European Journal of Pharmaceutics and Biopharmaceutics (v.69, #2)
Immune response by nasal delivery of hepatitis B surface antigen and codelivery of a CpG ODN in alginate coated chitosan nanoparticles
by Olga Borges; Anabela Cordeiro-da-Silva; Joana Tavares; Nuno Santarém; Adriano de Sousa; Gerrit Borchard; Hans E. Junginger (pp. 405-416).
Alginate coated chitosan nanoparticles were previously developed with the aim of protecting the antigen, adsorbed on the surface of those chitosan nanoparticles, from enzymatic degradation at mucosal surfaces. In this work, this new delivery system was loaded with the recombinant hepatitis B surface antigen (HBsAg) and applied to mice by the intranasal route. Adjuvant effect of the delivery system was studied by measuring anti-HBsAg IgG in serum, anti-HBsAg sIgA in faeces extracts or nasal and vaginal secretions and interferon-γ production in supernatants of the spleen cells. The mice were primed with 10μg of the vaccine associated or not with nanoparticles and associated or not with 10μg CpG oligodeoxynucleotide (ODN) followed by two sequential boosts at three week intervals. The association of HBsAg with the alginate coated chitosan nanoparticles, administered intranasally to the mice, gave rise to the humoral mucosal immune response. Humoral systemic immune response was not induced by the HBsAg loaded nanoparticles alone. The generation of Th1-biased antigen-specific systemic antibodies, however, was observed when HBsAg loaded nanoparticles were applied together with a second adjuvant, the immunopotentiator, CpG ODN. Moreover, all intranasally vaccinated groups showed higher interferon-γ production when compared to naïve mice.
Keywords: Intranasal vaccination; Hepatitis B surface antigen; CpG oligodeoxynucleotide; Alginate coated chitosan nanoparticles; Vaccines
Self-assembled polyelectrolyte nanocomplexes between chitosan derivatives and enoxaparin
by Wei Sun; Shirui Mao; Dan Mei; Thomas Kissel (pp. 417-425).
Polyelectrolyte complexes (PEC) formed from chitosan derivatives and enoxaparin were prepared and parameters influencing complex formation were characterized. Dynamic light scattering (DLS) and laser doppler anemometry (LDA) were used to study the complexation process. Surface morphology of the PECs was observed with atomic force microscopy (AFM). The PEC formation process was influenced by a variety of parameters, including the system pH, polymer/enoxaparin mass ratio, polymer molecular weight, concentration and structure. Soluble complexes in the size range of 200–500nm with spherical morphology could be obtained at optimized polymer/enoxaparin ratios in the pH range of 3.0–6.5, with positive charge and drug encapsulation efficiency of approximately 90%. An increase in ionic strength of the medium accelerated the dissociation of chitosan/enoxaparin complexes. In contrast, chitosan thiolation, methylation and PEGylation significantly improved the stability of the complexes. Physicochemical properties of the PECs, including particle size, charge density and morphology, could be modified by using different chitosan derivatives. On the basis of our results, we suggest that interactions involved in PEC formation were partly electrostatic in nature, involving the positively charged chitosan derivatives and the negatively charged enoxaparin at pH values in the vicinity of the p Ka interval of the two polymers. Oral absorption of the polyelectrolyte nanocomplexes will be studied in vivo.
Keywords: Chitosan; Thiolated chitosan; Trimethyl chitosan; PEGylation; LMWH; Enoxaparin; Polyelectrolyte complexes; Nanoparticle
Effective insulin delivery using starch nanoparticles as a potential trans-nasal mucoadhesive carrier
by Akhlesh Kumar Jain; Roop K. Khar; Farhan J. Ahmed; Prakash V. Diwan (pp. 426-435).
Mucoadhesive nanoparticles (NPs) could be an exciting prospect for trans-nasal insulin delivery as they have higher surface area to cover highly vascularised nasal absorptive area providing a greater concentration gradient; hence the present study makes an attempt in this regard. Starch NPs were prepared by different crosslinkers using various methodologies and were loaded with insulin. Emulsion crosslinked particles were smaller in size compared to gel method (351 vs 997nm), and size is further reduced when epichlorohydrin is used as crosslinking agent compared to POCl3 (194 vs 810nm). NPs of epichlorohydrin emulsion were further optimized with variable crosslinking to evaluate the effect of degree of crosslinking on in vivo performance. In vitro, a size dependent first order diffusion controlled insulin release with an initial burst effect was found, which is higher with NPs of small size and least crosslinking. Formulation of EE–NPs with Na glycocholate showed a superior hypoglycemic action compared to other NPs formulations containing the former and lysophosphatidylcholine as permeation enhancers. The hypoglycemic effects were more pronounced with medium crosslinked NPs (EE–L2–NPs), which showed a nadir of 70% reduction of plasma glucose and significant effects untill 6h. The peak plasma insulin level ( Cmax) of medium crosslinked EE–L2–NPs (258μIU/ml at 1h) vindicates the pharmacodynamic effect, which was found to be superior compared to all other formulations. The release rate and higher associated surface area might work in tandem, and could be greatly amplified when combined with permeation enhancers to make starch NPs an efficient trans-nasal mucoadhesive carrier of insulin.
Keywords: Nanoparticles; Insulin; Nasal delivery; Permeation enhancers; Mucoadhesion
Specific permeability modulation of intestinal paracellular pathway by chitosan-poly(isobutylcyanoacrylate) core-shell nanoparticles
by I. Bravo-Osuna; C. Vauthier; H. Chacun; G. Ponchel (pp. 436-444).
This work is focused on the evaluation of the in vitro permeation modulation of chitosan and thiolated chitosan (chitosan-TBA) coated poly(isobutylcyanoacrylate) (PIBCA) nanoparticles as drug carriers for mucosal administration. Core-corona nanoparticles were obtained by radical emulsion polymerisation of isobutylcyanoacrylate (IBCA) with chitosan of different molecular weights and different proportions of chitosan/chitosan-TBA. In this work, the effect of these nanoparticles on the paracellular permeability of intestinal epithelium was investigated using the Ussing chamber technique, by adding nanoparticle suspensions in the mucosal side of rat intestinal mucosa. Results showed that permeation of the tracer [14C]mannitol and the reduction of transepithelial electrical resistance (TEER) in presence of nanoparticles were more pronounced in those formulations prepared with intermediate amounts of thiolated polymer. This effect was explained thanks to the high diffusion capacity of those nanoparticles through the mucus layer that allowed them to reach the tight junctions in higher extent.It was concluded that, although a first contact between nanoparticles and mucus was a mandatory condition for the development of a permeation enhancement effect, the optimal effect depended on the chitosan/chitosan-TBA balance and the conformational structure of the particles shell.
Keywords: Chitosan; Thiolated chitosan; Poly(isobutylcyanoacrylate); Core-shell/core-corona nanoparticles; Permeation enhancement; TEER; Ussing-type chambers
Dual agents loaded PLGA nanoparticles: Systematic study of particle size and drug entrapment efficiency
by Xiangrong Song; Yu Zhao; Shixiang Hou; Fangyuan Xu; Rongli Zhao; Junyao He; Zheng Cai; Yuanbo Li; Qiuhong Chen (pp. 445-453).
PLGA nanoparticles simultaneously loaded with vincristine sulfate (VCR) and quercetin (QC) were prepared via O/W emulsion solvent evaporation. Six independent processing parameters and PLGA characteristics were assessed systematically to enhance the incorporation of the dual agents with different properties (VCR and QC, hydrophilic and hydrophobic molecule, respectively) into PLGA nanoparticles and control particle size. Approaches investigated for the enhancement of drug entrapment efficiencies and the controlling of particle size included the influence of the molecular weight (MW) of PLGA and the lactide-to-glycolide (L:G) ratio of PLGA, PLGA concentration, PVA concentration, initial QC content, acetone-to-dichloromethane (A/D) volume ratio, aqueous phase pH and aqueous to organic phase (W/O) volume ratio. The nanoparticles produced by optimal formulation were submicron size (139.5±4.3nm, n=3) with low polydispersity index (0.095±0.031, n=3). Nanoparticles observed by transmission electron microscopy (TEM) showed extremely spherical shape. The entrapment efficiencies determined by high performance liquid chromatography (HPLC) by ultracentrifuge method were 92.84±3.37% for VCR and 32.66±2.92% for QC ( n=3). The drug loadings were 0.0037±0.0001% for VCR and 1.36±0.12% for QC ( n=3).
Keywords: Vincristine sulfate; Quercetin; PLGA; Nanoparticles; O/W
Preparation, characterization and in vivo evaluation of amorphous atorvastatin calcium nanoparticles using supercritical antisolvent (SAS) process
by Min-Soo Kim; Shun-Ji Jin; Jeong-Soo Kim; Hee Jun Park; Ha-Seung Song; Reinhard H.H. Neubert; Sung-Joo Hwang (pp. 454-465).
In this work, amorphous atorvastatin calcium nanoparticles were successfully prepared using the supercritical antisolvent (SAS) process. The effect of process variables on particle size and distribution of atorvastatin calcium during particle formation was investigated. Solid state characterization, solubility, intrinsic dissolution, powder dissolution studies and pharmacokinetic study in rats were performed. Spherical particles with mean particle size ranging between 152 and 863nm were obtained by varying process parameters such as precipitation vessel pressure and temperature, drug solution concentration and feed rate ratio of CO2/drug solution. XRD, TGA, FT-IR, FT-Raman, NMR and HPLC analysis indicated that atorvastatin calcium existed as anhydrous amorphous form and no degradation occurred after SAS process. When compared with crystalline form (unprocessed drug), amorphous atorvastatin calcium nanoparticles were of better performance in solubility and intrinsic dissolution rate, resulting in higher solubility and faster dissolution rate. In addition, intrinsic dissolution rate showed a good correlation with the solubility. The dissolution rates of amorphous atorvastatin calcium nanoparticles were highly increased in comparison with unprocessed drug by the enhancement of intrinsic dissolution rate and the reduction of particle size resulting in an increased specific surface area. The absorption of atorvastatin calcium after oral administration of amorphous atorvastatin calcium nanoparticles to rats was markedly increased.
Keywords: Atorvastatin calcium; Supercritical antisolvent; Nanoparticle; Amorphous form
How to concentrate nanoparticles and avoid aggregation?
by C. Vauthier; B. Cabane; D. Labarre (pp. 466-475).
Most of the methods that are used to produce pharmaceutical suspensions of nanoparticles for drug-targeting yield suspensions having a low content in drug carriers. This can be a dramatic limitation when the volume of suspension that would have to be administered in vivo to reach therapeutic concentrations of the drug is much above the acceptable range. Concentrating the drug-carrier suspension by centrifugation, lyophilization and evaporation is often inapplicable because aggregates are formed. Here we present a simple method that is able to increase the concentration of nanoparticle suspensions without forming aggregates. It consists in a dialysis of the suspensions against a polymer solution. This causes an osmotic stress, which produces a displacement of water from the nanoparticle suspension towards the counter-dialysing solution. Various types of nanoparticle suspensions can be concentrated in near equilibrium conditions, and the result is controlled and reproducible. Concentration factors up to 50 were obtained in a few hours at room temperature. The original characteristics of the nanoparticles were fully preserved in the concentrated dispersion.
Keywords: Nanoparticles; Osmotic pressure; Dialysis; Dextran; Concentration
Preparation and evaluation of microparticles from thiolated polymers via air jet milling
by Herbert Hoyer; Wolfgang Schlocker; Kafedjiiski Krum; Andreas Bernkop-Schnürch (pp. 476-485).
Microparticles were formulated by incorporation of the model protein horseradish peroxidase in (thiolated) chitosan and (thiolated) poly(acrylic acid) via co-precipitation. Dried protein/polymer complexes were ground with an air jet mill and resulting particles were evaluated regarding size distribution, shape, zeta potential, drug load, protein activity, release pattern, swelling behaviour and cytotoxicity. The mean particle size distribution was 0.5–12μm. Non-porous microparticles with a smooth surface were prepared. Microparticles from (thiolated) chitosan had a positive charge whereas microparticles from (thiolated) poly(acrylic acid) were negatively charged. The maximum protein load for microparticles based on chitosan, chitosan–glutathione (Ch–GSH), poly(acrylic acid) (PAA) and for poly(acrylic acid)–glutathione (PAA–GSH) was 7±1%, 11±2%, 4±0.2% and 7±2%, respectively. The release profile of all microparticles followed a first order release kinetic. Chitosan (0.5mg), Ch–GSH, PAA and PAA–GSH particles showed a 31.4-, 13.8-, 54.2- and a 42.2-fold increase in weight, respectively. No significant cytotoxicity could be found. Thiolated microparticles prepared by jet milling technique were shown to be stable and to have controlled drug release characteristics. After further optimizations the preparation method described here might be a useful tool for the production of protein loaded drug delivery systems.
Keywords: Air jet mill; Co-precipitation; Microparticles; Chitosan; Poly(acrylic acid)
Preparation and characterisation of controlled release co-spray dried drug–polymer microparticles for inhalation 1: Influence of polymer concentration on physical and in vitro characteristics
by Rania Salama; Susan Hoe; Hak-Kim Chan; Daniela Traini; Paul M. Young (pp. 486-495).
A series of co-spray dried microparticles containing di-sodium cromoglycate (DSCG) and polyvinyl alcohol (PVA – 0%, 30%, 50%, 70% and 90% w/w, respectively), were prepared as potential controlled release (CR) viscous/gelling vehicles for drug delivery to the respiratory tract. The microparticles were characterised in terms of particle size, crystal structure, density, surface morphology, moisture sorption, surface energy and in vitro aerosolisation efficiency. The co-spray dried particles were amorphous in nature and had spherical geometry. High-resolution atomic force microscopy analysis of the surfaces of the DSCG/PVA suggested no significant differences in roughness between microparticles containing 30–90% w/w PVA (ANOVA, p<0.05), while no specific trend in either size or density was observed with respect to PVA concentration. In comparison, a linear decrease in the relative moisture sorption ( R2=0.997) and concurrent increase in total surface free energy ( R2=0.870) were observed as PVA concentration was increased. Furthermore a linear increase in the aerosolisation efficiency, measured by inertial impaction, was observed as PVA concentration was increased ( R2=0.993). In addition, the increase in aerosolisation efficiency showed good correlation with equilibrium moisture content ( R2=0.974) and surface energy measurement ( R2=0.905). These relationships can be attributed to the complex interplay of particle forces at the contiguous interfaces in this particulate system.
Keywords: DSCG; PVA; Dry powder inhalation; DPI; Aerosolisation; Surface energy
An investigation into the relationship between carrier-based dry powder inhalation performance and formulation cohesive–adhesive force balances
by Matthew D. Jones; Haggis Harris; Jennifer C. Hooton; Jagdeep Shur; Graeme S. King; Camilla A. Mathoulin; Katrina Nichol; Tracey L. Smith; Michelle L. Dawson; Alan R. Ferrie; Robert Price (pp. 496-507).
The inclusion of different carrier materials in a dry powder inhaler (DPI) system can alter formulation performance, which might be attributable to variation in the adhesion between drug and carrier particles. The aim of this study was, therefore, to further examine the relationship between drug-carrier adhesion and performance, by comparing data relating to many different drug-carrier combinations. Four drugs and four carriers were employed, giving a total of 16 combinations. The relative magnitude of the drug-carrier adhesion for each combination was quantified using the cohesion–adhesion balance (CAB) approach to colloidal probe atomic force microscopy. The in vitro inhalation performance of the 16 formulations (1.5% w/w drug) was investigated and found to vary significantly. Plots of fine particle dose against drug-carrier CAB ratio revealed that performance was optimised when the drug-carrier CAB ratio was slightly cohesive. This trend was found to fit with those from similar previous studies, although due to the smaller number of formulations investigated previously, the full extent of this relationship had not been revealed. It was concluded, therefore, that when developing a carrier-based DPI, the selection of a drug-carrier combination with a slightly cohesive CAB ratio might result in optimal performance.
Keywords: Adhesion; Agglomerate; Atomic force microscopy; Carrier; Cohesion; Dry powder inhaler
Development of enteric-coated calcium pectinate microspheres intended for colonic drug delivery
by Francesca Maestrelli; Marzia Cirri; Giovanna Corti; Natascia Mennini; Paola Mura (pp. 508-518).
Enteric-coated calcium pectinate microspheres (MS) aimed for colon drug delivery have been developed, by using theophylline as a model drug. The influence of pectin type (amidated or non-amidated) and MS preparation conditions (CaCl2 concentration and cross-linking time) was investigated upon the drug entrapment efficiency and its release behaviour. Drug stability and drug–polymer interactions were studied by Differential Scanning Calorimetry, thermogravimetry, X-ray diffractometry and FTIR spectroscopy. Enteric coating with Eudragit® S100 enabled maintenance of MS integrity until its expected arrival to colon. The coating was also useful to improve the stability of MS during storage, avoiding morphologic changes observed for uncoated MS stored under ambient conditions. Entrapment efficiency increased by reducing cross-linking time, and (only in the case of non-amidated pectin) by increasing CaCl2 concentration. On the other hand, release tests performed simulating the gastro-intestinal pH variation evidenced an inverse relationship between CaCl2 concentration and drug release rate, whereas no influence of both pectin type and cross-linking time was found. Unexpectedly, addition of pectinolytic enzymes to the colonic medium did not give rise to selective enzymatic degradation of MS. Notwithstanding this unforeseen result, coated MS prepared at 2.5% w/v CaCl2 concentration were able to adequately modulate drug release through a mixed approach of pH and transit time control, avoiding drug release in the gastric ambient, and reaching the colonic targeting where 100% release was achieved within less than 24h.
Keywords: Colon delivery; Amidated and non-amidated pectin; Calcium pectinate microspheres; Cross-linking conditions; Eudragit S100; Theophylline; Drug release
γ-Irradiation effects on biopharmaceutical properties of PLGA microspheres loaded with SPf66 synthetic vaccine
by Manoli Igartua; Rosa M Hernández; Jaiver Eduardo Rosas; Manuel Elkin Patarroyo; José Luís Pedraz (pp. 519-526).
γ-Irradiation is currently the method of choice for terminal sterilization of drug delivery systems made from biodegradable polymers. However, the consequences of γ-sterilization on the immune response induced by microencapsulated antigens have not yet been reported in the literature. The aim of the present work was to evaluate the effect of γ-irradiation on the biopharmaceutical properties of PLGA microspheres containing SPf66 malarial antigen. Microspheres were prepared by a (w/o/w) double emulsion/solvent extraction method. Once prepared, part of the formulation was irradiated at a dose of 25kGy using60Co γ as radiation source. The in vitro results obtained showed that the γ-irradiation exposure had no apparent effect on SPf66 integrity and formulation properties such us morphology, size and peptide loading. Only the release rate of SPf66 was slightly faster after γ-irradiation. Subcutaneous administration of irradiated and non-irradiated microspheres into mice induced a similar immune response (IgG, IgG1, IgG2a levels) and was comparable to that obtained with SPf66 emulsified with Freund’s complete adjuvant. These observations illustrate the applicability of γ-irradiation as a method of terminal sterilization of microparticulate delivery systems based on chemically synthesized antigens encapsulated into biodegradable PLGA microspheres.
Keywords: SPf66 malarial antigen; Microspheres; PLGA; γ-Irradiation; Sterilization
The antitumor effect of novel docetaxel-loaded thermosensitive micelles
by Baorui Liu; Mi Yang; Rutian Li; Yitao Ding; Xiaoping Qian; Lixia Yu; Xiqun Jiang (pp. 527-534).
To further evaluate the novel docetaxel-loaded micelle based on the biodegradable thermosensitive copolymer poly( N-isopropylacrylamide-co-acrylamide)- b-poly(dl-lactide) that we had synthesized before, in this paper, we studied its in vitro cytotoxicity in three different tumor cell lines by standard MTT assays using different tumor cell lines, followed by studies of acute toxicity and the tumor distribution studies which were conducted in Kunming mice. Meanwhile, the in vivo antitumor efficacy as well as toxicity of the micelle was evaluated in C57BL/6 mice. According to our findings, the in vitro cytotoxicity of docetaxel-loaded micelles was lower than that of the conventional docetaxel formulation at 37°C, while hyperthermia greatly enhanced the efficacy of drug-loaded micelles. The acute toxicity study showed reduced toxicity of docetaxel-loaded micelle compared to that of conventional docetaxel formulation. Moreover, docetaxel-loaded micelle enabled a prominent higher docetaxel concentration in tumor than conventional docetaxel formulation. Furthermore, a significantly higher antitumor efficacy was observed in mice treated with docetaxel-loaded micelles accompanied by hyperthermia; docetaxel-loaded micelles also caused less body weight loss of mice. This study demonstrates an increased antitumor efficacy and reduced toxicity of the novel docetaxel-loaded micelle and indicates its prospect of clinical applications.
Keywords: Abbreviation; LCST; low critical solution temperature; LD; 50; median lethal dose; LLC; Lewis lung carcinoma; poly(IPAAm-co-AAm)-; b; -PDLLA; poly(; N; -isopropylacrylamide-co-acrylamide)-; b; -poly(; dl; -lactide); RES; reticuloendothelial systemDocetaxel; Targeted drug delivery; Hyperthermia; Thermosensitive micelle; In vivo
Triclosan-loaded poloxamine micelles for enhanced topical antibacterial activity against biofilm
by Diego A. Chiappetta; José Degrossi; Sergio Teves; Miguel D’Aquino; Carlos Bregni; Alejandro Sosnik (pp. 535-545).
Our research group is interested in the study of different technological approaches to treat hospital biofilm as a means to constrain nosocomial-acquired infections. The present work investigated the effect of the incorporation of the antibacterial agent triclosan (TS) into polymeric micelles of poloxamine T1107 ( MW=15kDa, 70 wt% PEO). The aggregation phenomenon was primarily investigated by means of Critical Micellar Concentration in a broad range of pH. Then, the effect of the polymer concentration on the micellar size was evaluated by Dynamic Light Scattering. Solubility levels increased up to 4 orders of magnitude. The drug inclusion affected the micellization, resulting in size increase and micellar fusion. This phenomenon was only apparent in TS-saturated systems. TS-loaded aggregates proved to be active in vitro against a broad spectrum of bacteria but more importantly, also against two representative clinical pathogens: methicilin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VREF). While the former was sensitive to even very low TS levels attainable in poloxamine-free aqueous media, the later was inhibited only when exposed to higher drug levels affordable exclusively using an inclusion system. These findings indicated the release of the drug from the reservoir. Finally, the activity of a TS-containing 5% poloxamine combination of pH 7.4 was assessed on biofilms of Staphylococcus epidermidis. Results showed a significant decrease ( p<0.001) in the number of Colony-Formation Units when the biofilm was exposed to the TS/poloxamine as compared to the limited activity of the polymer-free TS control.
Keywords: Poloxamine polymeric micelles; Tetronic 1107; Triclosan water-solubilization; Methicillin-resistant; Staphyloccoccus aureus; Vancomycin-resistant; Enterococcus faecalis; Bacterial biofilm
The pH-controlled dual-drug release from mesoporous bioactive glass/polypeptide graft copolymer nanomicelle composites
by Wei Xia; Jiang Chang; Jiaping Lin; Jianqi Zhu (pp. 546-552).
Dual-drug delivery systems are investigated for combined therapy with drugs having distinct therapeutic effects. However, the majority of current dual-drug delivery systems are designed for simultaneous release of two different drugs; the release of each individual drug cannot be controlled. In this study, we have demonstrated a novel dual-drug delivery system based on mesoporous bioactive glass/polypeptide graft copolymer nanomicelle composites. Water-soluble gentamicin and fat-soluble naproxen were used as model drugs in the study of this system. A pH-controlled release of individual drugs was achieved by the predominant release of gentamicin from mesoporous bioactive glass in an acid environment and fast release of naproxen in an alkaline environment from polypeptide nanomicelles. Our results suggest that the mesoporous bioactive glass/PBLG-g-PEG nanomicelle composites can be used as a dual-drug delivery system, and that the individual drug release can be controlled by the pH of the surrounding environment.
Keywords: Drug delivery; Mesoporous materials; Polypeptide; Bioactive glass; Controlled release
Bioavailability of probucol from lipid and surfactant based formulations in minipigs: Influence of droplet size and dietary state
by Flemming Seier Nielsen; Kamilla Buchberg Petersen; Anette Müllertz (pp. 553-562).
The influence of droplet size on the absorption from lipid and surfactant based formulations was evaluated from two self-emulsifying formulations, a surfactant solution, and an oil solution. The self-emulsifying formulations was a self-emulsifying (SEDDS) and a self-nanoemulsifying (SNEDDS) formulation containing equal lipid and surfactant load, but exhibiting a large difference (approx 100 times) in the mean particle diameter of the resultant emulsion. The formulations were evaluated in a bioavailability study in fasted and fed Göttingen minipigs using probucol as model drug. In order to determine the bioavailability, an oil-in-water emulsion was included as i.v. formulation. The fasted group was fasted overnight and offered the first daily meal approx 4h after treatment. The fed group was offered the first daily meal (50% energy from fat) 30min prior to treatment. In the fasted group the SNEDDS exhibited a slightly faster absorption and higher bioavailability than the SEDDS, though non-significant. Furthermore, the bioavailability from the surfactant solution and the oil solution were slightly lower compared to the SNEDDS, indicating that both small particle size and digestibility are important in ensuring optimal bioavailability. Comparing the absorption in fasted and fed minipigs showed that probucol exhibited no significant food effect, when formulated in a lipid and surfactant based formulations.
Keywords: Self-emulsifying drug delivery system (SEDDS); Bioavailability; Oral absorption; Food interactions; Surfactants; Emulsion/nanoemulsion
Controlled nerve growth factor release from multi-ply alginate/chitosan-based nerve conduits
by Lukas A. Pfister; Eva Alther; Michaël Papaloïzos; Hans. P. Merkle; Bruno Gander (pp. 563-572).
The delivery kinetics of growth factors has been suggested to play an important role in the regeneration of peripheral nerves following axotomy. In this context, we designed a nerve conduit (NC) with adjustable release kinetics of nerve growth factor (NGF). A multi-ply system was designed where NC consisting of a polyelectrolyte alginate/chitosan complex was coated with layers of poly(lactide-co-glycolide) (PLGA) to control the release of embedded NGF. Prior to assessing the in vitro NGF release from NC, various release test media, with and without stabilizers for NGF, were evaluated to ensure adequate quantification of NGF by ELISA. Citrate (pH 5.0) and acetate (pH 5.5) buffered saline solutions containing 0.05% Tween 20 yielded the most reliable results for ELISA active NGF. The in vitro release experiments revealed that the best results in terms of reproducibility and release control were achieved when the NGF was embedded between two PLGA layers and the ends of the NC tightly sealed by the PLGA coatings. The release kinetics could be efficiently adjusted by accommodating NGF at different radial locations within the NC. A sustained release of bioactive NGF in the low nanogram per day range was obtained for at least 15days. In conclusion, the developed multi-ply NGF loaded NC is considered a suitable candidate for future implantation studies to gain insight into the relationship between local growth factor availability and nerve regeneration.
Keywords: NGF; Release kinetics; Nerve conduit; Nerve regeneration
Konjac glucomannan/xanthan gum enzyme sensitive binary mixtures for colonic drug delivery
by Felipe Alvarez-Manceñido; Mariana Landin; Ramón Martínez-Pacheco (pp. 573-581).
The polysaccharide konjac glucomannan (KGM) is degraded in the colon but not the small intestine, which makes it potentially useful as an excipient for colonic drug delivery. With xanthan gum (XG) KGM forms thermoreversible gels with hitherto unexplored biodegradation properties. In this work, rheological measurements of KGM and KGM/XG systems incubated with and without Aspergillus niger β-mannanase (used to mimic colonic enzymes) showed that KGM was degraded by the enzyme even when interacting with XG. Tablets with KGM/XG/sucrose matrices that varied in accordance with a simplex design and bore diltiazem as a typical highly soluble drug load were prepared by wet granulation, and in most cases were found to possess satisfactory mechanical strength and exhibit slow, nearly zero-order drug release. Drug release from these tablets remained zero-order, but was accelerated (presumably due to degradation of KGM), in the presence of A. niger β-mannanase at concentrations equivalent to human colonic conditions. However, marked differences between Japanese and American varieties of KGM as regards degree of acetylation and particle size led to significant differences in swelling rate and drug release between formulations prepared with one and the other KGM: whereas a formulation with Japanese KGM released its entire drug load within 24h in the presence of β-mannanase, only 60% release was achieved under the same conditions by the corresponding formulation with American KGM, suggesting that with this KGM it will be necessary to optimize technological variables such as compression pressure in order to achieve suitable porosity, swelling rate, and drug release. To sum up, the results of this study suggest that sustained release of water-soluble drugs in the colon from orally administered tablets may be achieved using simple, inexpensive formulations based on combinations of KGM and XG that take the variability of KGM characteristics into account.
Keywords: Konjac glucomannan; Xanthan gum; Synergistic interaction; Colonic drug delivery; Enzymatic degradation
Cation exchange resins as pharmaceutical carriers for methylene blue: Binding and release
by Felix Gut; Wolfgang Schiek; Walter E. Haefeli; Ingeborg Walter-Sack; Jürgen Burhenne (pp. 582-587).
Methylene blue is a competitive inhibitor of the glutathione reductase of Plasmodium falciparum and is used in combination with other antimalarial drugs leading to a renaissance of methylene blue in malaria therapy. Its bitter flavour and tissue colouring property impair compliance, especially in children. These problems may be solved by binding the cationic methylene blue to cation exchange materials as pharmaceutical carriers in order to mask the undesirable properties. However, such carriers are only useful if the antimalarial is released under physiological conditions. The binding to seven cation exchange resins was studied. Ion exchangers on acrylic or methacrylic acid basis bound between 1.54 and 2.16g methylene blue chloride trihydrate per gram ion exchanger. Polymers on divinylbenzene or styrene basis with sulphonic acid groups bound 306 and 384mg of methylene blue chloride trihydrate per gram ion exchanger. In aqueous solution at pH of 1.5, nearly all bound methylene blue was released. The release of methylene blue from (meth)acrylic acid polymers in the presence of proteins and fat was not affected. From these data ion exchangers present a promising group of pharmaceutical carrier for the safe and compliant drug administration of methylene blue to children.
Keywords: Malaria; Methylene blue; Cation exchange resins; Binding; Release
Nortriptyline hydrochloride skin absorption: Development of a transdermal patch
by Ana Melero; T.M. Garrigues; P. Almudever; A. Martı´n Villodre; C.M. Lehr; U. Schäfer (pp. 588-596).
The influence of propylen glycol (PG), ethanol, and oleic acid (OA) on nortriptyline hydrochloride (NTH) penetration through human epidermis was studied in vitro at two different pH values (5.5 and 7.4). The influence of lactic acid and polysorbate 80 was studied for a pH of 5.5. Permeation studies through Heat Separated Epidermis, as well as the enhancing effect of the different vehicles, showed a pH dependency. A pH value of 5.5 in the donor solution decreases significantly the permeability coefficient ( Kp) with respect to a pH value of 7.4 (0.011±0.004×10−6 versus 0.36±0.04×10−6cm/s). The vehicles showed an increasing enhancement effect in the order: polysorbate 80>ethanol/PG/OA>PG>ethanol>ethanol/lactic acid>lactic acid at pH 5.5 while they reduced the permeation of NTH at pH 7.4. Considering the results obtained at pH 5.5, the maximum enhancement ratios were found for polysorbate 80 and the combination ethanol/PG/OA (10.72 and 3.90). Both vehicles were selected for designing a NTH transdermal delivery system (NTH-TDS) using (hydroxypropyl)methyl-cellulose as polymer. The NTH-TDS based on the combination of ethanol/PG/OA showed an enhancement ratio with respect to control of 2.09 and the addition of polysorbate 80 to the matrix, of 5.82.
Keywords: Percutaneous absorption; Chemical enhancers; Nortriptyline; TDS; Skin
Transdermal and dermal delivery of adefovir: Effects of pH and permeation enhancers
by Kateřina Vávrová; Kateřina Lorencová; Jana Klimentová; Jakub Novotný; Antonı´n Holý; Alexandr Hrabálek (pp. 597-604).
The objective of this work was to investigate feasibility of transdermal and dermal delivery of adefovir (9-(2-phosphonomethoxyethyl)adenine), a broad-spectrum antiviral from the class of acyclic nucleoside phosphonates. Transport of 2% adefovir through and into porcine skin and effects of various solvents, pH, and permeation enhancers were studied in vitro using Franz diffusion cell. From aqueous donor samples, adefovir flux through the skin was 0.2–5.4μg/cm2/h with greatest permeation rate at pH 7.8. The corresponding adefovir skin concentrations reached values of 120—350μg/g of tissue. Increased solvent lipophilicity resulted in higher skin concentration but had only minor effect on adefovir flux. A significant influence of counter ions on both transdermal and dermal transport of adefovir zwitterion was observed at pH 3.4. Permeation enhancer dodecanol was ineffective, 1-dodecylazepan-2-one (Azone) and dodecyl 2-(dimethylamino)propionate (DDAIP) showed moderate activity. The highest adefovir flux (11.3±3.6μg/cm2/h) and skin concentration (1549±416μg/g) were achieved with 1% Transkarbam 12 (5-(dodecyloxycarbonyl)pentylammonium 5-(dodecyloxycarbonyl)pentylcarbamate) at pH 4. This study suggests that, despite its hydrophilic and ionizable nature, adefovir can be successfully delivered through the skin.
Keywords: Skin absorption; Transdermal drug delivery; Permeation enhancer; Adefovir; Acyclic nucleoside phosphonates
Influence of hydroxypropyl-β-cyclodextrin on transdermal penetration and photostability of avobenzone
by Jing Yang; Cody J. Wiley; Donald A. Godwin; Linda A. Felton (pp. 605-612).
The objective of the present study was to determine the effects of hydroxypropyl-β-cyclodextrin (HPCD) complexation on the transdermal penetration and photostability of a model ultraviolet A (UVA) absorber, butyl methoxydibenzoylmethane (avobenzone), and to determine the influence of complexation on in vivo photoprotection. Avobenzone–HPCD complexation was demonstrated by differential scanning calorimetry. Formulations containing 0.12mg/ml avobenzone and up to 30% (w/w) HPCD were prepared. Transdermal penetration was conducted using a modified Franz diffusion cell apparatus. As the concentration of HPCD was increased from 0% to 20%, transdermal permeation increased. Maximum flux occurred at 20% HPCD, where sufficient cyclodextrin was present to completely solubilize all avobenzone. When the concentration of HPCD was increased to 30%, transdermal penetration decreased, suggesting the formation of an avobenzone reservoir on the skin surface. Photostability of avobenzone was investigated under 100, 250, and 500kJ/m2 UVA irradiation. The 30% HPCD formulation was the most photostable, followed by 20%, 10%, and 0% formulations. In vivo, the 30% HPCD formulation afforded the best photoprotection, as evidenced by the lowest extent of sunburn cell formation and edema induction. This work indicates that inclusion of HPCD in sunscreen formulations may enhance photoprotection by reducing both skin penetration and photodecomposition of UV absorbers.
Keywords: Sunscreen; Avobenzone; Transdermal penetration; Photostability; Hydroxypropyl-β-cyclodextrin; Photoprotection
Association of nicotinamide with parabens: Effect on solubility, partition and transdermal permeation
by Sara Nicoli; Franca Zani; Stefania Bilzi; Ruggero Bettini; Patrizia Santi (pp. 613-621).
Nicotinamide is a hydrophilic molecule, freely soluble in water, used as cosmetic active ingredient for its moisturizing and depigmenting properties. Moreover it has the ability to augment the solubility of poorly water-soluble molecules acting as a hydrotrope. The aim of this work was to study the effect of nicotinamide on the transdermal permeation of methyl, ethyl, propyl and butyl paraben. Parabens flux was measured in vitro in the presence and absence of different amounts of nicotinamide. From solubility studies it was found that nicotinamide forms one or more complexes with methyl, propyl and butyl paraben in water, even though with low stability constants. The interaction of ethyl paraben seems to be less easy to explain. The association of nicotinamide with parabens causes a significant reduction of the permeability coefficients of these preservatives through rabbit ear skin, caused by a reduction of the stratum corneum/vehicle partition coefficient. The effects of nicotinamide on parabens solubility, permeation and partitioning are potentially very interesting because nicotinamide can facilitate paraben dissolution in aqueous media (solutions, gels), reduce parabens partitioning in the oily phase thus guaranteeing an effective concentration in the water phase in emulsion and reduce transdermal penetration, thus reducing the toxicological risk.
Keywords: Parabens; Nicotinamide; Topical formulations; Permeability coefficient; Partition coefficient
Performance of an in vitro mucoadhesion testing method for vaginal semisolids: Influence of different testing conditions and instrumental parameters
by José das Neves; Maria Helena Amaral; Maria Fernanda Bahia (pp. 622-632).
The purpose of this work was to develop an in vitro mucoadhesion testing method for vaginal semisolid formulations. The proposed method was based on the measurement of the force (detachment force, Fdt) and the work (work of adhesion, Wad) needed to detach a sample of cow vaginal mucosa from a semisolid formulation, using a commercially available texture analyzer. Several testing conditions and instrumental parameters were tested in order to evaluate the mucoadhesive potential of a model vaginal semisolid formulation (1% Carbopol® 974P gel). Also, mucoadhesive potential of several commercially available vaginal semisolid products was evaluated. Obtained results showed that the method is reproducible even when the same cow mucosa sample is used up to six times. The similarity of the fluid used to bathe the vaginal mucosa to the one naturally occurring in the vagina influenced considerably the performance of the test, advising that simulation of vaginal fluid properties is important when measuring mucoadhesive properties. Also, temperature of experiment was an important fact to be considered, as results showed slight but significant differences between body (37°C) and room (20°C) temperature. Fdt and Wad increased with increasing instrumental parameters while a plateau region was observable at higher values of probe speed, probe force, and mucosa/sample contact time. Comparison between results for Fdt and Wad demonstrated that although both parameters are generally in agreement, Wad seems to be more reliable and reproducible when evaluating mucoadhesion. Evaluation of commercially available formulations confirmed that experimental conditions are important features that can influence significantly the determination of mucoadhesive potential, being the proposed method an interesting and useful tool in the in vitro evaluation of vaginal semisolids.
Keywords: Mucoadhesion; Vaginal drug delivery; Texture analyzer; Semisolid formulations; Detachment force; Work of adhesion
Improved stomach selectivity of gene expression following microinstillation of plasmid DNA onto the gastric serosal surface in mice
by Junya Nishi; Shintaro Fumoto; Hiroki Ishii; Yukinobu Kodama; Mikiro Nakashima; Hitoshi Sasaki; Junzo Nakamura; Koyo Nishida (pp. 633-639).
Stomach-selective gene transfer is a promising approach as a therapeutic strategy for refractory gastric diseases. In this study, we improved the stomach selectivity of gene expression following microinstillation of naked plasmid DNA (pDNA) onto the gastric serosal surface in mice. pDNA encoding firefly luciferase was used as a reporter gene. It was confirmed that the gene expression level in the stomach 6h after gastric serosal surface microinstillation of pDNA was significantly higher than after intragastric, intraperitoneal and intravenous administration. Regarding selectivity of gene expression, the gene expression level in the stomach after gastric serosal surface microinstillation of 1μg/1μL (dose/volume) pDNA was 5.7 times higher than that in the spleen. In our previous study (30μg/30μL), the expression level in the stomach was 2.7 times higher than that in the spleen; therefore, the selectivity was 2.1 times higher in this study. When we investigated gene expression at various pDNA solution concentrations, the ratio of the gene expression level in the stomach to that in the spleen was the highest as 1μg/1μL of pDNA, which was considered the optimal concentration. Information in this study is useful for further development of target organ-selective gene delivery systems.
Keywords: Gene delivery; Targeting; Stomach; Gene therapy; Plasmid DNA; Mouse; Luciferase
Rationale for ibuprofen co-administration with antacids: Potential interaction mechanisms affecting drug absorption
by Jelena Parojčić; Owen I. Corrigan (pp. 640-647).
Ibuprofen is a widely used NSAID which is often co-administered with antacids because of its gastro-irritant effects. Literature data suggest that antacid interactions may increase or decrease the drug’s absorption rate and onset of action and that the interaction may be formulation specific. In the present study, literature data on ibuprofen absorption were evaluated in order to gain insight into the nature of the in vivo effect. Solubility determinations in reactive media containing magnesium or aluminium and dissolution studies in the presence of antacid suspension were performed in an attempt to simulate in vitro the effects observed in vivo. The results obtained indicate that magnesium hydroxide enhances ibuprofen solubility, dissolution and bioavailability, while aluminium hydroxide has a retarding effect. Solubility studies indicated formation of a soluble solid ibuprofen phase in the presence of Mg2+, in contrast, an insoluble ibuprofen salt was formed with Al3+. The introduction of magnesium based antacid suspension into the dissolution media resulted in a formulation specific increase in drug dissolution rate with the most pronounced effect observed for the slowest release tablet formulation. The results obtained indicate the potential for in vitro studies to predict physicochemical interactions that are likely to influence drug absorption rate in vivo.
Keywords: Ibuprofen–antacid interaction; Absorption rate; Solubility; Dissolution; In vitro–in vivo correlation
Using biorelevant dissolution to obtain IVIVC of solid dosage forms containing a poorly-soluble model compound
by Bena-Marie Lue; Flemming Seier Nielsen; Thomas Magnussen; Hanne Mette Schou; Kim Kristensen; Lene Orup Jacobsen; Anette Müllertz (pp. 648-657).
The usefulness of selected biorelevant dissolution media (BDM) to predict in vivo drug absorption was studied. Dissolution profiles of solid formulations of a poorly soluble model compound were compared in BDM simulating fasted and two levels of fed state. A non-physiologically relevant medium containing the cationic surfactant, cetrimide, was also investigated. All the media studied were capable of differentiating between the formulations employed, with formulation A consistently ranking high and formulations C and D ranking low. An in vivo dog study was carried out and an attempt was made to obtain a level A correlation between the plasma absorption curves and in vitro dissolution curves, using non-linear regression software. The in vitro–in vivo correlation (IVIVC) models developed indicated that fed state media (BDM 3) containing high levels of both bile salts (BS) and lipolysis products (LP) were best able to predict in vivo pharmacokinetic parameters ( Cmax and AUC) with prediction errors lower than 10%. Overall, design and use of appropriate media for in vitro dissolution is extremely important. This study demonstrates the potential of physiologically relevant media containing both BS and LP for use in formulation and early drug development.
Keywords: Biorelevant media; Solubility; Dissolution; Poorly soluble; In vivo–in vitro correlation (IVIVC)
Asymmetric membrane in membrane capsules: A means for achieving delayed and osmotic flow of cefadroxil
by Anil K. Philip; Kamla Pathak; Pragati Shakya (pp. 658-666).
In the present study, both disintegrating and non-disintegrating polymeric capsular system in achieving delayed as well as improved osmotic flow for the model drug cefadroxil was developed. Asymmetric membrane in membrane capsule (AMMC) was prepared on a glass mold pin via phase inversion process in two steps. Step 1 included formation of a non-disintegrating, asymmetric membrane capsule (AMC) and step 2 involved formation of a pH sensitive, disintegrating, asymmetric membrane (AM) formed over the non-disintegrating membrane. The effects of different formulation variables were studied namely, level of osmogen, membrane thickness, and level of pore former. Effects of varying osmotic pressure, agitational intensity and intentional defect in the inner membrane on drug release were also studied. Membrane characterization by scanning electron microscopy showed dense regions with less pores on the outer surface of the disintegrating membrane and porous regions on the inner surface of the non-disintegrating asymmetric membrane. In vitro release studies for all the prepared formulations were done ( n=6). The drug release was independent of pH, agitational intensity and intentional defect on the membrane but dependent on the osmotic pressure of the dissolution medium. The release kinetics followed the zero order and the mechanism of release was Fickian diffusion.
Keywords: Asymmetric membrane capsule; Agitational intensity; Intentional defect; Osmotic; Asymmetric membrane in membrane
Development of a novel osmotically driven drug delivery system for weakly basic drugs
by C. Guthmann; R. Lipp; T. Wagner; H. Kranz (pp. 667-674).
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.
Keywords: pH-independent; Extended release; Multiparticulates; Enteric coating; Osmotic active
Incidence of drying on microstructure and drug release profiles from tablets of MCC–lactose–Carbopol® and MCC–dicalcium phosphate–Carbopol® pellets
by Ana Gómez-Carracedo; Consuelo Souto; Ramón Martı´nez-Pacheco; Angel Concheiro; Jose Luis Gómez-Amoza (pp. 675-685).
The influence of intragranular excipients (lactose or dicalcium phosphate) and the drying procedure and conditions (oven-drying and freeze-drying after freezing at −30 or −196°C) on the properties of tablets of MCC–Carbopol® pellets was evaluated. The drying procedure caused remarkable differences in pellet size and porosity (freeze-dried pellets were 3-fold more porous than those oven dried). Theophylline release from pellets was completed in less than 30min and followed first-order kinetics, with a rate closely related to the intragranular porosity. The total porosity of the tablets (5–10%) was conditioned by the compression force (10–20N), the drying procedure applied to the pellets and the coexcipient nature. Their intergranular porosity ranged inversely to the initial porosity of pellets due to the greater deformability of the most porous ones. A wide range of theophylline release rates were achieved depending on the drying procedure; tablets prepared from freeze-dried pellets sustained the release for 3h. Most profiles showed a bimodal kinetics with an initial zero-order release (while the tablets did not completely disintegrate) that changed, after a certain time, to a first-order kinetics. The intergranular porosity determined drug release rate up to disintegration. Then, the release kinetics became first-order and the rate constant, which was conditioned by the intragranular porosity, showed a complex dependence on the drying procedure, the compression force, and the nature of coexcipient. In sum, the modulation of drug release profiles from tablets of MCC–Carbopol® pellets through an adequate control of the effects of the coexcipient nature, the drying procedure of pellets, and the compression force on the inter- and intragranular porosity opens interesting possibilities to control the release of hydrosoluble drugs.
Keywords: Freeze-drying; Oven-drying; Pellets; Controlled release; Mercury porosimetry; Tabletting
Bi-layered self-emulsifying pellets prepared by co-extrusion and spheronization: Influence of formulation variables and preliminary study on the in vivo absorption
by Tamara Iosio; Dario Voinovich; Mario Grassi; João F. Pinto; Beatrice Perissutti; Marina Zacchigna; Ugo Quintavalle; Francesca Serdoz (pp. 686-697).
The aim of this work was to produce by co-extrusion–spheronization pellets with two cohesive layers, one of them containing a self-emulsifying system for vinpocetine, a poorly water soluble model drug. Two layers were prepared: an inert layer of microcrystalline cellulose, lactose and water and a second one wetted with the self-emulsifying system. Different formulations of both layers were tested, evaluating the effects of formulation variables with an experimental design. The screening amongst formulations was performed preparing rod extrudates and using the extrusion profiles to assess their suitability for extrusion and to anticipate quality of the spheronized extrudates. Tubular extrudates and co-extrudates/spheronized pellets were then produced. Two types of bi-layered pellets were prepared: type I with the self-emulsifying system internally and the inert matrix externally, whereas type II vice versa. The pellets were characterized for sizing and shape, density, hardness, in vitro dissolution and disintegration and released droplets size and in vivo tests. Although both types of pellets demonstrated adequate morphological and technological characteristics, pellets type II revealed an improved drug solubility and in vivo bioavailability. These preliminary technological and pharmacokinetic data demonstrated that co-extrusion/spheronization is a viable technology to produce bi-layered cohesive self-emulsifying pellets of good quality and improved in vivo bioavailability.
Keywords: Bi-layer extrusion; Spheronization; Solid dosage form; Oral drug delivery
Effect of calcium ions on the gelling and drug release characteristics of xanthan matrix tablets
by Saša Baumgartner; Matej Pavli; Julijana Kristl (pp. 698-707).
Xanthan is a well-known biopolymer. It is an anionic polysaccharide, whose primary structure depends on the bacterial strain and fermentation conditions. Xanthan was extensively studied in combination with galactomannans, and over 90 patents cover the technology of this preparation. Our aim was to investigate the relation between the physical properties of a xanthan matrix in the absence or presence of calcium ions and its influence on the release of pentoxifylline. The release of pentoxifylline from xanthan tablets in purified water was shown to be very slow and governed by the process of polymer relaxation. The presence of calcium ions significantly increased the drug release, changing the release mechanism into a more diffusion controlled one. Xanthan matrices showed substantially faster and more extensive swelling in water than in the presence of Ca2+ ions. Surprisingly, negative correlation between drug release and degree of swelling was obtained for xanthan: the higher the swelling, the slower the drug release. Higher ionic strength led to lower erosion of xanthan tablets, and the gel layers formed were more rigid and of firmer texture, as shown by rheological experiments and textural profiling. The results indicate that the presence of Ca2+ ions in the solution or in matrices does not cause crosslinking of xanthan polymers, but causes charge screening of ionized groups on the trisaccharide side chains of xanthan, leading to lower inter-molecular repulsion and changing water arrangement. The understanding of the parameters influencing drug release leads to the conclusion that xanthan is suitable for controlled release formulations, especially with the incorporation of certain small counterions.
Keywords: Polysaccharide; Controlled release; Rheology; Texture analyzer; Polymer hydration
New insights on poly(vinyl acetate)-based coated floating tablets: Characterisation of hydration and CO2 generation by benchtop MRI and its relation to drug release and floating strength
by Sandra Strübing; Tâmara Abboud; Renata Vidor Contri; Hendrik Metz; Karsten Mäder (pp. 708-717).
The purpose of this study was to investigate the mechanism of floating and drug release behaviour of poly(vinyl acetate)-based floating tablets with membrane controlled drug delivery. Propranolol HCl containing tablets with Kollidon® SR as an excipient for direct compression and different Kollicoat® SR 30 D/Kollicoat® IR coats varying from 10 to 20mg polymer/cm2 were investigated regarding drug release in 0.1N HCl. Furthermore, the onset of floating, the floating duration and the floating strength of the device were determined. In addition, benchtop MRI studies of selected samples were performed. Coated tablets with 10mg polymer/cm2 SR/IR, 8.5:1.5 coat exhibited the shortest lag times prior to drug release and floating onset, the fastest increase in and highest maximum values of floating strength. The drug release was delayed efficiently within a time interval of 24h by showing linear drug release characteristics. Poly(vinyl acetate) proved to be an appropriate excipient to ensure safe and reliable drug release. Floating strength measurements offered the possibility to quantify the floating ability of the developed systems and thus to compare different formulations more efficiently. Benchtop MRI studies allowed a deeper insight into drug release and floating mechanisms noninvasively and continuously.
Keywords: Floating tablets; Coated tablets; Poly(vinyl acetate); MRI; Kollidon; ®; SR; Kollicoat; ®; IR; Kollicoat; ®; SR
A study on maize proteins as a potential new tablet excipient
by Dominique M.R. Georget; Susan A. Barker; Peter S. Belton (pp. 718-726).
This investigation has examined the use of zein proteins from maize as the major component in oral controlled-release tablets, such formulations often being required to improve patient compliance. Tablets containing ground zein proteins, calcium hydrogen orthophosphate, polyvinyl pyrrolidone, theophylline and magnesium stearate were produced by wet granulation and compression on a single station tablet press and were compared to directly compressed tablets based on zein proteins, calcium hydrogen orthophosphate and theophylline. Non invasive techniques such as Fourier Transform infrared spectroscopy and Fourier Transform Raman spectroscopy were employed to investigate any changes in the secondary structure of zein proteins during tablet production. Random coils, α helices and β sheets predominated and their relative content remained unaffected during grinding, wet granulation and compression, indicating that formulations based on zeins will be robust, i.e. insensitive to minor changes in the production conditions. Drug release from the tablets was studied using a standard pharmacopoeial dissolution test. Dissolution profiles in water, 0.1M HCl (pH=1) and phosphate buffer (pH=6.8) show that only a limited amount of theophylline was released after 4.5h, suggesting that zein proteins could act as a potential vehicle for oral controlled drug release. Analysis of the theophylline release profiles using the Peppas and Sahlin model reveals that diffusion and polymer relaxation occurred in acidic (pH=1) and buffered (pH=6.8) conditions for wet granulated tablets, whereas diffusion was predominant in directly compressed tablets. In conclusion, the present study has shown that zeins can be successfully used as a pharmaceutical excipient, and in particular as a matrix in monolithic controlled release tablets.
Keywords: Zein; Maize; Tablet; Protein; Secondary structure; FTIR; FT Raman; Dissolution
Effect of powder processing on performance of fenofibrate formulations
by Rajeev A. Jain; Luis Brito; Julie A. Straub; Todd Tessier; Howard Bernstein (pp. 727-734).
In this study, the effect of the order in which powder blending and jet-milling were performed for the production of the bulk powders on the performance of 200-mg dose orally disintegrating tablets (ODTs) of fenofibrate was evaluated. Bulk powders composed of fenofibrate, mannitol, copovidone S630, and docusate sodium in a 10:10:2:1.2 ratio were prepared by the following three processes: process A: fenofibrate+excipients→blending; process B: fenofibrate→jet-milling→blending with excipients; process C: fenofibrate+excipients→blending→jet-milling. The bulk powders were granulated followed by blending and tableting. The materials were tested for Differential Scanning Calorimetry (DSC), drug particle sizing post-reconstitution, dissolution, optical micrography, Scanning Electron Microscopy (SEM), Energy Dispersive X-ray Spectroscopy (EDS) and disintegration of the ODTs. It was found that the crystallinity of fenofibrate was not impacted by the blending and jet-milling processes. Process A produced materials having poorer fenofibrate reconstitution as compared to processes involving jet-milling. It was discovered that milling a blend of fenofibrate/excipient (process C) was advantageous over milling the raw drug alone (process B). Process C yielded bulk powder that showed rapid dissolution and ODTs which exhibited rapid disintegration.
Keywords: ODTs; Fenofibrate; Poorly soluble; Jet-milling
Sustained-release of buspirone HCl by co spray-drying with aqueous polymeric dispersions
by Nizar Al-Zoubi; Hatim S. AlKhatib; Yasser Bustanji; Khaled Aiedeh; Stavros Malamataris (pp. 735-742).
Sustained-release of buspirone HCl (BUH) was attempted by spray drying after dissolving in two commercially available aqueous polymeric dispersions (Eudragit® RS 30 D or Kollicoat® SR 30 D) at five different drug:polymer ratios (1:1, 1:2, 1:3, 1:6 and 1:9). The produced spray-dried agglomerates were evaluated in terms of their particle size and morphology, production yield, encapsulation efficiency and in-vitro release of BUH. Possible drug–polymer interactions were checked by Differential Scanning Calorimetry (DSC) and FT-IR spectroscopy. Scanning electron microscopy (SEM) was employed for the qualitative characterization of particle size and morphology. Encapsulation efficiency was generally high (around 100%) and independent of the polymeric dispersion type, while production yield was generally low (7.2–31.0%) and significantly lower for the case of Kollicoat SR 30 D (KSR) than for Eudragit RS 30 D (ERS). Scanning electron micrographs showed remarkable changes in size and shape of agglomerates due to the type of aqueous polymeric dispersion and drug:polymer ratio. In-vitro release of BUH from compacted co spray-dried agglomerates was remarkably slower and incomplete for the case of Kollicoat® at drug:polymer ratio below 1, presumably due to increased plastic deformation of the developed coating instead of fragmentation in the case of Eudragit® coating during compaction.
Keywords: Aqueous polymeric dispersions; Buspirone HCl; Sustained release; Spray drying; Eudragit; ®; RS 30 D; Kollicoat; ®; SR 30 D
Compaction behavior of roller compacted ibuprofen
by Sarsvatkumar Patel; Aditya Mohan Kaushal; Arvind Kumar Bansal (pp. 743-749).
The effect of roller compaction pressure on the bulk compaction of roller compacted ibuprofen was investigated using instrumented rotary tablet press. Three different roller pressures were utilized to prepare granules and Heckel analysis, Walker analysis, compressibility, and tabletability were performed to derive densification, deformation, course of volume reduction and bonding phenomenon of different pressure roller compacted granules. Nominal single granule fracture strength was obtained by micro tensile testing. Heckel analysis indicated that granules prepared using lower pressure during roller compaction showed lower yield strength. The reduction in tabletability was observed for higher pressure roller compacted granules. The reduction in tabletability supports the results of granule size enlargement theory. Apart from the granule size enlargement theory, the available fines and relative fragmentation during compaction is responsible for higher bonding strength and provide larger areas for true particle contact at constant porosity for lower pressure roller compacted granules. Overall bulk compaction parameters indicated that granules prepared by lower roller compaction pressure were advantageous in terms of tabletability and densification. Overall results suggested that densification during roller compaction affects the particle level properties of specific surface area, nominal fracture strength, and compaction behavior.
Keywords: Ibuprofen; Roller compaction; Heckel analysis; Compressibility; Tabletability; Compaction behavior
The effects of cryoprotectants on the freeze-drying of ibuprofen-loaded solid lipid microparticles (SLM)
by Lijuan Zhang; Lei Liu; Yu Qian; Yun Chen (pp. 750-759).
The effects of cryoprotectants on the diameter and the entrapment efficiency of ibuprofen-loaded solid lipid microparticles (SLM) during the freeze-drying process were investigated extensively. The SLM were prepared by the emulsion–congealing technique in which a glycerol behenate was used as the lipid matrix for the SLM and a soybean lecithin/bile salt used as the stabilizer. Also, trehalose, glucose, mannitol, and sucrose were chosen as the cryoprotectants. Trehalose and glucose proved to be the most effective in preventing particles aggregation and in inhibiting leakage from drug-loaded particles during the SLM freeze-drying process. The most suitable concentrations were proved to be 15% and 5% (wt), respectively.
Keywords: Solid lipid microparticles; Lyophilisation; Ibuprofen; Cryoprotectant
Parameters influencing polymer particle layering of the dry coating process
by Caroline Désirée Kablitz; Michael Kappl; Nora Anne Urbanetz (pp. 760-768).
The dry coating process is an emerging coating technology using neither organic solvents nor water. In contrast to liquid-borne coatings, coating material application and film formation are divided into two phases, the coating phase where the powdery coating material is applied together with the liquid plasticizer, and the curing phase. In this study the coating phase was characterized with respect to the forces acting between the polymer particles during material application. Atomic force microscopy was conducted measuring the interparticle forces which were related to the coating efficiency. The influence of different liquid additives on the interparticle forces and the coating efficiency were evaluated. HPMCAS was used as enteric resistant polymer, triethylcitrate (TEC), Myvacet® (diacetylated monoglyceride) and a mixture of both as liquid additives.Interparticle forces were found to be similar when using TEC or a mixture of TEC and Myvacet®. In contrast, interparticle forces were higher when using solely Myvacet®. This is attributed to the fact that Myvacet® does not penetrate into the polymer without TEC which is acting as a penetration enhancer. As Myvacet® remains predominantly on the particle surface, capillary forces act between the particles explaining high interparticle forces. The highest interparticle force determined by AFM is in accordance to the highest coating efficiency which has been found for the corresponding coating formulation containing HPMCAS and Myvacet®. Consequently, it is demonstrated that the ability of the liquid to remain on the surface of the polymer and to build up capillary forces is crucial for the material application.
Keywords: Dry coating; Atomic force microscopy; AFM; Interparticle interaction; Material application; Coating
Dissolution test for site-specific release isoniazid pellets in USP apparatus 3 (reciprocating cylinder): Optimization using response surface methodology
by Amita Joshi; Swati Pund; Manish Nivsarkar; Kamala Vasu; Chamanlal Shishoo (pp. 769-775).
The present work aims to predict drug release from novel site-specific release isoniazid pellets, in USP dissolution test apparatus 3, using the response surface methodology (RSM). Site-specific release isoniazid pellets were prepared by extrusion-spheronization followed by aqueous coating of Acryl-EZE®. RSM was employed for designing of the experiment, generation of mathematical models and optimization study. A 32 full factorial design was used to study the effect of two factors (at three levels), namely volume of dissolution medium (150, 200, 250ml) and reciprocation rate (5, 15, 25 dips per min). Amount of drug released in 0.1N hydrochloric acid at 2h and in pH 6.8 phosphate buffer at 45min were selected as responses. Results revealed that both, the volume of medium and reciprocation rate, are significant factors affecting isoniazid release. A second order polynomial equation fitted to the data was used to predict the responses in the optimal region. The optimized conditions resulted in dissolution data that were close to the predicted values. The proposed mathematical model is found to be robust and accurate for optimization of dissolution test conditions for site-specific release isoniazid pellets.
Keywords: Isoniazid; Site-specific release; USP apparatus 3; Response surface methodology; Optimization; Full factorial design
Designing biorelevant dissolution tests for lipid formulations: Case example – Lipid suspension of RZ-50
by Ekarat Jantratid; Niels Janssen; Hitesh Chokshi; Kin Tang; Jennifer B. Dressman (pp. 776-785).
Biorelevant dissolution test methods for lipid formulations of RZ-50, an experimental Roche compound, were developed and compared with standard compendial methods in terms of their in vivo predictability. Release of RZ-50, a poorly soluble weakly acidic drug, from lipid suspensions filled in soft gelatin capsules was studied in compendial and biorelevant media using the USP Apparatus 2 (paddle method) and the USP Apparatus 3 (Bio-Dis method). Pharmacokinetic data were obtained in dogs after oral administration of a single 2.5mg dose of RZ-50 soft gelatin capsules in the postprandial state. Level A IVIVC analysis and curve comparison of fraction drug dissolved vs. absorbed using the Weibull distribution were used to evaluate the in vitro methods in terms of their ability to fit the in vivo plasma profiles. Very low drug release was observed with the paddle method owing to poor dispersibility of the lipids in the dissolution media, whereas the Bio-Dis method hydrodynamics facilitated release of the drug by emulsifying the formulation in the medium. The best IVIVC was obtained using a dissolution medium representing fed gastric conditions in combination with the Bio-Dis method. Curve comparisons of the fraction drug absorbed and the fraction drug dissolved profiles based on Weibull distribution fits yielded similar results. The Bio-Dis/biorelevant in vitro method appears to be suitable for this type of lipid formulation.
Keywords: Dissolution; Lipid dosage forms; Paddle method; Bio-Dis method; Biorelevant; IVIVC; Curve comparisons
Developing a tool for the preparation of GMP audit of pharmaceutical contract manufacturer
by Anu Linna; Mirka Korhonen; Jukka-Pekka Mannermaa; Marja Airaksinen; Anne Mari Juppo (pp. 786-792).
Outsourcing is rapidly growing in the pharmaceutical industry. When the manufacturing activities are outsourced, control of the product’s quality has to be maintained. One way to confirm contract manufacturer’s GMP (Good Manufacturing Practice) compliance is auditing. Audits can be supported for instance by using GMP questionnaires. The objective of this study was to develop a tool for the audit preparation of pharmaceutical contract manufacturers and to validate its contents by using Delphi method. At this phase of the study the tool was developed for non-sterile finished product contract manufacturers. A modified Delphi method was used with expert panel consisting of 14 experts from pharmaceutical industry, authorities and university. The content validity of the developed tool was assessed by a Delphi questionnaire round. The response rate in Delphi questionnaire round was 86%. The tool consisted of 103 quality items, from which 90 (87%) achieved the pre-defined agreement rate level (⩾75%). Thirteen quality items which did not achieve the pre-defined agreement rate were excluded from the tool. The expert panel suggested only minor changes to the tool. The results show that the content validity of the developed audit preparation tool was good.
Keywords: Pharmaceutical industry; GMP; Outsourcing; Audits; Delphi method
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