Dragana Vasiljević

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.

Tablet disintegration and drug dissolution in viscous media: paracetamol IR tablets.

An investigation into the influence of viscous media on tablet disintegration and drug dissolution was performed with the aim to simulate the potential formulation-specific food effect for a selected highly soluble model drug. Literature data on the in vivo drug absorption in fasted and fed state have been evaluated for in vitro-in vivo correlation (IVIVC) purposes. In vitro studies were conducted in simple buffer media with or without addition of HPMC K4M as a viscosity enhancing agent. Good IVIVC correlation (r>0.95) was obtained for paracetamol dissolution in viscous media at 50rpm and fed state absorption profiles, while in vitro dissolution in simple media at lower stirring speed was predictable of drug products in vivo behaviour in the fasted state. The data obtained support the existing idea that relatively simple dissolution media and/or set of experimental conditions may be used to differentiate formulation-specific food-drug interactions. Such tests would be a useful tool in the development of formulations that would not be susceptible to the influence of co-administered meal and, furthermore, facilitate regulatory decision on the necessity to conduct food effect studies in vivo.

The characterization of the semi-solid W/O/W emulsions with low concentrations of the primary polymeric emulsifier

Semi‐solid multiple W/O/W emulsions with low concentrations (0.8, 1.6 and 2.4% w/w) of lipophilic polymeric primary emulsifier PEG‐30‐dipolyhydroxystearate (PDHS) have been formulated. Both emulsions, primary and multiple, were prepared with high content of inner phase (Φ1 = Φ2 = 0.8). All the formulations differ only in the lipophilic emulsifier concentration. Evaluating several parameters such as macroscopic and microscopic aspect, droplet size, accelerated stability under centrifugation and flow and oscillatory rheological behaviour, assessed the multiple systems. It is possible to formulate the semi‐solid W/O/W multiple emulsions with low concentrations of PDHS as the primary emulsifier. It appeared that the highest long‐term stable multiple emulsion with the lowest droplet size, the highest apparent viscosity and highest elastic characteristic, was the sample with the highest concentration (2.4% w/w) of the primary emulsifier.

Application of D‐optimal experimental design method to optimize the formulation of O/W cosmetic emulsions

This study investigates the application of D‐optimal mixture experimental design in optimization of O/W cosmetic emulsions. Cetearyl glucoside was used as a natural, biodegradable non‐ionic emulsifier in the relatively low concentration (1%), and the mixture of co‐emulsifiers (stearic acid, cetyl alcohol, stearyl alcohol and glyceryl stearate) was used to stabilize the formulations.

Computer-aided formulation development

Abstract: This chapter introduces the concept of formulation development assisted by computer applications. Development and optimization of various types of pharmaceutical emulsions microemulsions, self-microemulsifying systems, and double emulsions are presented. Illustrative examples are presented to demonstrate the ability of computer-aided tools to facilitate formulation development. Various techniques, such as design of experiments and artificial neural networks, are implemented for optimization of the formulation and/or processing parameters. Furthermore, some of the critical quality attributes and processing parameters are optimized simultaneously. The examples presented should serve as the foundation for the future quality-by-design development of pharmaceutical emulsion and (self) microemulsion formulations.

In vitro/in silico approach in the development of simvastatin-loaded self-microemulsifying drug delivery systems

Abstract Objective: The aims of this study were to formulate simvastatin (SV)-loaded self-microemulsifying drug delivery systems (SMEDDS), and explore the potential of these drug delivery systems to improve SV solubility, and also to identify the optimal place in the gastrointestinal (GI) tract for the release of SV using coupled in vitro/in silico approach. Significance: In comparison to other published results, this study considered the extensive pre-systemic clearance of SV, which could significantly decrease its systemic and hepatic bioavailability if SV is delivered into the small intestine. Methods: SV-loaded SMEDDS were formulated using various proportions of oils (PEG 300 oleic glycerides, propylene glycol monocaprylate, propylene glycol monolaurate), surfactant (PEG 400 caprylic/capric glycerides) and cosurfactant (polysorbate 80) and subjected to characterization, and physiologically-based pharmacokinetic (PBPK) modeling. Results: According to the in vitro results, the selected SMEDDS consisted of 10.0% PEG 300 oleic glycerides, 67.5% PEG 400 caprylic/capric glycerides, and 22.5% polysorbate 80. The use of acid-resistant capsules filled with SV-loaded SMEDDS was found helpful in protecting the drug against early degradation in proximal parts of the GI tract, however, in silico simulations indicated that pH-controlled drug release system that dissolve in the distal parts of the intestine might further improve SV bioavailability (up to 7.20%). Conclusion: The obtained results suggested that combined strategy for the improvement of SV bioavailability should comprise solubility enhancement and delayed drug release. The developed SV-specific PBPK model could potentially be used to assess the influence of formulation factors on drug absorption and disposition when developing SV oral dosage forms.

Application of the fractional factorial design in multiple W/O/W emulsions

ABSTRACT In presented research, multiple W/O/W emulsions were developed by using experimental design method. A 24-1 fractional factorial design was performed by varying the following input parameters: primary polymeric emulsifier (PEG 30-dipolyhydroxystearate) concentration (0.8% and 2.4%), secondary polymeric emulsifier (Poloxamer 407) concentration (0.8% and 1.2%), electrolyte magnesium sulfate heptahydrate (0.08% and 0.4%) and electrolyte sodium chloride (0.08% and 0.4%). Multiple emulsions were prepared by a two-step emulsification process. Obtained emulsions were characterized with rheological measurements, conductivity and centrifugation tests. Factorial analysis revealed that the concentration of the primary emulsifier was the predominant factor influencing the phase separation, conductivity and maximal apparent viscosity. Additionally, electrolyte magnesium sulfate heptahydrate was more efficient in stabilizing these systems, compared to sodium chloride. The applied fractional factorial design method enabled determination of the optimal concentrations of the primary and secondary emulsifier, as well as the concentration of electrolytes, in order to obtain W/O/W emulsions with desired maximal apparent viscosities, low values of conductivity and without phase separation after centrifugation. GRAPHICAL ABSTRACT

Cosmetic ingredients from the sea in skin care products

Sea water, salt and mud have been used for centuries in beautification treatments, but their active ingredients have become a recent challenge in formulating new cosmetic products. Cosmetic ingredients which originate from the sea, are mostly obtained from algae, microalgae, marine sponges, corals and microorganisms. Exopolysaccharides (EPS) are new cosmetic ingredients produced by marine micro-organisms. They are used to protect skin from harmful external influences, give it softness and minimize fine lines. Pseudopterosins, present in the extracts of corals, are used to soothe the skin, while marine sponges are one of the major alternative to animal-derived collagen. Algae have been the most researched group, with the greatest potential among different sources of marine ingredients. Carrageenan, agar, and alginates from algae act as humectants, thickeners and gelling agents. The active ingredients of algae extracts (polysaccharides, proteins, vitamins, minerals) could hydrate, minimize fine lines, protect the skin from UV radiation, decrease redness and cellulite.

Long-term stability investigation of o/w cosmetic creams stabilized by mixed emulsifier

Polyglyceryl-3 Methylglucose Distearate (PMD, TEGO® Care 450, Evonik, Germany)is natural (vegetable), non-ionic, PEG-free emulsifier, suitable for the formulation of oil-in-water (o/w) cosmetic creams and lotions. The oil phase components can be selected from mineral oils, vegetable oils and synthetic esters, which enable different variety of application profile of these emulsions. It is possible to prepare stable emulsions using low-level concentration of the PMD (2-3%) if lotions contain 10-25%, and creams 20-40 % of oil phase. PMD forms liquid crystal structure in the presence of stearic acid, glyceryl stearate, fatty alcohols, or their combinations. The o/w type creams, stabilized by these mixed emulsifiers are complex, multiphase systems. The aim of this work was to formulate, prepare and investigate long-term stability of the o/w creams stabilized by mixed emulsifier polyglyceryl-3 methylglucose distearate/glyceryl stearate/stearyl alcohol, depending on concentration levels of PMD (2% or 3%) and oil:water phase ratio (20:80 and 30:70). The samples were prepared using hot/hot procedure. Organoleptic inspection, centrifugation test, rheological measurements, electric conductivity and pH value measurements were performed 72 h, 1, 3, 12 and 30 months after preparation. The prepared samples were apparently white and homogenous creams. The consistency and homogeneity were preserved after centrifugation of the creams after 72 h, 1, 3, 12 and 30 months storage, and no phase separation could be detected. The pH values obtained are suitable for skin application. Conductivity values (25.2-63.7 μS cm1, 72 h after preparation) were attributed to the multiple phase o/w emulsions with high percentages of fixed water. Results of the rheological measurements have shown that the investigated creams exhibited non-Newtonian thyxotropic behavior. The concentration of emulsifier PMD and oil phase content had an influence on the rheological parameters of investigated samples. The creams prepared with higher content of emulsifiers (3%) and oil phase (30%) exhibited higher values of apparent viscosities and thyxotropic area. The observed decrease of electrical conductivity and increase of apparent viscosities values, which occurred in the creams during 3 months of storage, were probably attributed to bulk water content decreasing. These changes are mildly expressed in the samples with higher content of oil phase. The obtained results of organoleptic characteristics, pH, electric conductivity value and rheological parameters during 30 months of storage indicate good long-term stability of the o/w creams prepared with mixed emulsifier containing PMD at low concentration levels (2% or 3%). Changes during ageing, caused by structuration of creams were less expressed in samples with 30% of oil phase, however, the observed differences were not related with the PMD concentration. In this case, advantage could be given to o/w cream prepared with 30% of oil phase, stabilized by using 2% emulsifier polyglyceryl-3 methylglucose distearate.