Thermosensitive hydrogel containing ethosuximide-loaded multivesicular liposomes attenuates age-related hearing loss in C57BL/6J mice.

Ethosuximide is the first drug reported to protect against age-related hearing loss, but its benefits are hampered by the pronounced side effects generated through systemic administration. We prepared a thermosensitive hydrogel containing ethosuximide-encapsulated multivesicular liposomes (ethosuximide-loaded MVLs-Gel) and evaluated its functional and histological effects on age-related hearing loss in C57BL/6J mice. The MVLs-Gel showed slow sustained-release characteristics up to over 120 h. After 8 weeks of treatment, compared to the oral systemic administration of ethosuximide, intratympanic ethosuximide-loaded MVLs-Gel injection dramatically reduced the loss of age-related spiral ganglion neurons in the apical turns of the mice (low-frequency regions, p < 0.05). Correspondingly, compared to the oral systemic administration group, the intratympanic ethosuximide-loaded MVLs-Gel injection group showed significantly lower auditory brainstem response threshold shifts at stimulus frequencies of 4, 8, and 16 kHz (low-and middle-frequency regions, p < 0.05). In conclusion, intratympanic ethosuximide-loaded MVLs-Gel injection can reach the apical turn of the cochlea, which is extremely difficult with oral systemic administration of the drug. The ethosuximide-loaded MVLs-Gel, as a novel intratympanic sustained-release drug delivery system, attenuated age-related hearing loss in C57BL/6J mice.

Intramuscular injection of palmitic acid-conjugated Exendin-4 loaded multivesicular liposomes for long-acting and improving in-situ stability.

BACKGROUND: Exendin-4 (Ex4) is a promising drug for diabetes mellitus with a half-life of 2.4 h in human bodies. Besides, the Ex4 formulations currently employed in the clinic or under development have problems pertaining to stability. In this study, palmitic acid-modified Ex4 (Pal-Ex4) was prepared and purified to extend the half-life of Ex4. In addition, Pal-Ex4-MVLs were further designed and optimized as a long-acting delivery system for intramuscular injection. METHODS: Pal-Ex4 was encapsulated within multivesicular liposomes (MVLs) via a two-step double emulsification process. The formulated products were then assessed for their vesicle size, encapsulation efficiency, and in vitro and in vivo. RESULTS: Pal-Ex4-MVLs with a notable encapsulation efficiency of 99.18% were successfully prepared. Pal-Ex4-MVLs, administered via a single intramuscular injection in Sprague-Dawley rats, sustained stable plasma concentrations for 168 h, presenting extended half-life (77.28 ± 12.919 h) and enhanced relative bioavailability (664.18%). MVLs protected Ex4 through providing stable retention and slow release. This approach considerably improved the in-situ stability of the drug for intramuscular administration. CONCLUSIONS: The combination of palmitic acid modification process with MVLs provides dual protection for Ex4 and can be a promising strategy for other hydrophilic protein/polypeptide-loaded sustained-release delivery systems with high drug bioactivity.

Development of an Accelerated Rotator-based Drug Release Method for the Evaluation of Bupivacaine Multivesicular Liposomes.

PURPOSE: A multivesicular liposome (MVL) is a liposomal vehicle designed to achieve sustained release characteristics for drugs with short half-lives. For example, a commercial MVL formulation of bupivacaine has been approved by the U.S. Food and Drug Administration for local and regional analgesia. For complex formulations like those containing MVLs, challenges in developing an in vitro release testing (IVRT) method may hinder generic development and regulatory approval. In this study, we developed an accelerated rotator-based IVRT method with the ability to discriminate bupivacaine MVLs with different quality attributes. METHODS: Three IVRT experimental setups including mesh tube, horizontal shaker, and vertical rotator were screened to ensure that at least 50% of bupivacaine can release from MVLs in 24 h. Sample dilution factors, incubation temperature, and the release media pH were optimized for the IVRT. The reproducibility of the developed IVRT method was validated with commercial bupivacaine MVLs. The discriminative capacity was assessed via comparing commercial and compromised bupivacaine MVL formulations. RESULTS: The rotator-based release setup was chosen due to the capability to obtain 70% of drug release within 24 h. The optimized testing conditions were chosen with a 50-fold dilution factor, a temperature of 37ºC, and a media pH of 7.4. CONCLUSIONS: An accelerated rotator-based IVRT method for bupivacaine MVLs was developed in this study, with the discriminatory ability to distinguish between formulations of different qualities. The developed IVRT method was a robust tool for generic development of MVL based formulations.

Preparation of multivesicular liposomes for the loco-regional delivery of Vancomycin hydrochloride using active loading method: drug release and antimicrobial properties.

Over the last few years, among controlled-release delivery systems, multivesicular liposomes (MVLs) have attracted attention due to their unique benefits as a loco-regional drug delivery system. Considering the clinical limitations of the current treatment strategies for osteomyelitis, MVLs can be a suitable carrier for the local delivery of effective antibiotics. This study aimed to prepare vancomycin hydrochloride (VAN HL) loaded MVLs using the active loading method which to the best of our knowledge has not been previously reported. Empty MVLS were prepared by the double emulsion (w/o/w) method and VAN HL was loaded into the prepared liposomes by the ammonium gradient method. After full characterization, the release profile of VAN HL from MVLs was assessed at two different pH values (5.5 and 7.4), and compared with the release profile of the free drug and also passively loaded MVLs. In vitro antimicrobial activities were evaluated using the disc diffusion method. Our results demonstrated that the encapsulation efficiency was higher than 90% in the optimum actively loaded MVL. The free VAN HL was released within 6-8 h, while the passively loaded MVLs and the optimum actively loaded MVL formulation released the drug in 6 days and up to 19 days, respectively. The released drug showed effective antibacterial activity against osteomyelitis-causing pathogens. In conclusion, the prepared formulation offered the advantages of sustained-release properties, appropriate particle size as well as being composed of biocompatible materials, and thus could be a promising candidate for the loco-regional delivery of VAN HL and the management of osteomyelitis.

Characterization of exparel bupivacaine multivesicular liposomes.

Exparel is a bupivacaine multivesicular liposomes (MVLs) formulation developed based on the DepoFoam technology. The complex composition and the unique structure of MVLs pose challenges to the development and assessment of generic versions. In the present work, we developed a panel of analytical methods to characterize Exparel with respect to particle size, drug and lipid content, residual solvents, and pH. In addition, an accelerated in vitro drug release assay was developed using a rotator-facilitated, sample-and-separate experimental setup. The proposed method could achieve over 80% of bupivacaine release within 24 h, which could potentially be used for formulation comparison and quality control purposes. The batch-to-batch variability of Exparel was examined by the established analytical methods. Four different batches of Exparel showed good batch-to-batch consistency in drug content, particle size, pH, and in vitro drug release kinetics. However, slight variation in lipid contents were observed.

A Mini-review Based on Multivesicular Liposomes: Composition, Design, Preparation, Characteristics, and Therapeutic Importance as DEPOFOAM® Technology.

Vesicular delivery systems are a kind of drug delivery system that is gaining popularity due to its sustained release nature. This article was designed to understand the characteristics of a drug carrier called multivesicular liposomes, which have the potential to be the future of sustainedrelease drug delivery systems. Multivesicular liposomes have a honeycomb-like structure made up of non-concentric aqueous polyhedral compartments separated by continuous lipid membranes. Because of their unusual structure, they can encapsulate both hydrophilic and lipophilic pharmaceuticals and release them in a prolonged and controlled manner. They also have high encapsulation efficiency, bioavailability, biocompatibility, and stability, and are biodegradable by nature, making them suitable for treating chronic disorders. Encapsulating drugs into multivesicular liposomes is called DepoFoam® technology, which has the capability to release them in a timely manner, lowering the drug administration frequency. As a result, the FDA has approved several various approaches for this technology to treat chronic conditions. Multivesicular liposomes in the form of DepoFoam® technology hold a promising future as a novel drug delivery system. Much research needs to be done to extend their use across various aspects of the therapeutic field.

Arginine Supplementation Targeting Tumor-Killing Immune Cells Reconstructs the Tumor Microenvironment and Enhances the Antitumor Immune Response.

The tumor microenvironment (TME) is characterized by several immunosuppressive factors, of which weak acidity and l-arginine (l-arg) deficiency are two common features. A weak acidic environment threatens the survival of immune cells, and insufficient l-arg will severely restrain the effect of antitumor immune responses, both of which affect the efficiency of cancer treatments (especially immunotherapy). Meanwhile, l-arg is essential for tumor progression. Thus, two strategies, l-arg supplementation and l-arg deprivation, are developed for cancer treatment. However, these strategies have the potential risk of promoting tumor growth and impairing immune responses, which might lead to a paradoxical therapeutic effect. It is optimal to limit the l-arg availability of tumor cells from the microenvironment while supplying l-arg for immune cells. In this study, we designed a multivesicular liposome technology to continuously supply alkaline l-arg, which simultaneously changed the acidity and l-arg deficiency in the TME, and by selectively knocking down the CAT-2 transporter, l-arg starvation of tumors was maintained while tumor-killing immune cells were enriched in the TME. The results showed that our strategy promoted the infiltration and activation of CD8+ T cells in tumor, increased the proportion of M1 macrophages, inhibited melanoma growth, and prolonged survival. In combination with anti-PD-1 antibody, our strategy reversed the low tumor response to immune checkpoint blockade therapy, showing a synergistic antitumor effect. Our work provided a reference for improving the TME combined with regulating nutritional competitiveness to achieve the sensitization of immunotherapy.

Doxorubicin-Loaded Multivesicular Liposomes (DepoFoam) as a Sustained Release Carrier Intended for Locoregional Delivery in Cancer Treatment: Development, Characterization, and Cytotoxicity Evaluation.

Background: Despite the advantages of direct intratumoral (IT) injection, the relatively rapid withdrawal of most anti-cancer drugs from the tumor due to their small molecular size limits the effectiveness of this method of administration. To address these limitations, recently, increasing attention has been directed to using slow-release biodegradable delivery systems for IT injection. Objectives: This study aimed to develop and characterize a doxorubicin-loaded DepoFoam system as an efficient controlled-release carrier to be employed for locoregional drug delivery in cancer treatment. Methods: Major formulation parameters, including the molar ratio of cholesterol to the main lipid [Chol/egg phosphatidylcholine (EPC)], triolein (TO) content, and lipid-to-drug molar ratio (L/D), were optimized using a two-level factorial design approach. The prepared batches were evaluated for encapsulation efficiency (EE) and percentage of drug release (DR) after 6 and 72 hours as dependent variables. The optimum formulation (named DepoDOX) was further evaluated in terms of particle size, morphology, zeta potential, stability, Fourier-transform infrared spectroscopy, in vitro cytotoxicity, and hemolysis. Results: The analysis of factorial design indicated that TO content and L/D ratio had a negative effect on EE; between these two, TO content had the greatest effect. The TO content was also the most significant component, with a negative effect on the release rate. The ratio of Chol/EPC showed a dual effect on the DR rate. Using a higher percentage of Chol slowed down the initial release phase of the drug; nevertheless, it accelerated the DR rate in the later slow phase. DepoDOX were spherical and honeycomb-like structures (≈ 9.81 µm) with a desired sustained release profile, as DR lasted 11 days. Its biocompatibility was confirmed by the results of cytotoxicity and hemolysis assays. Conclusions: The in vitro characterization of optimized DepoFoam formulation demonstrated its suitability for direct locoregional delivery. DepoDOX, as a biocompatible lipid-based formulation, showed appropriate particle size, high capability for encapsulating doxorubicin, superior physical stability, and a markedly prolonged DR rate. Therefore, this formulation could be considered a promising candidate for locoregional drug delivery in cancer treatment.

Multivesicular liposomal depot system for sustained delivery of risperidone: development, characterization, and toxicity assessment.

OBJECTIVE: Considering the limitations of conventional risperidone (RSP) therapies, the present research characterizes the usefulness of multivesicular liposomes (MVLs) as an efficient controlled-release carrier for this widely used antipsychotic drug, to be employed for the treatment of schizophrenia. METHODS: A 23 full factorial design based on three independent variables was implemented to plan the experiments: the molar ratios of lipid to the drug, triolein to phospholipid, and cholesterol to phospholipid. The impacts of these parameters on the risperidone encapsulation efficiency and its release pattern within the first 24 and 48 h were investigated as dependent variables. Then, the optimized liposomal system was further in-depth analyzed in terms of size, morphological and structural features, release profile over 15 days, biocompatibility, and stability. RESULTS: Optimized formulation parameters gave rise to MVLs possessing a spherical morphology with a median diameter of about 8 µm, a relatively narrow size distribution (span value of 1.49), and an encapsulation efficiency of 57.6%. These carriers not only exhibited a sustained-release behavior in vitro, lasting until the end of the 15 days but also underwent a negligible change in their size and RSP incorporation over two months at refrigerator condition. Furthermore, in vitro cytotoxicity and hemolysis assessments revealed that the optimized MVL formulation is biocompatible. CONCLUSION: This study revealed the potential of MVLs as a promising system for the delivery of RSP and could open a new vista for the successful management of schizophrenia.

The preparation of dexamethasone sodium phosphate multivesicular liposomes thermosensative hydrogel and its impact on noise-induced hearing loss in the Guinea pigs.

OBJECTIVE: The aim of this study is to establish the dexamethasone sodium phosphate multivesicular liposomes thermosensative hydrogel (DEX-MVLs-Gel) drug delivery system and to analyze the pharmacodynamics, pharmacokinetics and safety of DEX-MVLs-Gel as well as to explore whether the prepared DEX-MVLs-Gel can protect the hearing in the guinea pigs following noise exposure. METHODS: DEX-MVLs formulations were constructed by double emulsion method, and the DEX-MVLs-Gel was prepared after adding P407 and P188 into the DEX-MVLs. A total of 20 adult albino guinea pigs were chosen to establish the animal models with noise-induced hearing loss. After animals were treated with DEX-MVLs-Gel at concentrations of 20, 6 and 2 mg/mL, and 5 mg/mL Dexamethasone Sodium Phosphate (DEX-P) solution, respectively, the hearing function, drug concentration in the peripheral lymph fluid, and hair cell morphology were assessed. RESULTS: The ABR threshold of the 20 mg/mL DEX-MVLs-Gel treated group at the frequencies of 4, 8, 16 and 24 kHz were measured as 47.5 ± 5.2, 48.3 ± 4.1, 55.8 ± 3.8 and 57.5 5 ± 5.2 dB SPL, respectively. Statistical significances were noted between the 20 mg/mL DEX-MVLs-Gel treated group and control group at each frequency (all P < 0.05), between the 2 mg/mL and 6 mg/mL DEX-MVLs-Gel treated groups at the frequencies of 4 and 8 kHz (both P < 0.05). High Performance Liquid Chromatography (HPLC) demonstrated that the drug concentrations in the peripheral lymph in all groups were gradually decreased on the 1st, 3rd and 7th d after intratympanic injection. Scattered hair cell loss could be observed mainly in the basal and middle turn in the saline administrated group and the 20 mg/mL DEX-MVLs-Gel administration group, and the hair cell loss was not identified in the apical turn. CONCLUSIONS: A high concentration (20 mg/mL) of DEX-MVLs-Gel exerts significant protective effects upon the guinea pigs with noise-induced hearing loss. The prepared DEX-MVLs-Gel can be effectively maintained in the peripheral lymph fluid of guinea pigs for 3-7 d and MVLs-Gel causes no obvious ototoxicity.

Multivesicular Liposomes for the Sustained Release of Angiotensin I-Converting Enzyme (ACE) Inhibitory Peptides from Peanuts: Design, Characterization, and In Vitro Evaluation.

The multivesicular liposome (MVL) provides a potential delivery approach to avoid the destruction of the structure of drugs by digestive enzymes of the oral cavity and gastrointestinal system. It also serves as a sustained-release drug delivery system. In this study, we aimed to incorporate a water-soluble substance into MVLs to enhance sustained release, prevent the destruction of drugs, and to expound the function of different components and their mechanism. MVLs were prepared using the spherical packing model. The morphology, structure, size distribution, and zeta potential of MVLs were examined using an optical microscope (OM), confocal microscopy (CLSM), transmission electron cryomicroscope (cryo-EM) micrograph, a Master Sizer 2000, and a zeta sizer, respectively. The digestion experiment was conducted using a bionic mouse digestive system model in vitro. An in vitro release and releasing mechanism were investigated using a dialysis method. The average particle size, polydispersity index, zeta potential, and encapsulation efficiency are 47.6 nm, 1.880, -70.5 ± 2.88 mV, and 82.00 ± 0.25%, respectively. The studies on the controlled release in vitro shows that MVLs have excellent controlled release and outstanding thermal stability. The angiotensin I-converting enzyme (ACE) inhibitory activity of ACE-inhibitory peptide (AP)-MVLs decreased only 2.84% after oral administration, and ACE inhibitory activity decreased by 5.03% after passing through the stomach. Therefore, it could serve as a promising sustained-release drug delivery system.

Adapting liposomes for oral drug delivery.

Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes, oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract, difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.

Multivesicular liposomes for sustained release of bevacizumab in treating laser-induced choroidal neovascularization.

Bevacizumab is an anti-vascular endothelial growth factor drug that can be used to treat choroidal neovascularization (CNV). Bevacizumab-loaded multivesicular liposomes (Bev-MVLs) have been designed and developed to increase the intravitreal retention time of bevacizumab and reduce the number of injection times. In this study, Bev-MVLs with high encapsulation efficiency were prepared by double emulsification technique, and antibody activity was determined. The results revealed that 10% of human serum albumin (HSA) could preserve the activity of bevacizumab. In vitro release of Bev-MVLs appeared to be in a more sustained manner, the underlying mechanisms of Bev-MVLs indicated that bevacizumab was released from MVLs through diffusion and erosion. Results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that bevacizumab could retain its structural integrity after being released from MVLs in vitro. In vivo imaging was used to evaluate the retention time of antibody in rat eyes, while pharmacokinetic analysis was performed on rabbit eyes. These results indicated that Bev-MVLs exhibited sustained release effects as compared to bevacizumab solution (Bev-S). Bev-MVLs could effectively inhibit the thickness of CNV lesion as compared to Bev-S at 28 days after treatment. Furthermore, these data suggest that Bev-MVLs are biologically feasible to increase the retention time of bevacizumab in vitreous humor. This novel Bev-MVLs may therefore serve as a promising sustained release drug delivery system for the treatment of CNV.

Study on Formulation Optimization and in vitro Release Characteristics of Bevacizumab Multivesicular Liposomes / 中国药房

OBJECTIVE:To prepare Bevacizumab(BEV)multivesicular liposomes(BEV-MVLs)with sustained-effect,and to study their in vitro release characteristics. METHODS:BEV-MVLs were prepared by double emulsion method. Box-Behnken design-response surface methodology was used to optimize the prescription with the concentration of glycerol trioleate(TO)in organic phase,ratio of 1,2-dioleoyl-sn-glycero-3-phosphocholine(DOPC)-cholesterol(CH)(mol/mol),the concentration of L-lysine in external water phase as factors,using encapsulation rate as index. The morphology of BEV-MVLs was observed by inverted fluorescence microscope and SEM;particle size was determined by laser particle size analyzer;the BEV content was determined by HPLC and calculate the encapsulation rate and in vitro accumulative release rate.RESULTS:The optimized prescription was as follows as TO of 2.72 mmol/L in organic phase,DOPC-CH ratio of 0.67(mol/mol)and L-lysine of 40 mmol/L in external water phase. The encapsulation rate of BEV-MVLs was(80.65±4.42)%(n=3),and relative error of it to predicted value was 2.54%. The liposomes were spherical in appearance shape and uniform in size,and they were typical non-concentric vesicle structure with average particle size of 16.80 μm. 30 d in vitro accumulative release rate was about 92%. CONCLUSIONS:Prepared BEV-MVLs show sustained-effect,and their encapsulation rate reaches the expected effect.

Optimized formulation of multivesicular liposomes loaded with oleanolic acid enhanced anticancer effect in vitro.

Invasion and metastasis are the main causes leading to the death of patients with hepatocellular carcinoma (HCC). Multivesicular liposomes loaded with oleanolic acid (OA-MVLs) have been well demonstrated to suppress survival, growth and angiogenesis of HCC cells. Emerging evidence demonstrates that OA was able to suppress the invasion of HCC cells by down-regulating myocyte enhancer factor-2. We hypothesized that the optimized OA-MVLs could inhibit the migration and invasion of HCC cells. In this study, we utilized central composite design and response surface methodology to assess the influence of some parameters on particle size and encapsulation efficiency and obtain the optimized formulation of OA-MVLs. Subsequently, the human HCC cell lines SMMC-7721 and HepG2 were treated with different doses of OA-MVLs and OA, respectively. Cellular survival, adhesion, migration and invasion in vitro were evaluated. We found that the optimized OA-MVLs significantly decreased the ability of HCC cells to adhere, migrate and invade in vitro. Furthermore, OA-MVLs significantly inhibited the survival of HCC cells at 160 µmol/L but showed no obvious inhibition effect on the cell vitality of normal liver cells. Our findings indicate that OA-MVLs did inhibit the cell survival, adhesion, invasion and metastasis of HCC cells in vitro. Although the involved mechanisms are still unclear, our findings can contribute to a better development of a preventive and therapeutic strategy for human HCC.

Characteristics in vitro and preliminary pharmacodynamics of hyaluronic acid-uricase multivesicular liposomes / 第二军医大学学报

Objective To investigate the characteristics of hyaluronic acid-uricase multivesicular liposomes (UHMVLs) in vitro and the pharmacodynamics of UHMVLs in rats. Methods UHMVLs was prepared by multiple emulsion method. The entrapment efficiency and physicochemical properties were detected. Twelve healthy male SD rats were enrolled in this study. The rat model of hyperuricemia was established with hypoxanthine and oteracil potassium, while the normal rats (n=3) were set as controls. Intravenous UHMVLs, uricase (UC) and nothing were given to the rats of UHMVLs group (n=3), UC group (n=3) and hyperuricemia model group (n=3), respectively; the levels of serum uric acid (UA) were detected in rats of the 4 groups. Results The average entrapment efficiency of UHMVLs was (62.48±3.87)%. The optimum temperatures of UHMVLs and UC were 40°, while the optimum pH values of UHMVLs and free UC were 8.0 and 8.5, respectively. The activity of UC in UHMVLs was significantly higher than that in free UC at the same temperature (20-70°) and pH value (6.5-9.5) (P<0.05). UHMVLs was more effective than free UC in decreasing serum UA in rats with hyperuricemia at all time points (P<0.05), except for 1 h, 36 h and 48 h. Conclusion Under the same condition, UHMVLs can improve not only the activity, but also the stability of UC. UHMVLs is more effective in decreasing serum uric acid in rats compared with free UC, which may pave a way for clinical application of UC.

Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo.

The aim of the present study was to develop a novel dosage form of multivesicular liposomes for oleanolic acid (OA) to overcome its poor solubility, prolong therapeutic drug levels in the blood, and enhance the antitumor effect on hepatocellular carcinoma. OA-encapsulated multivesicular liposomes (OA-MVLs) were prepared by a double-emulsion method, and the formulation was optimized by the central composite design. The morphology, particle size, and drug-loading efficiency of OA-MVLs were investigated. Furthermore, OA-MVLs were also characterized both in vitro and in vivo. The results showed that OA-MVLs were spherical particles with an average particle size of 11.57 µm and an encapsulation efficiency of 82.3%±0.61%. OA-MVLs exhibited a sustained-release pattern in vitro, which was fitted to Ritger-Peppas equation. OA-MVLs inhibited the growth of human HepG2 cells which was confirmed by the MTT assay and fluorescence microscopy detection. The in vivo release of OA from OA-MVLs exhibited a sustained manner, indicating a longer circulation time compared to OA solution. The in vivo toxicity study indicated that medium-dose OA-MVLs exerted no toxic effect on the hosts. Importantly, OA-MVLs suppressed the growth of murine H22 hepatoma and prolonged the survival of tumor-bearing mice. In conclusion, the poorly soluble OA could be encapsulated into MVLs to form a novel controlled-release drug delivery system. The present study may hold promise for OA-MVLs as a new dosage form for sustained-release drug delivery in cancer therapy.

Controlled-release drug delivery system based on fluocinolone acetonide-cyclodextrin inclusion complex incorporated in multivesicular liposomes.

Multivesicular liposomes (MVLs) have been widely studied for encapsulation of hydrophilic drugs due to their structural properties and large aqueous inner cavities. In this study, to investigate MVLs and their potential application for incorporation of hydrophobic drugs, new drug delivery system for fluocinolone acetonide (FA), as a lipophilic model drug, was developed combining the advantages of cyclodextrin inclusion complexes (CD-IC) and multivesicular liposomes. FA was complexed with several CDs to form inclusion complex (FA-CD-IC) and then FA-CD-IC was incorporated into MVLs by reverse-phase evaporation method. Physicochemical characterization of drug-CD-IC, at a molar ratio of 1:1 (drug to CD) was studied using 1HNMR, FT-IR, DSC and UV spectroscopy. The influence of various types of CDs on the aqueous solubility of FA, encapsulation efficiency and release profile in MVLs was studied. The results revealed the formation of inclusion complexes between the drug and CDs. Both the CD's type and proportion played an important role in the physicochemical properties of the systems. The inclusion complex of the drug with hydroxypropyl-ß-cyclodextrin exhibited the most appropriate loading and sustained-release profile over prolonged periods. The results reveal the promising potential of MVLs as a stable drug delivery system to release the drug in a sustained manner for the treatment of ocular inflammatory disease.

Determination of Content and Entrapment Efficiency of Ropivacaine Hydrochloride-loaded Multivesicular Liposomes / 中国药师

Objective:To establish a determination method for the content and entrapment efficiency of ropivacaine hydrochloride-loaded multivesicular liposomes. Methods: The separation of the multivesicular liposomes from the free drug was achieved by low-speed centrifugation. The concentration of ropivacaine hydrochloride in the supernatant and the multivesicular liposomes was determined by HPLC, and the entrapment efficiency was calculated. Results: The linear range of ropivacaine hydrochloride was 1. 0-80. 0μg· ml-1(r=0. 999 8). The average recovery was 99. 95% and RSD was 0. 72%(n=9). The content and entrapment efficiency of three batches of ropivacaine hydrochloride-loaded multivesicular liposomes was within the range of 99. 1%-100. 3% and 80. 06%-82. 14%, respectively. Conclusion:The method is simple and accurate, and can be used in the determination of content and entrapment efficien-cy of ropivacaine hydrochloride-loaded multivesicular liposomes.

Pharmacokinetics of neostigmine bromide multivesicular liposomes in rats / 第二军医大学学报

Objective To study the pharmacokinetics of neostigmine bromide multivesicular liposomes (NB-MVLs) and conventional neostigmine bromide (NB) injection in rats. Methods Twelve healthy rats, half male and half female, were randomly divided into two groups. One group was injected with NB-MVLs and the other with reference NB (0.15 mg/kg). RP-HPLC was used to examine neostigmine concentrations in rat plasma at different time points, and the pharmacokinetic parameters and relative bio-availability were calculated. Results Pharmacokinetic parameters of NB-MVLs and NB were as follows: AUC0-t (35.56±4.62) mg·h·L-1 vs (15.97±5.22) mg·h·L-1;Tmax(2.40±0.89) h vs (0.45±0.11) h; Cmax (2.49±0.31) mg/L vs (4.61±0.91) mg/L; and t1/2 (15.14± 6.81) h vs (1.79±0.27) h, respectively. AUC0-t, AUC0-∞ and Cmax were studied by DAS 2.1.1 software for double unilateral t test and [1-2α] 90% confidence interval, and Tmax was precessed by Wilcoxon nonparametric test to evaluate the bioequivalence of NB-MVLs and NB. The result showed that NB-MVLs and NB were not bioequivalent. Conclusion Neostigmine in the form of multivesicular liposomes has improved bioavailability and stable drug release; NB-MVLs and NB are not bioequivalent.