Ljiljana Djekic

Characterization and evaluation of solid self-microemulsifying drug delivery systems with porous carriers as systems for improved carbamazepine release

The purpose of this study was to investigate solid self-microemulsifying drug delivery system (SSMEDDS), as potential delivery system for poorly water soluble drug carbamazepine (CBZ). Self-microemulsifying drug delivery system (SMEDDS) was formulated using the surfactant polyoxyethylene 20 sorbitan monooleate [Polysorbate 80] (S), the cosurfactant PEG-40 hydrogenated castor oil [Cremophor(®) RH40] (C) and the oil caprylic/capric triglycerides [Mygliol(®) 812] (O). Four different adsorbents with high specific surface area were used: Neusilin(®) UFL2, Neusilin(®) FL2 (magnesium aluminometasilicate), Sylysia(®) 320 and Sylysia(®) 350 (porous silica). Microemulsion area at the surfactant to cosurfactant ratio (K(m)) 1:1 was evaluated and for further investigation SMEDDS with SC/O ratio 8:2 was selected. Solubilization capacity of selected SMEDDS for CBZ was 33.771±0.041 mg/ml. Rheological measurements of unloaded and CBZ-loaded SMEDDS at water content varied from 10 to 60% (w/w) were conducted. It has been found that CBZ has great influence on rheological behaviour of investigated system upon water dilution. Photon correlation spectroscopy has shown the ability of CBZ-loaded SMEDDS to produce microemulsion droplet size. SSMEDDS improved release rate of CBZ, but the type of adsorbent significantly affects release rate of CBZ. For SSMEDDS with different magnesium aluminometasilicate adsorbents, release rate of CBZ decreased with increasing specific surface area due to entrapment of liquid SMEDDS inside the pores and its gradual exposure to dissolution medium. With porous silica adsorbents no difference in release rate was found in comparison to physical mixtures. In physical mixtures at 12.5% (w/w) CBZ content, presence of amorphous CBZ led to high dissolution rate.

Investigation of surfactant/cosurfactant synergism impact on ibuprofen solubilization capacity and drug release characteristics of nonionic microemulsions

The current study investigates the performances of the multicomponent mixtures of nonionic surfactants regarding the microemulsion stabilisation, drug solubilization and in vitro drug release kinetic. The primary surfactant was PEG-8 caprylic/capric glycerides (Labrasol). The cosurfactants were commercially available mixtures of octoxynol-12 and polysorbate 20 without or with the addition of PEG-40 hydrogenated castor oil (Solubilisant gamma 2421 and Solubilisant gamma 2429, respectively). The oil phase of microemulsions was isopropyl myristate. Phase behaviour study of the pseudo-ternary systems Labrasol/cosurfactant/oil/water at surfactant-to-cosurfactant weight ratios (K(m)) 40:60, 50:50 and 60:40, revealed a strong synergism in the investigated tensides mixtures for stabilisation of microemulsions containing up to 80% (w/w) of water phase at surfactant +cosurfactant-to-oil weight ratio (SCoS/O) 90:10. Solubilization of a model drug ibuprofen in concentration common for topical application (5%, w/w) was achieved at the water contents below 50% (w/w). Drug free and ibuprofen-loaded microemulsions M1-M6, containing 45% (w/w) of water phase, were prepared and characterized by polarized light microscopy, conductivity, pH, rheological and droplet size measurements. In vitro ibuprofen release kinetics from the microemulsions was investigated using paddle-over-enhancer cell method and compared with the commercial 5% (w/w) ibuprofen hydrogel product (Deep Relief, Mentholatum Company Ltd., USA). The investigated microemulsions were isotropic, low viscous Bingham-type liquids with the pH value (4.70-6.61) suitable for topical application. The different efficiency of the tensides mixtures for microemulsion stabilisation was observed, depending on the cosurfactant type and K(m) value. Solubilisant gamma 2429 as well as higher K(m) (i.e., lower relative content of the cosurfactant) provided higher surfactant/cosurfactant synergism. The drug molecules were predominantly solubilized within the interface film. The amount of drug released from the formulations M3 (10.75%, w/w) and M6 (13.45%, w/w) (K(m) 60:40) was limited in comparison with the reference (22.22%, w/w) and follows the Higuchi model. Microemulsions M2 and M5 (K(m) 50:50) gave zero order drug release pattern and ∼15% (w/w) ibuprofen released. The release profiles from microemulsions M1 and M4 (K(m) 40:60) did not fit well with the models used for analysis, although the amounts of ibuprofen released (24.47%, w/w) and 17.99% (w/w), respectively) were comparable to that of the reference hydrogel. The drug release mechanism was related with the surfactant/cosurfactant synergism, thus the lower efficiency of the tensides corresponded to the faster drug release.

The application of artificial neural networks in the prediction of microemulsion phase boundaries in PEG-8 caprylic/capric glycerides based systems.

The objective of this study was to develop artificial neural network (ANN) model suitable to predict successfully the borders of the microemulsion region in the quaternary system PEG-8 caprylic/capric glycerides (Labrasol)/cosurfactant/isopropyl myristate/water, in order to minimise experimental effort. In our preliminary investigations of phase behaviour, two cosurfactants were used, PEG-40 hydrogenated castor oil (Cremophor) RH 40) and polyglyceryl-6 isostearate (Plurol Isostearique). Microemulsion existance area in pseudo-ternary phase diagrams was determined using titration method at constant: (a) oil-to-water ratio (alpha=50%, w/w); (b) surfactant-to-cosurfactant ratio (Km) 4:6; (c) Km 5:5; or (d) Km 6:4. It was found that the phase behaviour of systems involving polyoxyethylene type of cosurfactant depends significantly on oil-to-surfactant/cosurfactant mixture mass ratio (O/SCoS) but it is Km-independent. The formation of microemulsions in Labrasol/polyglyceryl-6 isostearate based systems was a complex function of Km and O/SCoS and there was employed a Generalized Regression Neural Network (GRNN) with four layers as a predictive mathematical model, using data obtained from the phase behaviour study (the surfactant concentration in surfactant/cosurfactant mixture (S, %, w/w), the oil concentration in the mixture with tensides (O, %, w/w) as two input variables, and the water solubilization limit (W(max), %, w/w) as output data). After network training, six independent pairs of input/output data were used for network testing. The resulting GRNN was tested statistically and found to be of quality predictive power. This results confirmed that the trained GRNN could be effective in predicting the size of the microemulsion area providing valuable tool in formulation of this type of colloidal vehicles.

Characterization of gelation process and drug release profile of thermosensitive liquid lecithin/poloxamer 407 based gels as carriers for percutaneous delivery of ibuprofen.

Suitability of liquid lecithin (i.e., solution of lecithin in soy bean oil with ∼ 60% w/w of phospholipids) for formation of gels, upon addition of water solution of poloxamer 407, was investigated, and formulated systems were evaluated as carriers for percutaneous delivery of ibuprofen. Formulation study of pseudo-ternary system liquid lecithin/poloxamer 407/water at constant liquid lecithin/poloxamer 407 mass ratio (2.0) revealed that minimum concentrations of liquid lecithin and poloxamer 407 required for formation of gel like systems were 15.75% w/w and 13.13% w/w, respectively, while the maximum content of water was 60.62% w/w. The systems comprising water concentrations in a range from 55 to 60.62% w/w were soft semisolids suitable for topical application, and they were selected for physicochemical and biopharmaceutical evaluation. Analysis of conductivity results and light microscopy examination revealed that investigated systems were water dilutable dispersions of spherical oligolamellar associates of phospholipids and triglyceride molecules in the copolymer water solution. Rheological behavior evaluation results indicated that the investigated gels were thermosensitive shear thinning systems. Ibuprofen (5% w/w) was incorporated by dispersing into the previously prepared carriers. Drug-loaded systems were physically stable at storage temperature from 5 ± 3°C to 40 ± 2°C, for 30 days. In vitro ibuprofen release was in accordance with the Higuchi model (rH>0.95) and sustained for 12h. The obtained results implicated that formulated LLPBGs, optimized regarding drug release and organoleptic properties, represent promising carriers for sustained percutaneous drug delivery of poorly soluble drugs.

Formulation of hydrogel-thickened nonionic microemulsions with enhanced percutaneous delivery of ibuprofen assessed in vivo in rats.

The study investigated usage of hydrogel of an anionic polymer xanthan gum for design of ibuprofen-loaded hydrogel-thickened microemulsions (HTMs) from the nonionic oil-in-water microemulsion (M). Xanthan gum demonstrated the performances of a thickening agent in physically stable HTMs at 5±3°C, 20±3°C, and 40±1°C during 6months. The results of physicochemical characterization (pH, conductivity, rheological behaviour, spreadability) indicated that HTMs containing 0.25-1.00% of the polymer had colloidal structure with oil nanodroplets of 14.34±0.98nm (PdI 0.220±0.075) dispersed in aqueous phase thickened with the polymer gel network which strength depended on the polymer concentration. HTMs with ibuprofen (5%) were evaluated as percutaneous drug delivery carriers. In vitro ibuprofen release from HTMs followed zero order kinetic (r>0.995) for 12h, while the referent hydrogel was described by Higuchi model. The HTM with optimized drug release rate and spreadability (HTM1) and the polymer-free microemulsion (M) were assessed and compared with the referent hydrogel in in vivo studies in rats. HTM1 and M were significantly more efficacious than reference hydrogel in producing antihyperalgesic and at lower extent antiedematous activity in prophylactic topical treatment protocol, whilst they were comparable in producing antihyperalgesic/antiedematous effects in therapeutic protocol. Topical treatments produced no obvious skin irritation.

Evaluation of critical formulation parameters in design and differentiation of self-microemulsifying drug delivery systems (SMEDDSs) for oral delivery of aciclovir.

The study investigated the influence of formulation parameters for design of self-microemulsifying drug delivery systems (SMEDDSs) comprising oil (medium chain triglycerides) (10%), surfactant (Labrasol(®), polysorbate 20, or Kolliphor(®) RH40), cosurfactant (Plurol(®) Oleique CC 497) (q.s. ad 100%), and cosolvent (glycerol or macrogol 400) (20% or 30%), and evaluate their potential as carriers for oral delivery of a poorly permeable antivirotic aciclovir (acyclovir). The drug loading capacity of the prepared formulations ranged from 0.18-31.66 mg/ml. Among a total of 60 formulations, three formulations meet the limits for average droplet size (Z-ave) and polydispersity index (PdI) that have been set for SMEDDSs (Z-ave≤100nm, PdI<0.250) upon spontaneous dispersion in 0.1M HCl and phosphate buffer pH 7.2. SMEDDSs with the highest aciclovir loading capacity (24.06 mg/ml and 21.12 mg/ml) provided the in vitro drug release rates of 0.325 mg cm(-2)min(-1) and 0.323 mg cm(-2)min(-1), respectively, and significantly enhanced drug permeability in the parallel artificial membrane permeability assay (PAMPA), in comparison with the pure drug substance. The results revealed that development of SMEDDSs with enhanced drug loading capacity and oral delivery potential, required optimization of hydrophilic ingredients, in terms of size of hydrophilic moiety of the surfactant, surfactant-to-cosurfactant mass ratio (Km), and log P of the cosolvent.

Design of Block Copolymer Costabilized Nonionic Microemulsions and Their In Vitro and In Vivo Assessment as Carriers for Sustained Regional Delivery of Ibuprofen via Topical Administration

Nonionic surfactants (caprylocaproyl macrogol-8 glycerides, octoxynol-12, polysorbate-20, and polyethylene glycol-40 hydrogenated castor oil) (47.03%, w/w), costabilizer (poloxamer 407) (12%-20%, w/w), oil (isopropyl myristate) (5.22%, w/w), water (q.s. ad 100%, w/w), and ibuprofen (5%, w/w) were used to develop oil-in-water microemulsions with Newtonian flow behavior, low viscosity (from 368 ± 38 to 916 ± 46 mPa s), and average droplet size from 14.79 ± 0.31 to 16.54 ± 0.75 nm. Ibuprofen in vitro release from the microemulsions was in accordance with zero-order kinetics (R0(2) > 0.99) for at least 12 h. The maximum drug release rate (3.55%h(-1) ) was from the microemulsion M3 comprising 16%, w/w of poloxamer 407. The release rate of ibuprofen from the reference hydrogel followed Higuchi kinetics (RH(2) > 0.99), and drug amount released after the 6th hour was negligible. In a rat model of inflammation, the microemulsion M3 was significantly more efficacious than the reference hydrogel in exerting antihyperalgesic effects in prophylactic topical treatment, whereas they were comparable in therapeutic treatment as well as in producing antiedematous effect in both protocols. No obvious skin irritation was observed in in vivo studies. The developed nonionic surfactants-based microemulsions containing the optimal concentration of poloxamer 407 could be promising carriers for sustained regional delivery of ibuprofen via topical administration.

Water-Dilutable Biocompatible Microemulsion Systems: Design and Characterisation

Abstract The present study describes a screening approach in design of microemulsion preconcentrates (self-microemulsifying systems) comprising: PEG-8 caprylic/capric glycerides (Labrasol®) (surfactant), PEG-40 hydrogenated castor oil (Cremophor® RH40) (cosurfactant) (at surfactant-to-cosurfactant mass ratios 9:1, 7:3, 5:5, 3:7 and 1:9), and 10% w/w or 20% w/w of medium-chain triglycerides or olive oil (oil). The self-microemulsifying ability of the prepared surfactant/cosurfactant/oil mixtures in water and 0.1 M HCl (pH 1.2), was evaluated by droplet size and zeta potential analysis and cross-polarized light microscopy. The formation of microemulsions was observed only in the presence of medium-chain triglycerides at surfactant-to-cosurfactant ratios 7:3 and 5:5 (in the mixtures containing 10% w/w of the oil phase) and 3:7 and 1:9 (when 20% w/w of the same oil was used). The obtained results provide new implications for development of microemulsion preconcentrates suitable as delivery systems for food and pharmaceutical applications.

Development of semisolid self-microemulsifying drug delivery systems (SMEDDSs) filled in hard capsules for oral delivery of aciclovir

The study aimed to develop semisolid self-microemulsifying drug delivery systems (SMEDDSs) as carriers for oral delivery of aciclovir in hard hydroxypropylmethyl cellulose (HPMC) capsules. Six self-dispersing systems (SD1-SD6) were prepared by loading aciclovir into the semisolid formulations consisting of medium chain length triglycerides (lipid), macrogolglycerol hydroxystearate (surfactant), polyglyceryl-3-dioleate (cosurfactant), glycerol (hydrophilic cosolvent), and macrogol 8000 (viscosity modifier). Their characterization was performed in order to identify the semisolid system with rheological behaviour suitable for filling in hard HPMC capsules and fast dispersibility in acidic and alkaline aqueous media with formation of oil-in-water microemulsions. The optimal SMEDDS was loaded with aciclovir at two levels (2% and 33.33%) and morphology and aqueous dispersibility of the obtained systems were examined by applying light microscopy and photon correlation spectroscopy (PCS), respectively. The assessment of diffusivity of aciclovir from the SMEDDSs by using an enhancer cell model, showed that it was increased at a higher drug loading. Differential scanning calorimetry (DSC) analysis indicated that the SMEDDSs were semisolids at temperatures up to 50°C and physically stable and compatible with HPMC capsules for 3 months storage at 25°C and 4°C. The results of in vitro release study revealed that the designed solid dosage form based on the semisolid SMEDDS loaded with the therapeutic dose of 200mg, may control partitioning of the solubilized drug from in situ formed oil-in-water microemulsion carrier into the sorrounding aqueous media, and hence decrease the risk for precipitation of the drug.

Polyphenolics-Phospholipid Complexes as Natural Cosmetic Ingredients: Properties and Application

Abstract Phospholipids and polyphenolic phytoconstituents may form specific molecular complexes (polyphenolics-phospholipid complexes, phyto-phospholipid complexes) with definite chemical structure, solubility, thermal and spectroscopic characteristics. Furthermore, such specific molecular entities may self-associate into spherical unilamellar vesicles (phyto-vesicles, herbosomes) with size at nano- or microscale. Phyto-phospholipid complexation was recognised as a promising strategy to improve formulation performances and enhance efficiency of herbal polyphenolics with cosmetic relevance in comparison with pure phytoconstituents. This concise review summarizes the current knowledge on preparation methods, physico-chemical properties and aspects of application of the selected phyto-complexes as cosmetic active ingredients.