International Journal of Pharmaceutics (v.388, #1-2)
Editorial Board (iii).
The interplay of membrane formation and drug release in solution-cast films of polylactide polymers by Decheng Ma; Anthony J. McHugh (1-12).
The interplay of phase inversion and drug release has been studied for films of several biodegradable polylactide polymers cast from solutions containing polymer, solvent, and drug (naproxen). Variables studied included polymer type and concentration, solvent type, and film casting conditions (i.e. free or forced convection, humidity). Film morphologies and thermal properties indicate that reduction of the T g of the amorphous poly (lactide-co-glycolide) (PLGA) and poly (d, l-lactide) (PDLLA) systems caused by the drug, inhibits stabilization of a porous, structure, regardless of dry casting conditions and drug loads. Porous membranes could be formed by wet casting; however, drug loss during casting, makes this a non-viable process. For semi-crystalline PLLA, membrane morphologies could be varied by controlling the mass transfer path to form a single-phase dense film by polymer crystallization or a liquid–liquid two-phase structure followed by locking-in by polymer crystallization. However, the lack of drug solubility in the crystalline phase leads to unfavorable drug distributions most often leading to a burst release. Release profiles for all three polymers were found to follow a two-stage release model, with a first stage diffusive release followed by zero-order release in the second stage due to polymer erosion.
Keywords: Membrane; Phase inversion; Controlled release; Biodegradable; Drug delivery;
A skin permeability model of insulin in the presence of chemical penetration enhancer by K.M. Yerramsetty; B.J. Neely; S.V. Madihally; K.A.M. Gasem (13-23).
Enhancing transdermal delivery of insulin using chemical penetration enhancers (CPEs) has several advantages over other non-traditional methods; however, lack of suitable predictive models, make experimentation the only alternative for discovering new CPEs. To address this limitation, a quantitative structure–property relationship (QSPR) model was developed, for predicting insulin permeation in the presence of CPEs. A virtual design algorithm that incorporates QSPR models for predicting CPE properties was used to identify 48 potential CPEs. Permeation experiments using Franz diffusion cells and resistance experiments were performed to quantify the effect of CPEs on insulin permeability and skin structure, respectively. Of the 48 CPEs, 35 were used for training and 13 were used for validation. In addition, 12 CPEs reported in literature were also included in the validation set. Differential evolution (DE) was coupled with artificial neural networks (ANNs) to develop the non-linear QSPR models. The six-descriptor model had a 16% absolute average deviation (%AAD) in the training set and 4 misclassifications in the validation set. Five of the six descriptors were found to be statistically significant after sensitivity analyses. The results suggest, molecules with low dipoles that are capable of forming intermolecular bonds with skin lipid bi-layers show promise as effective insulin-specific CPEs.
Keywords: Transdermal; Quantitative structure–property relationship; Chemical penetration enhancer; Permeability;
Transdermal iontophoretic delivery of terbinafine hydrochloride: Quantitation of drug levels in stratum corneum and underlying skin by Vishal Sachdeva; Srujana Siddoju; Yi-Ying Yu; Hyun D. Kim; Phillip M. Friden; Ajay K. Banga (24-31).
The objective of this study was to determine the effect of iontophoresis on the delivery of terbinafine hydrochloride (4%, w/w) into and across hairless rat skin. In vitro skin uptake and permeation studies were performed using Franz diffusion cells. Anodal iontophoresis was applied for 1 h at current densities of 0.2, 0.3 and 0.4 mA/cm2. In addition, iontophoresis was applied for 15, 30, 45 and 60 min. Studies were conducted in which the formulation was either removed or left in contact with the skin following iontophoresis and then passive delivery was assessed 23 h later. Tape stripping and skin extraction were performed to quantify drug levels in the stratum corneum and the underlying skin, respectively. The samples were analyzed using HPLC. The amount of drug delivered into the stratum corneum following iontophoresis was not significantly different from the amount delivered passively (p > 0.05). However, drug levels in the underlying skin were significantly higher for the iontophoretic group. The amount of terbinafine delivered into the skin layers was influenced by current density and duration of current application. Leaving the drug formulation in contact with the skin during the post-iontophoretic period had a significant effect on drug levels delivered into skin layers. Iontophoresis enhanced the delivery of terbinafine hydrochloride into the skin layers and, therefore, may be used to improve the treatment of skin fungal infections.
Keywords: Iontophoresis; Terbinafine hydrochloride; Antifungal; Stratum corneum;
Anti-atherosclerotic peptide delivery from a photocrosslinkable biodegradable network by Brian Amsden; Bo Qi (32-39).
A water-soluble, 19-mer peptide fragment of serum amyloid A called MFFD is being examined as a possible treatment for atherosclerosis. As a means of administering this drug in a sustained fashion through subcutaneous implantation, a biodegradable network formulation was prepared. The formulation consisted of 1000 and 4000 Da α,ω-diacrylate oligo(d,l-lactide)-b-poly(ethylene glycol)-b-oligo(d,l-lactide) (DLPEGDLDA) copolymerized with 2700 and 5000 Da ω,ω,ω-triacrylate star-poly(ɛ-caprolactone-co-d,l-lactide) using UV irradiation. The influence on the network properties and degradation rate of the network on the amount and type of DLPEGDLDA copolymerized with the two different molecular weight ASCPs were examined in vitro. The networks degraded by bulk hydrolysis at a rate controlled primarily by the molecular weight of the ASCP used. Nevertheless, all the networks were completely degraded within 16 weeks. The MFFD was released in a diffusional manner at a rate influenced by the degree of swelling of the network and the molecular weight of the ASCP used; using an ASCP of a lower molecular weight for a given DLPEGDLDA resulted in a slower release rate. The degree of swelling of the networks was controlled solely by the nature of the PEG used in preparing the DLPEGDLDA, with greater swelling observed with higher PEG molecular weight and for greater amounts of PEG incorporation. The MFFD was not degraded during the photocrosslinking reaction or by potential acidic degradation products that may have accumulated within the device. This formulation provides a means of achieving a desirable release rate from a degradable, water-swellable network through selection of ASCP molecular weight and DLPEGDLDA composition.
Keywords: Atherosclerosis; Photocrosslinking; Controlled release; Degradable polymer;
Aerodynamic deposition of combination dry powder inhaler formulations in vitro: A comparison of three impactors by Mohammed Taki; Christopher Marriott; Xian-Ming Zeng; Gary P. Martin (40-51).
Inertial impaction is generally regarded as the ‘gold standard’ for the in vitro assessment of aerodynamic deposition of inhaled formulations. Despite the availability of several impactors, few studies have compared measurements of aerodynamic deposition using multiple impactors and none employed a combination formulation. The aerodynamic deposition of the combination dry powder inhaler (DPI) Seretide® Accuhaler®, which contains salmeterol xinafoate (SX) and fluticasone propionate (FP), was assessed using the Andersen cascade impactor (ACI), multi-stage liquid impinger (MSLI) and next generation impactor (NGI) and the results were compared. Two Seretide products were tested at flow rates of 30 and Q L min−1, the latter corresponding to a pressure drop of 4 kPa across the device. Significant differences in the particle size distributions were observed when the same formulation was tested using various impactors. The ACI was found to be less suitable for DPI testing at flow rates considerably higher than 28.3 L min−1 due to the significant overlap in the cut-off curves of the pre-separator and stage 0. This was not the case with the MSLI but the data derived were limited by the relatively small number of stages. Deposition data determined by the three impactors were significantly different. The NGI produced good resolution and minimal inter-stage overlap and was regarded as the impactor of choice for DPI testing.
Keywords: Andersen cascade impactor; Multi-stage liquid impinger; Next generation impactor; Combination; Aerodynamic deposition; Dry powder inhaler;
A characterisation study on the application of inverted lyotropic phases for subcutaneous drug release by Erik Rosenbaum; Staffan Tavelin; Lennart B.-Å. Johansson (52-57).
An experimental characterisation of lipid mixtures consisting of inverted hexagonal and inverted cubic phases composed of soybean phosphatidylcholine (SPC) and glycerol dioleate (GDO) was performed. The release of five chromophores of varying lipophilicity, used as model drugs, was investigated. Two experimental setups were applied: one based on maintaining sink condition, while a constant volume release medium was employed for the other. For neither setup, no correlation between the model drug lipophilicity and the polarity of the carrier matrix was found. However, the lipid phases showed a prolonged release, spanning weeks, of the model drugs, which exhibit lipophilicity values ranging by four orders of magnitude.
Keywords: Subcutaneous drug delivery; Drug depot; Lipid formulations; Lipophilicity; Model drugs;
Novel pH-sensitive microgels prepared using salt bridge by Xia Yang; Jin-Chul Kim (58-63).
pH-sensitive microgels were prepared by crosslinking carboxymethylcellulose (CMC) and polymeric β-cyclodextrin (PβCD) using (2-hydroxyethyl)trimethylammonium chloride benzoate (TMACB) as a crosslinker. PβCD was prepared by reacting epichlorohydrin and β-CD in an aqueous phase (NaOH solution, 30% (w/w)). TMACB will interact with CMC by an electrostatic interaction and it will also interact with PβCD by a hydrophobic interaction. The size of microgel was tens of nanometers to several micrometers. The degree of calcein release in 24 h from the microgels was as low as 23% at pH 8.0. The degree of release at pH 3.0 was almost 100%. The carboxyl groups of CMC will lose their charge in an acidic condition and they would lose their ability to form salt bridges with TMACB, leading to the disintegration of microgels. The degree of release at pH 11, about 47%, was less than the value at pH 3.0 but it was greater than the value at pH 8.0. The CMC will be strongly electrostatically charged in the alkali condition, so the microgels would swell due to the electrostatic repulsion among CMC molecules, which could promote the release of their contents.
Keywords: Carboxymethylcellulose; (2-Hydroxyethyl)trimethylammonium chloride benzoate; pH-sensitive microgels; Polymeric β-cyclodextrin;
Multivariate optimization of formulation and process variables influencing physico-mechanical characteristics of site-specific release isoniazid pellets by Swati Pund; Amita Joshi; Kamala Vasu; Manish Nivsarkar; Chamanlal Shishoo (64-72).
In the present study, isoniazid was formulated as site-specific release pellets with high drug loading (65%, w/w) using extrusion-spheronization followed by aqueous coating of Sureteric® (35% weight gain). A statistical experimental strategy was developed to optimize simultaneously the effect of the two formulation variables and one process variable on the critical physico-mechanical properties of the core pellets of isoniazid. Amount of granulating fluid and amount of binder were selected as formulation variables and spheronization speed as a process variable. A 23 full factorial experimental design was employed for the present study. Pellets were characterized for physico-mechanical properties viz. usable yield, pellet size, pellips, porosity, abrasion resistance, mechanical crushing force, residual moisture and dissolution efficiency. Graphical and mathematical analysis of the results allowed the identification and quantification of the formulation and process variables active on the selected responses. A polynomial equation fitted to the data was used to predict the responses in the optimal region. The optimum formulation and process parameters were found to be 44.24% (w/w) of granulating fluid, 2.13% (w/w) of binder and spheronization speed of 1000 rpm. Optimized formulation showed usable yield 84.95%, particle size 1021.32 μm, pellips 0.945, porosity 46.11%, and abrasion resistance 0.485%. However, mechanical crushing force, residual moisture and dissolution efficiency were not significantly affected by the selected independent variables. These results demonstrate the importance of, amount of water, binder and spheronization speed, on physico-mechanical characteristics of the isoniazid core pellets with high drug loading.
Keywords: Isoniazid; Multiple response optimization; Pellets; Physico-mechanical characteristics; Full factorial design;
Measurement and prediction of solubilities of active pharmaceutical ingredients by Inga Hahnenkamp; Gitte Graubner; Jürgen Gmehling (73-81).
Solubilities of 2-acetoxy benzoic acid (aspirin), N-acetyl-p-aminophenol (paracetamol) and 2-(p-isobutylphenyl)propionic acid (ibuprofen) have been measured in various solvents and compared with published and predicted data. For the prediction besides the two group contribution models UNIFAC and modified UNIFAC (Dortmund) the quantum chemical approach COSMO-RS (Ol) was used. Additionally melting temperatures and heats of fusion for 2-acetoxy benzoic acid, N-acetyl-p-aminophenol and 2-(p-isobutylphenyl)propionic acid required for the calculations have been determined by differential scanning calorimetry.
Keywords: Active pharmaceutical ingredients; Solid–liquid equilibrium; UNIFAC; Mod. UNIFAC (Do); COSMO-RS (Ol);
Evaluation of droplet velocity and size from nasal spray devices using phase Doppler anemometry (PDA) by Xiaofei Liu; William H. Doub; Changning Guo (82-87).
To determine aerosol deposition during the inhalation drug delivery, it is important to understand the combination of velocity and droplet size together. In this study, phase Doppler anemometry (PDA) was used to simultaneously characterize the aerosol velocity and droplet size distribution (DSD) of three nasal spray pumps filled with water. Thirteen sampling positions were located in the horizontal cross-sectional area of the nasal spray plumes at a distance of 3 cm from the pump orifice. The results showed droplet velocities near the center of the spray plume were higher and more consistent than those near the edge. The pumps examined showed significant differences in their aerosol velocity at the center of the spray plume, which suggest that this metric might be used as a discriminating parameter for in vitro testing of nasal sprays. Droplet size measurements performed using PDA were compared with results from laser light scattering measurements. The ability of PDA to provide simultaneous measurements of aerosol velocity and size makes it a powerful tool for the detailed investigation of nasal spray plume characteristics.
Keywords: Nasal spray; In vitro test; Aerosol; Velocity; Size; Phase Doppler anemometry;
Influence of fines on the surface energy heterogeneity of lactose for pulmonary drug delivery by Raimundo Ho; Adrian S. Muresan; Gerald A. Hebbink; Jerry Y.Y. Heng (88-94).
The effects of the blending of lactose fines to the overall adhesion property of coarse α-lactose monohydrate carrier particles were investigated. Five samples, three of them commercial samples from DOMO (Lactohale® LH100, LH210, and LH250) whilst the other two are blends of LH210 and LH250, were studied. Characterisation included particle sizing, SEM, PXRD and IGC. Dispersive surface energy γ S V d was determined using a finite concentration IGC method to obtain a distribution profile. The γ S V d distribution of lactose crystals was found to vary from 40 to 48 mJ/m2. The unmilled coarse crystalline lactose sample (LH100) γ S V d was lowest and showed less heterogeneity than the milled sample (LH250). Fines (LH210) were found to have the highest γ S V d value. The samples with loaded LH210 were found to have a higher energy than LH100. The amount of LH210 in Blend 1 was not able to decrease surface energy heterogeneity, whereas sample Blend 2 showed adequate loading of fines to obtain a relatively homogeneous surface. Addition of fines resulted in an increase in γ S V d , suggesting that coarse lactose surfaces were replaced by surfaces of the fines. Increasing the loading of fines may result in a more homogeneous surface energy of lactose particles.
Keywords: Carrier particle; Lactose; Pulmonary drug delivery; Inverse gas chromatography; Surface energy;
5-Fluorouracil acetic acid/β-cyclodextrin conjugates: Drug release behavior in enzymatic and rat cecal media by Koichi Udo; Kazuhiro Hokonohara; Keiichi Motoyama; Hidetoshi Arima; Fumitoshi Hirayama; Kaneto Uekama (95-100).
5-Fluorouracil-1-acetic acid (5-FUA) was prepared and covalently conjugated to β-cyclodextrin (β-CyD) through ester or amide linkage, and the drug release behavior of the conjugates in enzymatic solutions and rat cecal contents were investigated. The 5-FUA/β-CyD ester conjugate was slowly hydrolyzed to 5-FUA in aqueous solutions (half lives (t 1/2) = 38 and 17 h at pH 6.8 and 7.4, respectively, at 37 °C), whereas the amide conjugate was hardly hydrolyzed at these physiological conditions, but hydrolyzed only in strong alkaline solutions (>0.1 M NaOH) at 60 °C. Both ester and amide conjugates were degraded in solutions of a sugar-degrading enzyme, α-amylase, to 5-FUA/maltose and triose conjugates, but the release of 5-FUA was only slight in α-amylase solutions. In solutions of an ester-hydrolyzing enzyme, carboxylic esterase, the ester conjugate was hydrolyzed to 5-FUA at the same rate as that in the absence of the enzyme, whereas the amide conjugate was not hydrolyzed by the enzyme. On the other hand, 5-FUA was rapidly released when the ester conjugate was firstly hydrolyzed by α-amylase, followed secondly by carboxylic esterase. The results indicated that the ester conjugate was hydrolyzed to 5-FUA in a consecutive manner, i.e. it was firstly hydrolyzed to the small saccharide conjugates, such as the maltose conjugate, by α-amylase, and the resulting small saccharide conjugates having less steric hindrance was susceptible to the action of carboxylic esterase, giving 5-FUA. The in vitro release behavior of the ester conjugate was clearly reflected in the hydrolysis in rat cecal contents and in the in vivo release after oral administration to rats.
Keywords: 5-Fluorouracil-1-acetic acid; β-Cyclodextrin conjugate; Colon-specific delivery; Prodrug;
Modelling of porosity and waterfronts in cellulosic pellets for understanding drug release behavior by Ana Gomez-Carracedo; Ramon Martinez-Pacheco; Angel Concheiro; Jose Luis Gomez-Amoza (101-106).
The microstructure of cellulose microcrystalline-Carbopol® pellets, prepared under different drying conditions (oven-dried or freeze-dried), was experimentally characterized using mercury intrusion porosimetry and then computationally modelled using Pore-Cor™ software. Connectivity (mean number of throats per pore), pore skew (σ), throat skew (q) and correlation level were estimated and simultaneously optimized from the mercury intrusion porosimetry cumulative curves using the Boltzmann-annealed simplex algorithm. Unit cells with percolation properties close to the real ones were generated. Water penetration rate in the simulated structures was also modelled using Pore-Cor™ and the waterfront position was calculated using the Bosanquet equation. A close correlation was found between the simulated water flow rate in the unit cell and the experimental theophylline first-order release rate constant. Thus, modelling of network microstructure and waterfronts appears as an useful tool for predicting drug release rate from matrix pellets.
Keywords: Network modelling; Pore-Cor™ software; Extrusion–spheronization; Pellet microstructure; Drug delivery; Water uptake;
Iontophoretic transport of charged macromolecules across human sclera by Poonam Chopra; Jinsong Hao; S. Kevin Li (107-113).
The mechanisms of transscleral iontophoresis have been investigated previously with small molecules in rabbit sclera. The objective of the present study was to examine transscleral iontophoretic transport of charged macromolecules across excised human sclera. Passive and 2 mA iontophoretic transport experiments were conducted in side-by-side diffusion cells with human sclera. The effects of iontophoresis upon transscleral transport of model permeants bovine serum albumin (BSA) and polystyrene sulfonic acid (PSS) as well as a model drug bevacizumab (BEV) were determined. Passive and iontophoretic transport experiments of tetraethylammonium (TEA) and salicylic acid (SA) and passive transport experiments of the macromolecules served as the controls. The results of iontophoresis enhanced transport of TEA and SA across human sclera were consistent with those in a previous rabbit sclera study. For the iontophoretic transport of macromolecules BSA and BEV, higher iontophoretic fluxes were observed in anodal iontophoresis as compared to passive and cathodal iontophoresis. This suggests the importance of electroosmosis. For the polyelectrolyte PSS, higher iontophoretic flux was observed in cathodal iontophoresis compared to anodal iontophoresis. Both electroosmosis and electrophoresis affected iontophoretic fluxes of the macromolecules; the relative contributions of electroosmosis and electrophoresis were a function of molecular size and charge of the macromolecules.
Keywords: Electrophoresis; Electroosmosis; Charged macromolecules; Human sclera;
A novel method for the production of crystalline micronised particles by Syed Anuar Faua’ad Syed Muhammad; Tim Langrish; Patricia Tang; Handoko Adi; Hak-Kim Chan; Sergei G. Kazarian; Fariba Dehghani (114-122).
The aim of this study was to develop a method for converting an amorphous drug to a crystalline form to enhance its stability and inhalation performance. Spray-dried amorphous salbutamol sulphate powder was conditioned with supercritical carbon dioxide (scCO2) modified with menthol. The effect of menthol concentration, pressure, temperature and time on the characteristics of the resulting salbutamol sulphate powder was investigated. Pure scCO2 had no effect on the physical properties of amorphous salbutamol sulphate; however, scCO2 modified with menthol at 150 bar and 50 °C was efficient in converting amorphous drug to crystalline form after 12 h of conditioning. The average particle size of powders decreased slightly after the conditioning process because of reducing agglomeration between particles by increasing surface roughness. Emitted dose measured by the fine particle fraction (FPFemitted) of amorphous salbutamol sulphate was enhanced from 32% to 43% after conditioning with scCO2 + menthol and its water uptake was significantly decreased. This study demonstrates the potential of scCO2 + menthol for converting amorphous forms of powders to crystalline, while preserving the particle size.
Keywords: Supercritical CO2; Salbutamol sulphate; Menthol; Crystallisation; Inhalation drug delivery;
Characterization of organogel as a novel oral controlled release formulation for lipophilic compounds by Kazunori Iwanaga; Toru Sumizawa; Makoto Miyazaki; Masawo Kakemi (123-128).
A low molecular mass gelator can form soft solids in a variety of organic liquids and vegetable oils. These soft solids are generally called organogels. In this study, we prepared organogel using 12-hydroxystearic acid (12-HSA) as a gelator for soybean oil and investigated its characteristics as a controlled release formulation for lipophilic compounds. The release rate of ibuprofen, a model lipophilic compound, from organogel decreased with the increase of 12-HSA concentration in the formulation; however, the difference in the concentration of 12-HSA in the formulation did not affect the diffusivity of ibuprofen in the organogel. The erosion constant of organogel in the intestinal tract was examined by using simulated gastric fluid and intestinal fluid. Regardless of 12-HSA concentration in the formulation, organogel is very stable in the simulated gastric fluid. On the other hand, the erosion constant of organogel in the simulated intestinal fluid increased with the decreasing concentration of 12-HSA. Therefore, it is speculated that the difference in the release rate of ibuprofen among organogels with various concentrations of 12-HSA was mainly caused by the difference in the erosion rate. To characterize the organogel effect in vivo, ibuprofen was orally administered to rats in an aqueous suspension or organogel. Ibuprofen concentration in plasma rapidly increased after administration with an aqueous suspension, whereas organogel suppressed the rapid absorption. In conclusion, organogel is clearly useful as an oral controlled release formulation for lipophilic compounds.
Keywords: Organogel; Controlled release; Lipid formulation; Intestinal absorption; Drug delivery system;
Erythritol: Crystal growth from the melt by A.J. Lopes Jesus; Sandra C.C. Nunes; M. Ramos Silva; A. Matos Beja; J.S. Redinha (129-135).
The structural changes occurring on erythritol as it is cooled from the melt to low temperature, and then heated up to the melting point have been investigated by differential scanning calorimetry (DSC), polarized light thermal microscopy (PLTM), X-ray powder diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR).By DSC, it was possible to set up the conditions to obtain an amorphous solid, a crystalline solid, or a mixture of both materials in different proportions. Two crystalline forms have been identified: a stable and a metastable one with melting points of 117 and 104 °C, respectively. The fusion curve decomposition of the stable form revealed the existence of three conformational structures.The main paths of the crystallization from the melt were followed by PLTM. The texture and colour changes allowed the characterization of the different phases and transitions in which they are involved on cooling as well as on heating processes. The type of crystallization front and its velocity were also followed by microscopic observation. These observations, together with the data provided by PXRD, allowed elucidating the transition of the metastable form into the stable one.The structural changes occurring upon the cooling and subsequent heating processes, namely those arising from intermolecular hydrogen bonds, were also accompanied by infrared spectroscopy. Particular attention was given to the spectral changes occurring in the OH stretching region.
Keywords: Erythritol; Crystallization from melt; Crystalline and amorphous phases; Metastable form; Thermal methods; Powder X-ray diffraction and infrared spectroscopy;
Freeze-dried, mucoadhesive system for vaginal delivery of the HIV microbicide, dapivirine: Optimisation by an artificial neural network by A. David Woolfson; Manish L. Umrethia; Victoria L. Kett; R. Karl Malcolm (136-143).
Dapivirine mucoadhesive gels and freeze-dried tablets were prepared using a 3 × 3 × 2 factorial design. An artificial neural network (ANN) with multi-layer perception was used to investigate the effect of hydroxypropyl-methylcellulose (HPMC): polyvinylpyrrolidone (PVP) ratio (X1), mucoadhesive concentration (X2) and delivery system (gel or freeze-dried mucoadhesive tablet, X3) on response variables; cumulative release of dapivirine at 24 h (Q 24), mucoadhesive force (F max) and zero-rate viscosity. Optimisation was performed by minimising the error between the experimental and predicted values of responses by ANN. The method was validated using check point analysis by preparing six formulations of gels and their corresponding freeze-dried tablets randomly selected from within the design space of contour plots. Experimental and predicted values of response variables were not significantly different (p > 0.05, two-sided paired t-test). For gels, Q 24 values were higher than their corresponding freeze-dried tablets. F max values for freeze-dried tablets were significantly different (2–4 times greater, p > 0.05, two-sided paired t-test) compared to equivalent gels. Freeze-dried tablets having lower values for X1 and higher values for X2 components offered the best compromise between effective dapivirine release, mucoadhesion and viscosity such that increased vaginal residence time was likely to be achieved.
Keywords: Freeze-drying; Vaginal drug delivery; Dapivirine; HIV-AIDS; Microbicides; Artificial neural network;
β-Cyclodextrins influence on E-3,5,4′-trimethoxystilbene absorption across biological membrane model: A differential scanning calorimetry evidence by Maria Grazia Sarpietro; Sara Ottimo; Maria Chiara Giuffrida; Carmela Spatafora; Corrado Tringali; Francesco Castelli (144-150).
E-3,5,4′-trimethoxystilbene (TMS) is a naturally occurring analog of resveratrol. The anti-neoplastic, antiallergic and anti-angiogenic activities of TMS have been recently reported. From the viewpoint of metabolism, TMS may be more favourable than resveratrol because all of its hydroxyl groups, which are subjected to extensive glucuronide or sulphate conjugation in the metabolic pathways of resveratrol, are protected by methylation. Moreover, methylation increases lipophilicity and may enhance cell membrane permeability, but it decreases its solubility in aqueous media. A way to increase TMS solubility can be represented by complexation with β-cyclodextrins. In the present paper, the differential scanning calorimetry technique has been used to study the interaction of TMS with a biomembrane model constituted by dimyristoylphosphatidylcholine multilamellar vesicles. Furthermore, kinetic experiments have been carried out to follow the uptake of TMS by biomembranes in the presence of β-cyclodextrins to gain information on the effect of β-cyclodextrins on the uptake process. Our results indicate that opportune concentrations of β-cyclodextrins greatly improve the uptake of TMS by biomembrane models.
Keywords: 3,5,4′-Trimethoxy-trans-stilbene; β-Cyclodextrins; Differential scanning calorimetry; Dimyristoylphosphatidylcholine; Biomembrane model;
Microencapsulation of self-microemulsifying system: Improving solubility and permeability of furosemide by A. Zvonar; K. Berginc; A. Kristl; M. Gašperlin (151-158).
The primary goal of this study was to formulate Ca-pectinate microcapsules with self-microemulsifying core to enhance the solubility and permeability of BCS class IV drug furosemide. An Inotech IE-50R encapsulator equipped with a concentric nozzle was utilized to transform liquid self-microemulsifying system (SMES) to solid microcapsules. Self-microemulsifying core was optimized with respect to drug loading capacity and encapsulation efficiency and evaluated for its impact on furosemide permeability through rat small intestine and Caco-2 cell monolayers. Retention of the core phase was considerably improved (up to 70–80%) by optimization of the SMES and microcapsules’ drying process. Incorporation of furosemide in self-microemulsifying core of microcapsules resulted in improved permeability and drug release characteristics in comparison to microspheres (without SMES in the core). The obtained results illustrate the prospective use of microcapsules with self-microemulsifying core for the delivery of compounds with poor biopharmaceutical properties via the oral route.
Keywords: Microcapsules; Self-microemulsifying systems; Vibrating nozzle; Furosemide; Drug release; Permeability;
Novel multifunctional pharmaceutical excipients derived from microcrystalline cellulose–starch microparticulate composites prepared by compatibilized reactive polymer blending by Philip F. Builders; Agbo M. Bonaventure; Adelakun Tiwalade; Larry C. Okpako; Anthony A. Attama (159-167).
The choice of excipients remains a critical factor in pharmaceutical formulations. Microcrystalline cellulose–maize starch composites (MCC–Mst) have been prepared by mixing colloidal dispersions of microcrystalline cellulose (MCC) with 10% (w/w) of chemically gelatinized maize starch (Mst) at controlled temperature conditions for use as multifunctional excipients with direct compression and enhanced disintegration abilities. The novel excipient was evaluated for its direct compression and enhanced disintegrant properties and the result compared with the properties of the individual components. Some of its physicochemical and thermal properties were also determined together with effects of freeze–thaw cycles of processing on the functional and physicochemical properties. The scanning electron micrograph (SEM) shows that the particles of the MCC–Mst were irregular in shape and multiparticulate with a marked degree of asperity. The indirect assessment of the powder flow properties as determined by Carr's compressibility index and angle of repose showed that the MCC–Mst possesses better flow compared with MCC and Mst. MCC–Mst is moderately hygroscopic and shows a Type III moisture sorption isotherm. The FT-IR spectra and DSC thermograms of the composite were different from those of MCC and Mst. The hardness of aspirin tablets was enhanced by incorporating MCC–Mst and MCC, but was reduced by Mst. While the tablets prepared with MCC–Mst and Mst disintegrated within 7 min, aspirin compacts devoid of any excipient and those prepared with MCC did not disintegrate even after 2 h. Acetaminophen compacts prepared with MCC and MCC–Mst showed similar compact hardness characteristics and loading properties. The loading capacity of the different samples of the composite decreased with increase in the freeze–thaw cycles. The loading capacity of the different materials as assessed by their compact hardness efficiency can be represented as follows (MCC > T0 > T1 > T4 > T3 > T2 > Mst). Generally, the different samples of MCC–Mst are characterized by physicochemical and functional properties that are similar at different degrees to MCC and Mst.
Keywords: Microcrystalline cellulose; Maize starch; Microcrystalline cellulose–maize starch composites; Direct compression;
Transport characteristics of mouse concentrative nucleoside transporter 1 by Miho Niitani; Kentaro Nishida; Hiroto Okuda; Katsuhito Nagai; Sadaki Fujimoto; Kazuki Nagasawa (168-174).
Concentrative nucleoside transporter 1 (CNT1, SLC28A1) is a key molecule for determining the pharmacokinetic/pharmacodynamic profile of a candidate compound derived from a pyrimidine nucleoside, but there is no available information on the differences in the functional profile of this ortholog between man and mouse. Here, using a clone of mouse CNT1 (mCNT1), we investigated its transport characteristics and substrate specificity for synthetic nucleoside analogues, and compared them with those of human CNT1 (hCNT1). In mCNT1-transfected Cos-7 cells, pyrimidine, but not purine, nucleosides showed sodium- and concentration-dependent uptake, and uridine uptake was competitively inhibited by uridine analogues, the rank order of the inhibitory effects being 5-bromouridine > 3′-deoxyuridine > 2′-deoxyuridine. cis- and trans-Inhibition studies involving synthetic nucleoside drugs revealed that gemcitabine and zidovudine greatly inhibited [3H]uridine uptake mediated by mCNT1 in the both cases, while cytarabine and zalcitabine showed small cis-inhibitory effect, and no trans-inhibitory effect on the uptake. These results demonstrate that the transport characteristics of mCNT1 are almost the same as those of hCNT1, suggesting that mice may be a good animal model in evaluation of pyrimidine nucleoside analogues as to their applicability in human therapy.
Keywords: Concentrative nucleoside transporter 1; Mouse; Substrate specificity; Nucleoside analogue;
Pharmacokinetics analysis of sustained release hGH biodegradable implantable tablets using a mouse model of human ovarian cancer by Ana Santoveña; José B. Fariña; Matías Llabrés; Yonglian Zhu; Priscilla Dannies (175-180).
This paper presents the pharmacokinetic of human growth hormone (hGH) implantable tablets tested on a human ovarian cancer mouse model. In order to obtain a sustained release device which permits to administer a high dose of the hormone that keeps its integrity and stability, three different formulations of hGH–poly (d,l-lactic-co-glycolic acid) (PLGA) were elaborated by direct compression method varying hormone load, PLGA content and compactation time. In vitro studies showed that drug release was mainly controlled by hormone load. Pharmacokinetic studies were conducted by using immunodeficient female mice. Four days before the insertion of hGH implantable tablets in the peritoneal cavity, every mouse received 5 × 106 human ovarian cancer cells (SKOV3.ip1). Hormone serum levels were monitored through bleeding from eye orbital vessels. The population pharmacokinetic model used was based on the in series tank model and model parameters were estimated using the maximum likelihood method. The null hypothesis test about differences between formulations leads us to the conclusion that the three formulations showed the same kinetic behavior except for the hGH load. The hormone release was extended all over 2 weeks but no increase or decrease in survival time was observed. These results suggest that hGH serum levels do not facilitate tumoral cells proliferation, an expected effect of hGH and this could explain why survival times of mice treated with implantable tablets are not shorter than those treated with the control ones.
Keywords: Proteins; Poly (d,l-lactic-co-glycolic acid); Polymeric drug delivery systems; Cancer; High performance liquid chromatography; Nonlinear pharmacokinetics;
Physicochemical properties of extruded and non-extruded liposomes containing the hydrophobic drug dexamethasone by Upkar Bhardwaj; Diane J. Burgess (181-189).
The physicochemical and release properties of non-extruded ‘multilamellar’ and small sonicated and extruded 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) liposomes containing hydrophobic drug dexamethasone were investigated. Non-extruded liposomes had similar diameter, however dexamethasone encapsulation decreased with increase in lipid chain length. Dexamethasone destabilized the liposome membranes as indicated by decrease in enthalpy and increase in the peak width of the main transition. Based on calorimetric analysis, it appeared that dexamethasone and cholesterol were heterogeneously distributed in the non-extruded liposomes. Sonication and extrusion reduced the diameter (DSPC > DPPC > DMPC) and decreased drug encapsulation (approximately 50%). Cholesterol incorporation decreased drug encapsulation in both extruded and non-extruded DMPC liposomes which appeared to be due to structural similarities between cholesterol and dexamethasone. Incorporation of dexamethasone and cholesterol in the same DMPC liposomes caused a marked perturbation in the phase transition. Dexamethasone release from extruded liposomes was fast, while non-extruded liposomes showed slower release. Release was fastest from DMPC liposomes and slowest from liposomes of high phase transition lipid DSPC. Incorporation of cholesterol did not decrease release from DMPC liposomes. These results indicated that change in the physicochemical properties and the phase transition behavior of liposomes, due to processing as well as incorporation of hydrophobic drug dexamethasone, changed their release properties.
Keywords: Extruded and non-extruded liposomes; Physicochemical properties; In vitro release; Hydrophobic drug; Dexamethasone; Sustained delivery;
Gastro intestinal tracking and gastric emptying of solid dosage forms in rats using X-ray imagining by Sigal Saphier; Amir Rosner; Rachel Brandeis; Yishai Karton (190-195).
The aim of this research was to study the gastrointestinal transit and gastric emptying of non-disintegrating solid dosage forms in rats using X-ray imaging. Commercial gelatin minicapsules were filled with barium sulfate and enterically coated using Eudragit S100. The capsules were administered orally to rats followed by a solution of iodine based contrast agent iopromide. Images were obtained using a standard X-ray camera and digital film processing. Capsules were followed through the GI tract from the stomach to the small intestine, cecum and large intestine and the capsule location could be easily identified. Gastric emptying of different sized capsules was studied. The effect of fasting and time of administration on gastric retention was also studied. It was found that shortened capsules of 3.5 and 4.8 mm length were emptied from the stomach whereas the commercial length 7.18 mm capsules were retained. Surprisingly, 2.5 h post administration more rats retained the capsules in the stomach in the fasted state than in the fed state. We found that X-ray imaging can be used for simple visualization and localization of solid dosage forms in rats in the fed state using shortened commercial minicapsules on rats.
Keywords: Rats; X-ray imaging; GI tract; Enteric-coated capsules; In vivo;
Effect of Eriochrome Black T on the gelatinization of xyloglucan investigated using rheological measurement and release behavior of Eriochrome Black T from xyloglucan gel matrices by Namon Hirun; Vimon Tantishaiyakul; Wiwat Pichayakorn (196-201).
A novel gel system was obtained by mixing aqueous solutions of tamarind seed xyloglucan (TSX) and Eriochrome Black T (EBT), an antiangiogenic compound. The shear-viscosity flow curves revealed that all the studies mixtures displayed a shear thinning behavior. Viscosity increased with increasing EBT concentrations. According to frequency sweep tests, mixtures at EBT concentration of 1.30% and 2.50% (w/v) in 1% (w/v) TSX formed a weak gel. The time sweep tests revealed that these mixtures remained as sol at room temperature (25 °C) for a long period of time but turned into gel in a short time at body temperature (37 °C). The in vitro EBT release profiles demonstrated sustained release of EBT. Loading concentration of EBT affected the gel strength and consequently the release mechanism of EBT. According to release kinetic analyses, the release profiles of 1.30% and 2.50% (w/v) EBT systems occur through an anomalous mechanism and Fickian diffusion, respectively. In conclusion, these EBT–TSX systems appear to be suitable as injectable implants for sustained delivery of EBT at a site of application, and as such they may be beneficial for the future treatment of solid malignant tumors.
Keywords: Tamarind seed xyloglucan; Eriochrome Black T; Rheological measurement; Fickian diffusion; Anomalous transport;
Nasal absorption of mixtures of fast-acting and long-acting insulins by Dennis J. Pillion; Michael D. Fyrberg; Elias Meezan (202-208).
Mixtures of fast-acting and long-acting insulins were administered nasally to anesthetized, hyperglycemic rats in the presence and absence of tetradecyl-β-d-maltoside (TDM). The fast-acting analogs, aspart insulin, lispro insulin and glulisine insulin, were all rapidly absorbed from the nose when applied individually with 0.125% TDM (T max = 15 min). One long-acting insulin analog, glargine insulin, was also absorbed from the nose when applied individually in the presence of 0.125% TDM (T max = 60 min). The other long-acting insulin analog, detemir insulin, was not soluble when formulated with 0.125% TDM. A series of mixtures (1:1) of the three rapid-acting insulins and long-acting glargine insulin were formulated with 0.125% TDM and applied nasally. The pharmacokinetic and pharmacodynamic profiles of the insulin mixtures reflected the additive contributions of both the rapid-acting and the long-acting insulins. These results support the possibility of formulating certain insulin mixtures in tandem to provide nasal insulin products that match the needs of patients with diabetes mellitus better than those currently available.
Keywords: Absorption enhancer; Nasal absorption; Surfactants; Insulin; Diabetes; Drug delivery;
The role of intermolecular interactions with penetratin and its analogue on the enhancement of absorption of nasal therapeutic peptides by El-Sayed Khafagy; Mariko Morishita; Kozo Takayama (209-212).
We investigated the relationship between intermolecular binding and the ability of novel cell-penetrating peptides (CPPs) to enhance the nasal absorption of therapeutic peptides and proteins. The absorption-enhancing effect of a novel l-penetratin analogue, ‘shuffle (R,K fix) 2’ coadministered with different biotherapeutic peptides was evaluated after nasal administration in rats. Shuffle (R,K fix) 2 significantly increased the nasal absorption of insulin, glucagon-like-peptide-1 (GLP-1) and exendin-4, compared with the absorption seen with l-penetratin. Intermolecular binding was analyzed by surface plasmon resonance (SPR)-based binding assay. The binding characteristics implied that the higher the amount of CPP bound, the greater the nasal drug absorption. In addition, the calculated binding ratio between CPP and drug proved a critical aspect in enhancing the absorption of insulin and GLP-1. This difference in the enhancing effect of CPPs on nasal drug absorption is attributed to the degree of binding with the therapeutic macromolecule.
Keywords: Cell-penetrating peptide (CPP); Penetratin analogues; Peptides; Nasal absorption; Intermolecular binding; Surface plasmon resonance (SPR);
Analysis of phase diagram and microstructural transitions in an ethyl oleate/water/Tween 80/Span 20 microemulsion system using high-resolution ultrasonic spectroscopy by Sinead Hickey; Sue A. Hagan; Evgeny Kudryashov; Vitaly Buckin (213-222).
High-resolution ultrasonic spectroscopy was applied to analyse a pseudo-ternary phase diagram for a mixture consisting of water/ethyl oleate/Tween 80 and Span 20 at 25 °C. The measured changes in the ultrasonic velocity and attenuation with concentration of water in oil/surfactants mixtures showed several, well defined stages and transitions between them, which allowed construction of an ‘ultrasonic’ phase diagram. Quantitative analysis of the ultrasonic parameters enabled characterisation of various phases (microemulsion, liquid crystals and pseudo-bicontinuous) as well as evaluation of the state of the water and particle size in microemulsion phase.
Keywords: Microemulsion; Ultrasonic spectroscopy; HR-US; Particle size; Ultrasonic velocity; Ultrasonic attenuation; Phase diagram; Hydration;
The in vitro and in vivo anti-tumor effect of layered double hydroxides nanoparticles as delivery for podophyllotoxin by Lili Qin; Meng Xue; Wenrui Wang; Rongrong Zhu; Shilong Wang; Jing Sun; Rui Zhang; Xiaoyu Sun (223-230).
In this research, we intercalated anti-tumor drug podophyllotoxin (PPT) into layered double hydroxides (LDHs) and investigated the in vitro cytotoxicity to tumor cells, the cellular uptake and in vivo anti-tumor inhibition of PPT-LDH. The nanohybrids were prepared by a two-step method with the size of 80–90 nm and the zeta potential of 20.3 mV. The in vitro cytotoxicity experiment indicated that PPT-LDH nanoparticles show better anti-tumor efficacy than PPT and are more readily taken up by Hela cells. PPT-LDH shows a long-term suppression effect on the tumor growth, and enhances the apoptotic process of tumor cells. The in vivo tests reveal that delivery of PPT via LDH nanoparticles is more efficient, but the mice toxicity of PPT in PPT-LDH hybrids is reduced in comparison with PPT alone. Pharmacokinetics study displays a prolonged circulation time and an increased bioavailability of PPT-LDH than PPT. These observations imply that LDH nanoparticles are the potential carrier of anti-tumor drugs in a range of new therapeutic applications.
Keywords: Nanoparticle; Drug delivery; Anti-tumor effect; In vitro test; In vivo test;
Enhanced bioavailability of lacidipine via microemulsion based transdermal gels: Formulation optimization, ex vivo and in vivo characterization by Ramesh Gannu; Chinna Reddy Palem; Vamshi Vishnu Yamsani; Shravan Kumar Yamsani; Madhusudan Rao Yamsani (231-241).
The purpose of the present study was to develop and optimize the microemulsion based transdermal therapeutic system for lacidipine (LCDP), a poorly water soluble and low bioavailable drug. The pseudo-ternary phase diagrams were developed for various microemulsion formulations composed of isopropyl myristate, Tween 80 and Labrasol. The microemulsion was optimized using a three-factor, three-level Box–Behnken design, the independent variables selected were isopropyl myristate, surfactant mixture (Tween 80 and Labrasol) and water; dependent variables (responses) were cumulative amount permeated across rat abdominal skin in 24 h (Q 24; Y 1), flux (Y 2), and lag time (Y 3). Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equations were generated for responses Y 1, Y 2 and Y 3. The statistical validity of the polynomials was established, and optimized formulation factors were selected by feasibility and grid search. Validation of the optimization study with 10 confirmatory runs indicated high degree of prognostic ability of response surface methodology. The gel of optimized formulation (ME-OPT) showed a flux of 43.7 μg cm−2 h−1, which could meet the target flux (12.16 μg cm−2 h−1). The bioavailability studies in rabbits showed that about 3.5 times statistically significant (p < 0.05) improvement in bioavailability, after transdermal administration of microemulsion gel compared to oral suspension. The ex vivo–in vivo correlation was found to have biphasic pattern and followed type A correlation. Microemulsion based transdermal therapeutic system of LCDP was developed and optimized using Box–Behnken statistical design and could provide an effective treatment in the management of hypertension.
Keywords: Microemulsion; Lacidipine; Microemulgel; Box–Behnken; Optimization; Pharmacokinetics; Bioavailability; EVIV correlation;
Silk fibroin nanoparticles for cellular uptake and control release by Joydip Kundu; Yong-Il Chung; Young Ha Kim; Giyoong Tae; S.C. Kundu (242-250).
Silk nanoparticles were prepared from silk fibroin solutions of domesticated Bombyx mori and tropical tasar silkworm Antheraea mylitta and investigated in respect to its particle size, surface charge, stability and morphology along with its cellular uptake and release of growth factors. The nanoparticles were stable, spherical, negatively charged, 150–170 nm in average diameter and exhibited mostly Silk II (β-sheet) structure and did not impose any overt toxicity. Cellular uptake studies showed the accumulation of fluorescence isothiocyanate conjugated silk nanoparticles in the cytosol of murine squamous cell carcinoma cells. In vitro VEGF release from the nanoparticles showed a significantly sustained release over 3 weeks, signifying the potential application as a growth factor delivery system.
Keywords: Silk fibroin; Nanoparticles; Biomaterials; TEM; Cellular uptake; VEGF;
Morphological effect of lipid carriers on permeation of lidocaine hydrochloride through lipid membranes by Jongwon Shim; Mi Jin Kim; Han-Kon Kim; Do-Hoon Kim; Seong Geun Oh; Seung Yong Ko; Ho Gyeom Jang; Jin-Woong Kim (251-256).
We have studied how the transdermal delivery of lidocaine hydrochloride (LHC) is affected by the morphology of lipid carriers, liposomes and micelles, having the same lipid composition of 1-stearoyl-sn-glycero-3-phosphocholine (LPC) and cholesteryl hemisuccinate (CHEMS). In vitro drug permeation study, carried out on guinea pig skin, has revealed that the liposomes made of LPC and CHEMS significantly enhance the permeation rate of entrapped LHC; by contrast, the mixed micelles with the same composition decrease the degree of delivering co-existing LHC. Basically, we have also investigated the release kinetics of LHC through the cellulose membrane and found that both liposomes and micelles have a similar releasing profile. To experimentally demonstrate this unique behavior, we have observed the fluidity of stratum corneum liposomal membranes in the presence of either our liposomes or micelles. From this study, we have found that LPC/CHEMS liposomes fluidize the lipid membrane of stratum corneum lipids; however, lipid micelles rather make the membrane rigid. These findings highlight that controlling the morphology of drug carriers provides us with a means to modulate the permeability of encapsulated drug molecules.
Keywords: Transdermal delivery; Morphology; Liposomes; Micelles; Membrane fluidity;
In vitro permeation and in vivo whitening effect of topical hesperetin microemulsion delivery system by Yi-Hung Tsai; Ko-Feng Lee; Yaw-Bin Huang; Chi-Te Huang; Pao-Chu Wu (257-262).
Hesperetin is one of the flavonoids and possess anti-inflammatory, UV-protecting and antioxidant effects. Permeation issues for topical delivery systems of such effects are occasionally problematic, and in view of the fact that microemulsions are potential carriers for transdermal delivery system, the objective of this study was to design an optimal microemulsion formulation by in vitro permeation study for hesperetin topical dosage form and determine its topical photoprotective effect and skin irritation by in vivo study. The hesperetin-loaded microemulsion showed an enhanced in vitro permeation compared to the aqueous and isopropyl myristate (IPM) suspension dosage form of hesperetin. In comparison, the effect of co-surfactant on the drug permeation capacity, propylene glycol showed highest permeation rate, followed by ethanol, glycerol and polyethylene glycol (PEG 400). Sunscreen agent padimate O, as a transdermal enhancer could increase the permeation rate of hesperetin. In case of in vivo study, the hesperetin-loaded microemulsion showed significant topical whitening effect and diminished skin irritation when compared with the non-treatment group, indicating that the hesperetin microemulsion could be used as an effective whitening agent.
Keywords: Hesperetin; Microemulsion; Transdermal delivery; Padimate O; Whitening effect;
Effect of aqueous solubility of grafted moiety on the physicochemical properties of poly(d,l-lactide) (PLA) based nanoparticles by Sherief Essa; Jean Michel Rabanel; Patrice Hildgen (263-273).
In order to evaluate the solubility effect of grafted moiety on the physicochemical properties of poly(d,l-lactide) (PLA) based nanoparticles (NPs), two materials of completely different aqueous solubility, polyethylene glycol (PEG) and palmitic acid were grafted on PLA backbone at nearly the same grafting density, 2.5% (mol of grafted moiety/mol of lactic acid monomer). Blank and ibuprofen-loaded NPs were fabricated from both polymers and their properties were compared to PLA homopolymer NPs as a control. NPs were analyzed for major physicochemical parameters such as encapsulation efficiency, size and size distribution, surface charge, thermal properties, surface chemistry, % poly(vinyl alcohol) (PVA) adsorbed at the surface of NPs, and drug release pattern. Encapsulation efficiency of ibuprofen was found to be nearly the same for both polymers ∼36% and 39% for PEG2.5%-g-PLA and palmitic acid2.5%-g-PLA NPs, respectively. Lyophilized NPs of palmitic acid2.5%-g-PLA either blank or loaded showed larger hydrodynamic diameter (∼180 nm) than PEG2.5%-g-PLA NPs (∼135 nm). PEG2.5%-g-PLA NPs showed lower % of PVA adsorbed at their surface (∼5%, w/w) than palmitic acid2.5%-g-PLA NPs (∼10%, w/w). Surface charge of palmitic acid2.5%-g-PLA NPs seems to be influenced by the large amount of PVA remains associated within their matrix. Thermal analysis using DSC revealed possible drug crystallization inside NPs. Both AFM phase imaging and XPS studies revealed the tendency of PEG chains to migrate towards the surface of PEG2.5%-g-PLA NPs. While, XPS analysis of palmitic acid2.5%-g-PLA NPs showed the tendency of palmitate chains to position themselves into the inner core of the forming particle avoiding facing the aqueous phase during NPs preparation using O/W emulsion method. The in vitro release pattern showed that PEG2.5%-g-PLA NPs exhibited faster release rates than palmitic acid2.5%-g-PLA NPs. PEG and palmitate chains when grafted onto PLA backbone, different modes of chain organization during NPs formation were obtained, affecting the physicochemical properties of the obtained NPs. The obtained results suggest that the properties of PLA-based NPs can be tuned by judicious selection of both chemistry and solubility profile of grafted material over PLA backbone.
Keywords: Poly(d,l-lactide); PEG–PLA NPs; Palmitic acid-PLA NPs; Chain organization; X-ray photoelectron spectroscopy (XPS); Phase imaging atomic force microscopy (AFM);
Monitoring the aggregation behaviour of self-assembling polymers through high-resolution ultrasonic spectroscopy by Marco Cespi; Giulia Bonacucina; Giovanna Mencarelli; Stefania Pucciarelli; Gianfabio Giorgioni; Giovanni F. Palmieri (274-279).
Poloxamer 407 is a well-known self-assembling polymer with a wide range of temperature- and concentration-dependent phase behaviour, such as micellization and gelation. This work was carried out to demonstrate the potential of high-resolution ultrasonic spectroscopy in evaluating aggregation–deaggregation behaviour of self-assembling polymers. In order to achieve this objective, six different concentrations of Poloxamer 407 water dispersion were prepared and analysed between 5 and 35 °C using ultrasonic spectroscopy. For comparison, the same samples were also analysed by the DSC technique. The results showed that polymer aggregation process can be successfully monitored using both ultrasonic parameters of sound speed and attenuation. Furthermore, good agreement with DSC data was observed in terms of characteristic transition temperatures and also in terms of micellization kinetics and related parameters.
Keywords: High-resolution ultrasonic spectroscopy; Self-assembling polymers; Aggregation; Micellization; Differential scanning calorimetry; Poloxamer 407;
Layered bionanocomposites as carrier for procainamide by Bhavesh D. Kevadiya; Ghanshyam V. Joshi; Hari C. Bajaj (280-286).
The study deals with the intercalation of procainamide hydrochloride (PA), an antiarrythmia drug in montmorillonite (MMT), as a new drug delivery device. Optimum intercalation of PA molecules within the interlayer space of MMT was achieved by means of different reaction conditions. Intercalation of PA in the MMT galleries was conformed by X-ray diffraction (XRD), Fourier transform infrared spectra (FT-IR), and thermal analysis (DSC). In order to retard the quantity of drug release in the gastric environment, the prepared PA–MMT composite was compounded with alginate (AL), and further coated with chitosan (CS). The surface morphology of the PA–MMT–AL and PA–MMT–AL–CS nanocomposites beads was analyzed by scanning electron microscope (SEM). The in vitro release experiments revealed that AL and CS were able to retard the drug release in gastric environments, and release the drug in the intestinal environments with a controlled manner. The release profiles of PA from composites were best fitted in Higuchi kinetic model, and Korsmeyer–Peppas model suggested diffusion controlled release mechanism.
Keywords: Procainamide hydrochloride (PA); Montmorillonite (MMT); Control release; Nanocomposites;
A novel USP apparatus 4 based release testing method for dispersed systems by Upkar Bhardwaj; Diane J. Burgess (287-294).
A novel dialysis adapter has been developed for USP apparatus 4 for in vitro release testing of dispersed system dosage forms. This USP apparatus 4 method was optimized and compared with currently used dialysis and reverse dialysis sac methods. Optimization studies for the USP apparatus 4 method showed that release from solution, suspension and liposome formulations was not flow rate limited and was not affected by change in the dialysis adapter sample volume from 250 μl to 500 μl. The USP apparatus 4 method could discriminate between solution, suspension and liposome formulations of dexamethasone. On comparing the different methods, only the USP apparatus 4 method provided discrimination between dexamethasone release from extruded and non-extruded liposomes, as well as among non-extruded DMPC, DPPC and DSPC liposomes. The dialysis sac method could not discriminate between the release profiles of non-extruded DMPC and DPPC liposomes. The reverse dialysis sac could not discriminate between the release profiles of extruded and non-extruded DMPC liposomes. In addition, the USP apparatus 4 method provided the highest release and the smallest variation in the data. This novel adapter might address the problem of the lack of a compendial apparatus for in vitro release testing of dispersed system dosage forms.
Keywords: In vitro release; Colloidal drug delivery systems; Dispersed systems; Liposomes; Suspensions; Sustained delivery; USP dissolution apparatus 4;