International Journal of Pharmaceutics (v.327, #1-2)
Editorial Board (iii).
A modified process for preparing cationic polylactide-co-glycolide microparticles with adsorbed DNA by Manmohan Singh; Jia-Hwa Fang; Jina Kazzaz; Mildred Ugozzoli; James Chesko; Padma Malyala; Raj Dhaliwal; Rebecca Wei; Maninder Hora; Derek O’Hagan (1-5).
We have previously shown that cationic polylactide-co-glycolide (PLG) microparticles can be effectively used to adsorb DNA and generate potent immune responses in vivo. We now describe a modified and easier process containing a single lyophilization step to prepare these cationic PLG microparticles with adsorbed DNA. Cationic PLG microparticle formulations with adsorbed DNA were prepared using a modified solvent evaporation technique. Formulations with a fixed CTAB content and DNA load were prepared. The loading efficiency and 24 h DNA release was evaluated for each formulation and compared to the earlier method of preparation. Select formulations were tested in vivo. The modified cationic PLG microparticle preparation method with a single lyophilization step, showed comparable physico-chemical behaviour to the two lyophilization steps process and induced comparable immune. The modified process with a single lyophilization step is a more practical process and can be utlized to prepare cationic PLG microparticles with adsorbed DNA on a large scale.
Keywords: PLG microparticles; Lyophilization; Double emulsion; Cationic surface;
The study of drug permeation through natural membranes by Mehdi Ansari; Maryam Kazemipour; Monireh Aklamli (6-11).
In this study, natural membranes such as the outer membrane of Prunus persica (peach) and Lycopersicon esculentum (tomato), the inner layer of the egg of Gallus domesticus (hen) and the middle membrane of the Allium cepa (onion) were used as controlling barriers for permeation of some model drugs with different MW and lipophilicities. Drug permeation studies were done by using modified Franz diffusion cell. The permeation of drugs through these natural membranes was compared to permeation of them through human skin and synthetic cellophane membrane. Results showed that the rate and amount of diclofenac permeated through onion membrane was not significantly different from that with tomato (p > 0.17), egg (p > 0.29) and human skin (p > 0.93). Permeation of diclofenac through tomato skin and cellophane was not significantly different (p > 0.35). Permeation of diclofenac through all studied membranes except for human skin that follows the Fickian kinetic followed non-Fickian mechanism and their permeabilities were not significantly different from each other (p > 0.05). Permeation of metronidazole through onion membrane and tomato skin were not significantly different from human skin (p > 0.053 and 0.38, respectively). All membranes were significantly different from each other (p < 0.0001) for permeation of erythromycin as a relatively large molecular weight and lipohilic molecule through human skin and other studied membranes. Permeation of diclofenac through human skin and metronidazole through egg and tomato skin followed Fick's first law. Diffusion of diclofenac through onion, tomato, egg, cellophane, and peach; metronidazole through onion, peach, cellophane, and human skin, and erythromycin through all studied membranes followed non-Fickian mechanism for diffusion. Statistical analysis showed the most similarity between onion and human skin for diclofenac, tomato and human skin for metronidazole, onion and cellophane for erythromycin.
Keywords: Drug; Permeation; Natural; Membrane; Diffusion;
Stability of cosmetic formulations containing esters of Vitamins E and A: Chemical and physical aspects by Thais Guaratini; Mirela D. Gianeti; Patrícia M.B.G.M. Campos (12-16).
Cosmetic stability prediction relies on quantitative chemical determinations of active components after certain times and in different temperatures. However, physical stability, an important parameter in skin care products is not considered in these conditions. This study proposes the determination of cosmetic stability chemical and physical parameters validated by (HPLC) chromatography and rheological measurements, respectively, using a gel-cream containing retinyl palmitate and tocopheryl acetate as a model system. The predicted shelf life addresses both the physical and chemical aspects of the system. Results emphasize the importance of studying both parameters by showing the relation of components degradation and physical stability. Moreover, they contribute to an improved understanding of physical and chemical stability aspects of cosmetic formulations, mainly if they contain Vitamins A and E derivatives.
Keywords: Stability studies; Cosmetics; Vitamins; Rheology; Physical and chemical aspects;
The effect of carrier surface treatment on drug particle detachment from crystalline carriers in adhesive mixtures for inhalation by B.H.J. Dickhoff; A.H. de Boer; D. Lambregts; H.W. Frijlink (17-25).
In this study, the effect of lactose carrier surface treatment on drug particle detachment during inhalation has been investigated. Crystals of marketed brands of alpha lactose monohydrate brands normally exhibit a certain surface rugosity and contain natural fines and impurities on their surface, which influence the drug-to-carrier interaction in adhesive mixtures for inhalation. Submersion treatment may change these surface characteristics. Two different sieve fractions (63–90 and 250–355 μm) were submerged in mixtures of ethanol and water (96 and 80% v/v, respectively). Microscopic observation and laser diffraction analysis revealed that neither the shape nor the size of the carrier particles was changed by the submersion treatment. However, the specific surface area and the amount of impurities appeared to decrease substantially after submersion, and the magnitude of the decrease was different for the different ethanol–water mixtures. The reduction in specific surface area was attributed particularly to the removal of the adhering lactose fines from the carrier surface. Mixtures with budesonide (in a wide range of carrier payloads) were prepared before and after treatment. Drug particle detachment from the various mixtures was studied with a sieve test and with a cascade impactor analysis at 30 and 60 l/min. Two different types of inhalers were used, one generating lift- and drag-forces (ISF inhaler) and one generating inertial forces (test inhaler), respectively. The cascade impactor and sieve test experiments showed that an increase in carrier surface smoothness results in a reduced drug particle detachment during inhalation, which was independent of the type of inhaler used. This reduction could be attributed to the removal of the adhering lactose fines which may provide shelter for the drug particles from press-on forces during mixing.
Keywords: Adhesion; Budesonide; Carrier lactose; Dry powder inhaler; Surface treatment; Rugosity;
Use of swirling airflow to enhance coating performance of bottom spray fluid bed coaters by P.W.S. Heng; L.W. Chan; E.S.K. Tang (26-35).
As there is strong interest in coating increasingly smaller particles or pellets for use in compacted dosage forms, there is a need for better small particle coating systems. This study explored the use of swirling airflow to enhance the performance of the bottom spray coating system. Firstly, pellet coating in the non-swirling airflow of conventional Wurster coating was compared with that of swirling airflow in precision coating under standardized conditions. Secondly, precision coating was studied in greater details at different airflow rates (60–100 m3/h) and partition gaps (6–22 mm). Precision coating was found to have higher Reynolds numbers (Re) than Wurster coating, indicating higher turbulence. It produced coated pellets of better properties than Wurster coating, having less agglomeration and gross surface defects, more uniform coats, increased flow and tapped density, and slower drug release. Higher surface roughness did not affect the yield. In precision coating, increasing airflow rates decreased the degree of agglomeration but had minimal effect on pellet quality attributes (colour intensity, colour uniformity and surface roughness) and yields. Increasing partition gaps increased the degree of agglomeration proportionally, but this effect was small. However, greater changes in yield, surface roughness, colour intensity and colour uniformity were detected. This study showed that precision coating, while having a higher drying ability, was able to maintain the same yield and produce coated pellets with superior quality compared to Wurster coating. In precision coating, airflow rate had greater influence on the drying of pellets while partition gap had greater influence on pellet quality attributes.
Keywords: Coating; Swirl; Pellets; Airflow; Partition gap;
Effect of milling conditions on the solid-state conversion of ranitidine hydrochloride form 1 by N. Chieng; Z. Zujovic; G. Bowmaker; T. Rades; D. Saville (36-44).
Powder samples of ranitidine hydrochloride forms 1 and 2 were milled using a vibrational ball mill (Retsch MM301) for periods up to 240 min at 4, 12 and 35 °C. X-ray powder diffraction (XRPD), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), solid-state nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC) were used to monitor solid-state properties of the milled samples. Milling of form 1 at 4 °C led to a powder temperature of 36 °C in the milling chamber and produced only amorphous drug; at 12 °C (powder temperature 45 °C) and at 35 °C (powder temperature 62 °C) progressive transformation of form 1 via amorphous drug to form 2 occurred. DSC of the milled samples showed a glass transition at 13–30 °C and a crystallization exotherm (T c) between 30 and 65 °C if the sample contained amorphous drug. The behaviour of the solid was speculated to be influenced by the relationship between powder temperature and T c; at powder temperatures below T c, amorphous drug is formed but no crystallization of form 2 occurs; at temperatures close to T c, amorphous content initially increases with transformation to form 2 on continued milling. At temperatures much higher than T c, at intermediate stages, less amorphous drug but both form 1 and form 2 are recovered, but continued milling gives only form 2. Form 2 did not transform to form 1 under any conditions used in this study.
Keywords: Ranitidine hydrochloride; Polymorphic transformation; Milling; Amorphous content; Glass transition; Crystallization;
Hot stage extrusion of p-amino salicylic acid with EC using CO2 as a temporary plasticizer by Geert Verreck; Annelies Decorte; Koen Heymans; Jef Adriaensen; Dehua Liu; David Tomasko; Albertina Arien; Jef Peeters; Guy Van den Mooter; Marcus E. Brewster (45-50).
The aim of the current research project was to explore the possibilities of combining pressurized carbon dioxide with hot stage extrusion during manufacturing of solid dispersions of the thermally labile p-aminosalicylic acid (p-ASA) and ethylcellulose 20 cps (EC 20 cps) and to evaluate the ability of the pressurized gas to act as a temporary plasticizer. The thermal stability of the p-ASA was investigated using DSC, TGA and HPLC. The compound decomposes completely upon melting. Below 110 °C and under atmospheric conditions, the compound is thermally stabile for 10 min.Pressurized carbon dioxide was injected into a Leistritz Micro 18 intermeshing co-rotating twin-screw melt extruder using an ISCO 260D syringe pump. Carbon dioxide acted as plasticizer for p-ASA/EC 20 cps, reducing the processing temperature during the hot stage extrusion process. HPLC showed that without carbon dioxide injection, approximately 17% of p-ASA degraded, while less than 5% degraded with CO2 injection. The experiments clearly showed that injecting pressurized carbon dioxide broadens the application of hot stage extrusion to thermally labile compounds in a one step process.
Keywords: Hot stage extrusion; p-Aminosalicylic acid; Ethylcellulose; Solid dispersion; Pressurized gas; Supercritical fluid;
Effect of pressure up to 5.5 GPa on dry powder samples of chlorpropamide form-A by Elena V. Boldyreva; Vladimir Dmitriev; Bruno C. Hancock (51-57).
The effect of pressure up to 5.5 GPa on a dry powder sample of chlorpropamide (4-chloro-N-((propylamino)-carbonyl)-benzenesulfonamide), form-A (sp. gr. P212121, a = 9.066 Å, b = 5.218 Å, c = 26.604 Å), was studied in situ in a Merrill–Bassett diamond anvil cell using high-resolution X-ray powder diffraction (a synchrotron radiation source at SNBL ESRF, Grenoble). No evidence of the polymorphic transformation of chlorpropamide form-A to form-C was observed. The A–C polymorphic transition on tabletting previously reported by is therefore likely to be due to local heating effects. Similarly, the phase transitions of form-A reported by to be induced by pressure applied to a sample in its saturated ethanol solution (at 0.9 and at 2.0 GPa) would appear to be solvent-mediated. In the dry sample, a phase transition may be supposed to occur at pressures above 4 GPa, but this requires further studies.
Keywords: Pressure; Polymorphism; Polymorphic transformation; X-ray powder diffraction; Chlorpropamide;
Enhancement of transdermal delivery of theophylline using microemulsion vehicle by X. Zhao; J.P. Liu; X. Zhang; Y. Li (58-64).
A microemulsion vehicle had been studied as a possible matrix for transdermal delivery of theophylline. The existence of microemulsion regions were investigated in pseudo-ternary phase diagrams, and various microemulsion formulations were prepared using oleic acid, Cremophor RH40/Labrasol (1:2) and water. The optimal formulation of the microemulsion was evaluated in vitro using Franz diffusion cells. The droplet size of microemulsion was characterized by photo correlation spectroscopy. Pharmacokinetic study in vivo was conducted using rabbits, and the results indicated that AUC0→∞ of transdermal administration was 1.65-fold higher than that of oral solution administration. These studies showed that microemulsion system of theophylline might be promising vehicles for the transdermal delivery of theophylline.
Keywords: Microemulsion; Theophylline; Transdermal delivery; Enhancer; Bioavailability;
Powder specific active dispersion for generation of pharmaceutical aerosols by T. Crowder; A. Hickey (65-72).
Dry powder inhalers are increasingly employed to deliver pharmaceutical aerosols. Efficient mechanisms of particle dispersion are central to their success in disease therapy. Creation of a powder aerosol requires the input of energy to transition the static powder bed into an entrained aerosol.The purpose of this study was to investigate the effects of input of vibrational energy into a powder on aerosol entrainment. Rotating drum characterization of powder flow was performed on lactose and maltodextrin excipients blended with albuterol sulfate. Dispersion experiments were conducted using an entrainment tube and a vibration actuator, vibrational energy input being derived from analysis of powder flow data from rotating drum analysis.Results of analysis of the rotating drum data showed that with increasing rotational speed powders reached a constant state of fluidization with a mean avalanche time dependent on the powder. Dispersion experiments demonstrated that the input of vibrational energy increased the dose emission while the input of frequencies specific to the powders improved the reproducibility. Frequency analysis of the vibration signals indicated that the reproducibility was determined by the bandwidth of the signal.This work suggests that an ability to tailor energy input to match the flow properties of a given powder formulation may significantly improve reproducibility of dose delivery from active dry powder inhalers.
Keywords: Inhalation drug delivery; Active dry powder inhaler; Powder flow; Powder avalanching; Vertical vibration;
Evaluation of the physical stability of two oleogels by Isabel F. Almeida; M. Fernanda Bahia (73-77).
Oleogels are semisolid systems obtained with an organogelator and a hydrophobic liquid that have been investigated over the past few years and that could play an important role as dermatological bases. Recently, we have developed an oleogel of sorbitan monostearate (19 wt.%) and sweet almond oil (SM–SAO) and another one of cholesterol (3.5 wt.%) and liquid paraffin (Ch–LP).The aim of this work is to access their physical stability using three different methodologies. The gels were stored at different temperatures (20 and 40 °C) over a 3-month period. Appearance and textural properties were assessed on each month. An accelerated test was also performed where the temperature changed between 4 and 40 °C every 24 h, during 7 days. Rheological tests were also carried out as they could provide useful elements to predict stability. The gels were quite stable at 20 °C, being the SM–SAO gel the most stable. The textural properties of both gels were influenced by temperature. The decrease of the textural parameters, observed after storage at 40 °C and in the cycling test, was more significant for the SM–SAO gel. A good correlation was found between rheological analysis and conventional stability tests. The heating/cooling cycle test provided useful information in a short period of time.
Keywords: Stability test; Rheology; Oleogels;
Use of lidocaine-prilocaine patch for the mantoux test: Influence on pain and reading by Jean-Christophe Dubus; Laurent Mely; André Lanteaume (78-80).
A formulation of a eutectic mixture of lidocaine-prilocaine (EMLA®) changes basal skin perfusion. Its use for alleviating pain associated with the Mantoux test may modify the recruitment of sensitised lymphocytes and then the response to tuberculin test. Twenty-four healthy BCG-vaccinated volunteers (26.7 ± 4.1 years) received on each forearm an intradermal injection of 10 IU tuberculin, one of the forearms being randomly pre-treated for 1 h with EMLA-patch®5%. Pain associated with the Mantoux test was evaluated using a visual analogue scale. The transversal diameter of the induration was read at 72 h. Subjects with 6 mm difference between diameters (i.e. twice the usual variation for a Mantoux test) were recorded. Results were compared using a paired t-test. When using lidocaine-prilocaine prior to the test, a three-fold decrease in pain was noted (p < 0.0001). Reading of the test were not affected by the lidocaine-prilocaine application (p = 0.26). Four subjects had 6 mm or more difference between their two tests, two of them having an induration greater than 15 mm with lidocaine-prilocaine. Lidocaine-prilocaine reduces significantly pain associated with the Mantoux test but does not normally affect the test reading. However, when the induration is more than 15 mm, a control without lidocaine-prilocaine has to be considered.
Keywords: Tuberculin skin test; Analgesia; Lidocaine-prilocaine; Tuberculosis;
Design of a transdermal delivery system for aspirin as an antithrombotic drug by H.O. Ammar; M. Ghorab; S.A. El-Nahhas; R. Kamel (81-88).
Aspirin has become the gold standard to which newer antiplatelet drugs are compared for reducing risks of cardiovascular diseases, while keeping low cost. Oral aspirin has a repertoire of gastrointestinal side effects even at low doses and requires high frequent dosing because it undergoes extensive presystemic metabolism. Transdermal delivery offers an alternative route that bypasses the gut and may be more convenient and safer for aspirin delivery especially during long-term use. This study comprised formulation of aspirin in different topical bases. Release studies revealed that hydrocarbon gel allowed highest drug release. In vitro permeation studies revealed high drug permeation from hydrocarbon gel. Several chemical penetration enhancers were monitored for augmenting the permeation from this base. Combination of propylene glycol and alcohol showed maximum enhancing effect and, hence, was selected for biological investigation. The biological performance of the selected formulation was assessed by measuring the inhibition of platelet aggregation relevant to different dosage regimens aiming to minimize both drug dose and frequency of application. The results demonstrated the feasibility of successfully influencing platelet function and revealed that the drug therapeutic efficacy in transdermal delivery system is dose independent. Biological performance was re-assessed after storage and the results revealed stability and persistent therapeutic efficacy.
Keywords: Aspirin; Transdermal; Cardiovascular diseases; Platelet aggregation inhibition;
Rapid-onset intranasal delivery of metoclopramide hydrochloride by N.M. Zaki; G.A.S. Awad; N.D. Mortada; S.S. Abd ElHady (89-96).
Intranasal (IN) administration is a promising approach for rapid-onset delivery of medications and to circumvent their first-pass elimination when taken orally. Metoclopramide (MCP) is a potent antiemetic, effective even for preventing emesis induced by cancer chemotherapy. The feasibility of developing an efficacious intranasal formulation of metoclopramide has been undertaken in this study. The nasal absorption of MCP was studied in anesthetized rats over 60 min using the in vivo in situ technique. The influence of several formulation variables, vis., pH and the addition of preservative, viscosity and absorption enhancing agents on the nasal MCP absorption was examined. The data obtained showed that MCP was well absorbed nasally where almost 90% of the drug was absorbed after 60 min from the rat nasal cavity. The MCP absorption was pH-dependant such that the apparent first-order rate constant of absorption (K app) was almost tripled when the pH of the solution was increased from 5 to 8. However, deviation from the classical pH-partition theory was observed pointing to the role of aqueous pore pathway in MCP nasal absorption. The K app was significantly increased (P < 0.05) by incorporation of 0.01% of the preservative benzalkonium chloride. Conversely, increasing the solution viscosity by the use of hydroxylpropyl methylcellulose adversely affected the rate of absorption. The use of enhancers namely sodium deoxycholate, sodium cholate, chitosan low and high molecular weight, protamine sulphate and poly-l-arginine resulted in significant increase in MCP absorption. The highest promoting effect was observed with the bile salt sodium deoxycholate where about 92% of the drug was absorbed in 25 min from the rat nasal cavity and the K app showed more than two-fold increase as compared to control (from 0.0452 to 0.1017 min−1).
Keywords: Nasal absorption; Metoclopramide; Rapid-onset; Absorption enhancers;
Rapid-onset intranasal delivery of metoclopramide hydrochloride by N.M. Zaki; N.D. Mortada; G.A.S. Awad; S.S. Abd ElHady (97-103).
In the present study, several nasal absorption enhancers, used in metoclopramide hydrochloride (MCP HCl) nasal solutions, have been screened for their possible damaging effect in the in vitro human erythrocytes lysis experiment. Moreover, the in vivo leaching of biological markers from the rat nasal epithelium was used as a quantitative assessment for possible nasal mucosal irritation whereby the extent of release of total protein and lactate dehydrogenase (LDH) in the nasal lavage fluid was determined. Results showed that insignificant hemolysis from normal saline (P < 0.05) occurred with the enhancer protamine sulphate while poly-l-arginine and sodium cholate demonstrated very low (<15%) hemolysis and caused insignificant protein and LDH release from the rat nasal mucosa. Conversely, sodium deoxycholate and chitosan polymers (either of low or high molecular weight) showed high (>60%) hemolysis in vitro and the release of the biological markers in vivo was significantly higher (P < 0.05) than the control solution (no enhancer).A significant correlation (P < 0.05) existed between the enhancement effect of MCP HCl nasal absorption and the amounts of protein (r = 0.85) and LDH (r = 0.88). Furthermore, the pharmacokinetics of MCP HCl was determined after intravenous (IV), per-oral and intranasal administration of 10 mg drug dose in rabbits. The application of a nasal spray (NS) solution containing 0.5% sodium cholate resulted in a significant improvement (P < 0.05) in both the rate and extent of absorption of MCP HCl where the T max achieved was 23.3 min as compared to 50 min in case of the oral solution while the area under the serum concentration–time curve (AUC0–∞) were 506.1, 434.9 and 278.7 μg/ml min for IV, NS and oral solutions, respectively. These values corresponded to absolute bioavailabilities of 87.21 and 55.61% for the NS and oral solutions, respectively. It could thus be concluded that NS of MCP HCl represents a viable approach to achieving rapid and high systemic drug absorption during the emergency treatment of severe emesis.
Keywords: Nasal absorption enhancers; Protein release; Hemolysis; Lactate dehydrogenase; Absolute bioavailability;
A simply and sensitive fluorometric method for determination of gentamicin in liposomal suspensions by Jerzy Gubernator; Zuzanna Drulis-Kawa; Arkadiusz Kozubek (104-109).
A new method for measuring gentamicin in liposomes fluorometrically is described. The assay is based on the reaction between the amino groups in the gentamicin molecule and o-phthaldialdehyde (OPA), under basic pH conditions; the product's fluorescence can be read directly on a simple fluorimeter. The effects of several factors (time of reaction, volume of the OPA reagent, and product stability) were investigated. The standard curve was linear in the concentration range of 0.5–4.0 μg, showing an excellent determination coefficient of r 2 = 0.99. Additionally, the influence of different liposomal lipids on gentamicin determination was tested. Liposomal lipids containing no free amino groups (PC, Chol, DOTAP) have no influence on the reaction when present in the reaction mixture. In contrast, amino groups containing lipid (SA) showed intense method interference. Therefore, a method of lipid extraction was adapted to remove undesired lipids. The described method was successfully utilised during 2 years of liposomal gentamicin experiments.
Keywords: Liposomes; Gentamicin determination;
Rupture and drug release characteristics of multi-reservoir type microspheres with poly(dl-lactide-co-glycolide) and poly(dl-lactide) by Akihiro Matsumoto; Yasuhisa Matsukawa; Yuji Horikiri; Takehiko Suzuki (110-116).
For the multi-reservoir type microspheres composed of polylactide (PLA) and poly(dl-lactide-co-glycolide) (PLGA), the influence of inner drug-holding layer/outer layer ratio on drug release profiles was studied. The microspheres were prepared by the O/W type emulsion-solvent evaporation technique, and cisplatin was used as a model drug. The water-uptake and the erosion of each polymer were evaluated to clarify the mechanism of drug release for multi-reservoir type microspheres. The formulations were classified by the influence of the blending ratio on drug-release profiles: the formulations with the drug-release profiles independent of the blending ratio (Typel group) and the formulations with drug-release profiles depending on the blending ratio (type 2 group). The formulations of type 1 group showed the uniform swelling during drug-release test, and provided the drug-release governed by the erosion of the inner drug-holding layer. On the other hand, the formulations of Type2 group showed the rupture of outer layer which was induced by the swelling of inner drug-holding layer, and the microspheres with the low ratio of the PLGA provided the drug-release rate which exceeded the estimate from the erosion profiles. The results of present study revealed that two types of drug-release mechanism exist for multi-reservoir type microspheres.
Keywords: Poly(dl-lactic-co-glycolide); Polylactide; PLA and PLGA microspheres; Swelling; Drug controlled release;
Platelet adsorption and hemolytic properties of liquid crystal/composite polymers by Mei-Fen Shih; Min-Da Shau; Meng-Ying Chang; Se-Kai Chiou; Jiunn-Kae Chang; Jong-Yuh Cherng (117-125).
The aim of this study is to investigate how the presence of liquid crystal, cholesteryl oleyl carbonate, embedded into polymers (PMMA, Eb270, PU) affects the biocompatibility of composite membranes with human blood. The effects of different surface textures of composite membranes on platelet adhesion and platelet activation were evaluated as well. The adhesion and geometric deformation of platelets were demonstrated by SEM. The quantitative assay of platelet activation was determined by measuring the production of P-Selectin, and by measurement of the blood clotting index when PRP blood was incubated with pure polymer films and composite membranes. Moreover, the hemolysis studies on the damage to red blood cells were performed to gain information on the hemocompatibility of these biomaterials. The results showed that inclusion of cholesteryl oleyl carbonate (COC) embedded in composite membranes, improves their biocompatibility with respect to a substantial reduction of platelet adhesion and the controlled decrease of platelet activation. As the COC content of composite membranes was increased, the value of the blood clotting index increased and the production of P-Selectin decreased. The results also showed that the presence of COC resulted in a decrease of hemolysis ratios. Comparing among three different composite membranes, the best biocompatibility is achieved when PU/COC ≧ Eb270/COC > PMMA/COC. The in vitro studies performed in this work suggest that it may be reasonable to use liquid crystal COC as a mean of surface modification to improve the blood compatibility of biopolymers.
Keywords: Polymer; Liquid crystal; Cholesteryl oleyl carbonate; Platelet; Blood compatibility;
Performance comparison of neural network training algorithms in modeling of bimodal drug delivery by A. Ghaffari; H. Abdollahi; M.R. Khoshayand; I. Soltani Bozchalooi; A. Dadgar; M. Rafiee-Tehrani (126-138).
The major aim of this study was to model the effect of two causal factors, i.e. coating weight gain and amount of pectin–chitosan in the coating solution on the in vitro release profile of theophylline for bimodal drug delivery. Artificial neural network (ANN) as a multilayer perceptron feedforward network was incorporated for developing a predictive model of the formulations. Five different training algorithms belonging to three classes: gradient descent, quasi-Newton (Levenberg–Marquardt, LM) and genetic algorithm (GA) were used to train ANN containing a single hidden layer of four nodes. The next objective of the current study was to compare the performance of aforementioned algorithms with regard to predicting ability. The ANNs were trained with those algorithms using the available experimental data as the training set. The divergence of the RMSE between the output and target values of test set was monitored and used as a criterion to stop training. Two versions of gradient descent backpropagation algorithms, i.e. incremental backpropagation (IBP) and batch backpropagation (BBP) outperformed the others. No significant differences were found between the predictive abilities of IBP and BBP, although, the convergence speed of BBP is three- to four-fold higher than IBP. Although, both gradient descent backpropagation and LM methodologies gave comparable results for the data modeling, training of ANNs with genetic algorithm was erratic. The precision of predictive ability was measured for each training algorithm and their performances were in the order of: IBP, BBP > LM > QP (quick propagation) > GA. According to BBP–ANN implementation, an increase in coating levels and a decrease in the amount of pectin–chitosan generally retarded the drug release. Moreover, the latter causal factor namely the amount of pectin–chitosan played slightly more dominant role in determination of the dissolution profiles.
Keywords: Artificial neural network (ANN); Bimodal drug delivery; Genetic algorithm (GA); Gradient descent algorithm; Levenberg–Marquardt (LM) algorithm; Modeling; Training algorithm;
Preparation of nanomagnetic absorbent for partition coefficient measurement by Shik Chi Tsang; Chih Hao Yu; Xin Gao; Kin Y. Tam (139-144).
In this paper, we report a new method based on supercritical carbon dioxide (scCO2) to fill and distribute the porous magnetic nanoparticles with n-octanol in a homogeneous manner. The high solubility of n-octanol in scCO2 and high diffusivity and permeability of the fluid allow efficient delivery of n-octanol into the porous magnetic nanoparticles. Thus, the n-octanol-loaded magnetic nanoparticles can be readily dispersed into aqueous buffer (pH 7.40) to form a homogenous suspension consisting of nano-sized n-octanol droplets. We refer this suspension as the n-octanol stock solution. The n-octanol stock solution is then mixed with bulk aqueous phase (pH 7.40) containing an organic compound prior to magnetic separation. The small-size of the particles and the efficient mixing enable a rapid establishment of the partition equilibrium of the organic compound between the solid supported n-octanol nano-droplets and the bulk aqueous phase. UV–vis spectrophotometry is then applied to determine the concentration of the organic compound in the aqueous phase both before and after partitioning (after magnetic separation). As a result, log D values of organic compounds of pharmaceutical interest determined by this modified method are found to be in excellent agreement with the literature data.
Keywords: Magnetic nanoparticle; Porous; Supercritical fluid; Partition coefficient; Magnetic separation;
DSC studies on interactions between low molecular mass peptide dendrimers and model lipid membranes by B. Klajnert; J. Janiszewska; Z. Urbanczyk-Lipkowska; M. Bryszewska; R.M. Epand (145-152).
It has recently been shown that a newly synthesized peptide dendrimers possess antimicrobial activity against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria as well as against fungal pathogens (Candida albicans) [Klajnert, B., Janiszewska, J., Urbanczyk-Lipkowska, Z., Bryszewska, M., Shcharbin, D., Labieniec, M., 2006. Biological properties of low molecular mass peptide dendrimers. Int. J. Pharm. 309, 208–217]. To extend our knowledge about their impact on biological systems, interactions between a group of low molecular mass lysine based dendrimers and model lipid bilayers were examined by differential scanning calorimetry (DSC). Conformational stability of dendrimers in 5–85 °C temperature range was confirmed by circular dichroism measurements (CD). The dendrimer structure has been shown to play an important role in interactions with the membranes. A two-step mechanism of dendrimer–bilayer interactions was proposed. The first step involves electrostatic attractions between dendrimers and polar lipid heads, while the second one is a result of hydrophobic interactions between acyl chains and arms of dendrimers. While one dendrimer did not interact with the membrane, another with long hydrophobic arms significantly perturbed the membrane. Nevertheless, for all tested dendrimers the main transition in DSC scans was retained that indicates that these compounds at the tested concentrations did not cause the loss of membrane integrity.
Keywords: Dendrimer; Peptide; DSC; CD; Liposome; Vesicle; MLV; Bilayer;
Lectin-modified solid lipid nanoparticles as carriers for oral administration of insulin by Na Zhang; Qineng Ping; Guihua Huang; Wenfang Xu; Yanna Cheng; Xiuzhen Han (153-159).
The aim of this study was to design and characterize lectin-modified solid lipid nanoparticles (SLNs) containing insulin and to evaluate the potential of the lectin-modified colloidal carriers for oral administration of peptide and protein drugs. SLNs were prepared by three different methods. For comparison, some insulin-loaded SLNs were modified with wheat germ agglutinin-N-glutaryl-phosphatidylethanolamine (WGA-N-glut-PE). The particle size, zeta potential and entrapment efficiency of insulin-loaded SLNs were determined. Insulin-loaded SLNs prepared by an appropriate modification of the double dispersion method yielded the highest drug entrapment efficiency, which was more than 60%. In vivo experiments were carried out using insulin-loaded SLNs and WGA-modified SLNs prepared by this method. SLNs and WGA-modified SLNs protected insulin against degradation by digestive enzymes in vitro. The stabilizing effect of WGA-modified SLNs was greater than that observed in SLNs.After oral administration of insulin-loaded SLNs or WGA-modified SLNs to rats, the relative pharmacological bioavailabilities were 4.46% and 6.08%, and the relative bioavailabilities were 4.99% and 7.11%, respectively, in comparison to subcutaneous injection of insulin. These results demonstrated that SLNs and WGA-modified SLNs promoted the oral absorption of insulin.
Keywords: Wheat germ agglutinin; Insulin; Solid lipid nanoparticles; Oral administration;
Effect of nanoparticulate polybutylcyanoacrylate and methylmethacrylate–sulfopropylmethacrylate on the permeability of zidovudine and lamivudine across the in vitro blood–brain barrier by Yung-Chih Kuo; Hung-Hao Chen (160-169).
Effect of size of nanoscaled polybutylcyanoacrylate (PBCA) and methylmethacrylate–sulfopropylmethacrylate (MMA–SPM) on the permeability of zidovudine (AZT) and lamivudine (3TC) across the blood–brain barrier (BBB) was investigated. Also, influence of alcohol on the permeability of AZT and 3TC incorporated with the two polymeric nanoparticles (NPs) was examined. The loading efficiency and the permeability of AZT and 3TC decreased with an increase in the particle size of the two carriers. By employing PBCA NPs, the BBB permeability of AZT and that of 3TC became, respectively, 8–20 and 10–18 folds. Application of MMA–SPM NPs leaded to about 100% increase in the BBB permeability of the two drugs. In the presence of 0.5% ethanol, 4–12% enhancement in the BBB permeability of the two drugs was obtained in the current carrier-mediated system.
Keywords: Permeability; Blood–brain barrier; Zidovudine; Lamivudine; Polybutylcyanoacrylate; Methylmethacrylate–sulfopropylmethacrylate;
Water–Tween 40®/Imwitor 308®–isopropyl myristate microemulsions as delivery systems for ketoprofen: Small-angle X-ray scattering study by Matija Tomšič; Filip Podlogar; Mirjana Gašperlin; Marija Bešter-Rogač; Andrej Jamnik (170-177).
Small-angle X-ray scattering technique has been used to study the structural properties of the quaternary microemulsion Tween 40®/Imwitor 308®/isopropyl myristate/water and of five-component system obtained by the addition of the drug ketoprofen to the original quaternary system. The results enlighten the structuration of the studied systems and represent new complementary findings to the previous study [Podlogar, F., Bešter-Rogač, M., Gašperlin, M., 2005. The effect of internal structure of selected water–Tween 40 (R)–Imwitor 308 (R)–IPM microemulsions on ketoprofene release. Int. J. Pharm. 302, 68–77] on the correlation between the structuration of these systems and the release rates of the ketoprofen. The present results indicate that in the samples with the moderate to high concentration of water where the latter is a continuous phase the addition of smaller amounts of the ketoprofen does not change their inner structuration significantly. The quaternary sample containing 46.2 wt.% of water seems to be very near the composition where the transition from the bicontinuous to the lamellar structure of the microemulsion occurs. In the samples containing from 46.2 to 62.7 wt.% of water the swelling of lamellar phases with constant thickness of double-layer can be characterized. At approximately the latter composition another noticeable transition in the inner structuration of the microemulsion has been observed. Interestingly, all these changes in the inner structuration of the studied systems did not affect the trend of the drug release rates in this regime of water concentrations.
Keywords: Microemulsions; Structural investigations; Small-angle X-ray scattering; Lamellar phases; Swelling law;
Corrigendum to “Inhibition of malarial topoisomerase II in Plasmodium falciparum by antisense nanoparticles” [Int. J. Pharm. 319 (2006) 139–146] by Florian Föger; Wilai Noonpakdee; Brigitta Loretz; Songwut Joojuntr; Willi Salvenmoser; Marlene Thaler; Andreas Bernkop-Schnürch (178).