European Journal of Pharmaceutics and Biopharmaceutics (v.80, #1)
Comparative pharmacoscintigraphic and pharmacokinetic evaluation of two new formulations of inhaled insulin in type 1 diabetic patients
by F. Depreter; A. Burniat; D. Blocklet; S. Lacroix; M. Cnop; F. Fery; N. Van Aelst; G. Pilcer; M. Deleers; S. Goldman; K. Amighi (pp. 4-13).
Lung deposition (assessed by scintigraphic imaging) and serum insulin levels obtained after administration of the two formulations.In this open, single-dose study, we compared the lung deposition and bioavailability of two newly developed insulin formulations for pulmonary delivery. Twelve type 1 diabetic patients were administered the two insulin products (2U/kgb.w.), which had been radiolabelled with99mTc. The formulations were either microparticles of insulin without excipients (F1) or lipid-coated insulin microparticles (F2). Lung deposition was assessed by γ-scintigraphy imaging performed immediately after administration. Bioavailability was evaluated by quantifying serum insulin levels over a period of 6h.Lung deposition was found to be 50±9% and 24±8% for the F1 and F2 formulations, respectively. The insulin AUC0–360 ratio of F1/F2 was 188%, which was consistent with scintigraphic imaging. The concordance between imaging and biological results suggests that the lower bioavailability of F2 is due to its lower lung deposition and not to a reduced absorption into the blood stream. Additional in vitro experiments indicated that the lower performance of F2 was most probably related to a lower disaggregation efficiency of the powder when administered at a sub-optimal flow rate.The two formulations showed interesting pharmacokinetic profiles ( Tmax of 26 and 16min for F1 and F2, respectively) that mimic the physiological insulin secretion pattern. The bioavailability of the developed formulations was within the range of other DPI insulin formulations that have reached the final stages of clinical development.
Keywords: Pulmonary delivery; Dry powder inhaler (DPI); Microparticles; Lipids; Bioavailability; Lung deposition
Factors influencing polycation/siRNA colloidal stability toward aerosol lung delivery
by Terry W.J. Steele; Xiaobin Zhao; Peter Tarcha; Thomas Kissel (pp. 14-24).
Hexanediol diacrylate cross-linked oligoethylenimine (OEI-HD) is a non-viral polymeric vector designed to deliver siRNA. To achieve safe and effective in vivo siRNA delivery using this vector, the polyplex must have sufficient colloidal stability if administered intravenously or nebulized for delivery by the pulmonary route. In this study, polyplexes from OEI-HD and siRNA were formulated for aerosol-based lung delivery, regarding their colloidal stability, optimal particle size, and in vitro biological activity. Herein, we describe how these properties are dependent upon the polymer-to siRNA weight ratios, buffer composition they were complexed in, PEG-grafting, and the addition of commercial lung surfactants and/or non-ionic surfactants to the formulation. Lastly, the effects of nebulization of the formulation into aerosol droplets, on the polyplex particle size and transfection efficiency, were evaluated.Polyplex size was monitored for up to 2h after polyplex formation to determine the extent of aggregation and final particle sizes when stability was achieved. Our results suggest that PEG-grafting and polyethylenimine-PEG mixing were effective in achieving colloidal stability in isotonic saline buffers. In addition, colloidal stability was achieved in isotonic glucose buffers using commercially available non-ionic surfactant Pluronic™ P68 or the lung-derived surfactant Alveofact™. The smallest particle size, 140nm, was obtained with Pluronic™ F68. For transfection efficiency, both Alveofact™ and Pluronic™ F68 achieved equal or better transfection when added to the OEI-HD/siRNA polyplexes. For long term storage of OEI-HD/siRNA formulations, we propose a lyophilization method that created in situ polyplexes upon addition of water. Preparation of OEI-HD/siRNA polyplexes by this method allowed dry storage at room temperature for up to the 3months. In conclusion, we have identified approaches to achieve formulation and colloidal stability of OEI-HD/siRNA complexes, a step toward successful application of polyplexes for in vivo siRNA delivery.
Keywords: Aerosol; Lung; Gene therapy; Transfection; Oligoethylenimine; Surfactant
Anthrax sub-unit vaccine: The structural consequences of binding rPA83 to Alhydrogel®
by Andrei Soliakov; Ian F. Kelly; Jeremy H. Lakey; Allan Watkinson (pp. 25-32).
A series of biophysical techniques have been used to compare a non-adjuvanted and adjuvanted rPA83. Adsorption of rPA83 to aluminium hydroxide had a minimal effect on the protein structure but altered the thermodynamic properties.An anthrax sub-unit vaccine, comprising recombinant Protective Antigen (rPA83) and aluminium hydroxide adjuvant (Alhydrogel®) is currently being developed. Here, a series of biophysical techniques have been applied to free and adjuvant bound antigen. Limited proteolysis and fluorescence identified no changes in rPA83 tertiary structure following binding to Alhydrogel and the bound rPA83 retained two structurally important calcium ions. For adsorbed rPA83, differential scanning calorimetry revealed a small reduction in unfolding temperature but a large decrease in unfolding enthalpy whilst urea unfolding demonstrated unchanged stability but a loss of co-operativity. Overall, these results demonstrate that interactions between rPA83 and Alhydrogel have a minimal effect on the folded protein structure and suggest that antigen destabilisation is not a primary mechanism of Alhydrogel adjuvancy. This study also shows that informative structural characterisation is possible for adjuvant bound sub-unit vaccines.
Keywords: Anthrax; Sub-unit vaccine; Alhydrogel; Fluorescence; Calorimetry; PA83
Photocrosslinked poly(ester anhydride)s for peptide delivery: Effect of oligomer hydrophobicity on PYY3-36 delivery
by Juha Mönkäre; Risto A. Hakala; Miia Kovalainen; Harri Korhonen; Karl-Heinz Herzig; Jukka V. Seppälä; Kristiina Järvinen (pp. 33-38).
Functionalization of poly(ester anhydride) oligomers with 12-carbon alkenyl chain delays PYY3-36 release in vivo in comparison with SAH-functionalized oligomers without alkenyl chain.The treatment for many diseases can be improved by developing more efficient peptide delivery technologies, for example, biodegradable polymers. In this work, photocrosslinked poly(ester anhydride)s based on functionalized poly(ε-caprolactone) oligomers were investigated for their abilities to achieve controlled peptide delivery. The effect of oligomer hydrophobicity on erosion and peptide release from poly(ester anhydride)s was evaluated by developing a sustained subcutaneous delivery system for an antiobesity drug candidate, peptide YY3-36 (PYY3-36). Oligomer hydrophobicity was modified with alkenylsuccinic anhydrides containing a 12-carbon alkenyl chain. PYY3-36 was mixed as a solid powder with methacrylated poly(ester anhydride) precursors, and this mixture was photocrosslinked at room temperature to form an implant for subcutaneous administration in rats. The oligomer hydrophobicity controlled the polymer erosion and PYY3-36 release as the increased hydrophobicity via the alkenyl chain prolonged polymer erosion in vitro and sustained in vivo release of PYY3-36. In addition, photocrosslinked poly(ester anhydride)s increased the bioavailability of PYY3-36 by up to 20-fold in comparison with subcutaneous administration of solution, evidence of remarkably improved delivery. In conclusion, this work demonstrates the suitability of photocrosslinked poly(ester anhydride)s for use in peptide delivery.
Keywords: Poly(ester anhydride); Photocrosslinking; Peptide YY3-36; Controlled release; Bioavailability; Pharmacokinetics
Nonpolymeric nanoassemblies for ocular administration of acyclovir: Pharmacokinetic evaluation in rabbits
by Barbara Stella; Silvia Arpicco; Flavio Rocco; Susi Burgalassi; Nadia Nicosia; Silvia Tampucci; Patrizia Chetoni; Luigi Cattel (pp. 39-45).
Ocular bioavailability of acyclovir (ACV) was increased by chemically linking ACV to squalene, obtaining 4′- trisnorsqualenoylacyclovir (SQACV), which spontaneously forms nanoassemblies. The graph shows tear fluid concentration vs time profiles of ACV after the administration of SQACV and ACV formulations.The aim of this study was to increase bioavailability of the antiviral drug acyclovir (ACV) when administered by the ocular route. For this purpose, a new lipophilic derivative of acyclovir was synthesized, both possessing greater lipophilicity and providing the formation of a homogeneous water dispersion with higher amount of ACV than the aqueous solution of the parent drug. This was done by chemically linking acyclovir to the isoprenoid chain of squalene, obtaining 4′- trisnorsqualenoylacyclovir (SQACV), in which squalene is covalently coupled to the 4′-hydroxy group of acyclovir. This new prodrug was then formulated as nonpolymeric nanoassemblies through nanoprecipitation; the resulting particles were characterized in terms of mean diameter, zeta potential, and stability. The pharmacokinetic profile of the prodrug in the tear fluid and in the aqueous humor of rabbits was evaluated and compared to that of the parent drug.Data showed that SQACV nanoassemblies increased the amount of ACV in the aqueous humor of rabbits compared to free ACV solution. This new amphiphilic prodrug of acyclovir is a very promising tool to increase the ocular bioavailability of the parent drug.
Keywords: Nanoassemblies; Acyclovir; Squalene; Ocular pharmacokinetic; Rabbits
Development of a new delivery system consisting in “drug – in cyclodextrin – in nanostructured lipid carriers” for ketoprofen topical delivery
by M. Cirri; M. Bragagni; N. Mennini; P. Mura (pp. 46-53).
% Ketoprofen permeated after 300min through the skin-simulating artificial membrane from hydrogel formulations loaded with drug alone or as co-ground product with EPI-βCd, or with NLC containing the drug alone or as physical mixture or co-ground product with EPI-βCd.A new delivery system based on drug cyclodextrin (Cd) complexation and loading into nanostructured lipid carriers (NLC) has been developed to improve ketoprofen therapeutic efficacy. The proposed strategy exploits both the solubilizing and stabilizing properties of Cds and the prolonged release, high tolerability and percutaneous absorption enhancer properties of NLC. Two different polymeric Cds, i.e. β-Cd-epichlorohydrin polymer (EPI-βCd) and carboxymethylathed-β-Cd-epichlorohydrin polymer (EPI-CMβCd) were tested and two different techniques to obtain solid ketoprofen-polymeric Cd complexes (i.e. co-grinding and co-lyophilization) were compared, to investigate the influence of the preparation method on the physicochemical properties of the end product. EPI-βCd was more effective than EPI-CMβCd in enhancing the solubility and dissolution properties of ketoprofen. Co-grinding in dry conditions was the best preparation technique of solid drug-Cd systems, allowing obtainment of homogeneous amorphous particles of nanometric range. NLC consisting in a mixture of Compritol® 888 ATO (glyceryl behenate) and Labrafac Lipophile were obtained by ultrasonication. Both empty and loaded NLC were suitably characterized for particle size, pH, entrapment efficiency and drug release behavior. The best (drug-Cd)-loaded NLC system, formulated into a xanthan hydrogel, exhibited drug permeation properties clearly better than those of the plain drug suspension or the plain drug-loaded NLC, in virtue of the simultaneous exploitation of the solubilizing effect of cyclodextrin and the penetration enhancer properties of NLC.
Keywords: Ketoprofen; Nanostructured lipid carriers (NLC); Polymeric cyclodextrins; Hydrogel; Topical formulation
Inhalable dry-emulsion formulation of cyclosporine A with improved anti-inflammatory effects in experimental asthma/COPD-model rats
by Satomi Onoue; Hideyuki Sato; Kumiko Ogawa; Yoshiki Kojo; Yosuke Aoki; Yohei Kawabata; Koichi Wada; Takahiro Mizumoto; Shizuo Yamada (pp. 54-60).
The main purpose of the present study was to develop a novel respirable powder (RP) formulation of cyclosporine A (CsA) using a spray-dried O/W-emulsion (DE) system. DE formulation of CsA (DE/CsA) was prepared by spray-drying a mixture of erythritol and liquid O/W emulsion containing CsA, polyvinylpyrrolidone, and glyceryl monooleate as emulsifying agent. The DE/CsA powders were mixed with lactose carriers to obtain an RP formulation of DE/CsA (DE/CsA-RP), and its physicochemical, pharmacological, and pharmacokinetic properties were evaluated. Spray-dried DE/CsA exhibited significant improvement in dissolution behavior with ca. 4500-fold increase of dissolution rate, and then, nanoemulsified particles were reconstituted with a mean diameter of 317nm. Laser diffraction analysis on the DE/CsA-RP suggested high dispersion of DE/CsA on the surface of the lactose carrier. Anti-inflammatory properties of the inhaled DE/CsA-RP were characterized in antigen-sensitized asthma/COPD-model rats, in which the DE/CsA-RP was more potent than the RP formulation of physical mixture containing CsA and erythritol in inhibiting inflammatory responses, possibly due to the improved dissolution behavior. Pharmacokinetic studies demonstrated that systemic exposure of CsA after intratracheal administration of the DE/CsA-RP at a pharmacologically effective dose (100μg-CsA/rat) was 50-fold less than that of the oral CsA dosage form at a toxic dose (10mg/kg). From these findings, use of inhalable DE formulation of CsA might be a promising approach for the treatment of airway inflammatory diseases with improved pharmacodynamics and lower systemic exposure.
Keywords: Cyclosporine A; Dry-emulsion; Dry powder inhaler; Dissolution; Inflammation
Microencapsulation of citronella oil for mosquito-repellent application: Formulation and in vitro permeation studies
by B. Solomon; F.F. Sahle; T. Gebre-Mariam; K. Asres; R.H.H. Neubert (pp. 61-66).
In-vitro membrane permeability profiles from microencapsulated (ME) and non-encapsulated (NE) VO extracts of Cymbopogon nardus dispersed in various ointment basesCitronella oil (CO) has been reported to possess a mosquito-repellent action. However, its application in topical preparations is limited due to its rapid volatility. The objective of this study was therefore to reduce the rate of evaporation of the oil via microencapsulation. Microcapsules (MCs) were prepared using gelatin simple coacervation method and sodium sulfate (20%) as a coacervating agent. The MCs were hardened with a cross-linking agent, formaldehyde (37%). The effects of three variables, stirring rate, oil loading and the amount of cross-linking agent, on encapsulation efficiency (EE, %) were studied. Response surface methodology was employed to optimize the EE (%), and a polynomial regression model equation was generated. The effect of the amount of cross-linker was insignificant on EE (%). The response surface plot constructed for the polynomial equation provided an optimum area. The MCs under the optimized conditions provided EE of 60%. The optimized MCs were observed to have a sustained in vitro release profile (70% of the content was released at the 10th hour of the study) with minimum initial burst effect. Topical formulations of the microencapsulated oil and non-microencapsulated oil were prepared with different bases, white petrolatum, wool wax alcohol, hydrophilic ointment (USP) and PEG ointment (USP). In vitro membrane permeation of CO from the ointments was evaluated in Franz diffusion cells using cellulose acetate membrane at 32°C, with the receptor compartment containing a water–ethanol solution (50:50). The receptor phase samples were analyzed with GC/MS, using citronellal as a reference standard. The results showed that microencapsulation decreased membrane permeation of the CO by at least 50%. The amount of CO permeated was dependent on the type of ointment base used; PEG base exhibited the highest degree of release. Therefore, microencapsulation reduces membrane permeation of CO while maintaining a constant supply of the oil.
Keywords: Citronella oil; Mosquito repellent; Microencapsulation; Simple coacervation; Membrane permeation
Quality by design approach for developing chitosan-Ca-alginate microspheres for colon delivery of celecoxib-hydroxypropyl-β-cyclodextrin-PVP complex
by N. Mennini; S. Furlanetto; M. Cirri; P. Mura (pp. 67-75).
Response surface plots showing the effect of variations of formulation parameters (% alginate, chitosan (CSL) and calcium chloride and time of cross-linking (TCl)) on entrapment efficiency (EE%) and % drug released at 4h (DR%) of colon-targeted celecoxib microspheres.The aim of the present work was to develop a new multiparticulate system, designed for colon-specific delivery of celecoxib for both systemic (in chronotherapic treatment of arthritis) and local (in prophylaxis of colon carcinogenesis) therapy. The system simultaneously benefits from ternary complexation with hydroxypropyl-β-cyclodextrin and PVP (polyvinylpyrrolidone), to increase drug solubility, and vectorization in chitosan-Ca-alginate microspheres, to exploit the colon-specific carrier properties of these polymers. Statistical experimental design was employed to investigate the combined effect of four formulation variables, i.e., % of alginate, CaCl2, and chitosan and time of cross-linking on microsphere entrapment efficiency (EE%) and drug amount released after 4h in colonic medium, considered as the responses to be optimized. Design of experiment was used in the context of Quality by Design, which requires a multivariate approach for understanding the multifactorial relationships among formulation parameters. Doehlert design allowed for defining a design space, which revealed that variations of the considered factors had in most cases an opposite influence on the responses. Desirability function was used to attain simultaneous optimization of both responses. The desired goals were achieved for both systemic and local use of celecoxib. Experimental values obtained from the optimized formulations were in both cases very close to the predicted values, thus confirming the validity of the generated mathematical model. These results demonstrated the effectiveness of the proposed jointed use of drug cyclodextrin complexation and chitosan-Ca-alginate microsphere vectorization, as well as the usefulness of the multivariate approach for the preparation of colon-targeted celecoxib microspheres with optimized properties.
Keywords: Celecoxib; Cyclodextrin complex; Microspheres; Colon delivery; Chitosan; Ca-alginate
Stability of polylactic acid particles and release of fluorochromes upon topical application on human skin explants
by Fiorenza Rancan; Antonia Todorova; Sabrina Hadam; Dimitrios Papakostas; Elsa Luciani; Christina Graf; Ulrich Gernert; Eckart Rühl; Bernard Verrier; Wolfram Sterry; Ulrike Blume-Peytavi; Annika Vogt (pp. 76-84).
Polylactic acid particles destabilize and release the loaded fluorochrome after topical application of human skin.Particle-based drug delivery systems allow the controlled and targeted release of incorporated active compounds to the skin and are promising tools to improve the efficacy of topical therapies. In this study we investigated the stability and release properties of biodegradable polylactic acid (PLA) particles upon topical application on human skin explants. PLA particles loaded with the hydrophilic fluorochrome 4-Di-2-Asp (DiAsp-PLA) were compared to PLA particles loaded with the lipophilic fluorochrome Bodipy 630/650 (BP-PLA). Changes of the particle morphology after their incubation on skin surface were investigated by means of electron microscopy while fluorescence microscopy and flow cytometry were used to evaluate particle penetration in hair follicles and fluorochrome release. We found that BP-PLA particles released rapidly the loaded fluorochrome and lost the particulate morphology within a few hours after application on skin surface. On the contrary, DiAsp-PLA particles maintained the particulate morphology, accumulated in hair follicles, and allowed a constant release of the incorporated fluorochrome for up to 16h. These results show that, once applied to skin surface, PLA particles release the incorporated fluorochromes in a time-dependent manner and suggest the perspective to modulate particle stability and release properties by incorporating excipients with different degree of lipophilicity.
Keywords: Polylactic acid (PLA); Drug delivery; Particle stability; Skin penetration; Hair follicle targetingAbbreviations; PLA; polylactic acid; DiAsp; 4-(4-diethylaminostyryl)-N-methylpyridinium iodide; BP; bodipy 630/650 methyl bromide; EM; electron microscopy; SEM; scanning electron microscopy; TEM; transmission electron microscopy; HFs; hair follicles; MFI; mean fluorescence intensity
Bioburden-responsive antimicrobial PLGA ultrafine fibers for wound healing
by Somiraa S. Said; Omar M. El-Halfawy; Hanan M. El-Gowelli; Affaf K. Aloufy; Nabila A. Boraei; Labiba K. El-Khordagui (pp. 85-94).
Polymer-based bioburden-responsive drug release enhancement of antimicrobial PLGA ultrafine fibers in relation to bioburden, esterase activity, and effective healing of lightly contaminated and heavily infected wounds in rats.Despite innovation in the design and functionalization of polymer nanofiber wound healing materials, information on their interaction with the biochemical wound environment is lacking. In an earlier study, we have reported the interaction of fusidic acid-loaded PLGA ultrafine fibers (UFs) with wound bacteria. Massive bacterial colonization and the formation of a dense biofilm throughout the mat were demonstrated. This was associated with a marked enhancement of initial drug release at concentrations allowing eradication of planktonic bacteria and considerable suppression of biofilm. The present study aimed at extending earlier findings to gain more mechanistic insights into the potential response of the fusidic acid-laden UFs under study to controlled microbial bioburden. Initial drug release enhancement was shown to involve surface erosion of the ultrafibrous mats likely mediated by microbial esterase activity determined in the study. Release data could be correlated with microbial bioburden over the inoculum size range 103–107CFU/ml, suggesting a bioburden-triggered drug release enhancement mechanism. Moreover, the effectiveness of fusidic acid-laden UFs in the healing of either lightly contaminated or Staphylococcus aureus heavily infected wounds in a rat model suggested in-use relevant antimicrobial release patterns. Findings indicated active participation of polymer ultrafine wound dressings in a dynamic interaction with the wound milieu, which affects their structure–function relationship. Understanding such an interaction is fundamental to the characterization and performance assessment of wound materials under biorelevant conditions and the design of polymer-based infection-responsive biomaterials.
Keywords: Bioburden-responsive; Release; Enzymes; Ultrafine fibers; Wound healing; PLGA
Thiolated chitosan: Development and in vivo evaluation of an oral delivery system for leuprolide
by Javed Iqbal; Gul Shahnaz; Glen Perera; Fabian Hintzen; Federica Sarti; Andreas Bernkop-Schnürch (pp. 95-102).
Enhanced absorption of leuprolide in the presence of chitosan-thioglycolic acid (chitosan-TGA)/reduced glutathione (GSH) (▴).The aim of the present study was to develop an oral delivery system for the peptide drug leuprolide. Gel formulations based on unmodified chitosan/reduced glutathione (GSH) and chitosan–thioglycolic acid (chitosan–TGA)/GSH were prepared, and their effect on the absorption of leuprolide was evaluated in vitro and in vivo in male Sprague Dawley rats. Transport studies were performed with freshly excised rat intestinal mucosa mounted in Ussing-type chambers. Due to the addition of gel formulations comprising 0.5% (m/v) unmodified chitosan/0.5% (m/v) GSH and 0.5% (m/v) chitosan–TGA/0.5% (m/v) GSH, the transport of leuprolide across excised mucosa was improved up to 2.06-fold and 3.79-fold, respectively, in comparison with leuprolide applied in buffer ( Papp=2.87±0.77×10−6cm/s).In vivo, the addition of oral gel formulation comprising 8mg of unmodified chitosan, 1mg of GSH and 1mg of leuprolide increased the area under the plasma concentration–time curve (AUC0–8) of leuprolide 1.39-fold in comparison with leuprolide having been administered just in saline. Moreover, the administration of oral gel formulation comprising 8mg of chitosan–TGA, 1mg of GSH and 1mg of leuprolide resulted in a further enhanced leuprolide plasma concentration, and the area under the plasma concentration–time curve (AUC0–8) of leuprolide was increased 3.72-fold in comparison with the control. With the oral gel formulation comprising 8mg of chitosan–TGA, a relative bioavailability (versus s.c. injection) of 4.5% was achieved in contrast to the control displaying a relative bioavailability of 1.2%. Thus, according to the achieved results, it is suggested that chitosan–TGA in combination with GSH is a valuable tool for improving the oral bioavailability of the peptide drug leuprolide.
Keywords: Thiomers; Chitosan–TGA; Leuprolide; Tight junctions; Oral drug delivery
Syringeable Pluronic–α-cyclodextrin supramolecular gels for sustained delivery of vancomycin
by S.M.N. Simões; F. Veiga; J.J. Torres-Labandeira; A.C.F. Ribeiro; M.I. Sandez-Macho; A. Concheiro; C. Alvarez-Lorenzo (pp. 103-112).
Mixtures of 6.5-13% Pluronic F127 with α-cyclodextrin at concentrations above 5% result in supramolecular viscoelastic and thixotropic injectable gels that are able to control antimicrobial drug release.The ability of Pluronic® F127 to form supramolecular gels in the presence of αCD has been explored as a way to design syringeable gel formulations able to sustain drug release while using the lowest proportion of both components. The effects of αCD concentration range (0–9.7%w/v) in copolymer (6.5%, 13% and 20%) gel features were evaluated at 4, 20 and 37°C. An effective complexation of Pluronic and αCD was evidenced as a change in the surface pressure of the π-A isotherm of Pluronic on a subphase of CD solution and the apparition of new peaks in the X-ray spectra. Once the Pluronic and αCD solutions were mixed, the systems became progressively turbid solutions or white gels. The greater the αCD concentration was, the faster the gel formation. The supramolecular hydrogels were thixotropic and those containing 5% or more αCD had G′ values above G″ at room temperature, but they were still easily syringeable. The values of both moduli increased as temperature raised; the effect being more evident for 13% and 20%w/v copolymer. The gels prepared with low proportions of αCD exhibited phase separation in few days, particularly when stored at 4 or 37°C. By contrast, those prepared with 6.5% copolymer were stable for at least two months when stored at 20°C. The gels were able to sustain vancomycin release for several days; the higher the αCD proportion, the slower the release was. Furthermore, the drug-loaded gels showed activity against Staphylococcus aureus. The results obtained highlight the role of the αCD concentration on the tuning of the rheological features and drug release profiles from Pluronic gels.
Keywords: In situ; gelling; Polypseudorotaxanes; Supramolecular drug delivery systems; Physical stability; Antibacterial activity; Syringeable implants
Fabrication of quercetin nanocrystals: Comparison of different methods
by Mitali Kakran; Ranjita Shegokar; Nanda Gopal Sahoo; Loaye Al Shaal; Lin Li; Rainer H. Müller (pp. 113-121).
The main aim of this study was to prepare quercetin nanocrystals using three fabrication methods, viz . high-pressure homogenization, bead milling, and cavi-precipitation. The three fabrication methods were compared in terms of particle size, saturation solubility, and dissolution of the products obtained. The average particle size of the coarse quercetin was 50.1μm. The three methods produced quercetin particles in the nanometre range (276–787nm) and the smallest nanocrystals of around 276.7nm were fabricated by bead milling. The particle size, polydispersity index, zeta potential, and saturation solubility values for the products fabricated by both high-pressure homogenization and bead mill were similar and thus both represented an efficient means to fabricate quercetin nanosuspensions. According to X-ray diffraction analysis, all nanocrystals were still in the crystalline state after being fabricated by the three methods. The cavi-precipitated product exhibited larger particle size and did not show an optimum stability as suggested by the zeta potential values. However, cavi-precipitated quercetin nanosuspension showed the higher saturation solubility due to the presence of ethanol. The bead milled products with the lowest particle size exhibited a saturation solubility of 25.59±1.11μg/ml, approximately nine times higher than coarse quercetin. Overall, the dissolution rates of the quercetin nanosuspensions fabricated by these three methods enhanced compared to the coarse quercetin.
Keywords: Quercetin; Nanosuspension; High-pressure homogenization; Bead mill; Cavi-precipitation; Saturation solubility
Drug release from extruded solid lipid matrices: Theoretical predictions and independent experiments
by Sinan Güres; Florence Siepmann; Juergen Siepmann; Peter Kleinebudde (pp. 122-129).
The diffusion coefficient of diprophylline was determined from dissolution curves of 1 mm extrudates. By using the diffuxion coefficient the release from extrudates of varying dimensions could be predicted successfully.The aim of this study was to use a mechanistically realistic mathematical model based on Fick‘s second law to quantitatively predict the release profiles from solid lipid extrudates consisting of a ternary matrix. Diprophylline was studied as a freely water-soluble model drug, glycerol tristearate as a matrix former and polyethylene glycol or crospovidone as a pore former (blend ratio: 50:45:5%w/w/w). The choice of these ratios is based on former studies. Strains with a diameter of 0.6, 1, 1.5, 2.7 and 3.5mm were prepared using a twin-screw extruder at 65°C and cut into cylinders of varying lengths. Drug release in demineralised water was measured using the USP 32 basket apparatus. Based on SEM pictures of extrudates before and after exposure to the release medium as well as on DSC measurements and visual observations, an analytical solution of Fick’s second law of diffusion was identified in order to quantify the resulting diprophylline release kinetics from the systems. Fitting the model to one set of experimentally determined diprophylline release kinetics from PEG containing extrudates allowed determining the apparent diffusion coefficient of this drug (or water) in this lipid matrix. Knowing this value, the impact of the dimensions of the cylinders on drug release could be quantitatively predicted. Importantly, these theoretical predictions could be confirmed by independent experimental results. Thus, diffusion is the dominant mass transport mechanism controlling drug release in this type of advanced drug delivery systems. In contrast, theoretical predictions of the impact of the device dimensions in the case of crospovidone containing extrudates significantly underestimated the real diprophylline release rates. This could be attributed to the disintegration of this type of dosage forms when exceeding a specific minimal device diameter. Thus, mathematical modelling can potentially significantly speed up the development of solid lipid extrudates, but care has to be taken that none of the assumptions the mathematical theory is based on is violated.
Keywords: Solid lipid extrusion; Release mechanism; Diffusion; Mathematical modelling; Pore former; Extrudate diameter
Enhancement of griseofulvin release from liquisolid compacts
by C.M. Hentzschel; M. Alnaief; I. Smirnova; A. Sakmann; C.S. Leopold (pp. 130-135).
Griseofulvin release from conventional tablets, silica aerogel tablets, and various liquisolid compacts.The potential of hydrophilic aerogel formulations and liquisolid systems to improve the release of poorly soluble drugs was investigated using griseofulvin as model drug. The in vitro release rates of this drug formulated as directly compressed tablets containing crystalline griseofulvin were compared to aerogel tablets with the drug adsorbed onto hydrophilic silica aerogel and to liquisolid compacts containing the drug dissolved or suspended in PEG 300. Furthermore, the commonly used carrier and coating materials in liquisolid systems Avicel® and Aerosil® were replaced by Neusilin®, an amorphous magnesium aluminometasilicate with an extremely high specific surface area of 339m2/g to improve the liquisolid approach.Both the liquisolid compacts containing the drug dissolved in PEG 300 and the aerogel tablets showed a considerably faster drug release than the directly compressed tablets. With liquisolid compacts containing the drug suspended in PEG 300, the release rate increased with rising fraction of dissolved drug in the liquid portion. It could be shown that Neusilin® with its sevenfold higher liquid adsorption capacity than the commonly used Avicel® and Aerosil® allows the production of liquisolid formulations with lower tablet weights.
Keywords: Abbreviations; BCS; biopharmaceutics classification system; SEDDS; self-emulsifying drug delivery system; PEG; polyethylene glycol; RH; relative humidity; LS; liquisolid; RESS; rapid expansion from supercritical solutionsRelease enhancement; Liquisolid compact; Silica aerogel; Griseofulvin; Poor solubility; Neusilin
Study of the critical points and the role of the pores and viscosity in carbamazepine hydrophilic matrix tablets
by Ángela Aguilar-de-Leyva; Celia Cifuentes; Ali R. Rajabi-Siahboomi; Isidoro Caraballo (pp. 136-142).
The figure shows that when low percentages as 15% of HPMC are employedin hydrophilic matrices manufactured with different viscosity grades of HPMC and different initial porosity levels, the porosity of the matrices exert much more influence in the drug release rate than the polymer viscosity.Percolation theory has been applied to estimate the Hypromellose (HPMC) percolation thresholds and the influence of the polymer viscosity and the initial porosity on these thresholds in carbamazepine multicomponent matrix formulations.Different batches containing two viscosity grades of HPMC as hydrophilic matrix forming polymer, MCC and lactose as fillers, and a lubricant mixture have been manufactured varying the compression pressure in order to obtain matrices with three levels of initial porosity. The results suggested the existence of an excipient percolation threshold between 13 and 15% v/v of HPMC for the different batches prepared. It has been found that the percolation threshold for this polymer is independent on the formulation factors studied in this paper: polymer viscosity and initial porosity of the matrices.
Keywords: Hydroxypropylmethyl cellulose; Hydrophilic matrices; Carbamazepine; Tablet porosity; Percolation threshold; extended release
The influence of degree-of-branching and molecular mass on the interaction between dextran and Concanavalin A in hydrogel preparations intended for insulin release
by Ian Benzeval; Adrian Bowyer; John Hubble (pp. 143-148).
Strength of interaction between dextran and Concanavalin A and NMR spectra of dextran and maltotriose. Together, data shows that a two-site binding model is most applicable.The interactions of a number of commercially available dextran preparations with the lectin Concanavalin A (ConA) have been investigated. Dextrans over the molecular mass range 6×103–2×106gmol−1 were initially characterised in terms of their branching and hence terminal ligand density, using NMR. This showed a range of branching ratios between 3% and 5%, but no clear correlation with molecular mass.The bio-specific interaction of these materials with ConA was investigated using microcalorimetry. The data obtained were interpreted using a number of possible binding models reflecting the known structure of both dextran and the lectin.The results of this analysis suggest that the interaction is most appropriately described in terms of a two-site model. This offers the best compromise for the observed relationship between data and model predictions and the number of parameters used based on the chi-squared values obtained from a nonlinear least-squares fitting procedure. A two-site model is also supported by analysis of the respective sizes of the dextrans and the ConA tetramer.Using this model, the relationship between association constants, binding energy and molecular mass was determined.
Keywords: Dextran; Hydrogel; Branching; Insulin; Concanavalin
Thermal ink-jet spray freeze-drying for preparation of excipient-free salbutamol sulphate for inhalation
by Wunlapa Mueannoom; Amon Srisongphan; Kevin M.G. Taylor; Stephan Hauschild; Simon Gaisford (pp. 149-155).
Salbutamol sulphate particles prepared with thermal ink-jetting spray freeze-drying (TIJ-SFD), left, and spray drying, right.The use of thermal ink-jet spray freeze-drying (TIJ-SFD) to engineer inhalable, excipient-free salbutamol sulphate (SS) particles was assessed. A modified Hewlett-Packard printer was used to atomise aqueous SS solutions into liquid nitrogen. The frozen droplets were freeze-dried. It was found that TIJ-SFD could process SS solutions up to 15%w/v; the porous particles produced had a physical diameter of ca. 35μm. Next generation impactor (NGI) analysis indicated that the particles had a smaller aerodynamic size (MMAD ranging from 6 to 8.7μm). Particles prepared from the lowest concentration SS solution were too fragile to withstand aerosolisation, but the 5%w/v solution yielded particles having the best combination of strength and aerodynamic properties. Comparison with a commercial SS formulation (Cyclocap®) showed that the SFD preparation had an almost equivalent FPF6.4μm when analysed with a twin-stage impinger (TSI; 24.0±1.2% and 26.4±2.2%, respectively) and good performance when analysed with NGI (FPF4.46μm:16.5±2.0 and 27.7±1.7, respectively). TIJ-SFD appears to be an excellent method to prepare inhalable particles. It is scalable yet allows assessment of the viability of the pulmonary route early in the development since it can be used with very small volumes (<0.5mL) of solution.
Keywords: Thermal ink-jet; Spray freeze-drying; Salbutamol sulphate; Dry powder inhaler; Excipient-free; Porous particles
Development of a novel model for comparative evaluation of intranasal pharmacokinetics and effects of anti-allergic nasal sprays
by Daniel Baumann; Claus Bachert; Petra Högger (pp. 156-163).
Human respiratory tissue embedded into a solid matrix coated with artificial nasal fluid served as a new model for comparing tissue binding and anti-inflammatory activity of fluticasone propionate, budesonide and azelastine hydrochloride from commercially available nasal sprays.For locally acting drugs, an extended residence time in the nasal cavity is desirable and related to a prolonged effect. We sought to develop a model for comparative determination of intranasal pharmacokinetics. We embedded human respiratory tissue into a solid matrix and coated the surface with artificial nasal fluid. Nasal spray suspensions of fluticasone propionate (FP) and budesonide (Bud) as well as a solution of azelastine hydrochloride (AZ) were applied onto the surface and removed after 30min to simulate mucociliary clearance. As exemplary anti-inflammatory measure, we evaluated the inhibition of IL-8 release from epithelial cells. FP and Bud were initially bound to the same extent to the tissue gel while AZ displayed a more 4-fold higher binding than FP or Bud. After equilibrium with plasma, approximately 5-fold higher tissue concentrations of AZ compared to FP and 77-fold higher levels in relation to Bud were determined. This tissue retention revealed an excellent correlation with the volume of distribution of the respective drugs ( r=0.9999, p⩽0.05). The inhibitory effect of FP on IL-8 release was approximately 5-fold more pronounced compared to AZ. The present model realistically mirrors conditions in vivo where solubility and tissue absorption of intranasally applied drugs compete with mucociliary clearance mechanisms.
Keywords: Fluticasone propionate; Budesonide; Azelastine; Tissue retention; Nasal spray; IL-8
Compounding of a topical drug with prospective natural surfactant-stabilized pharmaceutical bases: Physicochemical and in vitro/ in vivo characterization – A ketoprofen case study
by Ivana Jaksic; Milica Lukic; Andjelija Malenovic; Stephan Reichl; Christine Hoffmann; Christel Müller-Goymann; Rolf Daniels; Snezana Savic (pp. 164-175).
Alkyl polyglucoside stabilized bases as prospective ready-to-use vehicles in pharmaceutical compounding vs. traditional pharmacopoeial ones: in vivo skin absorption assessment through tape stripping method.Recently, healthcare professionals again began realizing the benefits of preparing customized medications to meet specific patient needs. The objective of this work was to develop and evaluate simple pharmaceutical bases stabilized with natural-origin surfactant of alkyl polyglucoside (APG) type as prospective ready-to-use bases and compare them to widely used pharmacopoeial ones. Additionally, the ability of the formulated bases to sustain isopropyl alcohol was assessed as well as its influence on ketoprofen skin absorption (as a co-solvent and potential penetration enhancer). In order to evaluate the manifold characteristics a topical drug product should possess, a comprehensive characterization was performed using different techniques.Physicochemical characterization demonstrated satisfactory physical stability of APG-stabilized bases upon the addition of alcohol. In vitro release/permeation studies failed to show significant difference in ketoprofen liberation/permeation profiles from different bases. However, the extent of ketoprofen delivery in vivo was clearly increased from APG bases, relative to that obtained from pharmacopoeia quality one, implying a distinct influence of the emulsion systems’ colloidal structures. Taking also into account the rheological behavior of APG bases, revealing their ameliorated sensory characteristics, it could be concluded that the investigated APG bases could be considered as preferential option in drug compounding related to the conventional ones.
Keywords: Alkyl polyglucosides; Ketoprofen; Ready-to-use bases; Isopropyl alcohol; Tape stripping; Skin performance
Red grape skin and seeds polyphenols: Evidence of their protective effects on endothelial progenitor cells and improvement of their intestinal absorption
by Francesca Felice; Ylenia Zambito; Giacomo Di Colo; Claudio D’Onofrio; Catia Fausto; Alberto Balbarini; Rossella Di Stefano (pp. 176-184).
The use of chitosan derivates can promote the absorption of polyphenols across the intestinal epithelium, to guarantee their bioavailability and hence their potential therapeutic value in atherosclerosis.To evaluate the ability of grape skin and seeds to protect endothelial progenitor cells (EPC) from oxidative stress induced by hyperglycemia (HG) compared to red wine (RW) and prepare innovative pharmaceutical systems for the oral administration of red grape extract allowing the overcoming of its poor intestinal absorption.Human EPC were characterized by expression of cell surface markers. Cells were incubated with different concentrations of total polyphenols from grape components or RW in the presence or absence of HG. Cell viability, migration, adhesion, and reactive oxygen species (ROS) production were assayed. Intestinal permeation of polyphenols was studied in the absence or presence of a quaternary ammonium-chitosan conjugate (N+(60)-Ch). Grape components and RW increased EPC viability, adhesion and migration, and prevented the HG effect ( P<0.01). ROS production induced by HG was significantly reduced only by grape seed extract and RW ( P<0.01). N+(60)-Ch acted as an effective enhancer of polyphenol permeability across the excised rat intestine.Red grape components are a source of antioxidant compounds that ameliorate EPC viability and function, while preventing endothelial dysfunction. The use of polycationic chitosan derivatives can promote the absorption of polyphenols across intestinal epithelium, thus increasing their bioavailability and potential therapeutic value in atherosclerosis.
Keywords: Abbreviations; Ch; chitosan; CHD; coronary heart disease; CVD; cardiovascular diseases; DS; degree of substitution of N; +; -Ch by pendant chains; eNOS; endothelial nitric oxide synthase; EPC; endothelial progenitor cells; GS; grape seed; GSE; grape seed extract; n; mean number of quaternary ammonium groups in N; +; -Ch pendant chains; N; +; -Ch; quaternary ammonium-chitosan conjugates; N; +; (60)-Ch; N; +; -Ch with DS; =; 60%,; n; =; 1.7; Ox-LDL; oxidized low-density lipoproteins; PBMC; peripheral blood mononuclear cells; ROS; reactive oxygen species; RW; red wine; S; grape skin; SE; grape skin extract; SMCs; smooth muscle cells; TMC; N-trimethylchitosan; VE-Cad; VE-cadherin; VEGF; vascular endothelial grow factor; vWF; vonWillebrand factor; WST-1; 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolium]-1,3-benzene disulfonate; KDR; vascular endothelial grow factor receptor 2Chitosan; Endothelial progenitor cells; Red grape skin and seed; Red wine
Effect of surface coating on the biodistribution profile of gold nanoparticles in the rat
by Tiago Morais; Maria Elisa Soares; José Alberto Duarte; Leonor Soares; Sílvia Maia; Paula Gomes; Eulália Pereira; Sónia Fraga; Helena Carmo; Maria de Lourdes Bastos (pp. 185-193).
The kinetic and biodistribution profile of citrate-, 11-MUA- and pentapeptide-coated gold nanoparticles (AuNPs) intravenously injected in the rat was evaluated based on the gold (Au) content measured by Graphite Furnace Atomic Absorption Spectrometry (GFAAS).All the tested AuNPs were rapidly distributed in the organism and the liver was the preferential organ for accumulation. Peptide capping significantly increased the hepatic uptake of AuNPs. In the liver, AuNPs are located both in hepatocytes and Kupffer cells, inside endosomes.Successful application of gold nanoparticles (AuNPs) in biomedicine requires extensive safety assessment for which biokinetic studies are crucial.We evaluated the biodistribution of AuNPs (∼20nm) with different surface coatings: citrate, 11-MUA and 3 pentapeptides, CALNN, CALND and CALNS, after i.v. administration to rats (0.6–1mg Au/kg). Biodistribution was evaluated based on Au tissue content measured by GFAAS.Citrate-AuNPs were rapidly removed from circulation with 60% of the injected dose depositing in the liver. Thirty minutes post-injection, the lungs presented about 6% of the injected dose with levels decreasing to 0.7% at 24h. Gold levels in the spleen were of 2.6%. After 24h, liver presented the highest Au level, followed by spleen and blood.A similar biodistribution profile was observed for MUA-coated AuNPs compared to Cit-AuNPs at 24h post-injection, while significantly higher levels of peptide-capped AuNPs were found in the liver (74–86%) accompanied by a corresponding decrease in blood levels.TEM analysis of liver slices showed AuNPs in Kupffer cells and hepatocytes, trapped inside endosomes.Our data demonstrate that AuNPs are rapidly distributed and that the liver is the preferential accumulation organ. Peptide capping significantly increased hepatic uptake, showing the influence of AuNPs functionalization in biodistribution.
Keywords: Abbreviations; 11-MUA; 11-mercaptoundecanoic acid; Au; gold; AuNPs; gold nanoparticles; CALND; Cys-Ala-Leu-Asn-Asp; CALNN; Cys-Ala-Leu-Asn-Asn; CALNS; Cys-Ala-Leu-Asn-Ser; DLS; Dynamic Light Scattering; i.p.; intraperitoneal; i.v.; intravenous; GFAAS; Graphite Furnace Atomic Absorption Spectrometry; NPs; nanoparticles; PEG; polyethylene glycol; RES; reticuloendothelial system; SEM; standard error of the mean; TEM; transmission electron microscopy; XPS; photoelectron spectroscopyAuNPs; Functionalization; Biodistribution; GFAAS; Intravenous injection; Rat
Preparation and solid-state characterization of ball milled saquinavir mesylate for solubility enhancement
by Michael Lee Branham; Thomas Moyo; Thirumala Govender (pp. 194-202).
A method for inproving the aqueous solubility of saquinavir mesylate using high-energy ball milling is described. Surface area, pore volume, and pore size were each affected by the duration of milling time. Maximum solubility enhancement was observed within 3h. Ball milling of the drug up to 60h produced no measureable degradation or evidence of contamination of the drug due stainless steel milling jars or balls.Saquinavir is an anti-retroviral drug with very low oral bioavailability (e.g. 0.7–4.0%) due to its affinity toward efflux transporters (P-gp) and metabolic enzymes (CYP3A4). The aim of this study was to characterize the effects of high-energy ball milling on saquinavir solid-state characteristics and aqueous solubility for the design of effective buccal drug delivery systems. The solubility of saquinavir mesylate was evaluated in simulated saliva before and after milling for 1, 3, 15, 30, 50, and 60h. To elucidate changes in crystallinity and long-range structure in the drug, analyses of the milled powders were performed using XRD, ATR-IR, DSC/TGA, BET surface area, EDX and SEM. In addition, the effects of milling time on saquinavir solubility were statistically correlated using repeated measures ANOVA. Results of this study indicate that the milling of saquinavir mesylate produces nanoporous particles with unique surface structures, thermal properties, and increased aqueous solubility. Optimal milling time occurred at 3h and corresponded to a 9-fold solubility enhancement in simulated saliva. Thermal analysis revealed only a slight decrease in melting point ( Tm) from 242°C to 236°C after 60h milling. XRD diffractograms indicate a gradual crystalline-to-amorphous transition with some residual crystallinity remaining after 60h milling time. Unstable polymorphic structures appeared between 15 and 30h which were converted to more stable isomorphs at 60h. Aggregate formation also seems to occur after 15h but no metal contamination of the drug was observed during the milling process as determined by EDX analysis. In conclusion, high-energy ball milling may be a method of choice for improving the solubility of saquinavir and facilitating novel drug formulations design.
Keywords: Saquinavir; Solubility enhancement; Ball milling; Solid-state characterization; Nanosizing; Drug delivery
Thermal degradation of amorphous glibenclamide
by Sönke Rehder; Albrecht Sakmann; Thomas Rades; Claudia S. Leopold (pp. 203-208).
In 2000, a new glibenclamide polymorph (form IV), obtained by sublimation from the amorphous state, was introduced. Analysis of the substance using various techniques led to the conclusion that the sublimate is not a glibenclamide polymorph, but a thermal degradation product, namely 1,3-dicyclohexylurea.A glibenclamide polymorph published by Panagopoulou-Kaplani and Malamataris (2000) , obtained by sublimation of amorphous glibenclamide, was analysed. A new interpretation of the data is presented and experimentally confirmed by X-ray powder diffractometry, Fourier transformation infrared spectroscopy, differential scanning calorimetry, and mass spectrometry. The crystals formed during sublimation of amorphous glibenclamide do not represent a glibenclamide polymorph, but a thermal degradation product, namely 1,3-dicyclohexylurea. The reaction mechanism is suggested to be an elimination of cyclohexylisocyanate from glibenclamide. Cyclohexylisocyanate may decompose to carbon monoxide and cyclohexylamine, which may react in an addition reaction with another cyclohexylisocyanate molecule forming 1,3-dicyclohexylurea.
Keywords: Glibenclamide; Polymorphism; Thermal degradation; 1,3-Dicyclohexylurea; Amorphous
A protocol for the classification of powder compression characteristics
by Josefina Nordström; Ingvild Klevan; Göran Alderborn (pp. 209-216).
Protocol for powder compression analysis as a test to identify functionality-related characteristics of particles in a formulation development programme.In this paper, a structured protocol for powder compression analysis as a test to assess the mechanical properties of particles in a formulation development programme is presented. First, the sequence of classification steps of the protocol is described, and secondly, the protocol is illustrated using compression data of six powders of two model substances, sodium chloride and mannitol. From powder compression data, a set of compression variables are derived, and by using critical values of these variables, the stages expressed during the compression of the powders are identified and the powders are classified into groups with respect to the expression of particle rearrangement, particle fragmentation and particle plastic deformation during compression. It is concluded that the proposed protocol could, in a satisfactorily way, describe and distinguish between the powders regarding their compression behaviour. Hence, the protocol could be a valuable tool for the formulation scientist to comprehensively assess important functionality-related characteristics of drugs and excipients.
Keywords: Classification system; Compression parameters; Heckel; Kawakita; Particle mechanical properties; Powder compression
Addressing potent single molecule AFM study in prediction of swelling and dissolution rate in polymer matrix tablets
by Biljana Govedarica; Tamás Sovány; Klara Pintye-Hódi; Miha Škarabot; Saša Baumgartner; Igor Muševič; Stane Srčič (pp. 217-225).
Prediction of the dissolution rate of polymer matrix tablets (bulk property) in media of various pH and ionic strengths according to the single molecules and polymer films properties determined by AFM.Our goal was to understand and thus be able to predict the swelling behavior of xanthan matrix tablets in media of various pH and ionic strengths using data obtained from single xanthan molecules and films with atomic force microscopy.Imaging was performed in 1-butanol using contact mode AFM in order to characterize single xanthan chains prepared from various solutions. Image analysis was used to calculate the molecular contour, persistence length, and radius of gyration. Nanoindentation measurements of xanthan films were carried out to evaluate their mechanical properties. Increasing the ionic strength of solutions induced reductions in chain parameters such as molecular contour, persistence length, and radius of gyration. Nanomechanical measurements demonstrated that Young’s moduli of xanthan films prepared from solutions with higher ionic strengths are twice as large as those prepared at lower ionic strengths. This may help explain xanthan matrix tablets’ reduced degree of swelling and faster dissolution rate in the presence of salts or ions. We successfully come to conclusion that microscopic polymer properties such as radius of gyration and persistence length are responsible for the macroscopic polymer behavior. For instance, longer persistence lengths and radius of gyration of xanthan’s chains result in a higher degree of swelling, corresponding to softer polymer films, increased gel layers in matrix, and a slower release rate of the incorporated drug from the tablets.
Keywords: Abbreviations; CRT; controlled-release technology; Xan; xanthan; AFM; atomic force microscopyAFM; Xanthan; Single molecule; Nanoindentation; Matrix tablets; Swelling
Design space approach in the optimization of the spray-drying process
by Pierre Lebrun; Fabrice Krier; Jérôme Mantanus; Holger Grohganz; Mingshi Yang; Eric Rozet; Bruno Boulanger; Brigitte Evrard; Jukka Rantanen; Philippe Hubert (pp. 226-234).
Design Space representation of the spray-drying process under study.Display Omitted► The aim was to identify the Design Space of a spray-drying process. ► Design Space is defined on the basis of a predictive risk-based methodology. ► It has allowed the setup of optimal values for three critical process parameters. ► Capability of the process has been tested with a validation study.From a quality by design perspective, the aim of the present study was to demonstrate the applicability of a Bayesian statistical methodology to identify the Design Space (DS) of a spray-drying process. Following the ICH Q8 guideline, the DS is defined as the “multidimensional combination and interaction of input variables (e.g., materials attributes) and process parameters that have been demonstrated to provide assurance of quality.” Thus, a predictive risk-based approach was set up in order to account for the uncertainties and correlations found in the process and in the derived critical quality attributes such as the yield, the moisture content, the inhalable fraction of powder, the compressibility index, and the Hausner ratio. This allowed quantifying the guarantees and the risks to observe whether the process shall run according to specifications. These specifications describe satisfactory quality outputs and were defined a priori given safety, efficiency, and economical reasons. Within the identified DS, validation of the optimal condition was effectuated. The optimized process was shown to perform as expected, providing a product for which the quality is built in by the design and controlled setup of the equipment, regarding identified critical process parameters: the inlet temperature, the feed rate, and the spray flow rate.
Keywords: Spray-drying; Design of experiments; Quality by design; Risk-based design space; Critical quality attributes; Specifications
Nanocapsules prepared via nanoprecipitation and emulsification–diffusion methods: Comparative study
by Claudia Elizabeth Mora-Huertas; Olivier Garrigues; Hatem Fessi; Abdelhamid Elaissari (pp. 235-239).
The effect of the used oil and the preparation method on the nanocapsules prepared via nanoprecipitation and via emulsification-diffusion. The colloidal stability of the final dispersions, drug location and the drug release are preparation method dependent.The encapsulation of hydrophobic drugs has been widely investigated using mainly oil phase in order to enhance the encapsulation efficiency. However, the effect of the starting materials on the colloidal properties of the final nanocapsules irrespective of the elaboration process has been neglected, and the hydrophobic drug location in the disperse media has not been completely elucidated. Therefore, this paper describes the effect of the oil used in the recipe and the preparation method on the behavior of nanocapsules prepared via nanoprecipitation and via emulsification–diffusion. The colloidal stability of the final dispersions, drug location and the drug release are preparation method dependent. In turn, the type of oil governs drug encapsulation efficiency regardless of the method and the size when nanocapsules are prepared by nanoprecipitation.
Keywords: Nanocapsule; Nanoparticle; Diclofenac; Oil; Nanoprecipitation; Emulsification–diffusion