International Journal of Pharmaceutics (v.497, #1-2)
EDITORIAL BOARD (iii).
Professor Jürgen Siepmann: IJP’s new editor-in-chief by Alexander T. Florence (1).
Letter to the Editor by Ana Santoveña Estévez (2).
Development and characterisation of sustained release solid dispersion oral tablets containing the poorly water soluble drug disulfiram by Mandip Shergill; Mina Patel; Siraj Khan; Ayesha Bashir; Christopher McConville (3-11).
Display OmittedAdministration of drugs via the oral route is the most common and preferred route due to its ease of administration, cost-effectiveness and flexibility in design. However, if the drug being administered has limited aqueous solubility it can result in poor bioavailability. Furthermore, the low pH of the stomach as well as enzymatic activity can result in drugs delivered via the oral route being rapidly metabolised and degraded. Here we demonstrate the development and characterisation of sustained release solid dispersion oral tablets, containing the poorly water-soluble drug disulfiram (DSF). The tablets, which are manufactured from two different polymers (Kolliphor® P 188 and P 237) specifically designed for the manufacture of solid dispersions and two different polymers (Kollidon® SR and HPMC) specifically designed to provide sustained release, can enhance the solubility of DSF, sustain its release, while protecting it from degradation in simulated gastric fluid (SGF). The paper demonstrates that when using the hot melt method at 80 °C the DSF loading capacity of the Kolliphor® P 188 and P 237 polymers is approximately 43 and 46% respectively, with the DSF completely in an amorphous state. The addition of 80% Kollidon® SR to the formulation completely protected the DSF in SGF for up to 70 min with 16% degradation after 120 min, while 75% degradation occurred after 120 min with the addition of 80% HPMC. The release rate of DSF can be manipulated by both the loading and type of sustained release polymer used, with HPMC providing for a much faster release rate compared to Kollidon® SR.
Keywords: Sustained release; Solid dispersion; Solubility enhancement; Hot melt; Disulfiram;
Barriers to administering non-oral formulations in a paediatric population: A semi-structured interview study by Rebecca Venables; Hannah Batchelor; Heather Stirling; John Marriott (12-17).
Display OmittedThere is a paucity of research exploring barriers to non-oral medicines administration in paediatric patients; however, these undoubtedly influence medicines adherence. Studies conducted with healthcare professionals have identified various issues with the administration and acceptance of non-oral medicines and devices (Venables et al., 2012; Walsh et al., 2015). EMA (2014) guidelines specify that formulation teams should demonstrate ‘acceptability’ of paediatric formulations when developing pharmaceutical formulations.Semi-structured interviews exploring barriers to administering non-oral medicines were conducted with young persons and the parents/legal guardians of children (0–17 years) with chronic conditions at the University Hospital of Coventry and Warwickshire, UK.90 children prescribed a total of 148 non-oral medicines were recruited to the study; 88 barriers to administering non-oral medicines were reported. The most commonly reported barriers were: poor acceptance of face mask/difficulties with spacer for inhaled formulations (38% of reports); disliking parenteral/preferring alternative formulations (38% of reports); greasy texture of topical preparations; difficulty with administering an ocular ointment and the large dose volume of a nasal preparation.Formulation teams should consider the use of child-friendly, age-appropriate designs to improve usability and acceptance, thus medicines adherence. These findings should be used to inform future development of non-oral formulations and devices, suitable in terms of safety, efficacy and acceptability to paediatric patients.
Keywords: Pediatric; Medicine; Formulation; Acceptability; Barriers to administration; Device; Usability;
Enhanced solubility and antibacterial activity of lipophilic fluoro-substituted N-benzoyl-2-aminobenzothiazoles by complexation with β-cyclodextrins by A. Trapani; N. De Laurentis; D. Armenise; A. Carrieri; I. Defrenza; A. Rosato; D. Mandracchia; G. Tripodo; A. Salomone; V. Capriati; C. Franchini; F. Corbo (18-22).
Display OmittedSome lipophilic fluoro-substituted N-benzoyl-2-aminobenzothiazole antibacterial agents have been evaluated for their activity in the presence of cyclodextrins (CDs) containing aqueous solutions where CDs are adopted as solubilizing excipients for improving the poor water solubility of these compounds. For such purpose both the natural β-CD and one of FDA/EMA approved CDs for parenteral use (i.e. HP-β-CD) have been employed. The solubility rank order observed was accounted for by thermal analysis (Differential Scanning Calorimetry) and FT–IR spectroscopy. The most promising compound was subjected to further NMR spectroscopic studies and molecular modelling simulations to verify the interactions between the guest molecule and the CD cavity. The assessment of the antibacterial activity of such compounds against selected Gram positive and Gram negative bacterial strains clearly showed that their antimicrobial effectiveness may, quite in all instances, be positively affected by complexation with β-CD and HP-β-CD. These results, which are in some ways in contrast with those already reported in the literature, are herein discussed on the basis of plausible mechanisms. Moreover, this investigation also reveals that the described methodology of complexing both lipophilic and hydrophilic antimicrobial agents with CDs may be an useful approach to enhance their effectiveness as well as a promising strategy to overcome even the microbial resistance problem.
Keywords: Antimicrobial agents; Cyclodextrins; Nuclear magnetic resonance; Molecular; modelling;
Lipoamino acid-based micelles as promising delivery vehicles for monomeric amphotericin B by Cláudia Serafim; Inês Ferreira; Patrícia Rijo; Lídia Pinheiro; Célia Faustino; António Calado; Luis Garcia-Rio (23-35).
Display OmittedLipoamino acid-based micelles have been developed as delivery vehicles for the hydrophobic drug amphotericin B (AmB). The micellar solubilisation of AmB by a gemini lipoamino acid (LAA) derived from cysteine and its equimolar mixtures with the bile salts sodium cholate (NaC) and sodium deoxycholate (NaDC), as well as the aggregation sate of the drug in the micellar systems, was studied under biomimetic conditions (phosphate buffered-saline, pH 7.4) using UV–vis spectroscopy. Pure surfactant systems and equimolar mixtures were characterized by tensiometry and important parameters were determined, such as critical micelle concentration (CMC), surface tension at the CMC (γ CMC), maximum surface excess concentration (Γmax), and minimum area occupied per molecule at the water/air interface (A min). Rheological behaviour from viscosity measurements at different shear rates was also addressed. Solubilisation capacity was quantified in terms of molar solubilisation ratio (χ), micelle–water partition coefficient (K M) and Gibbs energy of solubilisation (ΔG s°). Formulations of AmB in micellar media were compared in terms of drug loading, encapsulation efficiency, aggregation state of AmB and in vitro antifungal activity against Candida albicans. The LAA-containing micellar systems solubilise AmB in its monomeric and less toxic form and exhibit in vitro antifungal activity comparable to that of the commercial formulation Fungizone.
Keywords: Amphotericin B; Lipoamino acid; Bile salts; Mixed micelles;
Continuous production of controlled release dosage forms based on hot-melt extruded gum arabic: Formulation development, in vitro characterization and evaluation of potential application fields by Thomas Kipping; Hubert Rein (36-53).
Display OmittedControlled release matrices based on gum arabic are prepared by applying a continuous hot-melt extrusion technology: the pre-mixture consisting of gum arabic and the incorporated API is plasticized by a co-rotating twin-screw extruder, an intermediate strand is formed by a round nozzle. Single dosed matrices are prepared by cutting the semi elastic strand with a rotary fly cutter.Paracetamol and phenazone are used as model drug substances. High drug loadings up to 70% can be realized. Matrices are characterized concerning their crystalline structure, in vitro dissolution, disintegration time and various physical parameters including glass transition temperature (Tg).Release characteristic behavior is mainly influenced by erosion of the matrices. At higher drug loadings also diffusion based transport gain importance. The solubility of the API shows an influence on the erosion rate of the matrix and should therefore be considered during formulation development.Tg is mainly influenced by the solubility of the API in the surrounding matrix. High soluble phenazone shows a decrease, whereas paracetamol addition has nearly no influence on the Tg of the polymeric system. Activation energy (EA) of the glass transition is determined via dynamic mechanical analysis. The addition of APIs leads to a reduction of EA indicating an increased molecular movement at Tg region compared to placebo extrudates.X-ray diffraction is used to determine the crystalline state of the extruded matrices and interaction between matrix and incorporated APIs.The production of thin layer matrices is an interesting option to provide a fast drug delivery to the oral cavity. High mechanical strength combined with fast disintegration times can be a great advantage for the development of oro-dispersible tablets.A great benefit of the evaluated processing technology is the simple adaption of the final dose by varying either the cutting length or the diameter of the nozzle resulting in a cost-effective production of single dosed matrices without modification of the base formula.
Keywords: Gum arabic; Hot-melt extrusion; Continuous production; Matrices; Controlled release;
High-performance liquid chromatography as a technique to determine protein adsorption onto hydrophilic/hydrophobic surfaces by Tongtong Huang; Karine Anselme; Segolene Sarrailh; Arnaud Ponche (54-61).
Display OmittedThe purpose of this study is to evaluate the potential of simple high performance liquid chromatography (HPLC) setup for quantification of adsorbed proteins on various type of plane substrates with limited area (<3 cm2). Protein quantification was investigated with a liquid chromatography chain equipped with a size exclusion column or a reversed-phase column. By evaluating the validation of the method according to guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), all the results obtained by HPLC were reliable. By simple adsorption test at the contact of hydrophilic (glass) and hydrophobic (polydimethylsiloxane: PDMS) surfaces, kinetics of adsorption were determined and amounts of adsorbed bovine serum albumin, myoglobin and lysozyme were obtained: as expected for each protein, the amount adsorbed at the plateau on glass (between 0.15 μg/cm2 and 0.4 μg/cm2) is lower than for hydrophobic PDMS surfaces (between 0.45 μg/cm2 and 0.8 μg/cm2). These results were consistent with bicinchoninic acid protein determination.According to ICH guidelines, both Reversed Phase and Size Exclusion HPLC can be validated for quantification of adsorbed protein. However, we consider the size exclusion approach more interesting in this field because additional informations can be obtained for aggregative proteins. Indeed, monomer, dimer and oligomer of bovine serum albumin (BSA) were observed in the chromatogram. On increasing the temperature, we found a decrease of peak intensity of bovine serum albumin as well as the fraction of dimer and oligomer after contact with PDMS and glass surface. As the surface can act as a denaturation parameter, these informations can have a huge impact on the elucidation of the interfacial behavior of protein and in particular for aggregation processes in pharmaceutical applications.
Keywords: HPLC; Protein adsorption; Kinetics; Denaturation; Aggregation;
A facile system to evaluate in vitro drug release from dissolving microneedle arrays by Eneko Larrañeta; Sarah Stewart; Steven J. Fallows; Lena L. Birkhäuer; Maeliosa T.C. McCrudden; A. David Woolfson; Ryan F. Donnelly (62-69).
Display OmittedThe use of biological tissues in the in vitro assessments of dissolving (?) microneedle (MN) array mechanical strength and subsequent drug release profiles presents some fundamental difficulties, in part due to inherent variability of the biological tissues employed. As a result, these biological materials are not appropriate for routine used in industrial formulation development or quality control (QC) tests. In the present work a facile system using Parafilm M® (PF) to test drug permeation performance using dissolving MN arrays is proposed. Dissolving MN arrays containing 196 needles (600 μm needle height) were inserted into a single layer of PF and a hermetic “pouch” was created including the array inside. The resulting system was placed in a dissolution bath and the release of model molecules was evaluated. Different MN formulations were tested using this novel setup, releasing between 40 and 180 μg of their cargos after 6 h. The proposed system is a more realistic approach for MN testing than the typical performance test described in the literature for conventional transdermal patches. Additionally, the use of PF membrane was tested either in the hermetic “pouch” and using Franz Cell methodology yielding comparable release curves. Microscopy was used in order to ascertain the insertion of the different MN arrays in the PF layer. The proposed system appears to be a good alternative to the use of Franz cells in order to compare different MN formulations. Given the increasing industrial interest in MN technology, the proposed system has potential as a standardised drug/active agent release test for quality control purposes.
Keywords: Microneedles; Release tests; Polymeric films; Transdermal; Quality control;
An investigation into moisture barrier film coating efficacy and its relevance to drug stability in solid dosage forms by Enosh Mwesigwa; Abdul W. Basit (70-77).
Display OmittedBarrier coatings are frequently employed on solid oral dosage forms under the assumption that they prevent moisture sorption into tablet cores thereby averting premature degradation of moisture-sensitive active ingredients. However, the efficacy of moisture barrier coatings remains unproven and they may actually accelerate degradation. This study aimed to investigate the barrier performance of four coating systems following application onto a low hygroscopic tablet formulation containing aspirin as a model moisture sensitive drug. Tablets were prepared by direct compaction and coated with aqueous dispersions of Eudragit® L30 D-55, Eudragit® EPO, Opadry® AMB and Sepifilm® LP at the vendors’ recommended weight gains. Moisture uptake was studied by dynamic vapor sorption at 0 and 75% RH (25 °C). Accelerated stability studies were undertaken at 75% RH/25 °C for 90 days and HPLC assay was used to determine aspirin content. Uncoated tablet cores equilibrated rapidly and took up very little water (0.09%). The mean water uptake for coated cores was higher than for the uncoated formulation and varied as follows: 0.19% (Eudragit® L30 D-55), 0.35% (Opadry® AMB), 0.49% (Sepifilm® LP) and 0.76% (Eudragit® EPO). The level of aspirin decreased in all the samples such that by the time the study was terminated, the mean aspirin recovered was as follows: uncoated cores 80.0%; Eudragit® L30 D-55 coated cores 78.8%; Opadry® AMB coated cores 76.2%, Sepifilm® LP coated cores 76.0% and Eudragit® EPO coated samples 66.5%. From these results, it is concluded that the efficacy of moisture barrier polymer coatings on low hygroscopic cores is limited, and application of these coatings can, instead, enhance drug degradation in solid dosage forms.
Keywords: Sorption; Film coating; Aspirin; Accelerated stability; Moisture barrier; Hydrolysis; Tablets; Dicalcium phosphate;
Enhanced delivery of Paclitaxel using electrostatically-conjugated Herceptin-bearing PEI/PLGA nanoparticles against HER-positive breast cancer cells by Kongtong Yu; Jinlong Zhao; Zunkai Zhang; Yin Gao; Yulin Zhou; Lesheng Teng; Youxin Li (78-87).
Display OmittedWe have developed a novel nanoparticle delivery system fabricated from polyethylenimine (PEI) and poly(d,l-lactide-co-glycolide) (PLGA), which were able to deliver the chemotherapeutic agent Paclitaxel, while the biomacromolecule Herceptin acted as a targeting ligand that was conjugated onto the surfaces of the nanoparticles via electrostatic interactions. In this study, these electrostatically-conjugated Herceptin-bearing PEI/PLGA nanoparticles (eHER-PPNs) were optimized and employed as vectors to target HER2-positive breast cancer cells. The eHER-PPNs had an average diameter of ∼280 nm and a neutral surface charge (1.00 ± 0.73 mV), which remained stable under physiological conditions. The anticancer effects of eHER-PPNs were investigated in HER2-positive BT474 cells and HER2-negative MCF7 cells. The eHER-PPNs showed enhanced cytotoxicity that was dependent on the receptor expression levels and the incubation time. These conjugated nanoparticles deliver Paclitaxel more efficiently (p < 0.001) than unmodified PPNs, Herceptin and the combined effects of these two monotherapies. Furthermore, the chemically-conjugated Herceptin-bearing PEI/PLGA nanoparticles (cHER-PPNs) were fabricated as a comparison. The eHER-PPNs exhibited lower cell viability (46.7%) than that of cHER-PPNs (65.1%). The targeting ability of eHER-PPNs was demonstrated through confocal microscopy images and flow cytometry, which showed that eHER-PPNs displayed higher cellular uptake efficiency (p < 0.001) in comparison with cHER-PPNs. Therefore, eHER-PPNs could provide promising platforms for the delivery of therapeutic drugs against HER2-positive breast cancers.
Keywords: Targeted delivery; Electrostatic attraction; Herceptin; Paclitaxel; Polyethylenimine;
Nanoparticles of perfluorocarbon emulsion contribute to the reduction of methemoglobin to oxyhemoglobin by Еlena Kozlova; Аleksandr Chernysh; Victor Moroz; Victoria Sergunova; Аnna Zavialova; Аrtem Kuzovlev (88-95).
Display OmittedHere we show that methemoglobin is converted to oxyhemoglobin in the presence of perfluorocarbon (PFС) emulsion. Methemoglobin in blood at the level of above 30% can cause severe complications and lethal outcome. Some pharm chemicals in blood in vivo and in vitro can lead to oxidation of iron, Fe2+ → Fe3+, and to increased level of methemoglobin. The oxidized heme is not able to carry oxygen, hypoxia arises and irreversible changes are developing in vital organs. We added NaNO2 solution in different concentrations to blood in vitro in order to yield methemoglobin. Then the suspension of PFC nanoparticles was added. As methemoglobin interacted with PFC nanoparticles the optical density of peaks typical for oxyhemoglobin increased and spectral peak of methemoglobin decreased. The greater the concentration of PFC and the more was the incubation time, the more efficient was the process of reduction of methemoglobin to oxyhemoglobin. We proved experimentally that with an initial concentration of methemoglobin in average 95% the addition of nanoparticles of PFC decreases its concentration to 9% in average. At the same time the concentration of oxyhemoglobin increased in average from 5% to 81%.
Keywords: Oxyhemoglobin; Methemoglobin reduction; Perfluorocarbon emulsion;
Stability hierarchy between Piracetam forms I, II, and III from experimental pressure–temperature diagrams and topological inferences by Siro Toscani; René Céolin; Léon Ter Minassian; Maria Barrio; Nestor Veglio; Josep-Lluis Tamarit; Daniel Louër; Ivo B. Rietveld (96-105).
Display OmittedThe trimorphism of the active pharmaceutical ingredient piracetam is a famous case of polymorphism that has been frequently revisited by many researchers. The phase relationships between forms I, II, and III were ambiguous because they seemed to depend on the heating rate of the DSC and on the history of the samples or they have not been observed at all (equilibrium II–III). In the present paper, piezo-thermal analysis and high-pressure differential thermal analysis have been used to elucidate the positions of the different solid–solid and solid–liquid equilibria. The phase diagram, involving the three solid phases, the liquid phase and the vapor phase, has been constructed. It has been shown that form III is the high-pressure, low-temperature form and the stable form at room temperature. Form II is stable under intermediary conditions and form I is the low pressure, high temperature form, which possesses a stable melting point. The present paper demonstrates the strength of the topological approach based on the Clapeyron equation and the alternation rule when combined with high-pressure measurements.
Keywords: Crystal polymorphism; Solid state; Phase diagram; Phase transition; Physical stability; Preformulation;
Physicochemical and mechanical properties of paracetamol cocrystal with 5-nitroisophthalic acid by Stevanus Hiendrawan; Bambang Veriansyah; Edward Widjojokusumo; Sundani Nurono Soewandhi; Saleh Wikarsa; Raymond R. Tjandrawinata (106-113).
Display OmittedWe report novel pharmaceutical cocrystal of a popular antipyretic drug paracetamol (PCA) with coformer 5-nitroisophhthalic acid (5NIP) to improve its tabletability. The cocrystal (PCA-5NIP at molar ratio of 1:1) was synthesized by solvent evaporation technique using methanol as solvent. The physicochemical properties of cocrystal were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), fourier transform infrared spectroscopy (FTIR), hot stage polarized microscopy (HSPM) and scanning electron microscopy (SEM). Stability of the cocrystal was assessed by storing them at 40 °C/75% RH for one month. Compared to PCA, the cocrystal displayed superior tableting performance. PCA-5NIP cocrystal showed a similar dissolution profile as compared to PCA and exhibited good stability. This study showed the utility of PCA-5NIP cocrystal for improving mechanical properties of PCA.
Keywords: Cocrystal; Paracetamol; 5-Nitroisophhthalic acid; Mechanical properties; Dissolution rate;
Development of a novel sodium fusidate-loaded triple polymer hydrogel wound dressing: Mechanical properties and effects on wound repair by Sung Giu Jin; Kyeong Soo Kim; Dong Wuk Kim; Dong Shik Kim; Youn Gee Seo; Toe Gyung Go; Yu Seok Youn; Jong Oh Kim; Chul Soon Yong; Han-Gon Choi (114-122).
Display OmittedTo develop a novel sodium fusidate-loaded triple polymer hydrogel dressing (TPHD), numerious polyvinyl alcohol-based (PVA) hydrogel dressings were prepared with various hydrophilic polymers using the freeze-thaw method, and their hydrogel dressing properties were assessed. Among the hydrophilic polymers tested, sodium alginate (SA) improved the swelling capacity the most, and polyvinyl pyrrolidone (PVP) provided the greatest improvement in bioadhesive stength and mechanical properties. Thus, PVA based-TPHDs were prepared using different ratios of PVP:SA. The effect of selected PVP:SA ratios on the swelling capacity, bioadhesive strength, mechanical properties, and drug release, permeation and deposition characteristics of sodium fusidate-loaded PVA-based TPHDs were assessed. As the ratio of PVP:SA increased in PVA-loaded TPHD, the swelling capacity, mechanical properties, drug release, permeation and deposition were improved. The TPHD containing PVA, PVP, SA and sodium fusidate at the weight ratio of 10/6/1/1 showed excellent hydrogel dressing properties, release, permeation and deposition of drug. Within 24 h, 71.8 ± 1.3% of drug was released. It permeated 625.1 ± 81.2 μg/cm2 through the skin and deposited of 313.8 ± 24.1 μg/cm2 within 24 h. The results of in vivo pharmacodynamic studies showed that sodium fusidate-loaded TPHD was more effective in improving the repair process than was a commercial product. Thus, this sodium fusidate-loaded TPHD could be a novel tool in wound care.
Keywords: Sodium fusidate; Triple polymer hydrogel wound dressing; Permeation; Deposition; Wound repair effect;
Preactivated thiolated nanoparticles: A novel mucoadhesive dosage form by Claudia Menzel; Sonja Bonengel; Irene Pereira de Sousa; Flavia Laffleur; Felix Prüfert; Andreas Bernkop-Schnürch (123-128).
Display OmittedWithin this study a novel form of mucoadhesive nanoparticles (NPs) exhibiting a prolonged residence time on mucosal tissues was developed.In order to achieve this goal a new thiomer was synthesized by the covalent attachment of the amino acid l-cysteine ethyl ester to poly(acrylic acid) (100 kDa). The free thiol groups were in the following preactivated with the aromatic thiol bearing ligand 2-mercaptonicotinic acid (2-MNA) and the amount of coupled l-cysteine ethyl ester as well as the amount of attached 2-MNA was determined. Based on this, preactivated thiomer NPs were prepared by ionic gelation with polyethylenimine (PEI). The resulting NPs were characterized regarding size and zeta potential. Furthermore their mucoadhesive properties were investigated via rheological measurements with porcine intestinal mucus and via determination of the particles’ mucosal residence time.Results showed that 1666.74 μmol l-cysteine ethyl ester and 603.07 μmol 2-MNA could be attached per gram polymer. NPs were in a size range of 112.67–252.84 nm exhibiting a zeta potential of −29 mV. Thiolated NPs only led to a 2-fold increase in mucus viscosity whereas preactivated NPs showed a 6-fold higher mucus viscosity than unmodified NPs. The mucosal residence time of thiolated NPs was 1.6-fold prolonged and that of preactivated NPs even 4.4-fold higher compared to unmodified particles.Accordingly, preactivated thiolated NPs providing a prolonged residence time on mucosal membranes could be a promising dosage form for various applications.
Keywords: Nanoparticles; Mucoadhesion; Preactivated thiomers;
Vitamin B12 and derivatives—In vitro permeation studies across Caco-2 cell monolayers and freshly excised rat intestinal mucosa by Kesinee Netsomboon; Andrea Feßler; Lena Erletz; Felix Prüfert; Markus Ruetz; Christoph Kieninger; Bernhard Kräutler; Andreas Bernkop-Schnürch (129-135).
Display OmittedThe purpose of this study was to compare the intestinal permeation of vitamin B12 and various derivatives thereof. Permeation behavior and cytotoxicity of four derivatives (coenzyme B12, hydroxocobalamin, methylcobalamin and 4-ethylphenylcobalamin) in comparison to vitamin B12 were evaluated in two different in vitro models, Caco-2 cells and freshly excised rat intestinal mucosa. Resazurin assay was used to evaluate cytotoxicity of the test substances. All test compounds were used at a concentration of 200 μg/ml. Permeation experiments were carried out for 3 h and test compounds were quantified via reversed phase high performance liquid chromatography (HPLC). Cytotoxicity studies showed all test compounds are not toxic to cells. HPLC analyses of test compounds revealed the following rank order of increasing hydrophobicity: hydroxocobalamin < vitamin B12 < coenzyme B12 < methylcobalamin < 4-ethylphenylcobalamin. Apparent permeability coefficients of coenzyme B12, hydroxocobalamin, methylcobalamin and 4-ethylphenylcobalamin were 10.2, 0.3, 9.4 and 31.3 fold of vitamin B12 on Caco-2 cells while 0.2, 0.4, 2.6 and 1.9 fold of vitamin B12 on rat intestine, respectively. As various vitamin B12 derivatives showed a significantly higher permeation coefficient than vitamin B12, the use of certain derivatives might be a promising strategy for oral vitamin B12 substitution.
Keywords: Vitamin B12; Coenzyme B12; Hydroxocobalamin; Methylcobalamin; 4-Ethylphenylcobalamin;
Advanced stable lipid-based formulations for a patient-centric product design by Karin Becker; Eva-Maria Saurugger; Diana Kienberger; Diogo Lopes; Detlev Haack; Martin Köberle; Michael Stehr; Dirk Lochmann; Andreas Zimmer; Sharareh Salar-Behzadi (136-149).
Display OmittedMultiparticulate dosage forms are a recent strategy to meet the special needs of children, elderly people and patients suffering from dysphagia. Our study presents a novel and cost-efficient approach for the manufacturing of a taste-masked multiparticulate system with a stable immediate release profile by applying lipid-based excipients in a solvent-free hot melt coating process.The thermosensitive N-acetylcysteine (N-ac) was used as model drug and hot-melt coated with a mixture of tripalmitin and polysorbate 65.A predictive in vitro method for the evaluation of the taste masking efficiency was developed based on the deprotonation of the carboxyl group of N-ac and the decline of pH, responsible for the unpleasant sour taste of the compound. The method was confirmed using in vivo studies. Differential scanning calorimetry and X-ray scattering experiments revealed polymorphic transformation and its dependency on transformation time, temperature and emulsifier concentration. During the process, the coating was transformed almost completely into the stable β-polymorph, leading to an unaltered dissolution profile during storage. A statistical design was conducted that revealed the critical process parameters affecting the taste masking efficiency and drug release.This study shows the successful application of solvent-free hot-melt coating in the development of a taste-masked and stable formulation.
Keywords: Multiparticulate dosage forms; Taste masking; Triglyceride; Polymorph; Hot-melt coating; Immediate release; Stability;
pH-Responsive polymeric micelles based on amphiphilic chitosan derivatives: Effect of hydrophobic cores on oral meloxicam delivery by Thisirak Woraphatphadung; Warayuth Sajomsang; Pattarapond Gonil; Alongkot Treetong; Prasert Akkaramongkolporn; Tanasait Ngawhirunpat; Praneet Opanasopit (150-160).
Display OmittedThe amphiphilic chitosan derivatives, N-naphthyl-N,O-succinyl chitosan (NSCS), N-octyl-N-O-succinyl chitosan (OSCS) and N-benzyl-N,O-succinyl chitosan (BSCS), were synthesized. Meloxicam (MX) was loaded into polymeric micelles (PMs), and the effects of hydrophobic moieties of the inner core segment on the loading efficiency, stability of MX-loaded PMs, cytotoxicity, drug release, and porcine small intestine permeation were investigated. Among the hydrophobic cores, the N-octyl moiety revealed the highest MX loading efficiency and most stable MX-loaded PMs compared to the other hydrophobic cores. All PMs were spherically shaped (size 213–282 nm) and had low toxicity against Caco-2 cells. The release of MX from PMs was found to be dependent on both hydrophobic cores and hydrophilic shells. In acidic medium at 0–2 h, low cumulative MX release was obtained in the MX-loaded OSCS PMs compared to MX-loaded NSCS PMs and MX-loaded BSCS PMs as well as MX free drug. However, when the pH was increased to 6.8, the MX release significantly increased in all MX-loaded PMs. Furthermore, the intestinal permeation rates of MX from all MX-loaded PMs were not significantly different. These results suggest that MX was successfully incorporated into the PMs at high efficiency and good stability by optimizing the hydrophobic moieties of the inner core segments.
Keywords: pH Responsive polymeric micelles; Chitosan; Meloxicam; Hydrophobic cores;
Formulation design and in vitro physicochemical characterization of surface modified self-nanoemulsifying formulations (SNEFs) of gentamicin by Chukwuebuka Umeyor; Anthony Attama; Emmanuel Uronnachi; Franklin Kenechukwu; Calistus Nwakile; Ifeanyi Nzekwe; Eric Okoye; Charles Esimone (161-198).
Display OmittedSelf-nanoemulsifying formulations (SNEFs) structured with PEG 4000 as PEGylated SNEFs, were formulated after solubility studies using rational blends of soybean oil, a combination of Kolliphor® EL and Kolliphor® P188 as surfactants, and Transcutol® HP as co-surfactant, and evaluated for oral delivery of gentamicin. Incorporation of gentamicin and PEG 4000 reduced the initial area of nanoemulsion of the ternary phase diagrams produced by water titration method using oil, surfactant mixture and co-surfactant. Emulsion droplets were in the nanometer scale ranging from 80–210 nm. FT-IR study revealed that gentamicin structure remained intact in all formulations, and SEM micrographs showed spherical globules. Zeta potentials of SNEFs were in the range of −25.4 to −42.5 mV, and showed a stable system with minor flips in electrostatic charges. There was high in vitro diffusion-dependent permeation of gentamicin from the SNEFs. Results obtained in this work showed that oral delivery of gentamicin was improved by formulation as surface modified SNEFs.
Keywords: Self-nanoemulsifying formulations; Gentamicin; PEG 4000; Surface modification; Ternary phase diagrams; Zeta potential;
Rifabutin-loaded solid lipid nanoparticles for inhaled antitubercular therapy: Physicochemical and in vitro studies by Diana P. Gaspar; Vasco Faria; Lídia M.D. Gonçalves; Pablo Taboada; Carmen Remuñán-López; António J. Almeida (199-209).
Display OmittedSystemic administration of antitubercular drugs can be complicated by off-target toxicity to cells and tissues that are not infected by Mycobacterium tuberculosis . Delivery of antitubercular drugs via nanoparticles directly to the infected cells has the potential to maximize efficacy and minimize toxicity. The present work demonstrates the potential of solid lipid nanoparticles (SLN) as a delivery platform for rifabutin (RFB). Two different RFB-containing SLN formulations were produced using glyceryl dibehenate or glyceryl tristearate as lipid components. Full characterization was performed in terms of particle size, encapsulation and loading efficiency, morphology by transmission electron microscopy (TEM) and differential scanning calorimetry (DSC) studies. Physical stability was evaluated when formulations were stored at 5 ± 3 °C and in the freeze–dried form. Formulations were stable throughout lyophilization without significant variations on physicochemical properties and RFB losses. The SLN showed to be able to endure harsh temperature conditions as demonstrated by dynamic light scattering (DLS). Release studies revealed that RFB was almost completely released from SLN. In vitro studies with THP1 cells differentiated in macrophages showing a nanoparticle uptake of 46 ± 3% and 26 ± 9% for glyceryl dibehenate and glyceryl tristearate SLN, respectively. Cell viability studies using relevant lung cell lines (A549 and Calu-3) revealed low cytotoxicity for the SLN, suggesting these could be new potential vehicles for pulmonary delivery of antitubercular drugs.
Keywords: Solid lipid nanoparticles; Rifabutin; Tuberculosis; Pulmonary administration; Stability; Cell viability and uptake;
Nanocomposite hydrogel incorporating gold nanorods and paclitaxel-loaded chitosan micelles for combination photothermal–chemotherapy by Nan Zhang; Xuefan Xu; Xue Zhang; Ding Qu; Lingjing Xue; Ran Mo; Can Zhang (210-221).
Display OmittedDevelopment of combination photothermal–chemotherapy platform is of great interest for enhancing antitumor efficacy and inhibiting tumor recurrence, which supports selective and dose-controlled delivery of heat and anticancer drugs to tumor. Here, an injectable nanocomposite hydrogel incorporating PEGylated gold nanorods (GNRs) and paclitaxel-loaded chitosan polymeric micelles (PTX-M) is developed in pursuit of improved local tumor control. After intratumoral injection, both GNRs and PTX-M can be simultaneously delivered and immobilized in the tumor tissue by the thermo-sensitive hydrogel matrix. Exposure to the laser irradiation induces the GNR-mediated photothermal damage confined to the tumor with sparing the surrounding normal tissue. Synergistically, the co-delivered PTX-M shows prolonged tumor retention with the sustained release of anticancer drug to efficiently kill the residual tumor cells that evade the photothermal ablation due to the heterogeneous heating in the tumor region. This combination photothermal–chemotherapy presents superior effects on suppressing the tumor recurrence and prolonging the survival in the Heps-bearing mice, compared to the photothermal therapy alone.
Keywords: Photothermal therapy; Chemotherapy; Gold nanorod; Chitosan micelles; Combination therapy;
Molecular mobility of hydroxyethyl cellulose (HEC) films characterised by thermally stimulated currents (TSC) spectroscopy by Samuel K. Owusu-Ware; Joshua Boateng; Daniel Jordan; Sara Portefaix; Renata Tasseto; Camila D. Ramano; Milan D. Antonijević (222-227).
Display OmittedMolecular mobility has long been established to relate to textural properties and stability of polymer films and is therefore an important property to characterise to better understand pharmaceutical film formulations. The molecular mobility of solvent cast hydroxyethyl cellulose (HEC) films has been investigated by means of thermally stimulated current (TSC) below the temperature at which the film was formed. Preliminary physical characterisation of the films was performed using XRPD, TGA, DSC and texture analysis (tensile properties). XRPD results showed the films to be completely amorphous with T g determined by DSC to be 127 ± 1 °C. TGA analysis showed the films to contain 8 ± 1% water and film was dried to only 0.06 ± 0.01% water content when heated to 160 °C. Application of TSC detected molecular mobility in HEC films at sub-zero temperatures. Two motional transitions with average relaxation time of 50 ± 3 s were identified; a β-relaxation at −57 ± 2 °C, attributed to localised non-cooperative orientation of HEC polymer chain ends and the hydroxyethyl side groups and an α-relaxation, originating from cooperative segmental mobility, at −20 ± 2 °C. The tensile properties i.e., elongation, tensile strength and elastic modulus of the HEC film have been related to the molecular relaxation processes detected by TSC.
Keywords: Molecular mobility; Hydroxyethyl cellulose (HEC); Polymeric films; Thermally stimulated current (TSC); Tensile properties;
Evaluation of magnetic nanoparticles coated by 5-fluorouracil imprinted polymer for controlled drug delivery in mouse breast cancer model by Hamid Hashemi-Moghaddam; Saeed Kazemi-Bagsangani; Mahdi Jamili; Saeed Zavareh (228-238).
Display OmittedNanoparticles (NPs) have been extensively investigated to improve delivery efficiency of therapeutic and diagnostic agents. In this study, magnetic molecularly imprinted polymer (MIP) was synthesized by using polydopamine. Synthesized MIP was used for controlled 5-fluorouracil (5-FU) delivery in a spontaneous model of breast adenocarcinoma in Balb/c mice in the presence of an external magnetic field. Antitumor effectiveness of 5-FU imprinted polymer (5-FU-IP) was evaluated in terms of tumor-growth delay, tumor-doubling time, inhibition ratio, and histopathology. Results showed higher efficacy of 5-FU-IP in the presence of magnetic field upon suppressing tumor growth than free 5-FU and 5-FU-IP without magnetic field. The 5-FU and Fe distribution among tissues were evaluated by high-performance liquid chromatography and flame atomic absorption spectrometry, respectively. The obtained results, showed significantly deposition of 5-FU in the 5-FU-IP treated group with magnetic field. Thus, magnetic 5-FU-IP is promising for breast cancer therapy with high efficacy.
Keywords: 5-Fluorouracil; Imprinted polymer; Polydopamine; Magnetic nanoparticles;
Formulation of 20(S)-protopanaxadiol nanocrystals to improve oral bioavailability and brain delivery by Chen Chen; Lisha Wang; Fangrui Cao; Xiaoqing Miao; Tongkai Chen; Qi Chang; Ying Zheng (239-247).
Display OmittedThe aim of this study was to fabricate 20(S)-protopanaxadiol (PPD) nanocrystals to improve PPD’s oral bioavailability and brain delivery. PPD nanocrystals were fabricated using an anti-solvent precipitation approach where d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was optimized as the stabilizer. The fabricated nanocrystals were nearly spherical with a particle size and drug loading of 90.44 ± 1.45 nm and 76.92%, respectively. They are in the crystalline state and stable at 4 °C for at least 1 month. More than 90% of the PPD could be rapidly released from the nanocrystals, which was much faster than the physical mixture and PPD powder. PPD nanocrystals demonstrated comparable permeability to solution at 2.52 ± 0.44 × 10−5 cm/s on MDCK monolayers. After oral administration of PPD nanocrystals to rats, PPD was absorbed quickly into the plasma and brain with significantly higher C max and AUC0–t compared to those of the physical mixture. However, no brain targeting was observed, as the ratios of the plasma AUC0–t to brain AUC0–t for the two groups were similar. In summary, PPD nanocrystals are a potential oral delivery system to improve PPD’s poor bioavailability and its delivery into the brain for neurodegenerative disease and intracranial tumor therapies in the future.
Keywords: 20(S)-Protopanaxadiol; Nanocrystals; d-α-Tocopheryl polyethylene glycol 1000 succinate; Bioavailability; Brain delivery;
Shear rheology and in-vitro release kinetic study of apigenin from lyotropic liquid crystal by Jun Fan; Feng Liu; Zhongni Wang (248-254).
Display OmittedApigenin is a flavonoid compound with diverse pharmacological functions which could develop health benefit products, but its formulation is hampered by its poor water solubility and bioavailability. In this paper, in order to overcome these difficulties, apigenin was encapsulated in LLC formed by polyoxyethylene-10-oleyl ether (Brij 97) and sodium deoxycholate (NaDC) mixtures. The hexagonal liquid crystalline phase (H) and the cubic liquid crystalline phase (C) were found in this system. The shear rheology was used to study the structure change with temperature. It was shown that C3 (Brij 97-NaDC/IPM-PEG400/H2O = 36:9:55) was C at low temperature. But above 35.6 °C, the matrix of C3 completely transformed to polymer solution. The matrix of H3 was H (Brij 97-NaDC:IPM-PEG 400:H2O = 50:9:41) below 50 °C, but the structural strength change was obvious. Vitro release experiment was used to study drug release kinetics. It was indicated that apigenin encapsulated in LLC conformed to the concentration diffusion model, and cumulative percentage of apigenin released from C3 and H3 had corresponding relationship with the shear rheology at different temperatures.
Keywords: Apigenin; Lyotropic liquid crystal; Rheology; Vitro release;
Characterization and comparison of two novel nanosystems associated with siRNA for cellular therapy by E.M. André; A. Pensado; P. Resnier; L. Braz; A.M. Rosa da Costa; C. Passirani; A. Sanchez; C.N. Montero-Menei (255-267).
Display OmittedTo direct stem cell fate, a delicate control of gene expression through small interference RNA (siRNA) is emerging as a new and safe promising strategy. In this way, the expression of proteins hindering neuronal commitment may be transiently inhibited thus driving differentiation. Mesenchymal stem cells (MSC), which secrete tissue repair factors, possess immunomodulatory properties and may differentiate towards the neuronal lineage, are a promising cell source for cell therapy studies in the central nervous system. To better drive their neuronal commitment the repressor Element-1 silencing transcription (REST) factor, may be inhibited by siRNA technology. The design of novel nanoparticles (NP) capable of safely delivering nucleic acids is crucial in order to successfully develop this strategy. In this study we developed and characterized two different siRNA NP. On one hand, sorbitan monooleate (Span®80) based NP incorporating the cationic components poly-l-arginine or cationized pullulan, thus allowing the association of siRNA were designed. These NP presented a small size (205 nm) and a negative surface charge (−38 mV). On the other hand, lipid nanocapsules (LNC) associating polymers with lipids and allowing encapsulation of siRNA complexed with lipoplexes were also developed. Their size was of 82 nm with a positive surface charge of +7 mV. Both NP could be frozen with appropriate cryoprotectors. Cytotoxicity and transfection efficiency at different siRNA doses were monitored by evaluating REST expression. An inhibition of around 60% of REST expression was observed with both NP when associating 250 ng/mL of siRNA–REST, as recommended for commercial reagents. Span NP were less toxic for human MSCs than LNCs, but although both NP showed a similar inhibition of REST over time and the induction of neuronal commitment, LNC–siREST induced a higher expression of neuronal markers. Therefore, two different tailored siRNA NP offering great potential for human stem cell differentiation have been developed, encouraging the pursuit of further in vitro and in vivo in studies.
Keywords: Nanocarriers; siRNA; Mesenchymal stem cells; Neuronal differentiation; REST;
Pharmaceutical potential of tacrolimus-loaded albumin nanoparticles having targetability to rheumatoid arthritis tissues by Le Quang Thao; Hyeong Jun Byeon; Changkyu Lee; Seunghyun Lee; Eun Seong Lee; Han-Gon Choi; Eun-Seok Park; Yu Seok Youn (268-276).
Display OmittedAlbumin is considered an attractive dug carrier for hydrophobic drugs to target inflamed joints of rheumatoid arthritis. This study focused on the pharmaceutical potential of albumin-based nanoparticles (NPs) on delivery of tacrolimus (TAC) to enhance targetability and anti-arthritic efficacy. TAC-loaded human serum albumin (HSA) nanoparticles (TAC HSA-NPs) were prepared using the nab™ technology. The resulting NPs were 185.8 ± 6.8 nm in diameter and had a zeta potential value of −30.5 ± 1.1 mV, as determined by dynamic light scattering. Particles were uniformly spherical in shape as determined by transmission electron microscopy. The encapsulation efficacy of TAC was 79.3 ± 3.7% and the water solubility was over 46 times greater than that of free TAC. TAC was gradually released from NPs over 24 h, which is sufficient time for targeting and treatment of the NPs in inflamed arthritis via intravenous injection. In vitro study using splenocytes excised from spleens of mice following induction of arthritis using collagen clearly demonstrated the anti-proliferative activity of TAC HSA-NPs on activated T cells compared with non-activated T cells. Furthermore, TAC HSA-NPs displayed significantly more anti-arthritic activity than TAC formulations including intravenously administered TAC solution or oral TAC suspension, as reflected by the incidence of arthritis and clinical score (1.6 vs. 3.2 and 5.0, respectively). These improvements were due to the targetability of HSA that facilitated the accumulation of TAC HSA-NPs at inflamed arthritis sites. TAC HSA-NPs are a promising drug delivery system to enhance water solubility and increase accumulation in joints for treatment of rheumatoid arthritis.
Keywords: Albumin; Nanoparticles; Tacrolimus; Rheumatoid arthritis; Collagen-induced arthritis; Targeting;
What is the discrepancy between drug permeation into/across intact and diseased skins? Atopic dermatitis as a model by Yi-Ping Fang; Sien-Hung Yang; Chih-Hung Lee; Ibrahim A. Aljuffali; Hsiao-Ching Kao; Jia-You Fang (277-286).
Display OmittedThe discrepancy in drug absorption between healthy and diseased skins is an issue that needs to be elucidated. The present study attempted to explore the percutaneous absorption of drugs via lesional skin by using atopic dermatitis (AD) as a model. Tape-stripping and ovalbumin (OVA) sensitization induced AD-like skin. The lesions were evaluated by physiological parameters, histology, cytokines, and differentiation proteins. The permeants of tacrolimus, 8-methoxypsoralen, methotrexate, and dextran were used to examine in vitro and in vivo cutaneous permeation. Transepidermal water loss (TEWL) increased from 5.2 to 27.4 g/m2/h by OVA treatment. AD-like lesions were characterized by hyperplasia, skin redness, desquamation, and infiltration of inflammatory cells. Repeated OVA challenge produced a T-helper 2 (Th2) hypersensitivity accompanied by downregulation of filaggrin, involucrin, and integrin β. Tacrolimus, the most lipophilic permeant, revealed an increase of cutaneous deposition by 2.7-fold in AD-like skin compared to intact skin. The transdermal flux of methotrexate and dextran, the hydrophilic permeants, across AD-like skin increased about 18 times compared to the control skin. Surprisingly, AD-like skin showed less skin deposition of 8-methoxypsoralen than intact skin. This may be because the deficient lipids in the atopic-affected stratum corneum (SC) diminished drug partitioning into the superficial skin layer. The fluorescence and confocal microscopic images demonstrated a broad and deep passage of small-molecular and macromolecular dyes into AD-like skin. The results obtained from this report were advantageous for showing how the lesional skin influenced percutaneous absorption.
Keywords: Atopic dermatitis; Diseased skin; Percutaneous absorption; Stratum corneum; Tight junction;
Ethambutol plasma and intracellular pharmacokinetics: A pharmacogenetic study by Giovanna Fatiguso; Sarah Allegra; Andrea Calcagno; Lorena Baietto; Ilaria Motta; Fabio Favata; Jessica Cusato; Stefano Bonora; Giovanni Di Perri; Antonio D’Avolio (287-292).
We evaluated ethambutol plasma and intracellular pharmacokinetic according to single nucleotide polymorphisms in ABCB1, OATP1B1, PXR, VDR, CYP24A1 and CYP27B1 genes. Mycobacterium tubercolosis infected patients were enrolled. Standard weight-adjusted antitubercular treatment was administered intravenously for 2 weeks and then orally. Allelic discrimination was performed by real-time PCR. Ethambutol plasma and intracellular concentrations were measured by UPLC-MS/MS methods. Twenty-four patients were included. Considering weeks 2 and 4, median plasma C trough were 73 ng/mL and 247 ng/mL, intracellular C trough were 16,863 ng/mL and 13,535 ng/mL, plasma C max were 5627 ng/mL and 2229 ng/mL, intracellular C max were 133,830 ng/mL and 78,544 ng/mL. At week 2, ABCB1 3435 CT/TT (p = 0.023) and CYP24A1 8620 AG/GG (p = 0.030) genotypes for plasma C trough, BsmI AA (p = 0.036) for intracellular C trough and BsmI AA (p < 0.001) and ApaI AA (p = 0.048) for intracellular C max, remained in linear regression analysis as predictive factors. Concerning week 4 only ABCB1 3435 CT/TT (p = 0.035) and Cdx2 AG/GG (p = 0.004) genotypes for plasma C trough and BsmI AA (p = 0.028) for plasma C max were retained in final regression model. We reveal, for the first time, the possible role of single nucleotide polymorphisms on ethambutol plasma and intracellular concentrations; this may further the potential use of pharmacogenetic for tailoring antitubercular treatment.
Keywords: BsmI; Cdx2; FokI; CYP24A1; ABCB1;
HPLC analysis as a tool for assessing targeted liposome composition by Mira Oswald; Michael Platscher; Simon Geissler; Achim Goepferich (293-300).
Display OmittedFunctionalized phospholipids are indispensable materials for the design of targeted liposomes. Control over the quality and quantity of phospholipids is thereby key in the successful development and manufacture of such formulations. This was also the case for a complex liposomal preparation composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), Cholesterol (CHO), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000). To this end, an RP-HPLC method was developed. Detection was done via evaporative light scattering (ELS) for liposomal components. The method was validated for linearity, precision, accuracy, sensitivity and robustness. The liposomal compounds had a non-linear quadratic response in the concentration range of 0.012–0.42 mg/ml with a correlation coefficient greater than 0.99 with an accuracy of method confirmed 95–105% of the theoretical concentration. Furthermore, degradation products from the liposomal formulation could be identified. The presented method was successfully implemented as a control tool during the preparation of functionalized liposomes. It underlined the benefit of HPLC analysis of phospholipids during liposome preparation as an easy and rapid control method for the functionalized lipid at each preparation step as well as for the quantification of all components.
Keywords: Liposomes; Phospholipid analysis; ELSD; HPLC; DSPE-PEG2000;
Evaluation of critical formulation parameters in design and differentiation of self-microemulsifying drug delivery systems (SMEDDSs) for oral delivery of aciclovir by Jovana Janković; Ljiljana Djekic; Vladimir Dobričić; Marija Primorac (301-311).
Display OmittedThe 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 ≤ 100 nm, PdI < 0.250) upon spontaneous dispersion in 0.1 M 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.
Keywords: Self-dispersing drug delivery systems; Self-microemulsifying drug delivery systems (SMEDDS); Aciclovir; Acyclovir; In vitro drug release; Parallel artificial membrane permeability assay (PAMPA);