal retention time. In vivo biodistribution study indicated that VPGs could significantly improve drug bioavailability in ocular tissues. Moreover, FLB VPGs exhibited excellent anti-inflammatory effect in endotoxin induced uveitis in rabbits. Overall, VPGs are a promising ophthalmic drug delivery system for the treatment of anterior uveitis.

<p>Cationic/Anionic Polyelectrolyte (PLL/PGA) Coated Vesicular Phospholipid Gels (VPGs) Loaded with Cytarabine for Sustained Release and Anti-glioma Effects</p>

BackgroundCationic and anionic polymer-modified nanoparticles offer promising properties for the drug and gene delivery. Our study uses cationic/anionic polyelectrolyte coated vesicular phospholipid gels (VPGs) loaded with cytarabine (Ara-C) that enhance in vitro and in vivo anti-glioma effects.MethodsSodium cholesteryl sulfate (SCS) or octadecylamine (ODA) incorporated in a phospholipids phase were used to prepare charged VPGs, and cationic ε-polylysine (PLL) coated VPGs (PLL-SCS VPGs) and anionic γ-polyglutamic acid (PGA) coated VPGs (PGA-ODA VPGs) were prepared via electrostatic interactions, respectively. The morphology, particle size, zeta potential, rheology properties, and in vitro release were then characterized. The in vitro cytotoxicity and cellular uptake were evaluated on U87-MG glioma cells. The in vivo antitumor effects were studied on BALB/c nude mice bearing a right flank U87-MG glioma model.ResultsThe TEM images and physicochemical properties of cationic/anionic polyelectrolyte coated VPGs exhibited that polymers covered on the vesicular surface. The results of rheologic property analysis showed that cationic/anionic polyelectrolyte coated VPGs enhanced the viscosity of uncoated VPGs. The in vitro release experiments revealed that cationic/anionic polyelectrolyte coated VPGs kept Ara-C sustained release up to 18 days. Specially, compared with PLL-SCS VPGs, PGA-ODA VPGs demonstrated higher in vitro cytotoxicity and cellular uptake efficiency in U87-MG glioma cells, and enhanced in vivo antitumor effects when subcutaneously injected around the tumor. No severe toxicity appeared in the right flank U87-MG glioma model of BALB/c nude mice.ConclusionAnionic γ-PGA coated VPGs were superior to cationic PLL coated VPGs in terms of improving the anti-glioma effect for local delivery.

Primary and Secondary Binding of Exenatide to Liposomes

The interactions of exenatide, a Trp-containing peptide used as a drug to treat diabetes, with liposomes were studied by isothermal titration calorimetry (ITC), tryptophan (Trp) fluorescence, and microscale thermophoresis measurements. The results are not only important for better understanding the release of this specific drug from vesicular phospholipid gel formulations but describe a general scenario as described before for various systems. This study introduces a model to fit these data on the basis of primary and secondary peptide-lipid interactions. Finally, resolving apparent inconsistencies between different methods aids the design and critical interpretation of binding experiments in general. Our results show that the net cationic exenatide adsorbs electrostatically to liposomes containing anionic diacyl phosphatidylglycerol lipids (PG); however, the ITC data could not properly be fitted by any established model. The combination of electrostatic adsorption of exenatide to the membrane surface and its self-association (Kd = 46 μM) suggested the possibility of secondary binding of peptide to the first, primarily (i.e., lipid-) bound peptide layer. A global fit of the ITC data validated this model and suggested one peptide to bind primarily per five PG molecules with a Kd ≈ 0.2 μM for PC/PG 1:1 and 0.6 μM for PC/PG 7:3 liposomes. Secondary binding shows a weaker affinity and a less exothermic or even endothermic enthalpy change. Depending on the concentration of liposomes, secondary binding may also lead to liposomal aggregation as detected by dynamic light-scattering measurements. ITC quantifies primary and secondary binding separately, whereas microscale thermophoresis and Trp fluorescence represent a summary or average of both effects, possibly with the fluorescence data showing somewhat greater weighting of primary binding. Systems with secondary peptide-peptide association within the membrane are mathematically analogous to the adsorption discussed here.

Do interactions between protein and phospholipids influence the release behavior from lipid-based exenatide depot systems?

The release mechanism for proteins and peptides from vesicular phospholipid gels (VPGs) is very complex. Drug release proceeds via a combination of erosion of the gel and diffusion of the drug out of it. This diffusion can be retarded by a slow permeation of the drug across the lipid bilayers in the gel as well as by its direct binding or adsorption to the lipid bilayers. Finally, the viscosity and homogeneity of the formulation may affect the release behavior. So far a direct correlation between one of these parameters and the release kinetics is not possible.In the present study, we aimed to investigate the contribution of drug-membrane interactions to the release kinetics of exenatide from differently composed VPGs (POPC, POPG and mixtures of both). To this end, in vitro release of exenatide as well as in vitro release of the phospholipids was monitored. Binding affinities were determined by microscale thermophoresis (MST).The sustained release behavior of exenatide could not simply be correlated to high viscosity of the VPG formulation. Release of exenatide from VPGs of anionic membranes containing POPG proceeded with a half-life of the order of 5 days and it seems to be controlled by the erosion of the gel. Its rate is unaffected by the initial pH inside the gel, independently of the strong impact of pH on exenatide binding to the membrane. At pH 4.5, exenatide is cationic and binds to membranes containing anionic POPG with a high affinity (Kd ≈ 10–30 µM).No high affinity membrane binding of exenatide is detected in this at pH 7.4, where exenatide is anionic, and to zwitterionic membranes composed of POPC. Exenatide release from the latter has a significantly longer half-life of 30 to 55 days. That means, these VPGs are much more resistant to erosion and show a very slow diffusional release. In this case, diffusion should be slowed down by the barrier function of the membranes rather than membrane affinity.In conclusion, erosion of the VPG matrix and membrane permeability of the drug are the major parameters influencing the release of exenatide from VPGs of POPC-POPG, whereas drug binding to the membranes had a minor effect only.

Vesicular phospholipid gels as drug delivery systems for small molecular weight drugs, peptides and proteins: State of the art review

Lipid-based drug delivery has been investigated for a long time when it comes to liposomes and solid-lipid implants or solid-lipid nanoparticles. The promising, characteristic properties of these systems have led to the development of newer lipid-based drug delivery systems for the sustained release of drugs like liposomes for sustained delivery of substances, DepoFoam™ technology, phospholipid-based phase separation gels and vesicular phospholipid gels. Vesicular phospholipid gels (VPGs) are highly concentrated, viscous dispersions of high amounts of phospholipids in aqueous drug solution. The easy, solvent-free manufacturing process, high biocompatibility and various applications, as depot formulation for the sustained delivery of drugs and as a storage form of small unilamellar vesicles make VPGs highly attractive as drug carriers. Over the last years, the solvent free preparation process has advanced from high pressure homogenization to dual centrifugation (DC). Thereby a very simple one step process has been established for the preparation of VPGs. The semisolid VPG was first described in 1997 by Brandl et al. Since then, many formulations have been developed, encapsulating small molecular weight drugs like 5-FU (2003), cetrorelix (2005), cytarabine (2012) and exenatide (2015). In 2010, the first pharmaceutical protein, erythropoietin, was encapsulated in VPGs and sustained release of the substance was shown in vitro. In 2015, G-CSF was encapsulated in VPGs and tested in vivo for rotator cuff repair in a rat model and for PEGylated IFN-β-1b sustained release from vesicular phospholipid gels was demonstrated in vitro. Further, a very elegant administration technique for VPGs via needle-free injection was established. However this promising drug delivery system does still leave space for improvement and optimization.This review summarizes information about lipid-based depot systems in general and focuses on the historical development of VPGs. It emphasizes the advantages and drawbacks of VPGs as drug delivery device. Additionally, novel preparation methods and applications of VPGs will be discussed. A focus will be set on delivery of pharmaceutical proteins and peptides.

Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems.

Lipid-based drug delivery systems, or lipidic carriers, are being extensively employed to enhance the bioavailability of poorly-soluble drugs. They have the ability to incorporate both lipophilic and hydrophilic molecules and protecting them against degradation in vitro and in vivo. There is a number of physical attributes of lipid-based nanocarriers that determine their safety, stability, efficacy, as well as their in vitro and in vivo behaviour. These include average particle size/diameter and the polydispersity index (PDI), which is an indication of their quality with respect to the size distribution. The suitability of nanocarrier formulations for a particular route of drug administration depends on their average diameter, PDI and size stability, among other parameters. Controlling and validating these parameters are of key importance for the effective clinical applications of nanocarrier formulations. This review highlights the significance of size and PDI in the successful design, formulation and development of nanosystems for pharmaceutical, nutraceutical and other applications. Liposomes, nanoliposomes, vesicular phospholipid gels, solid lipid nanoparticles, transfersomes and tocosomes are presented as frequently-used lipidic drug carriers. The advantages and limitations of a range of available analytical techniques used to characterize lipidic nanocarrier formulations are also covered.

The stress regulator FKBP51: a novel and promising druggable target for the treatment of persistent pain states across sexes.

It is well established that FKBP51 regulates the stress system by modulating the sensitivity of the glucocorticoid receptor to stress hormones. Recently, we have demonstrated that FKBP51 also drives long-term inflammatory pain states in male mice by modulating glucocorticoid signalling at spinal cord level. Here, we explored the potential of FKBP51 as a new pharmacological target for the treatment of persistent pain across the sexes. First, we demonstrated that FKBP51 regulates long-term pain states of different aetiologies independently of sex. Deletion of FKBP51 reduced the mechanical hypersensitivity seen in joint inflammatory and neuropathic pain states in female and male mice. Furthermore, FKBP51 deletion also reduced the hypersensitivity seen in a translational model of chemotherapy-induced pain. Interestingly, these 3 pain states were associated with changes in glucocorticoid signalling, as indicated by the increased expression, at spinal cord level, of the glucocorticoid receptor isoform associated with glucocorticoid resistance, GRβ, and increased levels of plasma corticosterone. These pain states were also accompanied by an upregulation of interleukin-6 in the spinal cord. Crucially, we were able to pharmacologically reduce the severity of the mechanical hypersensitivity seen in these 3 models of persistent pain with the unique FKBP51 ligand SAFit2. When SAFit2 was combined with a state-of-the-art vesicular phospholipid gel formulation for slow release, a single injection of SAFit2 offered pain relief for at least 7 days. We therefore propose the pharmacological blockade of FKBP51 as a new approach for the treatment of persistent pain across sexes, likely in humans as well as rodents.

Long-lasting Insulin Treatment Via a Single Subcutaneous Administration of Liposomes in Thermoreversible Pluronic® F127 Based Hydrogel.

Repeated administrations of insulin injection on daily basis evoke pain and numerous complications with adverse effects on the diabetic patients' life quality. Moreover, wearing insulin pump is also associated with several problems of diabetic ketoacidosis, catheter site infection, contact dermatitis and high cost. We have developed an in situ gel system, consisting of insulin-loaded liposomes dispersed within a thermoreversible gel (Pluronic® F127 gel), which increases the duration of insulin action for the treatment of diabetes. Vesicular phospholipid gel technique was used to encapsulate the insulin into liposomes. The resulting liposomal gel formulation had a longer drug-release period in vitro than a free insulin solution or liposomes and Pluronic® F127 gel individually. Furthermore, the addition of liposomes to the Pluronic® F127 gel improved the stability of the encapsulated insulin at a physiological temperature. In vivo study was performed to investigate the bioactivity and absorption of insulin released from the liposomal gel and other formulations. The liposomal gel released insulin into the bloodstream continuously for up to 7 days and significantly enhanced drug bioavailability compared to insulin released from liposomes or Pluronic® F127 gel individually. Blood glucose levels were reduced for up to 4 days. Histology data demonstrated excellent biocompatibility of the Pluronic® F127 gel-based delivery systems, with no observable inflammatory response in rat subcutaneous tissues. Obtained results show that the insulin-loaded liposomes dispersed within Pluronic® F127 gel can be used as a long-acting drug delivery system, and replacement for conventional insulin therapy.

Needle-Free Injection of Vesicular Phospholipid Gels—A Novel Approach to Overcome an Administration Hurdle for Semisolid Depot Systems

Vesicular phospholipid gels (VPGs) are depot formulations for the sustained release of drugs which are characterized by a high amount of phospholipids in the formulation. They consist of physiological excipients only and therefore display high biocompatibility. Their manufacture is simple, cheap, solvent free, and ideal for the processing of proteins and peptides because of the low stress on the molecule, for example, by elevated temperatures. One major hurdle of VPGs is their high viscosity which makes them hard to almost impossible to inject with conventional, thin needles used for subcutaneous administration. However, so far no data are published to overcome this administration challenge. In the present study, needle-free injection was investigated and successfully applied as a technology for the easy and elegant administration of VPGs. VPGs with different phospholipid content were injected with a Biojector 2000 into gelatin blocks and full thickness pig skin postmortem as in vitro models and the injection depth was determined after injection. The release behavior was tested after shearing the VPG with the device to evaluate the effect of shearing on the drug release from the formulation. No differences were observed when compared to an ejection with needle and syringe.

Development and optimization of a new processing approach for manufacturing topical liposomes-in-hydrogel drug formulations by dual asymmetric centrifugation

Objective: The objective of the present study was to utilize dual asymmetric centrifugation (DAC) as a novel processing approach for the production of liposomes-in-hydrogel formulations.Materials and methods: Lipid films of phosphatidylcholine, with and without chloramphenicol (CAM), were hydrated and homogenized by DAC to produce liposomes in the form of vesicular phospholipid gels with a diameter in the size range of 200−300 nm suitable for drug delivery to the skin. Different homogenization processing parameters were investigated along with the effect of adding propylene glycol (PG) to the formulations prior to homogenization. The produced liposomes were incorporated into a hydrogel made of 2.5% (v/v) soluble β-1,3/1,6-glucan (SBG) and mixed by DAC to achieve a homogenous liposomes-in-hydrogel-formulation suitable for topical application.Results and discussion: CAM-containing liposomes with a vesicle diameter of 282 ± 30 nm and polydispersity index (PI) of 0.13 ± 0.02 were successfully produced by DAC after 50 min centrifugation at 3500 rpm, and homogenously (< 4% content variation) incorporated into the SBG hydrogel. Addition of PG decreased the necessary centrifugation time to 2 min and 55 s, producing liposomes of 230 ± 51 nm and PI of 0.25 ± 0.04. All formulations had an entrapment efficiency of approximately 50%.Conclusion: We managed to develop a relatively fast and reproducible new method for the production of liposomes-in-hydrogel formulations by DAC.

In vitro and in vivo sustained release of exenatide from vesicular phospholipid gels for type II diabetes

Diabetes is a chronic disease that requires daily treatment to maintain a stable blood glucose level. Sustained-release formulations can thus benefit the treatment of diabetes by reducing the repeated administration of therapeutics. Our study aimed to develop a sustained-release platform for exenatide that is biocompatible and capable of mass production. Vesicular phospholipid gels (VPGs) are semisolid phospholipid dispersions with controlled release profiles. Exenatide-VPGs prepared via simple magnetic stirring showed excellent biocompatibility with an average particle size of about 15 μm after redispersion. VPGs were shown to achieve sustained release for up to 21 days in vitro with no obvious burst effect. The in vivo release study showed that VPGs sustained the release of the exenatide for up to 11 days. Moreover, after subcutaneous injection of the exenatide-VPGs in the diabetic rats, the hypoglycemic effect lasted for 10 days compared with exenatide solution. In sum, the exenatide-VPGs system represents a promising sustained-release formulation for exenatide with a long-acting therapeutic efficacy in vivo.

Growth factor release by vesicular phospholipid gels: in-vitro results and application for rotator cuff repair in a rat model

BackgroundBiological augmentation of rotator cuff repair is of growing interest to improve biomechanical properties and prevent re-tearing. But intraoperative single shot growth factor application appears not sufficient to provide healing support in the physiologic growth factor expression peaks. The purpose of this study was to establish a sustained release of granulocyte-colony stimulating factor (G-CSF) from injectable vesicular phospholipid gels (VPGs) in vitro and to examine biocompatibility and influence on histology and biomechanical behavior of G-CSF loaded VPGs in a chronic supraspinatus tear rat model.MethodsG-CSF loaded VPGs were produced by dual asymmetric centrifugation. In vitro the integrity, stability and release rate were analyzed. In vivo supraspinatus tendons of 60 rats were detached and after 3 weeks a transosseous refixation with G-CSF loaded VPGs augmentation (n = 15; control, placebo, 1 and 10 μg G-CSF/d) was performed. 6 weeks postoperatively the healing site was analyzed histologically (n = 9; H&E by modified MOVIN score/Collagen I/III) and biomechanically (n = 6).ResultsIn vitro testing revealed stable proteins after centrifugation and a continuous G-CSF release of up to 4 weeks. Placebo VPGs showed histologically no negative side effects on the healing process. Histologically in vivo testing demonstrated significant advantages for G-CSF 1 μg/d but not for G-CSF 10 μg/d in Collagen III content (p = 0.035) and a higher Collagen I/III ratio compared to the other groups. Biomechanically G-CSF 1 μg/d revealed a significant higher load to failure ratio (p = 0.020) compared to control but no significant differences in stiffness.ConclusionsBy use of VPGs a continuous growth factor release could be obtained in vitro. The in vivo results demonstrate an improvement of immunohistology and biomechanical properties with a low dose G-CSF application via VPG. The VPG itself was well tolerated and had no negative influence on the healing behavior. Due to the favorable properties (highly adhesive, injectable, biocompatible) VPGs are a very interesting option for biologic augmentation. The study may serve as basis for further research in growth factor application models.

Sustained delivery of cytarabine-loaded vesicular phospholipid gels for treatment of xenografted glioma

This study described the development of vesicular phospholipid gels (VPGs) for sustained delivery of cytarabine (Ara-C) for the treatment of xenografted glioma. Ara-C-loaded VPGs in the state of a semisolid phospholipid dispersion looked like numerous vesicles tightly packing together under the freeze-fracture electron microscopy (FF-TEM), their release profiles displayed sustained drug release up to 384h in vitro. The biodistribution of Ara-C in the rat brain showed that Ara-C-loaded VPGs could maintain therapeutic concentrations up to 5mm distance from the implantation site in brain tissue within 28 days. At the same time, fluorescence micrograph confirmed drug distribution in brain tissue visually. Furthermore, after single administration, Ara-C-loaded VPGs group significantly inhibited the U87-MG glioma growth in right flank in comparison with Ara-C solution (p<0.01). It was explained that the entrapped drug in VPGs could avoid degradation from cytidine deaminase and sustained release of drug from Ara-C-loaded VPGs could maintain the effective therapeutic levels for a long time around the tumor. In conclusion, Ara-C-loaded VPGs, with the properties of sustained release, high penetration capacity, nontoxicity and no shape restriction of the surgical cavity, are promising local delivery systems for post-surgical sustained chemotherapy against glioma.

Sterilization stability of vesicular phospholipid gels loaded with cytarabine for brain implant

The aim of this study was to investigate the sterilization stability of cytarabine (Ara-C) loaded vesicular phospholipid gels (VPGs). VPGs were prepared by high pressure homogenization method intended for the treatment of glioblastoma multiforme (GBM) in brain as injectable implant. The particle size of VPGs after redispersion was 119.6±66.24nm, and entrapment efficiency (EE) was 32.6±2.1%. Drug release in vitro from VPGs sustained for 80h with 48.1% initial release within 1h, and rheological studies demonstrated a gel-like behavior. Comparatively, after autoclaved sterilization, increased particle size and EE were obtained as 165.6±71.89nm and 62.6±2.3%, respectively. Additionally, characteristics of drug release were significantly altered with obviously prolonged release time to 450h and remarkable reduced initial release to 24.7%. Also, the viscoelasticity was reinforced with clearly decreased fluidity. This result could be explained by the fusion of small vesicles witnessed in TEM observation, which resulted in percentages change of vesicle groups with different size. However, reduced Ara-C and increased lysophosphatidylcholine (LPC) were observed. Among the stabilizers, addition of sodium sulfite showed best effects with high stability of Ara-C and phospholipids. This may be explained by the presence of SO3−, free radicals produced by sodium sulfite. Being an hydroxyl radical scavenger, it can reduce the generation of HO free radicals. These results show that, with addition of appropriate stabilizers, VPGs can be autoclaved with high stability, and it is a promising dosage form for treatment of GBM after injection into resectable or nonresectable neoplasms with sustained release properties.

Liposomes prolong the therapeutic effect of anti-asthmatic medication via pulmonary delivery

PurposeThe main objective of this study was to develop a novel aerosolized liposome formulation for pulmonary delivery of anti-asthmatic medication and to explore the relationship between the bioavailability and anti-asthmatic efficacy of such a formulation. Asthma treatment usually requires frequent administration of medication for sustained bronchodilating response. Liposomes are known for their capability for sustained drug release and thus would be a suitable delivery system for anti-asthmatic medication for prolonged therapeutic effect. Salbutamol sulfate (SBS) was chosen as the model drug in this study because of its high water solubility and fast absorption after administration.MethodsSBS was efficiently encapsulated into liposomes by the vesicular phospholipid gel technique. SBS permeability across the pulmonary membrane of an Asian toad was determined by in vitro study. Intratracheal administration of liposomes labeled with the fluorescent dye 1,1′-dioctadecyltetramethyl indotricarbocyanine iodide (DiR) in a rat model was assessed by a small animal imaging system and pharmacokinetic analysis. Pharmacodynamic analysis was performed in guinea pigs using the Konzett–Rössler method.ResultsSBS was efficiently encapsulated into liposomes with encapsulation efficiency as high as 70%. The particle size of the SBS liposome suspension was approximately 57 ± 21 nm. In the in vitro study of permeability across the pulmonary membrane of Asian toads, SBS from liposomes demonstrated a slower transport rate compared to free SBS solution. Pulmonary delivery of liposomes in a rat model showed that the liposomes were effectively distributed in the respiratory tract and lungs, and that the release of SBS from liposomes was sustained for at least 48 hours. Pharmacodynamic analysis in a guinea pig model showed that the anti-asthmatic effect of SBS liposomes persisted for up to 18 hours, whereas that of free SBS solution was less than 8 hours.ConclusionThe overall results demonstrated that liposomes could increase the concentration and retention time of SBS in the lungs and therefore prolong its therapeutic effect.

Development of Liposomal Salbutamol Sulfate Dry Powder Inhaler Formulation

The purpose of our study was to develop a formulation of liposomal salbutamol sulfate (SBS) dry powder inhaler (DPI) for the treatment of asthma. Liposomes of high encapsulation efficiency (more than 80%) were prepared by a vesicular phospholipid gel (VPG) technique. SBS VPG liposomes were subjected to lyophilization using different kinds of cryoprotectants in various mass ratios. Coarse lactose (63-106 microm) in different mass ratios was used as a carrier. Magnesium stearate (0.5%) was added as a lubricator. The dry liposomal powders were then crushed by ball milling and sieved through a 400-mesh sieve to control the mean particle size at about 10 microm. The effects of different kinds of cryoprotectants and the amount of lactose carrier on the fine particle fraction (FPF) of SBS were investigated. The results showed that the developed formulation of liposomal dry powder inhaler was obtained using lactose as a cryoprotectant with a mass ratio of lyophilized powder to carrier lactose at 1 : 5; 0.5% magnesium stearate was used as a lubricator. The value of FPF for SBS was 41.51+/-2.22% for this formulation. Sustained release of SBS from the VPG liposomes was found in the in vitro release study. The study results offer the promising possibility of localized pulmonary liposomal SBS delivery in the anhydrous state.