Water-in-oil-in-water double emulsions loaded with chlorogenic acid: release mechanisms and oxidative stability

Abstract

Chlorogenic acid (CA) is a natural compound used as an antioxidant in the preparation of food, drugs, and cosmetics. Due to their low stability and bioavailability, many researchers have studied the encapsulation of CA in various delivery colloidal systems. The aim of this study was to evaluate the stability of water-in-oil-in-water (W/O/W) double emulsions loaded with CA and its antioxidant capacity. For this purpose, CA-W/O/W double emulsions were prepared using Span 80 and lecithin as lipophilic emulsifiers, and Tween 20 as a hydrophilic emulsifier. The influence of nature of lipophilic emulsifiers, the presence of chitosan (CH) in the internal and external aqueous phases, pH, temperature and the storage time of W/O/W double emulsions were also investigated. Depending on the preparation conditions, the W/O/W double emulsions showed the droplet size in the range 9.13?±?0.55?μm–38.21?±?1.87?μm, the creaming index 34%–78% and the efficiency encapsulation 79.45?±?1.5%–88.13?±?1.9%. Zeta potential values were negative for the W/O/W double emulsion without CH (?36.8?±?2.02mV; ?27.3?±?1.75mV) and positive for the W/O/W double emulsions with CH in the external aqueous phase (+6.5?±?0.42mV; 28.6?±?0.92mV). The study of the release of CA from W/O/W double emulsions has highlighted two mechanisms: one based on the coalescence between the water inner droplets or between the oil globules as well as a diffusion releasing mechanism. The oxidative stability parameters of the W/O/W double emulsions, such as the peroxide value (POV) and the conjugated diene content (CD) were measured.     

口服干乳剂研究进展

干乳剂是新型的药物载体传递系统，理化稳定性好，再分散性好，能显著改善难溶性药物的溶出，增加体外释放，促进肠吸收，提高口服生物利用度。对近年来国外文献以喷雾干燥法制备干乳剂的最新研究进展，该文做了主要概述，表明喷雾干燥乳剂作为一种含油的粉末制剂，其应用前景广阔。     

Carbomer-modified spray-dried respirable powders for pulmonary delivery of salbutamol sulphate

Abstract

The present study investigates the feasibility of using two types of carbomer (971 and 974) to prepare inhalable dry powders that exhibit modified drug release properties. Powders were prepared by spray-drying formulations containing salbutamol sulphate, 20–50% w/w carbomer as a drug release modifier and leucine as an aerosolization enhancer. Following physical characterization of the powders, the aerosolization and dissolution properties of the powders were investigated using a Multi-Stage Liquid Impinger and a modified USP II dissolution apparatus, respectively. All carbomer 974-modified powders and the 20% carbomer 971 powder demonstrated high dispersibility, with emitted doses of at least 80% and fine particle fractions of ～40%. The release data indicated that all carbomer-modified powders displayed a sustained release profile, with carbomer 971-modified powders obeying first order kinetics, whereas carbomer 974-modified powders obeyed the Higuchi root time kinetic model; increasing the amount of carbomer 971 in the formulation did not extend the duration of drug release, whereas this was observed for the carbomer 974-modified powders. These powders would be anticipated to deposit predominately in the lower regions of the lung following inhalation and then undergo delayed rather than instantaneous drug release, offering the potential to reduce dosing frequency and improve patient compliance.     

Formulation and characterization of clozapine and risperidone co-entrapped spray-dried PLGA nanoparticles

In the current study, polylactide-co-glycolide (PLGA) nanoparticles entrapping both clozapine (CLZ) and risperidone (RIS) were formulated by spray-drying using Buchi Nano Spray Dryer B-90 (Flawil, Switzerland). Parameters such as inlet temperature, spray mesh diameter, sample flow rate, spray rate and applied pressure were optimized to produce nanoparticles having desired release profile using both low- and high-molecular weight PLGA polymer. Smallest size nanoparticle of size around 248?nm could be prepared using a 4.0 μm mesh diameter with low-molecular weight polymer. The load of CLZ and RIS was 126.3 and 58.2?μg/mg of polymer particles, respectively. Entrapment efficiency of drugs in PLGA nanoparticles was 94.74% for CLZ and 93.12% for RIS. Both the drugs released continuously from the nanoparticle formulations. PLGA nanoparticles formulated using low-molecular weight polymer released around 80% of the entrapped drug over 10 days of time. Nature of drug inside polymer particles was amorphous, and there was no chemical interaction of CLZ and RIS with polymer. Polymeric nanoparticles were found to be non-toxic in nature using PC12 cell line. This nanospray drying process proved to be suitable for developing polymeric nanoformulation delivering dual drugs for the treatment of Schizophrenia.     

An improvement of double emulsion technique for preparing bovine serum albumin-loaded PLGA microspheres

A modified double emulsion technique was adopted to prepare bovine serum albumin (BSA) loaded poly (D,l-lactic-co-glycolic acid) (PLGA) microspheres. In the formulations, polysorbates (Tween) such as Tween20®, Tween40® or Tween80®, instead of frequently used poly (vinyl alcohol) (PVA), was used as the emulsifier. Microspheres with porous surface, large particle size, low microsphere yield (～65.4%) and BSA entrapment efficiency (～25.2%) were obtained when Tween80® aqueous solution alone was used as the outer aqueous phase. However, microspheres with smooth surface, high yield and BSA entrapment efficiency could be produced successfully by introducing sodium chloride or glucose into the outer aqueous phase. Adding 5.0%(w/v) sodium chloride into the continuous phase led to increase in microsphere yield and BSA entrapment efficiency from 65.4% and 25.2% to ～100% and 76.6%, respectively. Microsphere yield and BSA entrapment efficiency increased from 64.5% and 25.2% to 97.2% and 89.3%, respectively, when 15.0%(w/v) glucose was added into the continuous phase. In constrast to the microspheres prepared in the presence of additive, a more marked burst release was observed for microspheres prepared without additive in the continuous phase, which may be attributed to the porous morphology of the latter.     

口服喷雾干燥乳剂处方筛选

目的优化喷雾干燥乳剂处方。方法联用羟丙甲纤维素（HPMC）和蔗糖作固体载体,椰子油作油相,采用喷雾干燥工艺制备O/W型干乳剂。结果根据乳化性能及喷雾可操作性筛选出适于采用喷雾干燥法制备干乳剂的处方。即固体载体HPMC适宜黏度为3mPa.s,浓度为8%。结论HPMC的黏度和浓度对液体O/W乳剂的稳定性及经喷雾干燥制成干乳剂有一定影响,含高黏度HPMC的液体O/W乳剂不容易雾化,易堵塞雾化器的喷嘴。低黏度HPMC是一种有用的固体载体,并起到一定的乳化作用。     

Formulation and characterization of triclosan sub-micron emulsions and nanocapsules

Triclosan, a non-ionic, broad spectrum anti-microbic agent, has recently demonstrated its effectiveness as an anti-malarial drug by inhibition of the growth of Plasmodium Falciparum. The aim of this work was to formulate suitable triclosan colloidal carriers with the final objective of obtaining a drug delivery system suitable for a potential anti-malarial oral treatment. Two different nanotechnological approaches were experimented with that could be suitable for developing effective triclosan formulations against this established and re-emerging infectious disease. Sub-micron emulsions were prepared by the solvent displacement method, using different oily amounts in order to vary the drug amount entrapped in the formulation. Chitosan-coated nanocapsules were obtained with chitosan hydrochloride at two different viscosity degrees (Cl 113 and Cl 213). All formulations were appropriately characterized by determining drug loading capacity and encapsulation efficiency and measuring particle size and zeta potential. Morphological characterization of the different systems was performed by TEM analysis, whereas release studies were carried out by reverse bag dialysis method. All preparations resulted stable. Cl 113-coated nanocapsules appeared particularly suitable as triclosan carriers for obtaining a systemic drug release, owing to both chitosan's good mucoadhesive and enhancer properties as well as the effectiveness shown by its coating in adequately controlling drug release rate.     

In vitro release characteristics and cellular uptake of poly(D,L-lactic-co-glycolic acid) nanoparticles for topical delivery of antisense oligodeoxynucleotides

The efficacy of antisense oligodeoxynucleotides (AsODNs) is compromised by their poor stability in biological fluids and the inefficient cellular uptake due to their size and negative charge. Since chemical modifications of these molecules have resulted in a number of non-antisense activities, incorporation into particulate delivery systems has offered a promising alternative. The aim of this study was to evaluate various poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles for AsODN entrapment and delivery. PLGA nanoparticles were prepared using the double emulsion solvent evaporation method. The influence of formulation parameters such as PLGA concentration and volume ratio of internal aqueous phase volume (Va1) to organic phase volume (Vo) to external aqueous phase volume (Va2) on particle size, polydispersity index (PDI) and zeta potential (ZP) was investigated using a full factorial study. The particle size increased with increasing PLGA concentrations and volume ratios, with an interaction detectable between the two factors. AsODN entrapment efficiencies ranged between 49.97% and 54.95% with no significant difference between various formulations. By fitting the in vitro release profiles to a dual first order release model it was shown that the AsODN release occurred via two processes: a diffusion controlled process in the early phase (25 to 32% within one day) and a PLGA degradation process in the latter (39 to 70% after 14 days). Cellular uptake studies using primary corneal epithelial cells suggested active transport of nanoparticles via endocytosis. PLGA nanoparticles therefore show potential to successfully entrap AsODNs, transport them into cells and release them over time due to polymer erosion.     

Formulation of pH responsive peptides as inhalable dry powders for pulmonary delivery of nucleic acids

Nucleic acids have the potential to be used as therapies or vaccines for many different types of disease, but delivery remains the most significant challenge to their clinical adoption. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar lavage fluid (BALF), making this class of peptides attractive candidates for delivering nucleic acids to lung tissues. To further assess the suitability of pH responsive peptides for pulmonary delivery by inhalation, dry powder formulations of pH responsive peptides and plasmid DNA, with mannitol as carrier, were produced by either spray drying (SD) or spray freeze drying (SFD). The properties of the two types of powders were characterised and compared using scanning electron microscopy (SEM), next generation impactor (NGI), gel retardation and in vitro transfection via a twin stage impinger (TSI) following aerosolisation by a dry powder inhaler (Osmohaler™). Although the aerodynamic performance and transfection efficacy of both powders were good, the overall performance revealed SD powders to have a number of advantages over SFD powders and are the more effective formulation with potential for efficient nucleic acid delivery through inhalation.     

Excipient-free nanoporous microparticles of budesonide for pulmonary delivery

The aim of this study was to investigate the application of a spray-drying process for the production of nanoporous microparticles (NPMPs) to budesonide, and to characterise the particles produced in terms of their suitability for pulmonary delivery.Budesonide was spray dried with and without ammonium carbonate from ethanol/water or methanol/water solutions. The solid-state characteristics and micromeritic (particle size, density, surface area) properties of spray dried powders were assessed. In vitro deposition studies were performed to assess aerosol performance.The densities of the NPMPs were significantly lower and the surface areas significantly higher than for non-porous spray dried or micronised material. NPMPs of budesonide demonstrated improved aerosolisation properties compared to spray dried non-porous, micronised material and two budesonide commercial products. All spray dried materials were amorphous in nature. The glass transition temperature (90 °C) was sufficiently high to suggest good physical stability at room temperature. When stored at 25 °C/60% RH NPMPs showed a reduced tendency to recrystallise compared to the equivalent non-porous spray dried powder. The physical stability and amorphous nature of NPMPs was retained, under these storage conditions for at least one year and the in vitro aerosolisation properties were not affected by the storage conditions.Excipient-free porous microparticles, prepared by the novel process described, show good potential for drug delivery by oral inhalation with improved in vitro deposition properties compared to non-porous particles.     

Preparation,characterization and in vitro intestinal absorption of a dry emulsion formulation containing atorvastatin calcium

A redispersible dry emulsion (DE) formulation of atorvastatin calcium (AC) was developed to enhance the in vitro dissolution of AC, thereby increasing its gastrointestinal absorption. The spray-drying technology was used where Plurol Oleique CC 497 was chosen as the oil phase. Effects of carriers, surfactants, and homogenizers on the characteristics of DE containing AC were systematically investigated. The final formulation consisted of dextrin and Poloxamer 188 as carrier and surfactant, respectively, and was homogenized by a high pressure homogenizer before spray drying. The in vitro release of AC from the optimized DE was significantly higher than that of pure AC powder (76% vs. 30% at 24 hr). The in vitro intestinal absorption of AC from the DE formulation was 0.77 μg/cm² at 2 hr, which was a 2.33-fold increase compared to the pure unformulated AC powder. These results suggest that the oral dry emulsion formulation could improve the intestinal absorption of AC.     

Formulation of inhalable lipid-based salbutamol sulfate microparticles by spray drying technique

Background

The aim of this work was to develop dry powder inhaler (DPI) formulations of salbutamol sulfate (SS) by the aid of solid lipid microparticles (SLmPs), composed of biocompatible phospholipids or cholesterol.

Methods

The SLmPs were prepared by using two different solvent systems (ethanol and water-ethanol) and lipid carriers (dipalmitoylphosphatidylcholine (DPPC) and cholesterol) with/without L-leucine in the spray drying process. The spray-dried microparticles were physically-mixed with coarse lactose monohydrate in order to make our final DPI formulations and were investigated in terms of physical characteristics as well as in vitro drug release profile and aerosolization behavior.

Results

We observed significant differences in the sizes, morphologies, and in vitro pulmonary depositions between the formulations. In particular, the SS-containing SLmPs prepared with water-ethanol (30:70 v/v) solution of DPPC and L-leucine which had then been blended with coarse lactose (1:9 w/w) exhibited the highest emitted dose (87.9%) and fine particle fraction (42.7%) among the formulations. In vitro drug release study indicated that despite of having a significant initial burst release for both cholesterol and DPPC-based microparticles, the remained drug released more slowly than the pure drug.

Conclusion

This study demonstrated the potential of using lipid carriers as well as L-leucine in DPI formulations of SS to improve its aerosolization behavior and retard the release profile of the drug.     

含药干乳的研究概况

介绍近年来国内外有关含药干乳的研究概况，综述干乳的若干制备方法（包括喷雾干燥法、冷冻干燥法、减压蒸馏法和吸干法）、稳定性影响因索及应用前景，为干乳这种新型药物传递系统的研究提供参考。     

Formulation and development of metered dose inhalations of salbutamol in solution form

In the present study attempts were made to prepare metered dose inhalation of salbutamol in solution form and compared it with the marketed metered dose inhalation in suspension form. Solution form of the drug was found better than marketed suspension formulation with respect to homogeneity and content uniformity. Propellant blend P-11 and P-12 in the proportion 30:70 was selected as it gave optimum vapour pressure. Surfactant oleic acid in concentration 10 mg per can was selected as it gave best results with clarity, spray pattern, vapour pressure, content per spray and rate of evaporation. Ethyl alcohol 2 ml per can was used as a cosolvent to give a clear solution, optimum vapour pressure, maximum content per spray and fair rate of evaporation. The selected formulation was subjected to the physico-chemical evaluation tests as per the standard pharmacopoeial procedures and the characteristics of the formulations were further compared with a conventional marketed formulation. In vitro study reveled the net respirable fraction was better than marketed preparation.     

Sustained delivery of timolol maleate from poly(lactic-co-glycolic acid)/poly(lactic acid) microspheres for over 3 months

Abstract

It is estimated that 2.2 million people have glaucoma in the US and 67 million people worldwide. The majority of cases are associated with elevated intraocular pressure (IOP) and decreasing IOP eliminates or greatly reduces degeneration in most cases, including cases in which the IOP is in the normal range but optic neuropathy occurs. Timolol maleate has the longest record of safety and efficacy to lower IOP and is administered via eye drops one or more times per day. Unfortunately, compliance is poor across patient populations leading to degeneration. Patients typically see their ophthalmologist once every 3–4 months. If one could administer a long-acting treatment while in the doctor's office, one might overcome the compliance issue and effectively preserve sight. The critical step is to develop a formulation for timolol maleate that leads to sustained delivery for greater than 90 days and would permit a different treatment paradigm, namely subconjunctival administration once every 3–4 months. By using a 50 : 50 blend of PLGA 502H and PLA, this study was able to fabricate microspheres that delivered timolol maleate continually over 107 days, well within the time frame needed to make subconjunctival administration feasible and permit a new approach to treating glaucoma and diseases of the eye more broadly.     

Formulation,characterization and evaluation of cyclodextrin-complexed bendamustine-encapsulated PLGA nanospheres for sustained delivery in cancer treatment

PLGA nanospheres are considered to be promising drug carrier in the treatment of cancer. Inclusion complex of bendamustine (BM) with epichlorohydrin beta cyclodextrin polymer was prepared by freeze-drying method. Phase solubility study revealed formation of A_L type complex with stability constant (Ks?=?645?M^?1). This inclusion complex was encapsulated into PLGA nanospheres using solid-in-oil-in-water (S/O/W) technique. The particle size and zeta potential of PLGA nanospheres loaded with cyclodextrin-complexed BM were about 151.4?±?2.53?nm and???31.9?±?(?3.08)?mV. In-vitro release study represented biphasic release pattern with 20% burst effect and sustained slow release. DSC studies indicated that inclusion complex incorporated in PLGA nanospheres was not in a crystalline state but existed in an amorphous or molecular state. The cytotoxicity experiment was studied in Z-138 cells and IC₅₀ value was found to be 4.3?±?0.11?µM. Cell viability studies revealed that the PLGA nanospheres loaded with complex exerts a more pronounced effect on the cancer cells as compared to the free drug. In conclusion, PLGA nanospheres loaded with inclusion complex of BM led to sustained drug delivery. The nanospheres were stable after 3 months of storage conditions with slight change in their particle size, zeta potential and entrapment efficiency.     

三氯生水凝胶乳化抗菌剂在兔膝损伤关节腔内药代动力学的实验研究

目的:通过对4种三氯生水凝胶乳剂进行对比分析,比较不同乳剂给药后,兔关节腔的三氯生水平和作用时间。方法:实验分为三氯生乳剂组(对照组)、三氯生透明质酸乳剂组、三氯生几丁糖乳剂组、三氯生透明质酸几丁糖聚合水凝胶乳剂组,选取同窝雄兔32只(64膝)随机分为4组(A、B、C、D),每组8只(16膝),双膝手术,术后第7 d同时给药,分别于给药后6 h、12 h、24 h、48 h抽取关节液0.5 mL,采用高效液相色谱分析比较4种乳剂在兔损伤膝关节腔关节液内三氯生浓度及作用时间。结果:各组关节液三氯生维持时间无明显差异。各组关节液三氯生峰浓度比较:①对照组[三氯生乳剂组,(8.601±0.067)mg.mL-1]显著高于其他各组(P<0.05);②透明质酸组[(5.751±0.018)mg.mL-1]低于几丁糖组[(6.003±0.155)mg.mL-1]及聚合水凝胶组[(7.026±0.137)mg.mL-1],但仅对聚合水凝胶组有显著性意义(P<0.05)。各组关节液三氯生平均浓度比较:①对照组[(5.141±0.056)mg.mL-1]显著高于其他各组(P<0.05);②几丁糖组[(3.687±0.018)m...     

Redispersible spray-dried lipid-core nanocapsules intended for oral delivery: the influence of the particle number on redispersibility

Abstract

This study proposes a new approach to produce easily redispersible spray-dried lipid-core nanocapsules (LNC) intended for oral administration, evaluating the influence of the particle number density of the fed sample. The proposed approach to develop redispersible spray-dried LNC formulations intended for oral route is innovative, evidencing the needing of an optimization of the initial particle number density in the liquid suspension of nanocapsules. A mixture of maltodextrin and L-leucine (90:10 w/w) was used as drying adjuvant. Dynamic light scattering, turbidimetry, determination of surface area and pore size distribution, electron microscopy and confocal Raman microscopy (CRM) were used to characterize the proposed system and to better understand the differences in the redispersion behavior. An easily aqueous redispersion of the spray-dried powder composed of maltodextrin and L-leucine (90:10 w/w) was obtained, depending on the particle number density. Their surface area decreased in the presence of LNC. CRM enabled the visualization of the spatial distribution of the different compounds in the powders affording to better understand the influence of the particle number density of the fed sample on their redispersion behavior. This study shows the need for optimizing initial particle number density in the liquid formulation to develop redispersible spray-dried LNC powders.     

Formulation of ciprofloxacin hydrochloride loaded biodegradable nanoparticles: optimization of technique and process variables

Abstract

Poly lactic-co-glycolic acid (PLGA 502 H) nanoparticles incorporating ciprofloxacin HCl (CP) were prepared by double emulsion solvent diffusion technique.

Methods: The influence of the application of probe sonication besides the high pressure homogenization in the preparation of the secondary emulsion and its application during the solidification step were studied. Their effect on the particle size, Zeta potential and the percent encapsulation efficiency of the drug (EE %) were investigated. The effect of the addition of polyvinyl alcohol (PVA) during the preparation of the primary emulsion was studied. Moreover, the effect of the addition of 0.1?M sodium chloride and/or adjusting the external and extracting phases to pH 7.4 were investigated. The selected formula was examined using IR, X-ray, DSC and SEM and in vitro drug release.

Results: These formulations showed an appropriate particle size ranges between 135.7–187.85?nm, a mean zeta potential ranging from ?0.839 to ?6.81?mV and a mean EE% which ranged from 35% to 69%.

Conclusion: The presented data revealed the superiority of using probe sonication besides high pressure homogenization during the formation of secondary emulsion. Moreover, the results indicated that the tested factors had a pronounced significant effect on the EE%.     

Physical characteristics and aerosol performance of naringin dry powders for pulmonary delivery prepared by spray-drying

The aim of the present work was to develop dry powders containing naringin for a direct administration to the lung to combat oxidative stress. Naringin microparticles were prepared by spray-drying the neat flavonoid (2-5% w/v) from different water/ethanol co-solvents. The spray-dried powders were characterised for morphology, density, particle size distribution, residual humidity, crystallinity, solubility, thermal behaviour and respirable fraction.The fine fraction of the powders was measured by single-stage glass impinger and Andersen cascade impactor, using the Turbospin^® device for the deposition tests, wherein the dose to be aerosolised was premetered in a gelatine capsule.By increasing the ethanol content, the feed liquid turned from a suspension into a solution: the spray of flavonoid suspensions led to powders with high crystallinity degree, low water solubility and high bulk density, while the spray of drug solutions led to more amorphous particles, with higher solubility, lower density and improved aerodynamic behaviour.The optimisation of the operative parameters produced enhanced aerosol performance of the flavonoid powders containing only the active compound.