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International Journal of Pharmaceutics (v.317, #1)
Microprocessor controlled transdermal drug delivery by J. Anand Subramony; Ashutosh Sharma; J.B. Phipps (pp. 1-6).
Transdermal drug delivery via iontophoresis is reviewed with special focus on the delivery of lidocaine for local anesthesia and fentanyl for patient controlled acute therapy such as postoperative pain. The role of the microprocessor controller in achieving dosimetry, alternating/reverse polarity, pre-programmed, and sensor-based delivery is highlighted. Unique features such as the use of tactile signaling, telemetry control, and pulsatile waveforms in iontophoretic drug delivery are described briefly.
Keywords: Transdermal; Iontophoresis; Controller; Lidocaine; Fentanyl; Drug delivery
Evaluation of the interaction of surfactants with stratum corneum model membrane from Bothrops jararaca by DSC by André Rolim Baby; Aurea Cristina Lemos Lacerda; Maria Valéria Robles Velasco; Patrícia Santos Lopes; Yoshio Kawano; Telma Mary Kaneko (pp. 7-9).
The interaction of surfactants sodium dodecyl sulfate (SDS), cetyl trimethyl ammonium chloride (CTAC) and lauryl alcohol ethoxylated (12mol ethylene oxide) (LAE-12OE) was evaluated on the stratum corneum (SC) of shed snake skins from Bothrops jararaca, used as model membrane, and thermal characterized by differential scanning calorimetry (DSC). Surfactant solutions were employed above of the critical micellar concentration (CMC) with treatment time of 8h. The SDS interaction with the SC model membrane has increased the characteristic transition temperature of 130°C in ≈10°C for the water loss and keratin denaturation, indicating an augmentation of the water content. Samples treated with CTAC have a decrease of the water loss temperature, while, for the LAE-12OE treated samples, changes on the transition temperature have not been observed.
Keywords: Differential scanning calorimetry; Sodium dodecyl sulfate; Cetyl trimethyl ammonium chloride; Lauryl alcohol ethoxylated; Bothrops jararaca
PEGylated J591 mAb loaded in PLGA-PEG-PLGA tri-block copolymer for targeted delivery: In vitro evaluation in human prostate cancer cells by Stanley Moffatt; Richard J. Cristiano (pp. 10-13).
J591 monoclonal antibody (mAb) has high affinity for prostate specific membrane antigen (PSMA) on prostate cancer (PCA) cells. We coupled polyethylene glycol-J591 (PEGylated J591) to a salicyl hydroxamic acid (SHA)–derivatized polyethylenimine (PEI)/DNA-βgal vector to investigate the specificity and efficiency of targeting PSMA in PCA cells through encapsulation. Coupling was facilitated via the high affinity interaction between phenyl(di)boronic acid (PDBA) and SHA molecules yielding J591/PEG/PEI/DNA-βgal polyplex. After encapsulation with poly(d,l-lactic- co-glycolic acid)- b-polyethylene glycol- b-poly(d,l-lactic- co-glycolic acid) (PLGA-PEG-PLGA) tri-block copolymer, 8–10-fold increment of gene transfection levels were attained at the optimum concentration of 0.25% (w/v) using Pluronic F68 tri-block copolymer as a control. The enhanced transfection efficiency was attributed to increased internalization and uptake of the radiolabeled plasmid in the presence of PLGA-PEG-PLGA tri-block copolymer. The release of plasmid DNA (pDNA) from microparticles containing SHA–PEI-complexed pDNA showed little initial burst release followed by a 5% release over 48h. The release accelerated thereafter and approximately 60% was released after 28 days. Deconvolution confocal microscopy showed polyplex/microparticle formulation localized in the cell nucleus as opposed to the polyplex without PLGA-PEG-PLGA indicating that an optimal concentration of PLGA-PEG-PLGA tri-block copolymer can be utilized to enhance endocytic process of J591-mediated targeting of PCA cells.
Keywords: Polyethyleneimine (PEI); Phenyl(di)boronic acid (PDBA)–salicyl hydroxamic acid (SHA); PLGA-PEG-PLGA; J591mAb; Prostate specific membrane antigen (PSMA); Targeted gene delivery
Stability of valacyclovir: Implications for its oral bioavailability by Gladys E Granero; Gordon L Amidon (pp. 14-18).
The absolute bioavailability of the prodrug valacyclovir, thel-valyl ester of acyclovir, after oral administration is ∼54.5%. Since premature hydrolysis of this prodrug in the intestinal lumen may be a possible reason for its incomplete bioavailability and the chemical and enzymatic stability of the valacyclovir has been investigated. Release rates were investigated in both phosphate buffers with varying pH as well as in human and dog gastrointestinal fluids. The stability of the prodrug was found to be dependent on pH. This prodrug is chemically stable along the acidic pH side (under 4), while the prodrug degrades in alkaline medium through a base-catalyzed pseudo-first-order kinetics. The degradation of the prodrug valacyclovir progressed faster in intestinal fluid than in phosphate buffer at the same pH. There was no appreciable release of valacyclovir neither in the human and dog stomach contents nor in phosphate buffers at pHs fewer than 4, although its degradation was fastest in the human and dog stomach contents. In light of this result, we can conclude that the degradation of the valacyclovir in the upper intestinal lumen is probably one of the causes of its poor bioavailability.
Keywords: Valacyclovir; Stability; Luminal degradation; Oral availability; Acyclovir
Inhibitory effects of statins on human monocarboxylate transporter 4 by Masaki Kobayashi; Yukio Otsuka; Shirou Itagaki; Takeshi Hirano; Ken Iseki (pp. 19-25).
Human MCT4 (SLC16A3) is responsible for the efflux ofl-lactic acid from skeletal muscle cells and is essential for muscle homeostasis. However, the effects of monocarboxylate drugs, such as statins on the MCT4-mediated transport ofl-lactic acid have not been elucidated. Inhibition ofl-lactic acid transport mediated by MCT4 might to lead to collapse of muscle homeostasis. The aim of this study was to establish an MCT4 transfected cell line and to clarify the transport mechanism ofl-lactic acid and the effects of statins on this transport system. Results of Western blot analyses and immunohistochemistry studies indicated that the expression of CD147 and MCT4-FLAG protein were observed and was displayed clear plasma membrane localization in CD147 and MCT4-FLAG co-transfected cell line (cm cells). Uptake ofl-lactic acid in cm cells was significantly greater than that in cells transfected with a vector alone.l-lactic acid uptake was concentration-dependent with a Km value of 28.43±3.87mM. The results of a previous study showing a Km value of 28.5mM in hMCT4-expressed oocytes. Lipophilic statins significantly inhibited [14C]l-lactic acid uptake in a concentration-dependent manner. In contrast, the inhibitory effects of hydrophilic statins were very weak.
Keywords: Monocarbocarboxylate transporter 4; HMG-CoA reductase inhibitor; Transport; Side effect
In vitro transdermal delivery of caffeine, theobromine, theophylline and catechin from extract of Guarana, Paullinia Cupana by Charles M. Heard; Sarah Johnson; Gary Moss; Chris P. Thomas (pp. 26-31).
Extracts of guarana ( Paullinia cupana) feature as putatively stimulating ingredients in a number of foods, drinks and dietary/herbal supplements. The objective of this work was to investigate in vitro the transdermal delivery of the major pharmacologically active compounds contained in guarana extract. Saturated solutions of guarana were prepared in polyethylene glycol 400 (PEG400), propylene glycol (PG) and H2O at 32°C. Guarana extract was also formulated in Duro-tak® 2287 transdermal adhesive in a range of concentrations and the diffusional release was determined in addition to adhesive properties. Transdermal delivery across full thickness pig ear skin was investigated in vitro using Franz-type diffusion cells, with reverse-phase HPLC being used for the quantification of the permeation of theobromine (TB), theophylline (TP), (+)-catechin (C) and caffeine (CF). Based upon a combination of release and adhesive property data a patch containing 5.55mg guarana extract cm−2 was deemed optimal. The general trend for the delivery of the 4 analytes was: water >5.55mgcm−2 patch ≈PG>PEG400. For CF the greatest steady state flux was obtained from the water vehicle: 19μgcm−2h−1, with ∼420μgcm−2 permeating after 24h. This was some 6× times more than from the drug-in-adhesive patch and 10× greater than PG, a well-known penetration enhancer, and 50× that of the ‘regular’ excipient PEG400. A water vehicle also provided the greatest delivery of TB (0.45μgcm−2h−1), TP (0.022μgcm−2h−1), and C (0.10μgcm−2h−1). An inverse relationship was noted between lipophilicity and kp in each vehicle. The simultaneous transdermal delivery of the major actives of guarana was established, with permeation rates being highly concentration and vehicle dependent.
Keywords: Paullinia cupana; Guarana; Transdermal; Patch; Skin; Theobromine; Theophylline; (+)-Catechin; Caffeine
Development and optimization of a novel sustained-release dextran tablet formulation for propranolol hydrochloride by Eddy Castellanos Gil; Antonio Iraizoz Colarte; Bernard Bataille; José Luis Pedraz; Fernand Rodríguez; Jyrki Heinämäki (pp. 32-39).
A novel oral controlled delivery system for propranolol hydrochloride (PPL) was developed and optimized. The in vitro dissolution profiles of sustained-release matrix tablets of racemic PPL were determined and compared with the United States Pharmacopeia (USP) tolerance specifications for Propranolol Hydrochloride Extended-Release Capsules. The influence of matrix forming agents (native dextran, hydroxypropyl methylcellulose (HPMC), cetyl alcohol) and binary mixtures of them on PPL release in vitro was investigated. A central composite design was applied to the optimization of a sustained-release tablet formulation. The sustained-release matrix tablets with good physical, mechanical and technological properties were obtained with a matrix excipient:PPL ratio of 60:40 (w/w), with a dextran:HPMC ratio of 4:1 (w/w) and with a cetyl alcohol amount of 15% (w/w). A comparative kinetic study of the present matrix tablets and commercial SUMIAL RETARD capsules (Spain) was established. The value for the similarity factor ( f2=69.6) suggested that the dissolution profile of the present two sustained-release oral dosage forms are similar. Higuchi (diffusion) and Hixon–Crowell (erosion) kinetic profiles were achieved and this codependent mechanism of drug release was established.
Keywords: Native dextran; Sustained release; Optimization; Propranolol; Tablets
Evaluation of brain-targeting for the nasal delivery of estradiol by the microdialysis method by Xiaomei Wang; Haibing He; Wei Leng; Xing Tang (pp. 40-46).
The uptake of estradiol into the cerebrospinal fluid (CSF) after intranasal and intravenous administration in rats was investigated to study whether direct nose–CSF transport of estradiol exits or not. Animals received 0.48mgkg−1 estradiol randomly methylated β-cyclodextrin (RAMEB) inclusion complex intranasally and intravenously. Following nasal delivery, estradiol reached a Cmax value (mean±S.D.) in plasma (26.70±11.37ngml−1) and CSF (54.76±32.84ngml−1) after 20min in each case, while after intravenous infusion, estradiol reached a Cmax value in plasma (170.08±64.67ngml−1) and CSF (26.48±11.34ngml−1) at 5min and 60min, respectively. The AUCCSF/AUCplasma ratio (1.60±0.67) after intranasal delivery differed significantly from the ratio (0.61±0.16) observed after intravenous infusion ( P<0.05). All these results indicate that estradiol is transported into CSF via olfactory neurons, and, hence, there is a direct transport route from the nasal cavity into the CSF for estradiol.
Keywords: Nasal delivery; Intravenous administration; Estradiol; Microdialysis; Olfactory pathway
The effect of crystal imperfections on particle fracture behaviour by Onno de Vegt; Herman Vromans; Wim Pries; Kees van der Voort Maarschalk (pp. 47-53).
Micronisation of active pharmaceutical ingredients is a process which is sometimes difficult to control. The main purpose of this study was to assess the effect of the pre-existing flaws in the material to be milled. The rate of breakage of four samples of a model compound (sodium chloride), originating from different sources, was determined in a jet mill. It appeared that each type of sodium chloride has a distinct particle rate of breakage and breakage pattern. The numbers of flaws in the different types of sodium chloride have been determined by immersing the sodium chloride particles in a liquid with the same refractive index. This makes the cracks better visible. Microphotographs were made and flaws were counted manually.The study shows that the flaw density has an impact on the fracture behaviour of particles. The degree of fracture tends to increase with increasing flaw density. The paper shows however that the mechanical properties of the material as well as the starting particle size dominate the significance of the impact of flaws on fracture behaviour.
Keywords: Flaws; Milling; Micronisation; Particle rate of breakage; Particle size; Sodium chloride
High throughput microsomal stability assay for insoluble compounds by Li Di; Edward H. Kerns; Susan Q. Li; Susan L. Petusky (pp. 54-60).
High throughput metabolic stability assays are widely implemented in drug discovery to guide structural modification, predict in vivo performance, develop structure-metabolic stability relationships, and triage compounds for in vivo animal studies. However, these methods are often developed and validated using commercial drugs. Many drug discovery compounds differ from commercial drugs, with many having high lipophilicity, high molecular weight and low solubility. The impact of very low solubility on metabolic stability assay results was explored. Two metabolic stability assays, the ‘aqueous dilution method’ and the ‘cosolvent method, were compared. For commercial drugs and most discovery compounds having reasonable drug-like properties, the two methods gave comparable results. For highly lipophilic, insoluble drug discovery compounds, the ‘aqueous dilution method’ gave artificially higher stability results. The cosolvent method performs compound dilutions in solutions with higher organic solvent content and adds solutions directly to microsomes to assist with solubilization, minimize precipitation and reduce non-specific binding to plastics. This method is more applicable in drug discovery where compounds of a wide range of solubility are studied.
Keywords: Metabolism; stability; Solubility; High throughput; LC–MS; Automation; Robotics
Enhancement of the dissolution rate and oral absorption of a poorly water soluble drug by formation of surfactant-containing microparticles by S.M. Wong; I.W. Kellaway; S. Murdan (pp. 61-68).
The slow dissolution rate exhibited by poorly water-soluble drugs is a major challenge in the drug development process. Following oral administration, drugs with slow dissolution rates generally show erratic and incomplete absorption which may lead to therapeutic failure. The aim of this study was to improve the dissolution rate and subsequently the oral absorption and bioavailability of a model poorly water-soluble drug. Microparticles containing the model drug (griseofulvin) were produced by spray drying the drug in the absence/presence of a hydrophilic surfactant. Poloxamer 407 was chosen as the hydrophilic surfactant to improve the particle wetting and hence the dissolution rate. The spray dried particles were characterized and in vitro dissolution studies and in vivo absorption studies were carried out. The results obtained showed that the dissolution rate and absolute oral bioavailability of the spray dried griseofulvin/Poloxamer 407 particles were significantly increased compared to the control. Although spray drying griseofulvin alone increased the drug's in vitro dissolution rate, no significant improvement was seen in the absolute oral bioavailability when compared to the control. Therefore, it is believed that the better wetting characteristics conferred by the hydrophilic surfactant was responsible for the enhanced dissolution rate and absolute oral bioavailability of the model drug.
Keywords: Poor solubility; Dissolution; Oral bioavailability; Microparticles; Spray drying; Griseofulvin
Environmental-sensitive micelles based on poly(2-ethyl-2-oxazoline)- b-poly(l-lactide) diblock copolymer for application in drug delivery by Ging-Ho Hsiue; Chun-Hung Wang; Chun-Liang Lo; Chau-Hui Wang; Ju-Pi Li; Jia-Ling Yang (pp. 69-75).
Anticancer drug doxorubicin (DOX) was physically loaded into the micelles prepared from poly(2-ethyl-2-oxazoline)- b-poly(l-lactide) diblock copolymers (PEOz–PLLA). PEOz–PLLA consists of hydrophilic segment PEOz and hydrophobic segment PLLA showed pH-sensitivity in the aqueous solution. The DOX-loaded micelle exhibited a narrow size distribution with a mean diameter around 170nm. The micellar structure can preserve hydrophobic drug DOX under the physiological condition (pH 7.4) and selectively release DOX by sensing the intracellular pH change in late endosomes and secondary lysosomes (pH 4–5). At 37°C, the cumulated released rate of DOX from micelles was about 65% at pH 5.0 in the initial 24h. Additionally, polymeric micelles had low cytotoxicity in human normal fibroblast HFW cells for 72h by using MTT assay. Moreover, DOX-loaded micelles could slowly and efficiency decrease cell viability of non-small-cell lung carcinoma CL3 cells. Taken together, PEOz- b-PLLA diblock polymeric micelles may act as useful drug carriers for cancer therapy.
Keywords: Poly(2-ethyl-2-oxazoline) (PEOz); Poly(; l; -lactide) (PLLA); Diblock copolymers; Polymeric micelle; Drug delivery
Thiomers: Preparation and in vitro evaluation of a mucoadhesive nanoparticulate drug delivery system by Andreas Bernkop-Schnürch; Andrea Weithaler; Karin Albrecht; Alexander Greimel (pp. 76-81).
It was the aim of this study to develop a mucoadhesive nanoparticulate delivery system. Nanoparticles were generated by in situ gellation of the thiomer chitosan-4-thiobutylamidine (chitosan-TBA) with tripolyphosphate (TPP) followed by stabilization via the formation of inter- and intrachain disulfide bonds by oxidation with H2O2 in various concentrations. Afterwards TPP was removed by exhaustive dialysis at pH 1–2. Incorporation of the model compound fluorescein diacetate (FDA) was achieved by incubation of this fluorescence marker, dissolved in acetonitrile, with aqueous particle suspensions for 1h at room temperature. Mucoadhesion studies were performed on porcine intestinal mucosa.Results showed that the preparation method described above leads to nanoparticles of a mean diameter of 268±15nm and a FDA load of 2%. Due to the removal of the anionic crosslinker TPP, the zeta potential of the nanoparticles was raised from 4±1 up to 19±2mV without loosing stability of the nanoparticles. The more H2O2 was added to the particles, the more inter- and intrachain disulfide bonds were formed. The more thiol groups were oxidized within the particles, however, the lower was the improvement in mucoadhesive properties. Nevertheless, even when 91% of all thiol groups on the nanoparticles were oxidized, their mucoadhesive properties were still twice as high as the mucoadhesive properties of unmodified nanoparticles.Thiolated chitosan nanoparticles show a two-fold higher zeta potential (I), improved stability (II) and more than doubled mucoadhesive properties (III) than corresponding unmodified chitosan nanoparticles. Therefore, they seem to be advantageous over ionically crosslinked chitosan nanoparticles.
Keywords: Nanoparticles; Thiomers; Mucoadhesion; Crosslinking; Chitosan
Oral bioavailability of cyclosporine: Solid lipid nanoparticles (SLN®) versus drug nanocrystals by R.H. Müller; S. Runge; V. Ravelli; W. Mehnert; A.F. Thünemann; E.B. Souto (pp. 82-89).
For the development of an optimized oral formulation for cyclosporine A, 2% of this drug has been formulated in solid lipid nanoparticles (SLN™, mean size 157nm) and as nanocrystals (mean size 962nm). The encapsulation rate of SLN was found to be 96.1%. Nanocrystals are composed of 100% of drug. For the assessment of the pharmacokinetic parameters the developed formulations have been administered via oral route to three young pigs. Comparison studies with a commercial Sandimmun Neoral/Optoral® used as reference have been performed. The blood profiles observed after oral administration of the commercial microemulsion Sandimmun® revealed a fast absorption of drug leading to the observation of a plasma peak above 1000ng/ml within the first 2h. For drug nanocrystals most of the blood concentrations were in the range between 30 and 70ng/ml over a period of 14h. These values were very low, showing huge differences between the measuring time points and between the tested animals. On the contrary, administration of cyclosporine-loaded SLN led to a mean plasma profile with almost similarly low variations in comparison to the reference microemulsion, however with no initial blood peak as observed with the Sandimmun Neoral/Optoral®. Comparing the area under the curves (AUC) obtained with the tested animals it could be stated that the SLN™ formulation avoids side effects by lacking blood concentrations higher than 1000ng/ml. In this study it has been proved that using SLN™ as a drug carrier for oral administration of cyclosporine A a low variation in bioavailability of the drug and simultaneously avoiding the plasma peak typical of the first Sandimmun® formulation can be achieved.
Keywords: Solid lipid nanoparticles; SLN; Drug nanocrystals; Sandimmun Neoral/Optoral; ®; Oral administration
Cationic liposomes as potential carriers for ocular administration of peptides with anti-herpetic activity by R. Cortesi; R. Argnani; E. Esposito; A. Dalpiaz; A. Scatturin; F. Bortolotti; M. Lufino; R. Guerrini; G. Cavicchioni; C. Incorvaia; E. Menegatti; R. Manservigi (pp. 90-100).
In the present study the preparation, characterization and activity of cationic liposomes containing the secretory form of herpes simplex virus type 1 (HSV-1) glycoprotein B (gB1s) or two related polylysine rich peptides, namely DTK1 and DTK2, were described. The immunotherapeutic potential of these HSV antigens containing liposomes was examined with a rabbit ocular model of HSV-1 infection. Our study indicates that the liposomes (i) are able to encapsulate quantitatively gB1s and around 30% the DTK peptides, (ii) are characterized by dimensions compatible with ocular applications and (iii) can release the peptide comparably to the free solution. In addition, neutralization studies demonstrated that an anti-DTK specific polyclonal antiserum can inhibit HSV-1 infection, indicating that such peptides could be a good immunogen/antigen in an anti-HSV vaccine formulation. Although the vaccination protocol did not induce protection against the eye disease, a significative protection against a lethal ocular challenge was detectable together with the absence of reactivation episodes from latency on the survived animals. In this respect, the use of cationic liposomes coupled to gB1s and DTK peptides, as a local ocular vaccine, could represent an interesting approach in order to obtain a possible efficacy in protecting animals against a subsequent HSV-1 ocular challenge.
Keywords: Ocular delivery; Liposomes; HSV-1 vaccine; Peptide administration