Hydrogel-thickened nanoemulsion system for topical delivery of lipophilic drugs

In this work, a hydrogel-thickened nanoemulsion system (HTN) with powerful permeation ability, good stability and suitable viscosity was investigated for topical delivery of active molecules. HTN was prepared to deliver an oily mixture of 5% camphor, 5% menthol and 5% methyl salicylate for topical therapy of arthritis, minor joint and muscle pain using soybean oil as the oil phase, soybean lecithin, Tween 80 and poloxamer 407 as the surfactants, propylene glycol as the cosurfactant, carbomer 940 as a thickening agent. The HTN system was found to combine the o/w microstructure of nanoemulsion with the gel network of hydrogel and had a suitable viscosity of 133.2PaS. The system had small average diameters and good long-term stability. The abilities of HTN to deliver the high amounts of camphor, menthol and methyl salicylate were evaluated using the in vitro permeation studies. The permeation rates of camphor, menthol and methyl salicylate from the optimal HTN formulation were 138.0+/-6.5, 63.6+/-3.3, 53.8+/-3.2 microg cm(-2) h(-1) and showed the significant advantages over the control gel. The HTN with good stability and powerful permeation enhancing ability and suitable viscosity might be a promising prospective carrier for topical delivery of lipophilic drugs.     

A novel in situ forming drug delivery system for controlled parenteral drug delivery

The objective of this study was to investigate the in vitro drug (diltiazem hydrochloride and buserelin acetate) release from different in situ forming biodegradable drug delivery systems, namely polymer solutions (in situ implants) and in situ microparticle (ISM) systems. The drug release from ISM systems [poly(d,l-lactide) (PLA) or poly(d,l-lactide-co-glycolide) (PLGA)-solution dispersed into an external oil phase] was investigated as a function of the type of solvent and polymer, polymer concentration and internal polymer phase:external oil phase ratio and was compared to the drug release from in situ implant systems and microparticles prepared by conventional methods (solvent evaporation or film grinding). Upon contact with the release medium, the internal polymer phase of the ISM system solidified and formed microparticles. The initial drug release from ISM systems decreased with increasing polymer concentration and decreasing polymer phase:external oil phase ratio. The type of biocompatible solvent also affected the drug release. It decreased in the rank order DMSO>NMP>2-pyrrolidone. In contrast to the release of the low molecular weight diltiazem hydrochloride, the peptide release (buserelin acetate) was strongly dependent on the polymer degradation/erosion. One advantage of the ISM system when compared to in situ implant systems was the significantly reduced burst effect because of the presence of an external oil phase. ISM systems resulted in drug release profiles comparable to the drug release of microparticles prepared by the solvent evaporation method. Therefore, the ISM systems are an attractive alternative to existing complicated microencapsulation methods.     

Periodontal delivery of ipriflavone: new chitosan/PLGA film delivery system for a lipophilic drug

The aim of the present work was to design a film dosage form for sustained delivery of ipriflavone into the periodontal pocket.For this purpose, monolayer composite systems made of ipriflavone loaded poly(D,L-lactide-co-glycolide) (PLGA) micromatrices in a chitosan film form, were obtained by emulsification/casting/evaporation technique. Multilayer films, made of three layers of polymers (chitosan/PLGA/chitosan), were also prepared and compared to monolayer films for their "in vitro" characteristics. Morphology and physico-chemical properties of the different systems were evaluated. The influence of pH, ionic strength and enzymatic activity on film degradation, was also investigated. Significant differences in swelling, degradation and drug release were highlighted, depending on film structure and composition. In vitro experiments demonstrated that the composite micromatricial films represent a suitable dosage form to prolong ipriflavone release for 20 days.     

Transfer of lipophilic drugs between liposomal membranes and biological interfaces: consequences for drug delivery.

This review paper describes the present knowledge on the interaction of lipophilic, poorly water soluble, drugs with liposomal membranes and the reversibility of this interaction. This interaction is discussed in the context of equilibrium and spontaneous transfer kinetics of the drug, when the liposomes are brought in co-dispersion with other artificial or natural phospholipid membranes in an aqueous medium. The focus is on drugs, which have the potential to partition (dissolve) in a lipid membrane but do not perturb membranes. The degree of interaction is described as solubility of a drug in phospholipid membranes and the kinetics of transfer of a lipophilic drug between membranes. Finally, the consequences of these two factors on the design of lipid based carriers for oral, as well as parenteral use, for lipophilic drugs and lead selection of oral lipophilic drugs is described. Since liposomes serve as model-membranes for natural membranes, the assessment of lipid solubility and transfer kinetics of lipophilic drug using liposome formulations may additionally have predictive value for bioavailability and biodistribution and the pharmacokinetics of lipophilic drugs after parenteral as well as oral administration.     

Lipid drug delivery and rational formulation design for lipophilic drugs with low oral bioavailability, applied to cyclosporine

By using a rational formulation approach, we have tried to find the general characteristics for promising self-emulsifying drug delivery systems (SEDDS) based on natural lipid components, for the oral delivery of lipophilic drugs. Galactolipids, which are polar lipids commonly found in the chloroplast membranes of green plants, and a natural part of the human diet, were the main surfactants in these formulations. This was done in three clinical studies: a screening study, followed by a prediction study and, finally, a confirmatory study; in all 17 experimental formulations were investigated. The clinical trials were performed in healthy volunteers. Cyclosporine, a well-known lipophilic peptide, was incorporated in different SEDDS, and administered orally, followed by the measurement of the blood concentration of the drug over time. The pharmacokinetic parameters, which describe the rate and extent of absorption, were estimated. We found that fractionated oat oil (FOO) and medium chain monoglycerides (60:30:10 mono-, di- and tri-glycerides) promoted absorption, and resulted in a formulation with absorption characteristics nearly equal to the commercial formulation of cyclosporine, Sandimmun Neoral^®.     

Stabilization of supersaturated solutions of a lipophilic drug for dermal delivery

The stability of supersaturated solutions of a model lipophilic drug (LAP, a lavendustin derivative) in propylene glycol-water mixtures prepared using the method of mixed cosolvents was investigated. The solutions had a fixed degree of saturation (DS=4), but contained different ratios of propylene glycol-water. The absolute concentrations of LAP in these solutions varied by approximately a factor of 40, but the solutions at lower concentrations were no more stable than the more concentrated solutions. This shows that stability is primarily a question of the degree of saturation and not of the absolute drug concentration. Solutions of up to 5 degrees of saturation in 7:3 propylene glycol-water mixture were stable when stored for several hours; those at higher degrees of saturation recrystallized immediately. When the solutions were stirred, recrystallization occurred more rapidly. The influence of various polymeric additives on the stability of the supersaturated solutions showed that only sodium carboxymethyl cellulose had a stabilizing effect; however, the solution was very viscous and it is not clear whether the stabilizing effect was due to this high viscosity or to a specific interaction between drug and polymer.     

Self-emulsifying drug delivery system and the applications in herbal drugs

Abstract

Herbal drugs have been used for thousands of years in the east and have had a recent resurgence in popularity among consumers in the west. However, most of herbal drug are poorly soluble and have hydrophobic properties and poor distribution, leading to reduced bioavailability and hence decreased treatment efficacy, requiring repeated administration or increased dose. In the past few decades, considerable attention has been focused on the development of self-emulsifying drug delivery system (SEDDS) for herbal drugs. SEDDS is isotropic and thermodynamically stable solutions consisting of oil, surfactant, co-surfactant and drug that can spontaneously form oil-in-water micro/nanoemulsion when mixed with water under gentle stirring. The formulation can be a viable alternative to classical formulations to take advantage of their lipophilic nature and to solve their problems of poor solubility, poor bioavailability, low oral absorption and instability. The mechanism of self-emulsification, solubility studies, construction of phase diagram, optimization and characterization of herbal drugs-loaded SEDDS formulation and in situ absorption evaluation of herbal drugs in rat intestine are presented in our article.     

胞内酶敏感肿瘤靶向递药体系的合成及应用

目的利用对乳腺癌肿瘤细胞MDA-MB-435内特有酶豆蛋白酶(legumain)敏感的多肽(AANL)连接阿霉素(DOX)构建具有胞内特异性释药功能的纳米递药系统,并对AANL在含有legumain环境下的断裂效率进行研究。方法将DOX用AANL修饰得到AANL-DOX(AD),再将AD连接至4-arm PEG上,最后将细胞穿膜肽(TAT)连接至4-arm PEG-AD上,制备出TAT-PEG-AD并自组装形成纳米粒(TPAD)。核磁表征TAT-PEG-AANL-DOX;粒度分析仪和透射电镜测定纳米粒的粒径及外观形貌;模拟体内、肿瘤微环境和胞内环境通过动态透析法研究legumain对AANL的断裂效率并模拟DOX的药物控释效率;细胞毒性研究TPAD对MDA-MB-435细胞的毒性作用。结果核磁共振氢谱证实TAT-PEG-AANL-DOX合成成功;测定TPAD的粒径为126.3 nm;透射电镜(TEM)观察纳米粒结构圆整,粒径为80 nm;24 h的累积释药量为82.2%;体外细胞毒性研究表明,TPAD对MDA-MB-435细胞有较好的杀伤作用,其效果接近游离DOX的细胞毒性。结论利用legumain敏感多肽连接DOX制备具有胞内特异性释药功能的纳米粒,能够有效实现肿瘤细胞内晚期内涵体和溶酶体精准释药,提高抗肿瘤药物的生物利用度,值得进一步研究。     

A novel hybrid delivery system: Polymer-oil nanostructured carrier for controlled delivery of highly lipophilic drug all-trans-retinoic acid (ATRA)

Many recently developed drugs encounter delivery issues due to their high lipophilicity and poor aqueous solubility. This study reports the development of a novel hybrid nanocarrier known as polymer-oil nanostructured carrier (PONC), in which highly lipophilic drugs such as all-trans-retinoic acid (ATRA) and indomethacin pre-solubilized in oil phase were dispersed in a polymeric matrix of poly(d,l-lactic-co-glycolic acid) (PLGA). In comparison to the standard PLGA only nanoparticles, PONC substantially increased the encapsulation efficiency of ATRA and indomethacin by up to 259% and 124%, respectively. Differential scanning calorimetry analysis revealed that the inclusion of oil introduced nanostructure into the polymeric matrix of the carrier. This feature facilitated more uniform distribution of the drug molecules which subsequently led to improved drug release kinetics with significantly reduced burst release effects (p<0.05). PONC was lyophilizable, remained physically stable when stored at low temperatures, and demonstrated low non-specific carrier toxicity. Delivery of ATRA by PONC also significantly improved its anticancer activity over the standard PLGA only nanoparticles (p<0.05). Our findings have therefore validated a promising delivery system that integrates the advantages of lipid-based (e.g. efficient encapsulation of highly lipophilic drugs) and polymeric colloidal carriers (e.g. uniform size, good stability), plus potential therapeutic benefits for delivery of poorly water-soluble anticancer drugs like ATRA.     

Development of a novel osmotically driven drug delivery system for weakly basic drugs

The drug substance SAG/ZK has a short biological half-life and because of its weakly basic nature a strong pH-dependent solubility was observed. The aim of this study was to develop a controlled release (cr) multiple unit pellet formulation for SAG/ZK with pH-independent drug release. Pellets with a drug load of 60% were prepared by extrusion/spheronization followed by cr-film coating with an extended release polyvinyl acetate/polyvinyl pyrrolidone dispersion (Kollidon SR 30 D). To overcome the problem of pH-dependent drug release the pellets were then coated with a second layer of an enteric methacrylic acid and ethyl acrylate copolymer (Kollicoat MAE 30 DP). To increase the drug release rates from the double layered cr-pellets different osmotically active ionic (sodium and potassium chloride) and nonionic (sucrose) additives were incorporated into the pellet core. Drug release studies were performed in media of different osmotic pressure to clarify the main release mechanism. Extended release coated pellets of SAG/ZK demonstrated pH-dependent drug release. Applying a second enteric coat on top of the extended release film coat failed in order to achieve pH-independent drug release. Already low enteric polymer levels on top of the extended release coated pellets decreased drug release rates at pH 1 drastically, thus resulting in a reversal of the pH-dependency (faster release at pH 6.8 than in 0.1N HCl). The addition of osmotically active ingredients (sodium and potassium chloride, and sucrose) increased the imbibing of aqueous fluids into the pellet cores thus providing a saturated drug solution inside the beads and increasing drug concentration gradients. In addition, for these pellets increased formation of pores and cracks in the polymer coating was observed. Hence drug release rates from double layered beads increased significantly. Therefore, pH-independent osmotically driven SAG/ZK release was achieved from pellets containing osmotically active ingredients and coated with an extended and enteric polymer. In contrast, with increasing osmotic pressure of the dissolution medium the in vitro drug release rates decreased significantly.     

Polymerized rosin: novel film forming polymer for drug delivery

Polymerized rosin (PR) a novel film forming polymer is characterized and investigated in the present study for its application in drug delivery. Films were produced by a casting/solvent evaporation method from plasticizer free and plasticizer containing solutions. Films prepared from different formulations were studied for their mechanical (tensile strength, percent elongation and Young's modulus), water vapour transmission and moisture absorption characteristics. Neat PR films were slightly brittle and posed the problem of breaking during handling. Hydrophobic plasticizers, dibutyl sebacate and tributyl citrate, improved the mechanical properties of free films with both the plasticizers showing significant effects on film elongation. Release of diclofenac sodium (model drug) from coated pellets was sustained with high coating levels. Concentration of plasticizer was found to affect the release profile. PR films plasticized with hydrophobic plasticizers could therefore be used in coating processes for the design of oral sustained delivery dosage forms.     

Intelligent hydrogels for drug delivery system

Intelligent hydrogel, also known as smart hydrogels, are materials with great potential for development in drug delivery system. Intelligent hydrogel also has the ability to perceive as a signal structure change and stimulation. The review introduces the temperature-, pH-, electric signal-, biochemical molecule-, light- and pressure- sensitive hydrogels. Finally, we described the application of intelligent hydrogel in drug delivery system and the recent patents involved for hydrogel in drug delivery.     

Anticancer drug delivery of PEG based micelles with small lipophilic moieties

Herein, we reported a new type of self-assembly micelles based on amphiphilic polymers of cinnamate and coumarin derivatives modified PEG for drug delivery applications. Lipophilic cinnamic acid (CIN) and 7-carboxyl methoxycoumarin (COU) were immobilized on the terminal groups of poly(ethylene glycol) (PEG) to prepare amphiphiles. The amphiphiles self-assembled into micelles. The amphiphiles and micelles were characterized by ¹H NMR, FT-IR, DLS and TEM. Doxorubicin (DOX) was used as a model drug to investigate the lipophilic moieties effects on the drug release behaviors. The DOX loaded micelles were incubated with HepG2 liver cancer cells to study the in vitro anticancer activities. The results showed that DOX could be encapsulated in the micelles efficiently. The mean diameter of the drug loaded micelles was around 100 nm. Drug release profile revealed that the release rate of DOX loaded COU-PEG-COU micelles was significantly slower than that of CIN-PEG-CIN micelles. The DOX loaded micelles could be internalized in HepG2 cells. Both CLSM and flow cytometry results showed that the DOX loaded CIN-PEG-CIN micelles exhibited better anticancer efficacy.     

Solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine for enhanced bioavailability of highly lipophilic bioactive carotenoid lutein

The objectives of this study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine (PC), an endogenous phospholipid with excellent in vivo solubilization capacity, as oil phase for the delivery of bioactive carotenoid lutein, by spray drying the SNEDDS (liquid system) containing PC using colloidal silica (Aerosil® 200 VV Pharma) as the inert solid carrier, and to evaluate the enhanced bioavailability (BA) of lutein from S-SNEDDS. The droplet size analyses revealed droplet size of less than 100 nm. The solid state characterization of S-SNEDDS by SEM, DSC, and XRPD revealed the absence of crystalline lutein in the S-SNEDDS. The bioavailability study performed in rabbits resulted in enhanced values of C_max and AUC for S-SNEDDS. The enhancement of C_max for S-SNEDDS was about 21-folds and 8-folds compared with lutein powder (LP) and commercial product (CP), respectively. The relative BA of S-SNEDDS compared with CP or LP was 2.74-folds or 11.79-folds, respectively. These results demonstrated excellent ability of S-SNEDDS containing PC as oil phase to enhance the BA of lutein in rabbits. Thus, S-SNEDDS containing PC as oil phase could be a useful lipid drug delivery system for enhancing the BA of lutein in vivo.     

Effect of curing conditions and plasticizer level on the release of highly lipophilic drug from coated multiparticulate drug delivery system

The study aimed to investigate the effect of triethyl citrate (TEC) plasticizer level (10, 15, and 20%), curing temperature (40, 50, and 60 degrees C) and time (0 to 168 h) on the release of a highly lipophilic drug bumetanide from pellets coated with methacrylate ester copolymer (Eudragit RS). Bumetanide was layered onto sugar pellets followed by coating with 6% Eudragit RS with and without hydroxypropyl methyl cellulose (HPMC) seal coat using Wurster Fluid Bed equipment. Coated pellets were stored for 3 months at room temperature and the release was tested in USP purified water. At 10% TEC level, increasing curing time and temperature lead to slower drug release. At 15 and 20% TEC levels, curing initially decreased drug release followed by increase in the release at longer curing time and higher temperature. Drug release from coated pellets plasticized with 15% TEC and completely cured followed zero order kinetic models. At plasticizer level of 20%, bumetanide release from the completely cured pellets was better modeled using the Higuchi's equation reflecting possible drug migration during curing. Storage led to an increase in drug release. The use of HPMC seal coat stabilized drug release after storage. It was concluded that bumetanide migration into Eudragit RS film coat was the main cause of the accelerated release after curing and storage. The drug migration during storage at room temperature was prevented by seal coating the pellets with HPMC.     

Novel drug delivery system using autologous fibrin glue--release properties of anti-cancer drugs

To clarify the release properties of anti-cancer drugs from fibrin glue, a study was performed using several anti-cancer drugs with remarkably different physical properties. Concentrated fibrinogen, fibronectin, and coagulation factor XIII were prepared from healthy human plasma according to the cryoprecipitate method. Fibrin glue containing anti-cancer drugs was prepared as follows; the cryoprecipitate was mixed with each anti-cancer drug and aprotinin, then thrombin was added. These glues were incubated in PBS containing plasminogen and urokinase at 37 degrees C for seven days, and the medium was then sampled several times after centrifugation. The drug concentration in each sample was measured using HPLC. Fibrin glue without aprotinin was quickly hemolyzed and disappeared after 2--4 h. That with aprotinin was only slightly hemolyzed and more than half remained after 7 days. Mitomycin C and fluorouracil were quickly released from the glue regardless of the presence or absence of aprotinin. However, enocitabine was gradually released from glue with aprotinin although quickly released from that without. The rate of release of each drug from the glue with aprotinin correlated well with its hydrophobicity. Thus, to establish a sustained release system using fibrin glue, one should use the more lipophilic anti-cancer drugs and a fibrinolytic enzyme inhibitor.     

Solid lipid nanoparticles (SLN) for topical drug delivery: incorporation of the lipophilic drugs N,N-diethyl-m-toluamide and vitamin K

Solid lipid nanoparticles (SLN) for topical delivery were prepared by high pressure homogenization using solid lipids. The lipophilic agents DEET (N,N-diethyl-m-toluamide) and vitamin K were used as model drugs. These topical agents were incorporated into SLN which were characterized. Differential scanning calorimetry studies were performed in order to detect probable interactions in the SLN dispersions. Physical stability of SLN in aqueous dispersions and the effect of drug incorporation into SLN were investigated by photon correlation spectroscopy and zeta potential measurements. Characterization and short-term stability studies showedthat DEET and vitamin K are good candidates for topical SLN formulations.