European Journal of Pharmaceutics and Biopharmaceutics (v.79, #2)
Mechanistic modelling of fluidized bed drying processes of wet porous granules: A review
by Séverine Thérèse F.C. Mortier; Thomas De Beer; Krist V. Gernaey; Jean Paul Remon; Chris Vervaet; Ingmar Nopens (pp. 205-225).
The implementation of continuous production processes in industrial pharmaceutical applications necessitates the development of mechanistic models. The step-wise approach for the development is discussed, focusing on drying of granules in a fluidized bed dryer.Display OmittedFluidized bed dryers are frequently used in industrial applications and also in the pharmaceutical industry. The general incentives to develop mechanistic models for pharmaceutical processes are listed, and our vision on how this can particularly be done for fluidized bed drying processes of wet granules is given. This review provides a basis for future mechanistic model development for the drying process of wet granules in pharmaceutical processes. It is intended for a broad audience with a varying level of knowledge on pharmaceutical processes and mathematical modelling. Mathematical models are powerful tools to gain process insight and eventually develop well-controlled processes. The level of detail embedded in such a model depends on the goal of the model. Several models have therefore been proposed in the literature and are reviewed here. The drying behaviour of one single granule, a porous particle, can be described using the continuum approach, the pore network modelling method and the shrinkage of the diameter of the wet core approach. As several granules dry at a drying rate dependent on the gas temperature, gas velocity, porosity, etc., the moisture content of a batch of granules will reside in a certain interval. Population Balance Model (ling) (PBM) offers a tool to describe the distribution of particle properties which can be of interest for the application. PBM formulation and solution methods are therefore reviewed. In a fluidized bed, the granules show a fluidization pattern depending on the geometry of the gas inlet, the gas velocity, characteristics of the particles, the dryer design, etc. Computational Fluid Dynamics (CFD) allows to model this behaviour. Moreover, turbulence can be modelled using several approaches: Reynolds-averaged Navier–Stokes Equations (RANS) or Large Eddy Simulation (LES). Another important aspect of CFD is the choice between the Eulerian–Lagrangian and the Eulerian–Eulerian approach. Finally, the PBM and CFD frameworks can be integrated, to describe the evolution of the moisture content of granules during fluidized bed drying.
Keywords: Pharmaceutical tablets; Drying; Porous material; Mechanistic modelling; PBM; CFD
Induction of Th1 polarized immune responses by thiolated Eudragit-coated F4 and F18 fimbriae of enterotoxigenic Escherichia coli
by Won-Jung Lee; Seungbin Cha; Minkyoung Shin; Mohammad Ariful Islam; Chong-su Cho; Han Sang Yoo (pp. 226-231).
F4 or F18 loaded TEMS induces Th1 related immune responses in RAW 264.7 cells and mouse splenocytes.Diarrhea in newborn and weaned piglets is mainly induced by enterotoxigenic Escherichia coli (ETEC) with fimbriae F4 (K88) and F18 (F107). In this study, we evaluated F4 and F18 coated with thiolated Eudragit microspheres (TEMS) as a candidate for an oral vaccine. The average particle sizes of TEMS, F4-loaded TEMS, and F18-loaded TEMS were measured as 4.2±0.75μm, 4.7±0.50μm, and 4.5±0.37μm, respectively. F4 is more efficiently encapsulated than F18 in the loading with TEMS. In the release test, F4 and F18 fimbriae were protected in acidic circumstances, whereas most were released at pH 7.4 of intestine circumstances. Production of TNF-α and NO from RAW 264.7cells was increased in a time-dependent manner after exposure to all groups, whereas only F4- or F18-loaded TEMS-stimulated IL-6 secretion. The levels of IFN-γ from mouse splenocytes after exposure to F4 or F18 were increased while IL-4 was not detectable. These results suggest that F4- and F18-loaded TEMS may effectively induce immune response with the efficient release of antigens to appropriate target sites.
Keywords: Microsphere; In vitro test; Interleukin; Nitric oxide; Immune response
RGD-modified PEG–PAMAM–DOX conjugates: In vitro and in vivo studies for glioma
by Lihong Zhang; Saijie Zhu; Lili Qian; Yuanying Pei; Yongming Qiu; Yanyan Jiang (pp. 232-240).
Acid-sensitive RGD-modified PEG-PAMAM-DOX Conjugates (RGD-PPCD) exhibited strong anti-glioma activity.This work was based on our recent studies that a promising conjugate, RGD-modified PEGylated polyamidoamine (PAMAM) dendrimer with doxorubicin (DOX) conjugated by acid-sensitive cis-aconityl linkage (RGD-PPCD), could increase tumor targeting by binding with the integrin receptors overexpressed on tumor cells and control release of free DOX in weakly acidic lysosomes. To explore the application of RGD-PPCD to glioma therapy, the effects of the conjugate were further evaluated in glioma model. For comparative studies, DOX was also conjugated to PEG–PAMAM by acid-insensitive succinic linkage to produce the PPSD conjugates, which was further modified by RGD to form RGD-PPSD. In vitro cytotoxicity of the acid-sensitive conjugates against C6 cells was higher than that of the acid-insensitive ones, and further the modification of RGD enhanced the cytotoxicity of the DOX-polymer conjugates as a result of the increased cellular uptake of the RGD-modified conjugates by C6 cells. In vivo pharmacokinetics, biodistribution and antitumor activity were investigated in an orthotopic murine model of C6 glioma by i.v. administration of DOX-polymer conjugates. In comparison with DOX solution, all the conjugates showed significantly prolonged half-life and increased AUC and exhibited higher accumulation in brain tumor than normal brain tissue. Although RGD-PPCD was more than 2-fold lower tumor accumulation than RGD-PPSD, it exhibited the longest survival times among all treatment groups, and therefore, RGD-PPCD conjugate provide a desirable candidate for targeted therapy of glioma.
Keywords: Poly(amidoamine) dendrimer; Poly(ethylene glycol); RGD-peptide; Doxorubicin; Cellular uptake; Glioma
Improved efficacy in the treatment of contact dermatitis in rats by a dermatological nanomedicine containing clobetasol propionate
by M.C. Fontana; J.F.P. Rezer; K. Coradini; D.B.R. Leal; R.C.R. Beck (pp. 241-249).
Graphical representation of the higher efficacy of the hydrogel containing clobetasol propionate-loaded nanocapsules in a contact dermatitis model.We developed a dermatological nanomedicine containing clobetasol propionate-loaded nanocapsules and evaluated its efficacy in a model of contact dermatitis after topical administration in rats. Hydrogels containing clobetasol propionate-loaded lipid-core nanocapsules or nanoemulsion (HG-CP-NC and HG-CP-NE, respectively) were prepared to evaluate the influence of the polymeric wall. They presented adequate pH values (5.50–6.50) and drug content (0.5mgg−1) and their rheograms exhibited a non-Newtonian pseudoplastic behavior. The best in vitro drug release control was obtained for HG-CP-NC (1.03±0.11μgcm−2h) compared to the HG-CP-NE (1.65±0.19μgcm−2h) and the hydrogels containing nonencapsulated drug (HG-CP) (2.79±0.22μgcm−2h). A significant increase in NTPDase activity was observed in lymphocytes for the group treated with 0.05% HG-CP-NC every other day compared to the group treated with 0.05% HG-CP every day using the in vivo model of contact dermatitis. The nanoencapsulation of clobetasol in nanocapsules led to a better control of the drug release from the semisolid nanomedicine and provided better in vivo dermatological efficacy.
Keywords: Clobetasol propionate; Contact dermatitis; Hydrogels; In vitro; release; Nanocapsules; NTPDase activity
Solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine for enhanced bioavailability of highly lipophilic bioactive carotenoid lutein
by Srinivasan Shanmugam; Rengarajan Baskaran; Prabagar Balakrishnan; Pritam Thapa; Chul Soon Yong; Bong Kyu Yoo (pp. 250-257).
Bioavailability of lutein from SNEDDS and S-SNEDDS was comparable and significantly higher than LP and CP.The objectives of this study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine (PC), an endogenous phospholipid with excellent in vivo solubilization capacity, as oil phase for the delivery of bioactive carotenoid lutein, by spray drying the SNEDDS (liquid system) containing PC using colloidal silica (Aerosil® 200 VV Pharma) as the inert solid carrier, and to evaluate the enhanced bioavailability (BA) of lutein from S-SNEDDS. The droplet size analyses revealed droplet size of less than 100nm. The solid state characterization of S-SNEDDS by SEM, DSC, and XRPD revealed the absence of crystalline lutein in the S-SNEDDS. The bioavailability study performed in rabbits resulted in enhanced values of Cmax and AUC for S-SNEDDS. The enhancement of Cmax for S-SNEDDS was about 21-folds and 8-folds compared with lutein powder (LP) and commercial product (CP), respectively. The relative BA of S-SNEDDS compared with CP or LP was 2.74-folds or 11.79-folds, respectively. These results demonstrated excellent ability of S-SNEDDS containing PC as oil phase to enhance the BA of lutein in rabbits. Thus, S-SNEDDS containing PC as oil phase could be a useful lipid drug delivery system for enhancing the BA of lutein in vivo.
Keywords: Self-emulsifying; Poorly soluble drugs; Bioavailability; Spray drying; Lipid-based oral delivery; Phosphatidylcholine
Ex vivo decrease in uranium diffusion through intact and excoriated pig ear skin by a calixarene nanoemulsion
by Aurélie Spagnul; Céline Bouvier-Capely; Guillaume Phan; Géraldine Landon; Christine Tessier; David Suhard; François Rebière; Michelle Agarande; Elias Fattal (pp. 258-267).
A new oil-in-water nanoemulsion containing calixarene molecules was developed to treat intact or injured skins contaminated by uranium soluble compounds. The ability of the calixarene nanoemulsion to trap uranium and prevent its percutaneous diffusion was assessed with Franz cells using pig ear skin.Cutaneous contamination by radionuclides is a major concern in the nuclear industry. In case of skin exposure to uranium, no efficient emergency treatment is available to remove the actinide from the skin. For this purpose, we developed a nanoemulsion containing calixarene molecules displaying good chelating properties towards uranium. In this paper, we describe the ability of this formulation to trap uranium and limit its transfer from the cutaneous contaminated site into the blood. Uranium percutaneous diffusion kinetics was assessed with Franz cells over 24h through intact and excoriated pig ear skin biopsies, after or without application of the nanoemulsion. Uranium distribution in the skin layers was analysed by SIMS microscopy. The results showed that prompt application of the calixarene nanoemulsion allows a 94% and 98% reduction of the amount of uranium diffused respectively through intact and excoriated skin. The formulation is still efficient in case of delayed application up to 30minutes since the 24h-uranium transfer through excoriated skin is reduced by 71%. Besides, no accumulation of uranium or uranium-calixarene chelate was observed in the different skin layers. In conclusion, this study demonstrated the efficiency of the calixarene nanoemulsion, which can be regarded as a promising treatment for uranium cutaneous contamination.
Keywords: Calixarene; Nanoemulsion; Uranium; Cutaneous contamination; Decontamination; Pig ear skin; Franz cells
PEG-OCL micelles for quercetin solubilization and inhibition of cancer cell growth
by Ruttiros Khonkarn; Samlee Mankhetkorn; Wim E. Hennink; Siriporn Okonogi (pp. 268-275).
Effect of QCT-loaded micelles on cancer cell cycle progression.In this study, quercetin (QCT), a flavonoid with high anticancer potential, was loaded into polymeric micelles of PEG-OCL (poly(ethylene glycol)- b-oligo(ε-caprolactone)) with naphthyl or benzyl end groups in order to increase its aqueous solubility. The cytostatic activity of the QCT-loaded micelles toward different human cancer cell lines and normal cells was investigated. The results showed that the solubility of QCT entrapped in mPEG750- b-OCL micelles was substantially increased up to 1mg/ml, which is approximately 110 times higher than that of its solubility in water (9μg/ml). The average particle size of QCT-loaded micelles ranged from 14 to 19nm. The QCT loading capacity of the polymeric micelles with naphthyl groups was higher than that with benzyl groups (10% and 6%, respectively). QCT-loaded, benzyl- and naphthyl-modified micelles effectively inhibited the growth of both sensitive and resistance cancer cells (human erythromyelogenous leukemia cells (K562) and small lung carcinoma cells (GLC4)). However, the benzyl-modified micelles have a good cytocompatibility (in the concentration range investigated (up to 100μg/ml), they are well tolerated by living cells), whereas their naphthyl counterparts showed some cytotoxicity at higher concentrations (60–100μg/ml). Flow cytometry demonstrated that the mechanism underlying the growth inhibitory effect of QCT in its free form was inducing cell cycle arrest at the G2/M phase. Benzyl-modified micelles loaded with QCT also exhibited this cycle arresting the effect of cancer cells. In conclusion, this paper shows the enhancement of solubility and cell cycle arrest of QCT loaded into micelles composed of mPEG750- b-OCL modified with benzyl end groups. These micelles are therefore considered to be an attractive vehicle for the (targeted) delivery of QCT to tumors.
Keywords: Quercetin; Solubility; Polymeric micelles; Poly(caprolactone); Cytotoxicity; Cell cycle arrest
Paclitaxel loaded PEG5000–DSPE micelles as pulmonary delivery platform: Formulation characterization, tissue distribution, plasma pharmacokinetics, and toxicological evaluation
by Kanwaldeep K. Gill; Sami Nazzal; Amal Kaddoumi (pp. 276-284).
Pulmonary delivery of paclitaxel encapsulated in polymeric micelles resulted in slower drug release and sustained drug concentrations in lungs.The objective of the present study was to evaluate the potential of paclitaxel loaded micelles fabricated from PEG5000–DSPE as a sustained release system following pulmonary delivery. PEG5000–DSPE micelles containing paclitaxel were prepared by solvent evaporation technique followed by investigation of in vitro release of paclitaxel in lung simulated fluid. Tissue distribution and plasma pharmacokinetics of the PEG–lipid micelles after intratracheal and intravenous administrations were investigated in addition to intratracheally administered taxol. Finally, toxicological profile of PEG5000–DSPE was investigated. Paclitaxel was successfully formulated in PEG–lipid micelles with encapsulation efficiency of 95%. The PEG–lipid micelles exhibited a sustained release behavior in the simulated lung fluid. Intratracheally administered polymeric micellar paclitaxel showed highest accumulation of paclitaxel in the lungs with AUC0–12 in lungs being 45-fold higher than intravenously administered formulation and 3-fold higher than intratracheally delivered taxol. Paclitaxel concentration in other non-targeted tissues and plasma were significantly lower as compared to other groups. Furthermore, toxicity studies showed no significant increase in levels of lung injury markers in PEG5000–DSPE treated group as compared to saline-treated group. PEG5000–DSPE micelles delivered intratracheally were able to sustain highest paclitaxel concentrations in lungs for long periods of time, thus apprehending their suitability as pulmonary drug carriers.
Keywords: Abbreviations; PEG; 5000; –DSPE; polyethylene glycol 5000–distearoylphosphatidylethanolamine; DSC; differential scanning calorimetry; 1; H NMR; proton nuclear magnetic resonance spectroscopy; T; e; targeting efficiency; AUC; area under the curvePEG; 5000; –DSPE; Sustained release; PEG–lipid micelles; Intratracheal administration; Tissue distribution; Pharmacokinetics
Development and physico-chemical characterization of a liposomal formulation of istaroxime
by Paola Luciani; Maréva Fevre; Jean-Christophe Leroux (pp. 285-293).
Istaroxime encapsulated in liposomes is quickly released in serum, and thereby potentially useful to reduce side effects upon injection, without altering its pharmacokinetic profile.Istaroxime, an investigational new drug that targets defective Ca2+ cycling without compromising cardiac efficiency, may represent a promising and safe treatment of both acute and chronic heart failure. Even though the compound demonstrated good tolerability in a phase I/II safety study, symptoms related to the gastro-intestinal tract and pain at the injection site were reported as the most frequent side effects. The aim of this study was to encapsulate istaroxime in a drug delivery system (DDS) that could minimize the pain perceived upon administration. The DDS was designed tobe quicklydestabilized in plasma, in order to minimize alteration of the pharmacokinetic profile of istaroxime. To meet those requirements, a balance between the encapsulation efficiency and the release rate was sought. Transmembrane pH-gradient liposomes formulated with different phosphatidylcholines were investigated as vehicles for an efficient active drug loading. Poly(ethylene glycol)–660-hydroxystearate (PEG–HS) was chosen as excipient to modulate the bilayer fluidity and the release properties of the liposomes. A fast and efficient encapsulation was obtained by modulating the drug-to-lipid ratio, the amount of PEG–HS, and the incubation temperature. High encapsulation efficiency was achieved by incubating the drug with liposomal dispersions at room temperature for 10min. Almost complete release was obtained in physiological conditions in less than 10min, suggesting a model formulation potentially useful for drugs presenting similar features and side effects.
Keywords: Abbreviations; DPPC; 1,2-myristoyl-sn-glycero-3-phosphocholine; DMPC; 1,2-palmitoyl-sn-glycero-3-phosphocholine; DOPC; 1,2-oleoyl-sn-glycero-3-phosphocholine; EPC; egg phosphocholine; PEG–HS; poly(ethylene glycol)–660-hydroxystearate; HPTS; 1-hydroxypyrene-3,6,8-trisulfonic acid; DPX; p-xylenebis(pyridinium bromide; FBS; fetal bovine serum; Ch-BODIPY; cholesteryl 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoate; HEPES; 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidIstaroxime; Liposome; Controlled release; Congestive heart failure treatment; pH gradient; Poly(ethylene glycol)–660-hydroxystearate
Enzymatic synthesis of catechol and hydroxyl-carboxic acid functionalized chitosan microspheres for iron overload therapy
by Ivana Brzonova; Walter Steiner; Armin Zankel; Gibson S. Nyanhongo; Georg M. Guebitz (pp. 294-303).
Laccase oxidizes catechol resulting in the formation of radical quinone which then reacts with the NH2 group of the chitosan. The catechol fnctionalized chitosan is further processed to produce microspheres.Excess “free” iron which occurs under certain physiological conditions participates in the formation of toxic reactive oxygen species via the “fenton” chemistry. The reactive oxygen species oxidize biomolecules and have been implicated in many oxidative stress-related diseases. However, the ideal therapy for treating iron overload problems in humans has not yet been developed. In this study, the phenolic molecules catechol, caffeic acid, and 2,5-dihydroxybenzoic acid were successfully coupled to glucosamine as model substrate in a 1:1 ratio using laccase. Furthermore, coupling of these molecules onto chitosans of different sizes was demonstrated, resulting in decrease in –NH2 groups as quantified via derivatization. A concomitant increase in iron-chelating capacity from below 3% to up to 70% upon phenolic functionalization was measured for the chitosans based on reduced ferrozine/Fe2+ complex formation. Interesting these phenolic compounds seems to also participate as cross-linkers in producing characteristic microspheres. This work therefore opens-up new strategies aimed at developing a new generation of iron-chelating biomedical polymers.
Keywords: Iron chelators; Oxidative stress; Catechol; Hydroxyl-carboxic acid; Chitosan microspheres
Photosensitive controlled release with polyethylene glycol–anthracene modified alginate
by L.A. Wells; H. Sheardown (pp. 304-313).
Photoresponsive alginate – 365-nm UV light causes anthracene dimerization along the alginate polymer backbones of photogels to cause decreases in the release rates of small and large molecules.Covalent modification of alginate with polyethylene glycol–conjugated anthracene molecules has the potential to both stabilize the alginate and act as a photosensitive crosslinker. Release studies with Coomassie Blue show lengthy release times from the alginate photogels that extend past 70days with, for example, 17% versus 27% release at 1750h (73days) for photogels with and without 365-nm UV light treatment for 30min at 10mW/cm2 in the initial release period. Photocrosslinking of the photogels after loading effectively “locks” in drug compounds to control their release. Effective crosslinking densities and controls of polyethylene glycol-crosslinked alginate and physically crosslinked calcium alginate gels suggest strong interactions between Coomassie Blue and both alginate and anthracene. Photogels containing anthracene-capped star-polyethylene glycol show increased photosensitivity with modified release profiles. Ultimately, the covalent modification of alginate with photoactive crosslinkers has the potential to produce a long-term, photosensitive, controlled release system.
Keywords: Abbreviations; PEG; polyethylene glycol; Photogel; PEG–anthracene grafted alginate; Control PEG hydrogel; PEG–diamine crosslinked alginate; Boc-PEG-amine; O; -(2-aminoethyl)-; O; ′-[2-(Boc-amino)ethyl]decaethylene glycol; PEG–diamine; O; ,; O; ′-bis(2-aminoethyl)octadecaethylene glycol; EDC; 1-ethyl-(dimethylaminopropyl) carbodiimide hydrochloride; NHS; N-hydroxysuccinimide; MES; 4-morpholinoethanesulfonic acid; PBS; phosphate-buffered saline; TBS; TRIS-buffered saline; UV; ultravioletAlginate; Photoresponsive; Anthracene; Drug delivery; Smart biomaterials
Diuretic bioactivity optimization of furosemide in rats
by Bryan Laulicht; Anubhav Tripathi; Edith Mathiowitz (pp. 314-319).
Scanning electron micrographs acquired at 1000× of the stock (left), phase inversion micronized (center), and Eudragit co-precipitated (right) furosemide formulations evaluated for diuretic activity in a rat model.Furosemide is a loop diuretic widely used by patients with congestive heart failure (CHF) to rid excess body water, reducing blood pressure, and mobilizing edemas. However, due to the narrow window of furosemide absorption, occurring only in the proximal gastrointestinal tract, only immediate release oral formulations are clinically available. Comparisons of bolus and continuous administration of furosemide in intravenous settings demonstrate that continuous administration at lower concentrations produced greater diuretic efficiency and reduced subsequent hospitalization rates in patients experiencing severe CHF. We report a systematic investigation of the diuretic bioactivity profiles of phase inversion micronized furosemide and furosemide co-precipitated with Eudragit L100, as well as their blends with stock furosemide, targeted at reducing the rapid spike in diuresis associated with immediate release formulations while maintaining cumulative urine output. Of the formulations tested, an equal parts blend of micronized furosemide and stock furosemide demonstrated optimal diuretic bioactivity profiles in a rat model.
Keywords: Controlled release; Furosemide; Frusemide; Lasix; Phase inversion; Micronization
Enhancing and sustaining the topical ocular delivery of fluconazole using chitosan solution and poloxamer/chitosan in situ forming gel
by Taís Gratieri; Guilherme Martins Gelfuso; Osvaldo de Freitas; Eduardo Melani Rocha; Renata F.V. Lopez (pp. 320-327).
FLU aqueous humor concentrations assessed by microdialysis in rabbits after the topical administration of the following: (i) poloxamer/chitosan in situ forming gel, (ii) chitosan solution, and (iii) aqueous solution.Fungal keratitis is a serious disease that can lead to loss of vision. Unfortunately, current therapeutic options often result in poor bioavailability of antifungal agents due to protective mechanisms of the eye. The aim of this work was to evaluate the potential of a chitosan solution as well as an in situ gel-forming system comprised of poloxamer/chitosan as vehicles for enhanced corneal permeation and sustained release of fluconazole (FLU). For this, in vitro release and ex vivo corneal permeation experiments were carried out as a function of chitosan concentration from formulation containing the chitosan alone and combined with the thermosensitive polymer, poloxamer. Microdialysis was employed in a rabbit model to evaluate the in vivo performance of the formulations. The in vitro release studies showed the sustained release of FLU from the poloxamer/chitosan formulation. Ex vivo permeation studies across porcine cornea demonstrated that the formulations studied have a permeation-enhancing effect that is independent of chitosan concentration in the range from 0.5 to 1.5% w/w. The chitosan solutions alone showed the greatest ex vivo drug permeation; however, the poloxamer/chitosan formulation presented similar in vivo performance than the chitosan solution at 1.0%; both formulations showed sustained release and about 3.5-fold greater total amount of FLU permeated when compared to simple aqueous solutions of the drug. In conclusion, it was demonstrated that both the in situ gelling formulation evaluated and the chitosan solution are viable alternatives to enhance ocular bioavailability in the treatment of fungal keratitis.
Keywords: In situ; forming gel; Fluconazole; Poloxamer; Chitosan; In vivo; microdialysis; Ocular permeation
ToF-SIMS analysis of ocular tissues reveals biochemical differentiation and drug distribution
by Jenifer Mains; Clive Wilson; Andrew Urquhart (pp. 328-333).
Principal component analysis of time-of-flight secondary ion mass spectrometry data from non-dosed and drug dosed ocular tissue reveals ocular biochemical differences and drug distribution.Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to obtain mass spectra from three ocular tissues, the lens, the vitreous and the retina. All three tissues were extracted from control ovine eyes and ovine eyes treated with model drug. To identify variations in surface biochemistry of each ocular tissue, principal component analysis (PCA) was applied to ToF-SIMS data. Interesting physiological differences in Na+ and K+ distribution were shown across the three tissue types, with other elements including Ca2+ and Fe2+ distribution also detected. In addition to the identification of small molecules and smaller molecular fragments, larger molecules such as phosphocholine were also detected. The ToF-SIMS data were also used to identify the presence of a model drug compound (amitriptyline – chosen as a generic drug structure) within all three ocular tissues, with model drug detected predominantly across the vitreous tissue samples. This study demonstrates that PCA can be successfully applied to ToF-SIMS data from different ocular tissues and highlights the potential of coupling multivariate statistics with surface analytical techniques to gain a greater understanding of the biochemical composition of tissues and the distribution of pharmaceutically active small molecules within these tissues.
Keywords: Ocular; Drug; Time-of-flight secondary ion mass spectrometry; Principle component analysis; Multivariate statistics
Investigating the barrier function of skin lipid models with varying compositions
by Daniël Groen; Dana S. Poole; Gert S. Gooris; Joke A. Bouwstra (pp. 334-342).
Schematic overview of the permeation experiment using a flow-through diffusion cell.Display OmittedThe lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the barrier function. The main lipid classes in stratum corneum are ceramides, cholesterol, and free fatty acids. In previous publications, a lipid model was presented, referred to as the stratum corneum substitute (SCS), that closely mimics the SC lipid organization and SC barrier function. In the present study, we use the SCS to study the effect of changes in lipid organization on the lipid barrier function using benzoic acid as permeation compound. First, in the SCS, we increased the level of one of the three major lipid classes keeping the ratio between the other lipid classes constant. An increased cholesterol level resulted in an increase in phase-separated cholesterol and a reduction in the permeability. An increase in ceramide or free fatty acid level resulted in the formation of additional phases, but had no significant influence on the permeability. We also examined models that mimic selected changes in lipid composition reported for dry or diseased skin. The SCS that mimics the composition in recessive X-linked ichthyosis skin displayed a twofold increase in permeability. This increase is possibly related to the formation of an additional, less ordered phase in this model.
Keywords: Skin; Lipids; Stratum corneum; Model; In vitro; Permeation
Rat intestinal precision-cut slices as an in vitro model to study xenobiotic interaction with transporters
by Mariapia Possidente; Stefania Dragoni; Giulia Franco; Maila Gori; Eugenio Bertelli; Elisabetta Teodori; Maria Frosini; Massimo Valoti (pp. 343-348).
ATP-binding cassette (ABC) proteins play key role in tissue defence by transporting metabolic waste and toxic chemicals out of the cells. Consequently, intact cell systems are required to study xenobiotic interactions with ATP-dependent transporters. The aim of the present study was to set up an intestinal precision-cut slice technique to study the interactions of ABC transporters with xenobiotics. Rat intestinal slices were incubated with verapamil, indomethacin and glibenclamide, and the ability of the above-mentioned drugs to inhibit the multidrug resistance glycoprotein (MDR) and/or multidrug-resistance-associated protein (MRP) was assessed by measuring the intracellular conversion of calcein-AM to fluorescent calcein. The ABC transporters’ inhibitors caused a time-dependent florescence increase which reached the maximum value at 30min. Verapamil and glibenclamide promoted a concentration-dependent intracellular accumulation of calcein (IC50 8.1×10−6M, 1.9×10−4M, respectively). The effect of glibenclamide was fully reversed by washing the slices, suggesting the reversible nature of calcein accumulation. These data suggest that the precision-cut intestinal slices are a reliable, simple and fast system to evaluate xenobiotic interactions with ABC transporters in rat and, hopefully, in human intestine.
Keywords: ABC transporter; Calcein-AM; Intestine; Precision-cut slice; Multidrug resistance glycoprotein
Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: Case example nelfinavir
by Yasushi Shono; Ekarat Jantratid; Jennifer B. Dressman (pp. 349-356).
Model structure used for in silico simulation of nelfinavir absorption, incorporating drug precipitation.The aim of this study was to evaluate the utility of biorelevant dissolution tests coupled with in silico simulation technology to forecast in vivo bioperformance of poorly water-soluble bases, using nelfinavir mesylate as a model compound.An in silico physiologically based pharmacokinetic (PBPK) model for poorly water-soluble, weakly basic drugs was used to generate plasma profiles of nelfinavir by coupling dissolution results and estimates of precipitation with standard gastrointestinal (GI) parameters and the disposition pharmacokinetics of nelfinavir. In vitro dissolution of nelfinavir mesylate film-coated tablets was measured in biorelevant and compendial media. Drug precipitation in the small intestine was estimated from crystal growth theory. GI parameters (gastric emptying rate and fluid volume) appropriate to the dosing conditions (fasting and fed states) were used in the PBPK model. The disposition parameters of nelfinavir were estimated by fitting compartmental models to the in vivo oral PK data. The in vivo performance in each prandial state was simulated with the PBPK model, and predicted values for AUC and Cmax were compared to observed values.Dissolution results in FaSSIF-V2 and FeSSIF-V2, simulating the fasting and fed small intestinal conditions, respectively, correctly predicted that there would be a positive food effect for nelfinavir mesylate, but overestimated the food effect observed in healthy human volunteers. In order to better predict the food effect, an in silico PBPK simulation model using STELLA® software was evolved. Results with the model indicated that invoking drug precipitation in the small intestine is necessary to describe the in vivo performance of nelfinavir mesylate in the fasted state, whereas a good prediction under fed state conditions is obtained without assuming any precipitation. In vitro– in silico– in vivo relationships (IVISIV-R) may thus be a helpful tool in understanding the critical parameters that affect the oral absorption of poorly soluble weak bases.
Keywords: Nelfinavir mesylate; Food effect; Precipitation; Biorelevant dissolution testing; In silico; simulation; Absorption modeling
Enhanced transbuccal salmon calcitonin (sCT) delivery: Effect of chemical enhancers and electrical assistance on in vitro sCT buccal permeation
by Dong-Ho Oh; Kyeung-Hwa Chun; Sang-Ok Jeon; Jeong-Won Kang; Sangkil Lee (pp. 357-363).
The flux (J s) of sCT was increased by the aid of absorption enhancers and iontophoresis. HoweverJ s of transbuccal sCT was more enhanced by the combination of absorption enhancers and electrical assistance.This study investigates the combined effect of absorption enhancers and electrical assistance on transbuccal salmon calcitonin (sCT) delivery, using fresh swine buccal tissue. We placed 200IU (40μg/mL) of each sCT formulation—containing various concentrations of ethanol, N-acetyl-l-cysteine (NAC), and sodium deoxyglycocholate (SDGC)—onto the donor part of a Franz diffusion cell. Then, 0.5mA/cm2 of fixed anodal current was applied alone or combined with chemical enhancers. The amount of permeated sCT was analyzed using an ELISA kit, and biophysical changes of the buccal mucosa were investigated using FT-IR spectroscopy, and hematoxylin–eosin staining methods were used to evaluate histological alteration of the buccal tissues. The flux (J s) of sCT increased with the addition of absorption enhancer groups, but it was significantly enhanced by the application of anodal iontophoresis (ITP). FT-IR study revealed that all groups caused an increase in lipid fluidity but only the groups containing SDGC showed statistically significant difference. Although the histological data of SDGC groups showed a possibility for tissue damage, the present enhancing methods appear to be safe. In conclusion, the combination of absorption enhancers and electrical assistance is a potential strategy for the enhancement of transbuccal sCT delivery.
Keywords: Salmon calcitonin; Buccal delivery; Peptide delivery; Absorption enhancers; Iontophoresis; Electrical assistance
Study on dissolution and absorption of four dosage forms of isosorbide mononitrate: Level A in vitro– in vivo correlation
by Zi-qiang Li; Xin He; Xiumei Gao; Yan-yan Xu; Yue-fei Wang; Hui Gu; Rui-feng Ji; Shu-jun Sun (pp. 364-371).
Drug dissolution/absorption simulating system (DDASS) is a novel method to monitor the process of dissolution and permeation of complete oral solid formulations simultaneously. Four commercial dosage forms of isosorbide mononitrate (ISMN) were chosen as model formulations. An in vitro-in vivo correlation study was carried out between DDASS methods and beagle dogs, and between the classical method and beagle dogs.The objective of the present study was to develop a novel in vitro system to simulate the process of dissolution and permeation of oral solid dosage forms in vivo, and to establish a correlation between in vitro permeation and in vivo absorption that could predict the bioavailability (BA) and bioequivalence (BE) of congeneric products. The in vitro dissolution and absorption kinetics of four dosage forms of isosorbide mononitrate (ISMN) were evaluated by the USP basket/paddle system and drug dissolution/absorption simulating system (DDASS). The corresponding pharmacokinetic study was performed in beagle dogs. A comparative study was carried out between the classical and the novel method to estimate the effectiveness of the modified DDASS in simulating the course of dissolution and absorption in vivo. Indeed, the correlation coefficients of in vitro dissolution and in vivo absorption obtained from DDASS and dogs were higher. Moreover, a higher level A in vitro– in vivo correlation (IVIVC) between DDASS permeation and dog absorption was established, with correlation coefficients of 0.9968, 0.9872, 0.9921, and 0.9728. The DDASS method was more accurate at modeling the process of dissolution and absorption in vivo for both immediate-release (IR) and sustained-release (SR) dosage forms of ISMN.
Keywords: Isosorbide mononitrate (ISMN); Drug dissolution/absorption simulating system (DDASS); In vitro; –; in vivo; correlation (IVIVC); Bioavailability (BA); Immediate-release (IR); Sustained-release (SR)
Tailor-made release triggering from hot-melt extruded complexes of basic polyelectrolyte and poorly water-soluble drugs
by Christoph Kindermann; Karin Matthée; Jutta Strohmeyer; Frank Sievert; Jörg Breitkreutz (pp. 372-381).
Formulation of polyelectrolyte complexes by hot-melt extrusion enabling a tailor-made release pattern by the addition of inorganic salts.The aim of the study was the formulation of polyelectrolyte complexes composed of poorly water-soluble acid drugs and basic polymethacrylates by hot-melt extrusion enabling a tailor-made release pattern by the addition of inorganic salts. The influence of different electrolytes was analyzed at varying conditions in order to control drug delivery from the complexes. Poorly water-soluble model drugs naproxen and furosemide were applied in their non-ionic form.After hot-melt extrusion of the naproxen-polymethacrylate powder blend, XRPD and DSC measurements indicated the formation of a single-phase amorphous system. Milled extrudates were stable under storage at long-term and intermediate conditions. Polyelectrolyte complex formation by an acid–base reaction during hot-melt extrusion could be proven by the lack of vibrations of dimethylamino and carboxylic groups by FT-IR and Raman spectroscopy. The complexes did not dissolve in demineralized water. Drug release could be immediately induced by addition of neutral electrolytes. Tailor-made dissolution profiles were realized by controlled electrolyte triggering. Maximal effects were achieved by concentrations of 0.05–0.15M NaCl. Different anions of alkali halogenides revealed variant magnitudes of the effect depending on the anion radius. Polyelectrolyte complex formation and dissolution principles were also confirmed for furosemide.
Keywords: Polyelectrolyte complex; Hot-melt extrusion; Acid–base reaction; Electrolyte triggering; Tailor-made dissolution
The influence of dissolution conditions on the drug ADME phenomena
by Sara Cascone; Felice De Santis; Gaetano Lamberti; Giuseppe Titomanlio (pp. 382-391).
The kinetic of the drug release, and the subsequent ADME phenomena, are strongly influenced by the dissolution conditions.In this work, a review of the apparatuses available to mimic what happens to a drug (or to foodstuffs) once ingested is presented. Similarly, a brief review of the models proposed to simulate the fate of a drug administered to a living body is reported. Then, the release kinetics of extended release of diclofenac from a commercial enteric-coated tablet was determined both in a conventional dissolution tester (USP Apparatus 2, Method A) as well as in an apparatus modified to reproduce a given pH evolution, closer to the real one than the one suggested by USP. The two experimental release profiles were reported and discussed; therefore, they were adopted as input functions for a previously proposed pharmacokinetic model. The obtained evolutions with time of plasma concentration were presented and used to assess the effectiveness of the commercial pharmaceutical products. The importance of a correct in vitro simulation for the design of pharmaceutical dosage systems was thus emphasized.
Keywords: Dissolution; Pharmacokinetic modeling; Enteric coated; ADME
Influence of polymer hydrolysis on adjuvant effect of Gantrez®AN nanoparticles: Implications for oral vaccination
by Katrien Vandamme; Vesna Melkebeek; Eric Cox; Peter Adriaensens; Sandra Van Vlierberghe; Peter Dubruel; Chris Vervaet; Jean Paul Remon (pp. 392-398).
Partial hydrolysis of the anhydride groups of methylvinylether-co-maleic anhydride (Gantrez AN) reduced its adjuvant effect during oral vaccination of mice with F4-adhesins of Escherichia coli, formulated in nanoparticles. A higher degree of crosslinking during nanoparticle synthesis could overcome this negative effect of partial polymer hydrolysis.The adjuvant effect of methylvinylether-co-maleic anhydride (Gantrez®AN) nanoparticles was investigated during oral vaccination of mice with F4 adhesins of F4-positive Escherichia coli. To differentiate whether the adjuvant effect originated from a nanoparticle effect or a polymer effect, 20μgF4 was administered as slightly crosslinked F4-containing nanoparticles (g(F4)0.01) or as F4 mixed with slightly crosslinked pure nanoparticles (F4+g0.01).The F4-specific immune response was reduced using F4-containing nanoparticles due to complete shielding of F4, whereas oral administration of F4+g0.01 increased the level of F4-specific antibody-secreting cells (ASC) in the spleen. When repeating the vaccination study after 6months using freshly prepared nanoparticles, the adjuvant effect of F4+g0.01 was lost due to an altered polymer reactivity caused by partial hydrolysis of anhydride groups of Gantrez®AN. Combining F4 with nanoparticles stabilised with a higher crosslinker amount during nanoparticle synthesis (F4+g0.22) could overcome the effect of partial polymer hydrolysis, as higher levels of ASC were detected. Hence, an in-depth characterisation of the Gantrez®AN polymer is required as stability issues can alter its biological effect during oral vaccination.
Keywords: Abbreviations; F4; F4 fimbriae (solution); NP; nanoparticle; DP; 13-diaminopropane (nanoparticle crosslinking agent); g0.01/g0.22; pure Gantrez® AN nanoparticles, crosslinked with 0.01 or 0.22 mg DP/mg polymer; F4+g; F4 + pure Gantrez® AN nanoparticles; g(F4); F4-containing Gantrez® AN nanoparticles; ASC; antibody secreting cellsGantrez®AN; Polymer hydrolysis; Altered polymer reactivity; Nanoparticles; Oral vaccination; Adjuvant
Effects of PEG size on structure, function and stability of PEGylated BSA
by Bitten Plesner; Conan J. Fee; Peter Westh; Anders D. Nielsen (pp. 399-405).
The binding of surfactant, SDS, to BSA appears to be altered upon PEGylation, as two distinct classes of binding sites (high and low affinity) for BSA and one class (low affinity) for PEGylated BSA were identified at 25°C. Hence, PEGylation appears to alter the function of BSA as a transport protein.The effects of PEGylation on the structural, thermal and functional stability of bovine serum albumin (BSA) were investigated using BSA and 6 linear mono-PEGylated BSA compounds. The secondary and tertiary structure of BSA measured by circular dichroism (CD) was independent of PEGylation. In contrast, the thermal stability of BSA was affected by PEGylation. The apparent unfolding temperature Tmax measured by differential scanning calorimetry (DSC) decreased with PEGylation, whereas the temperature of aggregation, Tagg, measured by dynamic light scattering (DLS) increased with PEGylation. The unfolding temperature and the temperature of aggregation were both independent of the molecular weight of the PEG chain. Possible functional changes of BSA after PEGylation were measured by Isothermal Titration Calorimetry (ITC), where the binding of sodium dodecyl sulphate (SDS) to BSA and PEGylated BSA was analysed. At 25°C, two distinct classes of binding sites (high affinity and low affinity) for BSA and one class of binding site (low affinity) for PEGylated BSA were identified. The binding isotherm was modelled assuming independence and thermodynamic equivalence of the sites within each class. From the present biophysical characterisation, it is concluded that after PEGylation BSA appears to be unaffected structurally (secondary and tertiary structure), slightly destabilised thermally (unfolding temperature), stabilised kinetically (temperature of aggregation) and has an altered functionality (binding profile). These biophysical characteristics are all independent of the molecular weight of the attached polymer chain.
Keywords: PEGylation; Protein stability; Protein aggregation; Calorimetry; Dynamic light scattering; Circular dichorism
Development of potential novel cushioning agents for the compaction of coated multi-particulates by co-processing micronized lactose with polymers
by Xiao Lin; Chin Wun Chyi; Ke-feng Ruan; Yi Feng; Paul Wan Sia Heng (pp. 406-415).
The cushioning effects of polymer-co-processed spray-dried micronized lactose (SML).This work aimed to explore the potential of lactose as novel cushioning agents with suitable physicomechanical properties by micronization and co-spray drying with polymers for protecting coated multi-particulates from rupture when they are compressed into tablets. Several commercially available lactose grades, micronized lactose (ML) produced by jet milling, spray-dried ML (SML), and polymer-co-processed SMLs, were evaluated for their material characteristics and tableting properties. Hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and polyvinylpyrrolidone (PVP) at three different levels were evaluated as co-processed polymers for spray drying. Sugar multi-particulates layered with chlorpheniramine maleate followed by an ethylcellulose coat were tableted using various lactose types as fillers. Drug release from compacted multi-particulate tablets was used to evaluate the cushioning effect of the fillers. The results showed that the cushioning effect of lactose principally depended on its particle size. Micronization can effectively enhance the protective action of lactose. Although spray drying led to a small reduction in the cushioning effect of ML, it significantly improved the physicomechanical properties of ML. Co-spray drying with suitable polymers improved both the cushioning effect and the physicomechanical properties of SML to a certain degree. Among the three polymers studied, HPC was the most effective in terms of enhancing the cushioning effect of SML. This was achieved by reducing yield pressure, and enhancing compressibility and compactibility. The combination of micronization and co-spray drying with polymers is a promising method with which new applications for lactose can be developed.
Keywords: Micronized lactose; Cushioning effect; Spray drying; Hydroxypropylcellulose; Hydroxypropylmethylcellulose; Polyvinylpyrrolidone
Effect of the non-ionic surfactant Poloxamer 188 on passive permeability of poorly soluble drugs across Caco-2 cell monolayers
by Sarah Maud Fischer; Martin Brandl; Gert Fricker (pp. 416-422).
We found that the permeability in Caco-2 monolayers was depressed in the presence of Poloxamer 188 micelles in a concentration-dependent way, when other than the passive pathway could be excluded. These findings corrobate the theory that the micelle associated drug is not readily absorbed, but that only the free drug is.Drug permeability of the model drugs ketoprofen and nadolol across Caco-2 cell monolayers was determined in the absence and presence of the non-ionic surfactant Poloxamer 188 (Pluronic® F68, P-188). Stringent controls confirmed that P-188 in concentrations up to 50mg/ml did not adversely affect cell viability or monolayer integrity. Equilibrium experiments confirmed that the drugs were merely passively transported. Caco-2 permeability of both drugs was found to be decreased by the surfactant in a concentration-dependent manner. Ultrafiltration revealed that both drugs were associated with surfactant micelles. The systematic investigation of micellization on passive absorption showed that association of drugs with P-188 micelles appears to depress their passive permeability under conditions where other transport mechanisms can be neglected.
Keywords: Passive drug permeability; Micelle; Solubilisation; Pluronic; Ketoprofen; Nadolol; Trans-epithelial electrical resistance
Inhibition of lipase-catalyzed hydrolysis of emulsified triglyceride oils by low-molecular weight surfactants under simulated gastrointestinal conditions
by Yan Li; David Julian McClements (pp. 423-431).
Small molecule surfactants may either inhibit or promote lipid digestion depending on their concentration and electrical characteristics.The effect of low-molecular weight surfactants on the digestibility of lipids in protein-stabilized corn oil-in-water emulsions was studied using an in vitro digestion model. The impact of non-ionic (Tween 20, Tween 80, Brij35), anionic (SDS), and cationic (DTAB) surfactants on the rate and extent of lipid digestion was studied. All surfactants were found to inhibit lipid digestion at sufficiently high concentrations, with half-maximal inhibitory concentrations (IC50) of 1.2% for Tween 20, 0.7% for Tween 80, 2.8% for Brij35, 1.1% for SDS, and 1.4% for DTAB. The effectiveness of the surfactants at inhibiting lipid digestion was therefore not strongly correlated to the electrical characteristics of the surfactant head group, since the IC50 increased in the following order: Tween 80>SDS>Tween 20>DTAB>Brij35. The ability of these low-molecular weight surfactants to inhibit lipid digestion was attributed to a number of potential mechanisms: (i) prevention of lipase/co-lipase adsorption to the oil–water interface; (ii) formation of interfacial complexes; (iii) direct interaction and inactivation of lipase/co-lipase. Interestingly, DTAB increased the rate and extent of lipid digestion when present at relatively low concentrations. This may have been because this cationic surfactant facilitated the adsorption of lipase to the droplet surfaces through electrostatic attraction, or it bound directly to the lipase molecule thereby changing its structure and activity. A number of the surfactants themselves were found to be susceptible to enzyme digestion by pancreatic enzymes in the absence of lipids: Tween 20, Tween 80, Brij35, and DTAB. This work has important implications for the development of emulsion-based delivery systems for food and pharmaceutical applications.
Keywords: Digestion; Emulsions; Lipids; Surfactants; Delivery systems; pH stat
Spray-drying enteric polymers from aqueous solutions: A novel, economic, and environmentally friendly approach to produce pH-responsive microparticles
by Mohamed A. Alhnan; Erfan Kidia; Abdul W. Basit (pp. 432-439).
The major steps involved in the fabrication of enteric microparticles using a novel aqueous-based spray drying method.We describe a novel method to fabricate pH-responsive microparticles suitable for oral delivery using an aqueous-based spray-drying approach. The approach involves the neutralization and generation of water-soluble salt forms of enteric polymers. The methacrylic acid polymers (Eudragit L and Eudragit S) were added separately to aqueous solutions of ammonium hydrogen carbonate; the solutions were then spray-dried. FTIR analysis of the harvested microparticle products identified the presence of ammonium methacrylate with the appearance of a peak at 1550cm−1 corresponding to the stretching of the N–H bond. Incubating the microparticles for three hours at 70°C and 130°C for the Eudragit S and L products, respectively, was sufficient to eradicate the ammonium residues. The microparticles, loaded with the model drug prednisolone, were spherical and small in size (2–5μm). Moreover, the particles were gastro-resistant, and release was rapid and complete at small intestinal conditions. The pH threshold of release of the Eudragit S and Eudragit L microparticles was lowered from 7 and 6 to 6.5 and 5.5, respectively. In bicarbonate media, which are physiological and representative of the conditions of the proximal small intestine (mHanks) and the distal small intestine (Kreb’s), drug release from these spray-dried microparticles was faster compared to microparticles produced from conventional emulsion solvent evaporation methods. This new microparticle preparation concept obviates the need for organic solvents and utilizes spray-drying techniques that are amenable to industrial application; the approach therefore offers economic, safety, and environmental benefits.
Keywords: Green pharmaceutics; Microspheres; Ammonium solutions; Polymethacrylic acid; Polymethacrylates; Enteric polymers; Microencapsulation
Preparation of starch-based pellets by hot-melt extrusion
by Sebastian Bialleck; Hubert Rein (pp. 440-448).
By hot-melt extrusion and die-face pelletisation of starch melts (1), spherical pellets with particle sizes from 0.5 to 2.0mm, very narrow particle size distributions (2) and controllable drug release rate can continuously be produced (3).Spherical starch pellets were directly and continuously produced using hot-melt extrusion and die-face pelletisation. In contrast to conventional pelletisation procedures, a discontinuous spheronisation step can be dropped. Pellets were produced based on four different starches (corn starch, pea starch, potato starch and waxy corn starch), four different active ingredients (ibuprofen, paracetamol, phenazon and tramadol-HCl) and various additives. The resulting pellets exhibit a large mechanical stability, low porosity and small surface area. Pellets with a very narrow particle size distribution and particle sizes even in the micron scale can be produced. The drug is either dispersed or dissolved in the starch melt. Drug loadings of up to 80% are achievable. The drug release rate is controlled by the particle size, the combination of starch, active ingredient and additives. The release mechanism is determined by the used starch and the additives. Under normal circumstances, the starch matrix remains intact during dissolution with the exception of waxy corn starch pellets. Pellets based on that starch completely erode. Mathematical modelling revealed that the drug release mechanism from corn starch, pea starch and potato starch pellets is complex and based on diffusion as well as relaxation of the matrix.
Keywords: Hot-melt extrusion; Melt pelletisation; Pellets; Starch; Controlled release devices; Release mechanisms
Use of photoacoustic spectroscopy in the characterization of inclusion complexes of benzophenone-3-hydroxypropyl-β-cyclodextrin and ex vivo evaluation of the percutaneous penetration of sunscreen
by Fernanda Berbicz; Ana Claudia Nogueira; Antonio Medina Neto; Maria Raquel Marçal Natali; Mauro Luciano Baesso; Graciette Matioli (pp. 449-457).
Photoacoustic spectroscopy (PAS) was used in the characterization of inclusion complexes of benzophenone-3 and hydroxypropyl-β-cyclodextrin and suggested a complexation in the stoichiometric ratio of 1:2. PAS was also used to analyze the ex vivo percutaneous penetration of sunscreens and showed that the formulation with the complex resulted in lower penetration of BZ-3.This work is aimed to evaluate the application of photoacoustic spectroscopy (PAS) in the characterization of inclusion complexes of benzophenone-3 (BZ-3) and hydroxypropyl-β-cyclodextrin (HPCD) and to analyze the ex vivo percutaneous penetration of sunscreens and their reaction with the skin. The formation of inclusion complexes of BZ-3 and HPCD was performed by co-precipitation in stoichiometric ratios of 1:1 and 1:2. Thermal analysis and PAS characterized these inclusion complexes, and they indicated that the stoichiometric ratio of 1:2 was best. Sunscreen formulations were prepared and applied on the ears of rabbits. PAS suggested that the formulation with the complex resulted in lower penetration of BZ-3. Histological analysis demonstrated that the use of the formulation with BZ-3 was associated with an increase in the comedogenic effect and the presence of acanthosis, while no such effect was found in the formulation with the complex. The formulation with the BZ-3-HPCD complex is a promising strategy for improving the photoprotective effect of BZ-3. PAS can be used in the study of inclusion complexes with cyclodextrins and the evaluation of the percutaneous penetration of sunscreen formulations. Further tests are being conducted using PAS to monitor in vivo changes in the optical absorption spectra of formulations and to investigate their photostability.
Keywords: Abbreviations; PAS; photoacoustic spectroscopy; BZ-3; benzophenone-3; HPCD; hydroxypropyl-β-cyclodextrin; CDs; cyclodextrins; β-CD; beta-cyclodextrin; BZ-3-HPCD; inclusion complex benzophenone-3-hydroxypropyl-β-cyclodextrinPhotoacoustic spectroscopy; Inclusion complex; Benzophenone-3; Hydroxypropyl-β-cyclodextrin; Percutaneous penetration
Dynamic mechanical thermal analysis of hypromellose 2910 free films
by Marco Cespi; Giulia Bonacucina; Giovanna Mencarelli; Luca Casettari; Giovanni Filippo Palmieri (pp. 458-463).
DMA measurements showed as the hypromellose films glass transitions and the parameters associated with it are dependent by the polymer chain length.It is common practice to coat oral solid dosage forms with polymeric materials for controlled release purposes or for practical and aesthetic reasons. Good knowledge of thermo-mechanical film properties or their variation as a function of polymer grade, type and amount of additives or preparation method is of prime importance in developing solid dosage forms. This work focused on the dynamic mechanical thermal characteristics of free films of hypromellose 2910 (also known as HPMC), prepared using three grades of this polymer from two different manufacturers, in order to assess whether polymer chain length or origin affects the mechanical or thermo-mechanical properties of the final films. Hypromellose free films were obtained by casting their aqueous solutions prepared at a specific concentrations in order to obtain the same viscosity for each. The films were stored at room temperature until dried and then examined using a dynamic mechanical analyser. The results of the frequency scans showed no significant differences in the mechanical moduli E′ and E″ of the different samples when analysed at room temperature; however, the grade of the polymer affected material transitions during the heating process. Glass transition temperature, apparent activation energy and fragility parameters depended on polymer chain length, while the material brand showed little impact on film performance.
Keywords: Hypromellose (HPMC); Dynamic mechanical thermal analysis; DMA TDMA; Glass transition; Activation energy; Coating films
Optimization of parameters of the SeDeM Diagram Expert System: Hausner index (IH) and relative humidity (%RH)
by Josep M. Suñé-Negre; Pilar Pérez-Lozano; Manel Roig; Roser Fuster; Carmen Hernández; Ramon Ruhí; Encarna García-Montoya; Montserrat Miñarro; Josep R. Ticó (pp. 464-472).
SeDeM Diagram for Avicel® PH 101.As a methodology for characterizing substances in relation to their viability in direct compression, the SeDeM Diagram Expert System may be considered an open system in terms of the number of parameters applied and the optimization of these parameters. With the experience acquired from applying the SeDeM Diagram, in this study, we propose optimizing the parameters corresponding to the Hausner index (IH) and relative humidity (%HR) in order to simplify the mathematical calculation, so that it provides reliable data that can be extrapolated. The proposed optimization does not involve a conceptual change in the parameters considered nor a significant change in the results obtained compared with the previous calculation methodology initially established for the SeDeM Diagram Expert System, which means that the conclusions obtained by applying this method are equivalent.
Keywords: SeDeM Diagram Expert System; Hausner index (IH); Relative humidity (%HR); Parameters optimization; Direct compression; Tablet excipients