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Pharmaceutics, Volume 4, Issue 3 (September 2012), Pages 334-493

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Research

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Open AccessArticle Development and Validation of a Successful Microbiological Agar Assay for Determination of Ceftriaxone Sodium in Powder for Injectable Solution
Pharmaceutics 2012, 4(3), 334-342; doi:10.3390/pharmaceutics4030334
Received: 23 March 2012 / Revised: 22 May 2012 / Accepted: 12 June 2012 / Published: 29 June 2012
Cited by 2 | PDF Full-text (151 KB) | HTML Full-text | XML Full-text
Abstract
Ceftriaxone sodium is a cephalosporin with broad-spectrum antimicrobial activity and belongs to the third generation of cephalosporins. Regarding the quality control of medicines, a validated microbiological assay for the determination of ceftriaxone sodium in powder for injectable solution has not been reported yet.
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Ceftriaxone sodium is a cephalosporin with broad-spectrum antimicrobial activity and belongs to the third generation of cephalosporins. Regarding the quality control of medicines, a validated microbiological assay for the determination of ceftriaxone sodium in powder for injectable solution has not been reported yet. This paper reports the development and validation of a simple, accurate and reproducible agar diffusion method to quantify ceftriaxone sodium in powder for injectable solution. The assay is based on the inhibitory effect of ceftriaxone sodium on the strain of Bacillus subtilis ATCC 9371 IAL 1027 used as test microorganism. The results were treated statistically by analysis of variance and were found to be linear (r = 0.999) in the selected range of 15.0–60.0 μg/mL, precise with a relative standard deviation (RSD) of repeatability intraday = 1.40%, accurate (100.46%) and robust with a RSD lower than 1.28%. The results demonstrated the validity of the proposed bioassay, which allows reliable ceftriaxone sodium quantitation in pharmaceutical samples and therefore can be used as a useful alternative methodology for the routine quality control of this medicine. Full article
Open AccessArticle Design of Skin Penetration Enhancers Using Replacement Methods for the Selection of the Molecular Descriptors
Pharmaceutics 2012, 4(3), 343-353; doi:10.3390/pharmaceutics4030343
Received: 3 May 2012 / Revised: 25 June 2012 / Accepted: 28 June 2012 / Published: 11 July 2012
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Abstract
Transdermal delivery of certain drugs is challenging because of skin barrier resistance. This study focuses on the implementation of feature-selection algorithms to design chemical penetration enhancers. A database, consisting of 145 polar and nonpolar chemicals, was chosen for the investigation. Replacement, enhanced replacement
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Transdermal delivery of certain drugs is challenging because of skin barrier resistance. This study focuses on the implementation of feature-selection algorithms to design chemical penetration enhancers. A database, consisting of 145 polar and nonpolar chemicals, was chosen for the investigation. Replacement, enhanced replacement and stepwise algorithms were applied to identify relevant structural properties of these compounds. The descriptors were calculated using Molecular Modeling Pro™ Plus. Based on the coefficient of determination, the replacement methods outperformed the stepwise approach in selecting the features that best correlated with the flux enhancement ratio. An artificial neural network model was built to map a subset of descriptors from sixty-one nonpolar enhancers onto the output vector. The R2 value improved from 0.68, for a linear model, to 0.74, which shows that the improved framework might be effective in the design of compounds with user-defined properties. Full article
Open AccessArticle Application and Characterization of Gum from Bombax buonopozense Calyxes as an Excipient in Tablet Formulation
Pharmaceutics 2012, 4(3), 354-365; doi:10.3390/pharmaceutics4030354
Received: 23 April 2012 / Revised: 19 July 2012 / Accepted: 26 July 2012 / Published: 3 August 2012
Cited by 4 | PDF Full-text (236 KB) | HTML Full-text | XML Full-text
Abstract
This study was undertaken to explore gum from Bombax buonopozense calyxes as a binding agent in formulation of immediate release dosage forms using wet granulation method. The granules were characterized to assess the flow and compression properties and when compressed, non-compendial and compendial
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This study was undertaken to explore gum from Bombax buonopozense calyxes as a binding agent in formulation of immediate release dosage forms using wet granulation method. The granules were characterized to assess the flow and compression properties and when compressed, non-compendial and compendial tests were undertaken to assess the tablet properties for tablets prepared with bombax gum in comparison with those prepared with tragacanth and acacia gums. Granules prepared with bombax exhibited good flow and compressible properties with angle of repose 28.60°, Carr’s compressibility of 21.30% and Hausner’s quotient of 1.27. The tablets were hard, but did not disintegrate after one hour. Furthermore, only 52.5% of paracetamol was released after one hour. The drug release profile followed zero order kinetics. Tablets prepared with bombax gum have the potential to deliver drugs in a controlled manner over a prolonged period at a constant rate. Full article
(This article belongs to the Special Issue Oral and Buccal Drug Delivery)
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Open AccessArticle Using Ion-Selective Electrodes to Study the Drug Release from Porous Cellulose Matrices
Pharmaceutics 2012, 4(3), 366-376; doi:10.3390/pharmaceutics4030366
Received: 21 June 2012 / Revised: 13 July 2012 / Accepted: 27 July 2012 / Published: 7 August 2012
Cited by 1 | PDF Full-text (218 KB) | HTML Full-text | XML Full-text
Abstract
Polyvinyl chloride (PVC)-based solid-contact ion-selective electrodes (SC-ISEs), responding to propranolol hydrochloride (Pr+) and lidocaine hydrochloride (Ld+) cations as the model drugs with potassium tetrakis(4-chlorophenyl) borate (KTpClPB) as the ion exchanger, were studied. Different drug-polymer solutions were prepared with the
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Polyvinyl chloride (PVC)-based solid-contact ion-selective electrodes (SC-ISEs), responding to propranolol hydrochloride (Pr+) and lidocaine hydrochloride (Ld+) cations as the model drugs with potassium tetrakis(4-chlorophenyl) borate (KTpClPB) as the ion exchanger, were studied. Different drug-polymer solutions were prepared with the model drugs, using different blend ratios of ethylcellulose (EC) and hydroxypropyl cellulose (HPC). Two different solid dosage forms were used. Polymer films were produced by solvent casting method and drug containing porous cellulose samples were prepared by depositing the drug-polymer solutions onto filter paper substrates. The quality of the electrodes and the release profile of Pr+ and Ld+ were investigated with the potentiometric method. The results were compared to UV spectrophotometry. The electrodes were found to be sensitive, precise and functional with a Nernstian behavior over the range of 1.0 × 10−3–3.1 × 10−6 M (9.2 × 10−4–3.0 × 10−1 mg/mL) and 1 × 10−3–2 × 10−6 M (5.4 × 10−4–2.7 × 10−1 mg/mL) at 25 °C for Pr+ and Ld+ sensitive electrodes, respectively. The dynamic response time for the electrodes was less than 10 s. The Pr+ release from porous filter paper was always higher than its equivalent film formulation. Also, lidocaine had higher and faster release from the samples with higher drug concentration. The comparison of the two analytical methods showed near identical results. The ISEs provided a powerful and flexible alternative to UV method in determination of drug release from porous cellulose substrates in a small scale dissolution testing. Full article
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Open AccessArticle The Effect of Diluted Penetration Enhancer in Nebulized Mist versus Liquid Drop Preparation Forms on Retrobulbar Blood Flow in Healthy Human Subjects
Pharmaceutics 2012, 4(3), 377-384; doi:10.3390/pharmaceutics4030377
Received: 10 April 2012 / Revised: 25 July 2012 / Accepted: 1 August 2012 / Published: 8 August 2012
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Abstract
The aim of this study was to compare the effects of nebulized mist and liquid drop applications on retrobulbar blood flow. A prospective, non-randomized clinical trial was used to collect data from 40 healthy human eyes. Color Doppler Imaging determined peak systolic (PSV)
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The aim of this study was to compare the effects of nebulized mist and liquid drop applications on retrobulbar blood flow. A prospective, non-randomized clinical trial was used to collect data from 40 healthy human eyes. Color Doppler Imaging determined peak systolic (PSV) and end diastolic (EDV) blood flow velocities and resistance index (RI) in the ophthalmic artery after both applications. Measurements were taken at baseline and at 1 min post-treatment in both eyes with 5 min measurements in the treatment eye only. p values ≤ 0.05 were considered statistically significant. Mist application to treatment eye produced an increase in 1 min and 5 min PSV and EDV (0.001 < p < 0.03) and a decrease in 5 min RI (p = 0.01), with no significant changes in PSV, EDV or RI of control eye or in treatment eye 1 min RI (p > 0.05). Drop application to treatment eye produced an increase in PSV (p < 0.001) and EDV (p = 0.01) at 1 min, with an increase in control eye 1 min PSV and EDV (p = 0.03). There were no statistically significant changes in treatment eye PSV, EDV and RI after 5 min (p > 0.05). The use of nebulized mist may provide an effective alternative to liquid drop medication application. Full article
Open AccessArticle Levofloxacin-Proliposomes: Opportunities for Use in Lung Tuberculosis
Pharmaceutics 2012, 4(3), 385-412; doi:10.3390/pharmaceutics4030385
Received: 8 May 2012 / Revised: 5 July 2012 / Accepted: 26 July 2012 / Published: 13 August 2012
Cited by 11 | PDF Full-text (5745 KB) | HTML Full-text | XML Full-text
Abstract
Levofloxacin (LEV) is a relatively new-generation fluoroquinolone antibiotic that has good activity against Mycobacterium tuberculosis. The aims of this study were to develop and evaluate LEV-proliposomes in a dry powder aerosol form for pulmonary delivery. LEV-proliposomes containing LEV, soybean phosphatidylcholine, cholesterol and
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Levofloxacin (LEV) is a relatively new-generation fluoroquinolone antibiotic that has good activity against Mycobacterium tuberculosis. The aims of this study were to develop and evaluate LEV-proliposomes in a dry powder aerosol form for pulmonary delivery. LEV-proliposomes containing LEV, soybean phosphatidylcholine, cholesterol and porous mannitol were prepared by a spray drying technique. The physicochemical properties of LEV-proliposomes were determined using a cascade impactor, X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The toxicity of proliposomes to respiratory-associated cell lines and its potential to provoke immunological responses from alveolar macrophages (AMs) were evaluated. Antimycobacterial activity using flow cytometry and an in vivo repeated dose toxicity test in rats were carried out. LEV-proliposomes were successfully prepared with mass median aerodynamic diameters of 4.15–4.44 μm and with fine particle fractions (aerosolized particles of less than 4.4 µm) of 13%–38% at 60 L/min. LEV-proliposomes were less toxic to respiratory-associated cells than LEV, and did not activate AMs to produce inflammatory mediators that included interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nitric oxide. The minimum inhibitory concentration (MIC) against M. bovis of LEV and LEV-proliposomes containing LEV 10% were 1 and 0.5 µg/mL, respectively. The efficacy of LEV-proliposomes against M. bovis was significantly higher than that of free LEV (p < 0.05). The efficacy of the LEV-proliposomes against M. tuberculosis was equal to that of the free LEV (MIC = 0.195 µg/mL). In a repeated dose toxicity study in rats, renal and liver toxicity was not observed. LEV-proliposomes should now be tested as an alternative formulation for delivering LEV to the lower airways. Full article
Open AccessArticle Diclofenac Salts, VIII. Effect of the Counterions on the Permeation through Porcine Membrane from Aqueous Saturated Solutions
Pharmaceutics 2012, 4(3), 413-429; doi:10.3390/pharmaceutics4030413
Received: 16 July 2012 / Revised: 29 August 2012 / Accepted: 29 August 2012 / Published: 12 September 2012
Cited by 7 | PDF Full-text (211 KB) | HTML Full-text | XML Full-text
Abstract
The following bases: monoethylamine (EtA), diethylamine (DEtA), triethylamine (TEtA), monoethanolamine (MEA), diethanolamine (DEA), triethanolamine (TEA), pyrrolidine (Py), piperidine (Pp), morpholine (M), piperazine (Pz) and their N-2-hydroxyethyl (HE) analogs were employed to prepare 14 diclofenac salts. The salts were re-crystallized from water in
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The following bases: monoethylamine (EtA), diethylamine (DEtA), triethylamine (TEtA), monoethanolamine (MEA), diethanolamine (DEA), triethanolamine (TEA), pyrrolidine (Py), piperidine (Pp), morpholine (M), piperazine (Pz) and their N-2-hydroxyethyl (HE) analogs were employed to prepare 14 diclofenac salts. The salts were re-crystallized from water in order to obtain forms that are stable in the presence of water. Vertical Franz-type cells with a diffusional surface area of 9.62 cm2 were used to study the permeation of these diclofenac salts from their saturated solutions through an internal pig ear membrane. The receptor compartments of the cells contained 100 mL of phosphate buffer (pH 7.4); a saturated solution (5 mL) of each salt was placed in the donor compartment, thermostated at 37 °C. Aliquots were withdrawn at predetermined time intervals over 8 h and then immediately analyzed by HPLC. Fluxes were determined by plotting the permeated amount, normalized for the membrane surface area versus time. Permeation coefficients were obtained dividing the flux values J by the concentration of the releasing phase—that is, water solubility of each salt. Experimental results show that fluxes could be measured when diclofenac salts with aliphatic amines are released from a saturated aqueous solution. Different chemical species (acid, anion, ion pairs) contribute to permeation of the anti-inflammatory agent even though ion-pairs could be hypothesized to operate to a greater extent. Permeation coefficients were found higher when the counterion contains a ring; while hydroxy groups alone do not appear to play an important role, the ring could sustain permeation, disrupting the organized domains of the membrane. Full article
Open AccessArticle Influence of the Efavirenz Micronization on Tableting and Dissolution
Pharmaceutics 2012, 4(3), 430-441; doi:10.3390/pharmaceutics4030430
Received: 8 August 2012 / Revised: 2 September 2012 / Accepted: 2 September 2012 / Published: 12 September 2012
Cited by 3 | PDF Full-text (590 KB) | HTML Full-text | XML Full-text
Abstract
The purpose of this study was to propose an analytical procedure that provides the effects of particle size and surface area on dissolution of efavirenz. Five different batches obtained by different micronization processes and with different particle size distribution and surface area were
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The purpose of this study was to propose an analytical procedure that provides the effects of particle size and surface area on dissolution of efavirenz. Five different batches obtained by different micronization processes and with different particle size distribution and surface area were studied. The preformulation studies and dissolution curves were used to confirm the particle size distribution effect on drug solubility. No polymorphic variety or amorphization was observed in the tested batches and the particle size distribution was determined as directly responsible for the improvement of drug dissolution. The influence of the preparation process on the tablets derived from efavirenz was observed in the final dissolution result in which agglomeration, usually seen in non-lipophilic micronized material, was avoided through the use of an appropriate wet granulation method. For these reasons, micronization may represent one viable alternative for the formulation of brick dust drugs. Full article
Open AccessArticle Quantitative Evaluation of Compliance with Recommendation for Sulfonylurea Dose Co-Administered with DPP-4 Inhibitors in Japan
Pharmaceutics 2012, 4(3), 479-493; doi:10.3390/pharmaceutics4030479
Received: 11 June 2012 / Revised: 8 August 2012 / Accepted: 30 August 2012 / Published: 19 September 2012
Cited by 4 | PDF Full-text (240 KB) | HTML Full-text | XML Full-text
Abstract
After the launch of dipeptidyl peptidase-4 (DPP-4), a new oral hypoglycemic drug (OHD), in December 2009, severe hypoglycemia cases were reported in Japan. Although the definite cause was unknown, co-administration with sulfonylureas (SU) was suspected as one of the potential risk factors. The
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After the launch of dipeptidyl peptidase-4 (DPP-4), a new oral hypoglycemic drug (OHD), in December 2009, severe hypoglycemia cases were reported in Japan. Although the definite cause was unknown, co-administration with sulfonylureas (SU) was suspected as one of the potential risk factors. The Japan Association for Diabetes Education and Care (JADEC) released a recommendation in April 2010 to lower the dose of three major SUs (glimepiride, glibenclamide, and gliclazide) when adding a DPP-4 inhibitor. To evaluate the effectiveness of this risk minimization action along with labeling changes, dispensing records for 114,263 patients prescribed OHDs between December 2008 and December 2010 were identified in the Nihon-Chouzai pharmacy claims database. The adherence to the recommended dosing of SU co-prescribed with DPP-4 inhibitors increased from 46.3% before to 63.8% after the JADEC recommendation (p < 0.01 by time-series analysis), while no change was found in those for SU monotherapy and SU with other OHD co-prescriptions. The adherence was significantly worse for those receiving a glibenclamide prescription. The JADEC recommendation, along with labeling changes, appeared to have a favorable effect on the risk minimization action in Japan. In these instances, a pharmacy claims database can be a useful tool to evaluate risk minimization actions. Full article
(This article belongs to the Special Issue Drug Safety and Pharmacovigilance)

Review

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Open AccessReview Practical Dynamic Contrast Enhanced MRI in Small Animal Models of Cancer: Data Acquisition, Data Analysis, and Interpretation
Pharmaceutics 2012, 4(3), 442-478; doi:10.3390/pharmaceutics4030442
Received: 20 July 2012 / Revised: 1 September 2012 / Accepted: 10 September 2012 / Published: 19 September 2012
Cited by 10 | PDF Full-text (537 KB) | HTML Full-text | XML Full-text
Abstract
Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) consists of the continuous acquisition of images before, during, and after the injection of a contrast agent. DCE-MRI allows for noninvasive evaluation of tumor parameters related to vascular perfusion and permeability and tissue volume fractions, and
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Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) consists of the continuous acquisition of images before, during, and after the injection of a contrast agent. DCE-MRI allows for noninvasive evaluation of tumor parameters related to vascular perfusion and permeability and tissue volume fractions, and is frequently employed in both preclinical and clinical investigations. However, the experimental and analytical subtleties of the technique are not frequently discussed in the literature, nor are its relationships to other commonly used quantitative imaging techniques. This review aims to provide practical information on the development, implementation, and validation of a DCE-MRI study in the context of a preclinical study (though we do frequently refer to clinical studies that are related to these topics). Full article
(This article belongs to the Special Issue DCE-MRI in Preclinical Imaging)

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