Drug Development and Industrial Pharmacy (DRUG DEV IND PHARM)

Publications in this journal

• Article: Mechanistic analysis of drug release from theophylline pellets coated by films containing pectin, chitosan and Eudragit RS.

  Alireza Ghaffari, Mohammad Reza Avadi, Hamid Reza Moghimi, Mahvash Oskoui, Khosrow Bayati, Morteza Rafiee-Tehrani
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  ABSTRACT: The objective of this study was to obtain detailed information on the mechanism of drug release from mixed-film of pectin-chitosan/Eudragit RS. Pellets (710-840 microm in diameter) containing 60% theophylline and 40% microcrystalline cellulose were prepared by extrusion-spheronization method. Eudragit L100-55 enteric coating capsules included film-coated pellets of theophylline in theoretical coating weight gains of 10, 15, and 20%, with pectin-chitosan complex contents of 5, 10, 15, and 20% for each level of weight gain were prepared and subjected to in vitro drug release. Drug release from this system showed a bimodal release profile characteristic with the drug release enhancement, being triggered (burst release) in the colonic medium. The reason for burst drug release may be due to the enzymatic degradation of pectin via pectinolytic enzymes in the simulated colonic medium. The mechanism of drug release from each formulation was evaluated in the terms of zero-order, first-order, Higuchi and Korsmeyer-Peppas models. It was observed that none of the enteric coating capsules showed any drug release in the simulated gastric medium (phase I). The analysis of release profiles showed that zero-order kinetics was found as the better fitting model for all formulations in the simulated small intestine (phase II) and it could be due to the pectin-chitosan swelling and subsequent formation of aqueous channels. In the colonic medium (phase III), due to degradation of pectin and its leaching from the mixed-film, there was a modification in drug release kinetics from swelling-controlled at phase II to anomalous at phase III. It also was found that both zero-order and Higuchi models contributed in colonic drug release from most of the formulations.
  Drug Development and Industrial Pharmacy 05/2008; 34(4):390-402.
• Article: A novel superdisintegrating agent made from physically modified chitosan with silicon dioxide.

  Musa El-Barghouthi, Ala'a Eftaiha, Iyad Rashid, Mayyas Al-Remawi, Adnan Badwan
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  ABSTRACT: Disintegrants and fillers represent important excipients for immediate-release solid dosage forms in many pharmaceutical applications. A new excipient based on the coprecipitation of chitosan and silica has been achieved. The "intimate" physical association between chitosan and silica creates an insoluble, hydrophilic, highly absorbent material, consequently, resulting in superiority in water uptake, water saturation for gelling formation, and compactability among other superdisintegrants. The new excipient has an outstanding functionality that does not primarily depend on water wicking and swelling properties. In fact, it translates it into superior disintegration characteristics with improved powder flow and compaction properties. Thus, the new excipient could act as a superdisintegrant and pharmaceutical filler at the same time. Studies have shown that chitosan-silica delivers superior performance in wet granulation formulations and is the only disintegrant that is effective at all concentrations in tablet formulation.
  Drug Development and Industrial Pharmacy 05/2008; 34(4):373-83.
• Article: A thermo-sensitive polymeric gel containing a gadolinium (Gd) compound encapsulated into liposomes significantly extended the retention of the Gd in tumors.

  Uyen Minh Le, Dalia S Shaker, Brian R Sloat, Zhengrong Cui
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  ABSTRACT: Gadolinium neutron capture therapy (Gd-NCT) is a promising approach to fight cancer. One key factor for the success of Gd-NCT is to deliver and maintain a sufficient amount of Gd inside tumors. A large amount of Gd can be readily introduced into tumors by direct intratumor injection. However, an innovative approach is needed to maintain the Gd in the tumors. We encapsulated a Gd compound into a liposome formulation and then dispersed the liposomes into a thermo-sensitive polymeric gel. In murine tumor models, we showed that this liposome-in-thermo-sensitive gel system significantly extended the retention of the Gd compound in tumors. This similar concept may be applied to prolong the retention of other cytotoxic chemicals in tumors, and thus, improve their anti-tumor efficacy.
  Drug Development and Industrial Pharmacy 05/2008; 34(4):413-8.
• Article: Encapsulation of indomethacin using coaxial ultrasonic atomization followed by solvent evaporation.

  Richard A Graves, Daniel Poole, Raisa Moiseyev, Levon A Bostanian, Tarun K Mandal
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  ABSTRACT: We have encapsulated indomethacin into poly (lactide-co-glycolide) (PLGA) using coaxial ultrasonic atomization technique. The specific aims of this study were to evaluate the effect of drug loading and a change in relative concentration of polymer in the inner and outer layers of coflowing spray liquids on the physicochemical characteristics of the particles. Indomethacin, a non steroidal anti-inflammatory drug, was selected as a model compound. The micro/nanocapsules prepared using a drug free PLGA solution as an outer layer showed higher encapsulation efficiency. Thermal analysis of the formulations indicated that indomethacin was dissolved within the PLGA matrix. The formulations prepared with 25 mg indomethacin showed relatively smaller particle size compared with the formulations prepared with 50 mg indomethacin. The particles, in general, showed bi- and tri-modal distribution. Irrespective of the compositions of the liquids 1 and 2, all the particles were smooth and spherical. A cross-section view of the particles revealed the presence of three different internal morphologies. These formulations were a mixture of hollow or solid spheres, and single or multiple spheres encapsulated into a larger sphere. To the best of our knowledge, this is the first study revealing the cross-sectional view of particles prepared with coaxial ultrasonic atomization technique.
  Drug Development and Industrial Pharmacy 05/2008; 34(4):419-26.
• Article: In situ ophthalmic gel of ciprofloxacin hydrochloride for once a day sustained delivery.

  Satishkumar P Jain, Sejal P Shah, Namita S Rajadhyaksha, Pirthi Pal Singh P S, Purnima D Amin
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  ABSTRACT: This article focuses on preparation and evaluation of a once a day ophthalmic delivery system for ciprofloxacin hydrochloride based on the concept of pH-triggered in situ gelation. The in situ gelling system involves the use of polyacrylic acid (Carbopol 980NF) as a phase transition polymer, hydroxypropyl methylcellulose (Methocel K100LV) as a release retardant, and ion exchange resin as a complexing agent. Ciprofloxacin hydrochloride was complexed with ion exchange resin to avoid incompatibility between drug and polyacrylic acid. The developed formulation was stable, and nonirritant to rabbit eyes and in vitro drug release was found to be around 98% over a period of 24 hours.
  Drug Development and Industrial Pharmacy 05/2008; 34(4):445-52.
• Article: Investigation of nanostructured lipid carriers for transdermal delivery of flurbiprofen.

  Fei Han, Sanming Li, Ran Yin, Xiaolei Shi, Qiang Jia
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  ABSTRACT: The aim of this study was to develop nanostructured lipid carriers (NLC) for transdermal delivery of Flurbiprofen (FP). The physical stability of FP-NLC and its in vitro permeation profile were investigated. After three months of storage at 4 degrees C, 20 degrees C, and 40 degrees C, no significant differences between the evaluated parameters, such as pH value, the entrapment efficiency, particle size, and zeta potential were observed. In in vitro permeation studies, the cumulative permeated amounts and the release rate from FP-NLC were 412.53 +/- 21.37 microg/cm(2) and 35.25 microg/cm(2)/h after 12 h (n = 6), respectively, while from saturated FP-PBS (pH = 7.4) were 90.83 +/- 8.67 microg/cm(2) and 6.99 microg/cm(2)/h, respectively. These results indicated that the FP-NLC were with good physical stability and were able to improve the permeated amounts and the release rate of FP. It could potentially be exploited as a carrier with improved drug entrapment efficiency and permeated amount in the transdermal delivery of FP.
  Drug Development and Industrial Pharmacy 05/2008; 34(4):453-8.
• Article: Enhanced percutaneous permeability of diclofenac using a new U-type dilutable microemulsion.

  Marina Shevachman, Nissim Garti, Arnon Shani, Amnon C Sintov
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  ABSTRACT: Enhanced systemic absorption in vivo and percutaneous penetration in vitro was demonstrated after transdermal administration of diclofenac sodium formulated in U-type microemulsion. Diclofenac sodium was solubilized in a typical four-component system consisting of an oil, polyoxyethylene-10EO-oleyl alcohol (Brij 96V) as the surfactant, and 1-hexanol along water dilution line W46 (40 wt % surfactant and 60 wt % oil phase before water titration). Viscosity and small angle X-ray scattering measurements have evidenced bicontinuous structures within water fractions of 0.25 and 0.5 along the dilution line. Self-diffusion NMR studies showed that drug molecules accumulated in the interfacial film and, to some extent, dissolved in the oil. Relative to a commercial macro-emulsion cream (Voltaren Emulgel), microemulsions containing paraffin oil or isopropyl myristate increased the in vivo transdermal penetration rate of diclofenac by two order of magnitude, whereas the rat plasma levels were increased by one order of magnitude. The in vitro data obtained from excised rat skin were comparable to the in vivo results, but suffered from discrepancies from the ideal in vivo-in vitro correlation, which might be explained by optimal in vitro conditions of perfusion and hydration. It has also been found that when jojoba oil is formulated as the oil phase in the microemulsion, the penetration rate of the drug decreases significantly. Based on the three-dimensional structure of jojoba oil, the wax is presumed to prevent the drug from being freely diffused into the skin while migrating from the interfacial film into the continuous oil phase.
  Drug Development and Industrial Pharmacy 05/2008; 34(4):403-12.
• Article: Antimicrobial activity of parabens in submicron emulsions stabilized with lecithin.

  Malgorzata Młynarczyk, Malgorzata Sznitowska, Dorota Watrobska-Swietlikowska
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  ABSTRACT: Antimicrobial efficacy of methyl and propylparaben combination as potential preservatives for submicron emulsions, and the effect of oil and lecithin concentration on the microbial growth were investigated. Parabens were ineffective in standard or doubled concentrations as per pharmacopoeial criteria. Poor growth inhibition and multiplication of reference strains point to protective and growth properties of submicron emulsions. No correlation was observed between oil/lecithin ratio and efficacy of parabens; partitioning of the latter into the oily phase and lipophilic domains could be the reason for such effect. Further studies are necessary to establish a stable and safe composition of such formulations.
  Drug Development and Industrial Pharmacy 05/2008; 34(4):355-62.
• Article: Optimization and evaluation of time-dependent tablets comprising an immediate and sustained release profile using artificial neural network.

  Huijun Xie, Yong Gan, Suwei Ma, Li Gan, Qinghua Chen
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  ABSTRACT: The aim of this work was to optimize time-dependent tablets using artificial neural network (ANN). The time-dependent tablet consisted of a tablet core, which contained sustained release pellets (70% isosorbide-5-mononitrate [5-ISMN]), immediate release granules (30% 5-ISMN), superdisintegrating agent (sodium carboxymethylstarch, CMS-Na), and other excipients, surrounded by a coating layer composed of a water-insoluble ethylcellulose and a water-soluble channeling agent. The chosen independent variables, i.e., X(1) coating level of tablets, X(2) coating level of pellets, and X(3) CMS-Na level, were optimized with a three-factor, three-level Box-Behnken design. Data were analyzed for modeling and optimizing the release profile using ANN. Response surface plots were used to relate the dependent and the independent variables. The optimized values for the factors X(1)-X(3) were 4.1, 14.1, and 29.8%, respectively. Optimized formulations were prepared according to the factor combinations dictated by ANN. In each case, the observed drug release data of the optimized formulations were close to the predicted release pattern. An in vitro model for predicting the effect of food on release behavior of optimized products was used in this study. It was concluded that neural network technique could be particularly suitable in the pharmaceutical technology of time-dependent dosage forms where systems were complex and nonlinear relationships often existed between the independent and the dependent variables.
  Drug Development and Industrial Pharmacy 05/2008; 34(4):363-72.
• Article: Temperature-responsive, Pluronic-g-poly(acrylic acid) copolymers in situ gels for ophthalmic drug delivery: rheology, in vitro drug release, and in vivo resident property.

  Wen-di Ma, Hui Xu, Shu-fang Nie, Wei-san Pan
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  ABSTRACT: To prolong the precorneal resident time and improve ocular bioavailability of the drug, Pluronic-g-poly(acrylic acid) copolymers were studied as a temperature-responsive in situ gelling vehicle for an ophthalmic drug delivery system. The rheological properties and in vitro drug release of Pluronic-g-PAA copolymer gels, as well as the in vivo resident properties of such in situ gel ophthalmic formulations, were investigated. The rheogram and in vitro drug release studies indicated that the drug release rates decreased as acrylic acid/Pluronic molar ratio and copolymer solution concentration increased. It was also shown that the drug concentration had no obvious effect on drug release. The release rates of drug from such copolymer gels were mainly dependent on the gel dissolution. In vivo resident experiments showed the drug resident time and the total resident amount increased by 4-fold and 1.2-fold for in situ gel compared with eye drops. These in vivo experimental results, along with the rheological properties and in vitro drug release studies, demonstrated that in situ gels containing Pluronic-g-PAA copolymer may significantly prolong the drug resident time and thus improve bioavailability. The results showed that the Pluronic-g-PAA copolymer can be a promising in situ gelling vehicle for ophthalmic drug delivery.
  Drug Development and Industrial Pharmacy 04/2008; 34(3):258-66.
• Article: Tailoring the release rates of fluconazole using solid dispersions in polymer blends.

  George Z Papageorgiou, Dimitrios Bikiaris, Feras I Kanaze, Evangelos Karavas, Anagnostis Stergiou, Emmanouil Georgarakis
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  ABSTRACT: Formulations of the drug Fluconazole with different release characteristics were prepared by dispersing the active pharmaceutical ingredient (API) in various polymeric carriers, and especially in polymer blends. Fluconazole was tested as a model drug with low solubility in water. First solid dispersions in pure polymers were studied. Use of pure polyvinylpyrrolidone (PVP) as carrier even for high drug load (30 wt%) resulted in rapid release. The drug release rates decreased by increasing the API content. The dissolution rate enhancement was attributed to drug amorphization, particle size reduction, and possible improvement of the drug wetting characteristics. Hydroxypropyl methylcellulose (HPMC) gave solid dispersions, from which the release rates of the drug varied from immediate to sustaining. As the drug amount increased, the rates became higher. Similar behavior also was found when Chitosan was used as carrier, with much more controlled rates close to those for sustained release. These differences were mainly attributed to the limited solubility and swelling of HPMC and Chitosan in aquatic media. To study the effectiveness of polymer blends in adjusting the release rates of the drug, solid dispersions in PVP/HPMC and PVP/Chitosan miscible blends were studied. The release rates of Fluconazole were adequately adjusted by differentiating the weight ratio of the polymers in the blends. PVP/HPMC blends with high PVP content can be used for immediate release formulations but PVP/Chitosan blends are inappropriate for such formulations and can only be used for controlled release.
  Drug Development and Industrial Pharmacy 04/2008; 34(3):336-46.
• Article: Differences in characteristics of pellets prepared by different pelletization methods.

  Adam Häring, David Vetchý, Lucie Janovská, Katerina Krejcová, Miloslava Rabisková
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  ABSTRACT: Pellets are currently a very popular dosage form for oral application. They can be prepared by several pelletization techniques. Extrusion/spheronization, commonly used in the pharmaceutical industry, and modern agglomeration in a rotoprocessor were the methods chosen for pellet preparation in our study. Theophylline (in 10% to 65% concentration) was the model drug, lactose monohydrate was used as filler, microcrystalline cellulose Avicel PH 101 was thespheronization enhancer, and the wetting agent was purified water. Both techniques led to the formation of pellets of appropriate shape and mechanical properties. Pellets of a higher density, hardness, lower friability, and slightly slower dissolution profiles were obtained by extrusion/spheronization. This method of pelletization also led to production of particles with narrower size distribution and bigger yield of pellets with the requested size.
  Drug Development and Industrial Pharmacy 04/2008; 34(3):289-96.
• Article: Development of the ambroxol gels for enhanced transdermal delivery.

  Cheong-Weon Cho, Jun-Shik Choi, Sang-Chul Shin
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  ABSTRACT: Ambroxol is an expectoration improver and mucolytic agent that has been used to treat acute and chronic disorders. However, ambroxol needs to be administered percutaneously in order to avoid systemic adverse effects, such as headache, drowsiness, dizziness, and insomnia, which can occur after oral administration. The aim of this study was to develop a gel preparation containing a permeation enhancer to enhance the delivery of ambroxol. The ambroxol gels were prepared using hydroxypropyl methylcellulose (HPMC) and poloxamer 407. The release characteristics of the drug from the gels were examined according to the receptor medium, drug concentration, and temperature. The rate of drug permeation into the skin was enhanced by incorporating various enhancers such as the ethylene glycols, the propylene glycols, the glycerides, the non-ionic surfactants, and the fatty acids into the gels. The permeation study through mouse skin was examined at 37 C. The rate of drug release increased with increasing drug concentration and temperature. Among the enhancers used, propylene glycol mono caprylate showed the best enhancing effects. The estimated activation energy of release (Ea), which was calculated from the slope of a log P versus 1000/T plot, was 14.80, 14.22, 13.91, and 12.46 kcal/mol for ambroxol loading doses of 2, 3, 4, and 5%, respectively. The results of this study show that the gel preparation of ambroxol containing a permeation enhancer could be developed for the enhanced transdermal delivery of ambroxol.
  Drug Development and Industrial Pharmacy 04/2008; 34(3):330-5.
• Article: In vitro assessment of acyclovir permeation across cell monolayers in the presence of absorption enhancers.

  Pranav Shah, Viral Jogani, Pushpa Mishra, Anil Kumar Mishra, Tamishraha Bagchi, Ambikanandan Misra
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  ABSTRACT: The aim of the investigation was to establish transepithelial permeation of acyclovir across Caco-2 and Madin-Darby canine kidney (MDCK) cell monolayers and attempt to improve its permeation by employing absorption enhancers (dimethyl beta cyclodextrin, chitosan hydrochloride and sodium lauryl sulfate) and combinations thereof. Caco-2 and MDCK cell monolayers have been widely employed in studying drug transport, mechanisms of drug transport, and screening of absorption enhancers and excipients. Transepithelial electrical resistance and permeation of 99mTc-mannitol were employed as control parameters to assess the tight junction and paracellular integrity. Permeation of acyclovir in the presence of absorption enhancers was found to be significantly higher compared with drug permeation in their absence when assessed as apparent permeability coefficients (Papp). Synergistic improvements in Papp values of acyclovir were obtained in case-selected combinations of absorption enhancers; dimethyl beta cyclodextrin-chitosan hydrochloride, chitosan hydrochloride-sodium lauryl sulfate, and dimethyl beta cyclodextrin-sodium lauryl sulfate, were used. Recovery and viability assessment studies of both cell monolayers suggested reestablishment of paracellular integrity and no damage to cell membranes. Significantly improved permeation of acyclovir in the presence of selected combinations of absorption enhancers may be used as a viable approach in overcoming the problem of limited oral bioavailability of acyclovir.
  Drug Development and Industrial Pharmacy 04/2008; 34(3):279-88.
• Article: Precursor system of liquid crystalline phase containing propolis microparticles for the treatment of periodontal disease: development and characterization.

  Marcos Luciano Bruschi, Osvaldo de Freitas, Elza Helena Guimarã Es Lara, Heitor Panzeri, Maria Palmira Daflon Gremião, David Simon Jones
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  ABSTRACT: Precursor systems of liquid crystalline phase were prepared using the surfactant PPG-5-Ceteth-20, isopropyl myristate, and water; gelatin microparticles containing propolis were then added into these systems. Homogeneity of dispersion, the in-system microparticle morphology, and sedimentation behavior of each formulation were evaluated. The rheological and mechanical properties (hardness, compressibility, and adhesiveness), the work of syringing, and the propolis release profile were also evaluated. All the formulations exhibited pseudoplastic flow and thixotropy, and they displayed storage modulus, loss modulus, dynamic viscosity, and loss tangent that depended on temperature, frequency, and composition. Mechanical properties varied significantly among the formulations being affected by changes in the composition and temperature. Raising the concentration of surfactant and adding propolis microparticles significantly decreased the work of syringing. The drug release was non-Fickian (anomalous) and there was no significant difference between the tested systems in the times required for 10%, 30%, and 50% release of the initial drug loading.
  Drug Development and Industrial Pharmacy 04/2008; 34(3):267-78.
• Article: Formulation and in vitro studies of a fixed-dose combination of a bilayer matrix tablet containing metformin HCl as sustained release and glipizide as immediate release.

  Uttam Mandal, Tapan Kumar Pal
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  ABSTRACT: The emerging new fixed dose combination of metformin hydrocholride (HCl) as sustained release and glipizide as immediate release were formulated as a bilayer matrix tablet using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, and the tablets were evaluated via in vitro studies. Three different grades of HPMC (HPMC K 4M, HPMC K 15M, and HPMC K 100M) were used. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. In vitro release studies were carried out at a phosphate buffer of pH 6.8 with 0.75% sodium lauryl sulphate w/v using the apparatus I (basket) as described in the United States Pharmacopeia (2000). The release kinetics of metformin were evaluated using the regression coefficient analysis. There was no significant difference in drug release for different viscosity grade of HPMC with the same concentration. Tablet thus formulated provided sustained release of metformin HCl over a period of 8 hours and glipizide as immediate release.
  Drug Development and Industrial Pharmacy 04/2008; 34(3):305-13.
• Article: An in vitro evaluation of fenugreek mucilage as a potential excipient for oral controlled-release matrix tablet.

  Ali Nokhodchi, Hossein Nazemiyeh, Afagh Khodaparast, Tarifeh Sorkh-Shahan, Hadi Valizadeh, J L Ford
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  ABSTRACT: A polysaccharide mucilage derived from the seeds of fenugreek, Trigonella foenum-graceum L (family Fabaceae) was investigated for use in matrix formulations containing propranolol hydrochloride. Methocel hypomellose K4M was used as a standard controlled release polymer for comparison purposes. In this study the effect of lactose on the release behaviour of propranolol hydrochloride from matrices formulated to contain the fenugreek mucilage also was investigated. An increase in concentration of the mucilage in matrices resulted in a reduction in the release rate of propranolol hydrochloride comparable to that observed with hypomellose matrices. The rate of release of propranolol hydrochloride from fenugreek mucilage matrices was mainly controlled by the drug:mucilage ratio. However, the mechanism of release from matrices containing drug:mucilage ratios of 1:1, 1:1.25, 1:1.5, and 1:2 remained the same. The kinetics of release, utilising the release exponent n, showed that the values of n were between 0.46-0.57 indicating that the release from fenugreek mucilage matrices was predominantly by diffusion. The presence of lactose in matrices containing mucilage increased the release rate of propranolol hydrochloride. This is due to a reduction in tortuoisity and increased pore size of channels caused by lactose through which propranolol diffuses and therefore diffusion of water into the tablet is facilitated.
  Drug Development and Industrial Pharmacy 04/2008; 34(3):323-9.
• Article: Basil oil is a promising skin penetration enhancer for transdermal delivery of labetolol hydrochloride.

  Rahul Jain, Mohammed Aqil, Abdul Ahad, Asgar Ali, Roop K Khar
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  ABSTRACT: The present work investigates effectiveness of basil oil, a volatile oil containing alcoholic terpenes, as a potential penetration enhancer for improved skin permeation of labetolol hydrochloride (LHCl) with reference to camphor, geraniol, thymol, and clove oil. Saturation solubilities of LHCl were determined in water, vehicle (ethanol:water, 60:40 v/v) and vehicle containing 5% w/v terpenes. Comparable (P > 0.05) saturation solubilities were found suggesting an insignificant increase in LHCl flux across rat skin on account of thermodynamic activity. Permeation of LHCl in vehicle per se and in presence of 5% w/v enhancer was investigated by performing in vitro rat abdominal skin permeation studies using a side-by-side glass diffusion cell. Various parameters viz. steady state flux, permeability coefficient, lag time, partition coefficient, diffusion coefficient, and enhancement ratios (ER) were calculated from the permeation data. Basil oil produced the maximum enhancement (ER = 46.52) over neat vehicle, among all enhancers. Activation energies for LHCl permeation in water, vehicle per se and in presence of 5% w/v basil oil were found to be 23.16, 18.71, and 10.98 kcal/mole, respectively. Lowering of activation energy in presence of basil oil suggests creation of new polar pathways in the skin for enhanced permeation of LHCl. Basil oil is proposed as a promising penetration enhancer for improved transdermal drug delivery of labetolol.
  Drug Development and Industrial Pharmacy 04/2008; 34(4):384-9.
• Article: Formation, physical stability and in vitro antimalarial activity of dihydroartemisinin nanosuspensions obtained by co-grinding method.

  Jiraporn Chingunpitak, Satit Puttipipatkhachorn, Porntip Chavalitshewinkoon-Petmitr, Yuichi Tozuka, Kunikazu Moribe, Keiji Yamamoto
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  ABSTRACT: The purpose of this study was to investigate the formation of drug nanoparticles from binary and ternary mixtures, consisting of dihydroartemisinin (DHA), a poorly water-soluble antimalarial drug, with water-soluble polymer and/or surfactant. Binary mixtures of drug/polyvinyl pyrrolidone K30 (PVP K30), binary mixtures of drug/sodium deoxycholate (NaDC), and ternary mixtures of drug/PVP K30/NaDC were prepared at different weight ratios and then ground by vibrating rod mill to obtain ground mixtures. Nanosuspension was successfully formed after dispersing ternary ground mixtures or DHA/NaDC ground mixtures in water. The ternary ground mixtures did not give superior nanosuspension in terms of particle size reduction and recovery of drug nanoparticles, but they provided more physically stable nanosuspensions than DHA/NaDC ground mixtures. The size of drug nanoparticles was decreased with increasing grinding time and lowering amount of PVP K30 and NaDC. About 95% of drug nanoparticles were found in the nanosuspension from ternary ground mixtures. Zeta potential measurement suggested that stable nanosuspension was attributable to adsorption of NaDC and PVP K30 onto surface of drug particles. Atomic force microscopy and transmission electron microscopy with selected area diffraction indicated that DHA in nanosuspension was existed as nanocrystals. The obtained nanosuspensions had higher in vitro antimalarial acitivity against Plasmodium falciparum than microsuspensions. The results suggest that co-grinding of DHA with PVP K30 and NaDC seems to be a promising method to prepare DHA nanosuspension.
  Drug Development and Industrial Pharmacy 04/2008; 34(3):314-22.