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Absorption Enhancer (absorption + enhancer)
Selected AbstractsORIGINAL ARTICLE: Solubilization of vorinostat by cyclodextrinsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2010Y. Y. Cai BSc Summary Background:, Vorinostat (suberoylanilide hydroxamic acid) is the first histone deacetylase inhibitor approved by US FDA for use in oncology. However, as a hydrophobic acid, its limited aqueous solubility poses a problem for parenteral delivery. Such limited solubility may also affect its oral bioavailability. Objective:, The aim of this study was to evaluate whether cyclodextrins (CDs), common excipients used in pharmaceutical industry, could increase the aqueous solubility of vorinostat. Methods:, The actual aqueous solubility of vorinostat was investigated by phase-solubility method. Molecular simulation was employed to predict the interaction energy and preferred orientation of vorinostat in CD cavities. Results:, Phase-solubility studies indicated that the solubility of vorinostat (7·24 × 10,1 mm) was substantially increased when complexed with various CDs, in the following order: randomly methylated-,-cyclodextrin (RM-,-CD) > hydroxypropyl-,-cyclodextrin (HP-,-CD) > ,-cyclodextrin > hydroxypropyl-,-cyclodextrin > Hydroxypropyl-,-cyclodextrin > ,-cyclodextrin. RM-,-CD 300 mm increased vorinostat solubility to 70·8 mm, almost two orders of magnitude higher than the baseline solubility. Such findings were in good agreement with the results obtained from molecular simulation. Conclusion:, CDs, particularly RM-,-CD and HP-,-CD, increased vorinostat's solubility. Future studies could be focused on the application of HP-,-CD in parenteral delivery of vorinostat or using RM-,-CD as an oral absorption enhancer. Molecular simulation appeared to be a useful tool for the selection of appropriate CD as excipient for drug delivery. [source] Improvement of insulin absorption from intratracheally administrated dry powder prepared by supercritical carbon dioxide processJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2003Hiroaki Todo Abstract The purpose of this study was to improve insulin absorption from dry powder after administration in lung without an absorption enhancer. The dry powders, with mannitol as a carrier, were prepared with or without an absorption enhancer (citric acid) by supercritical carbon dioxide (SCF) and spray drying (SD) processes. Insulin powder was precipitated from dimethyl sulfoxide and aqueous solutions by dispersing the insulin solutions from parallel and V-type nozzles, respectively, into supercritical carbon dioxide, which is an antisolvent for insulin. In vitro aerosol performance was evaluated with a cascade impactor. Insulin powder containing citric acid prepared by the SCF method (MIC SCF) showed improved inhalation performance compared with insulin powder prepared by the SD process, although the particle size of the former powder was larger than that in powders prepared by SD. Insulin absorption was estimated from the change in plasma glucose level. The blood glucose level after administration of the insulin powder without citric acid prepared by the SCF process (MI SCF) decreased rapidly, and a significant difference was observed for areas under the curve of change in plasma glucose concentration versus time (AUCs) between MI SCF and the insulin powder without citric acid prepared by the SD process (MI SD). These results suggest that the SCF technique would be useful to prepare dry powders suitable for inhalation. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2475,2486, 2003 [source] Nasal administration of low molecular weight heparinJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2002John Arnold Abstract The main objective of this study was to determine if the systemic absorption of therapeutic amounts of heparin was possible following nasal administration. Sprague-Dawley rats received nosedrops containing a low molecular weight heparin (LMWH) or unfractionated heparin (UFH) formulated with or without tetradecylmaltoside (TDM). TDM is a nonionic surfactant that has been previously shown to be a potent absorption enhancer in studies with peptide drugs. LMWH/UFH absorption was determined by measuring plasma anti-Factor Xa activity. The inclusion of 0.25% TDM in nasal formulations containing LMWH resulted in a significant increase in the Cmax and area under the curve (AUC) of anti-Factor Xa activity when compared to LMWH formulated in saline alone. The addition of TDM to a nasal formulation containing UFH resulted in a much smaller increase in the Cmax and the AUC of anti-Factor Xa activity. The absolute bioavailability of LMWH was increased from 4.0,±,0.4% in the absence of TDM to 19,±,0.3% in the presence of TDM. The reversibility of the absorption enhancing effect of TDM was studied by applying LMWH nasally 60 or 120 min after the enhancer. The effect of TDM on the nasal epithelia appeared to be rapidly reversible. In conclusion, nasal delivery of LMWH, but not UFH, was successful when an absorption enhancer was included to increase nasal permeability. © 2002 Wiley-Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91:1707,1714, 2002 [source] Mechanisms of cytoprotective effect of amino acids on local toxicity caused by sodium laurate, a drug absorption enhancer, in intestinal epitheliumJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2002Yoko Endo Abstract Several amino acids, including L -glutamine (L -Gln), were found to protect the intestinal epithelial cells from the local toxicity caused by a drug absorption enhancer, sodium laurate (C12), in our previous study. To develop more efficient and safer formulations for enhancing drug absorption, the mechanisms of cytoprotection by amino acids were studied using rats and Caco-2 cells. Four amino acids, including L -Gln, could generally maintain the absorption-promoting action of C12, although taurine tended to attenuate it. Three amino acids, except for L -Gln, significantly suppressed the decrease in the transepithelial electrical resistance caused by C12. Quercetin, an inhibitor for biosynthesis of heat shock protein 70 (HSP70), masked only the protective effect of L -Gln in both rat large intestine and Caco-2 cells. Western blot analysis indicated clearly that HSP70 is induced extensively only by the addition of L -Gln in both rat large-intestinal cells and Caco-2 cells. C12 was found to increase the intracellular concentration of Ca2+ ([Ca2+]i) remarkably, and amino acids, especially L -arginine, L -methionine, and taurine, significantly attenuated the increase in [Ca2+]i caused by C12. Furthermore, although C12 stimulated the release of histamine, an inflammatory mediator, from rat large-intestinal tissue, amino acids were also found to suppress the release of histamine enhanced by C12. The results in the present study showed that an induction of HSP70, a decrease in [Ca2+]i elevated by C12, and a suppression of histamine release stimulated by C12 should be involved in the mechanisms behind the cytoprotective action of amino acids against the local toxicity caused by C12. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:730,743, 2002 [source] Amino acids protect epithelial cells from local toxicity by absorption enhancer, sodium laurateJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2001Takashi Yata Abstract To develop the safe absorption-enhancing formulation attenuating the local toxicity caused by an absorption enhancer, sodium laurate (C12), the effects of amino acids on the local toxicity by C12 were examined in rats. The absorption of phenol red, an unabsorbable marker drug, was significantly enhanced by 10 mM C12 in an in situ colon loop study and the addition of L -glutamine (L -Gln), L -arginine, or L -methionine at 10 mM did not change the promoting effect of C12. However, C12 significantly increased the elution of phospholipids, total protein, and lactate dehydrogenase, which are markers for local toxicity, from colon, but these amino acids attenuated the local toxicity caused by C12 significantly. Transport study using an Ussing-type chamber showed that the permeability of colonic membrane to phenol red was significantly enhanced by C12 and that L -Gln did not decrease the permeability enhanced by C12. Transmucosal electrical resistance was extensively decreased by C12, indicating that C12 could enhance the drug absorption at least partly by expanding the paracellular route. L -Gln significantly, but not completely, recovered resistance lowered by C12. Electrical potential difference was markedly reduced by C12, suggesting that C12 lowered the viability of mucosal cells, but 10 mM L -Gln significantly recovered potential difference almost to the control level. These results suggested the possibility that absorption-enhancing formulation with low local toxicity, which is low enough to be used practically, could be developed by using an amino acid like L -Gln as an ingredient attenuating the local toxicity caused by C12. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1456,1465, 2001 [source] Potential prospects of chitosan derivative trimethyl chitosan chloride (TMC) as a polymeric absorption enhancer: synthesis, characterization and applicationsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2008Jasjeet K. Sahni ABSTRACT In recent years, researchers have been working extensively on various novel properties of polymers to develop increased efficiency of drug delivery and improve bioavailability of various drug molecules, especially macromolecules. Chitosan, a naturally occurring polysaccharide, because of its protonated/polymeric nature, provides effective and safe absorption of peptide and protein drugs. Its transmucosal absorption is, however, limited to acidic media because of its strong intermolecular hydrogen bonds. A new partially quaternized chitosan derivative, N-trimethyl chitosan chloride (TMC), has been synthesized with improved solubility, safety and effectiveness as an absorption enhancer at neutral pH and in aqueous environment. It enhances the absorption, especially of peptide drugs, by reversible opening of tight junctions in between epithelial cells, thereby facilitating the paracellular diffusion of peptide drugs. This derivative thus opens new perspectives as a biomaterial for various pharmaceutical applications/drug delivery systems. This review deals with the potential use of the quaternized chitosan derivative as a permeation enhancer for the mucosal delivery of macromolecular drugs along with its other biomedical applications. [source] Aminated gelatin as a nasal absorption enhancer for peptide drugs: evaluation of absorption enhancing effect and nasal mucosa perturbation in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2002Jian Wang This study was carried out to evaluate the potential of aminated gelatin as a nasal absorption enhancer for peptide drugs. The absorption-enhancing effect was investigated in rats using insulin and fluorescein isothiocyanate-dextran with a molecular weight of 4.4 kDa (FD-4) as model drugs. The absorption of insulin was estimated by measuring the changes in plasma glucose levels following intranasal administration, and that of FD-4 was determined by measuring its plasma concentration after dosing. The hypoglycaemic effect after intranasal administration of insulin with aminated gelatin significantly increased compared with that after intranasal administration of insulin in phosphate buffered saline, indicating that aminated gelatin effectively enhanced the nasal absorption of insulin. In contrast, neither kind of native gelatin (isoelectric point = 5.0 and 9.0) showed any absorption-enhancing effect. The pH of the formulations and the concentration of aminated gelatin were found to affect the hypoglycaemic effect. In addition, aminated gelatin at a concentration of 0.2 % significantly enhanced the absorption and the efflux of FD-4 through the rat nasal mucosa. The possible perturbation of aminated gelatin to nasal mucosa was evaluated by measuring the leaching of lactate dehydrogenase (LDH) using an in-situ perfusion rat model. Aminated gelatin presented a concentration-dependent (0.1-0.4 %) but relatively small effect on the LDH leaching from the rat nasal epithelial membrane. These results suggest that positively charged aminated gelatin could be a new absorption enhancer for nasal delivery of peptide drugs. [source] Acceleration of ALA-induced PpIX fluorescence development in the oral mucosaLASERS IN SURGERY AND MEDICINE, Issue 3 2003Sirintra Charoenbanpachon Abstract Background and Objectives The development of 5-aminolevulinic acid (ALA)-induced tissue fluorescence is optimal 2,4 hours after ALA application. Goal of this work was to develop a means of accelerating oral topical ALA-induced tissue fluorescence. Study Design/Materials and Methods In 300 hamsters, DMBA (9,10 dimethyl-1,2-benzanthracene) cheek pouch carcinogenesis produced dysplasia in 3,5 weeks. Topical application of 20% ALA in Eucerin was followed by localized ultrasound treatment (1, 3.3 MHz) in 150 animals. In 75 animals, ALA was applied in an Oral Pluronic Lecithin Organogel (OPLO,an absorption enhancer) vehicle. Seventy-five animals received only topical ALA in Eucerin. Hamsters were sacrificed and cryosections underwent fluorescence measurements, histological evaluation, 20,180 minutes after ALA application. One-way ANOVA detected independent effects of pathology on laser-induced fluorescence (LIF). Two-way ANOVA tested for independent effect of pathology and of OPLO, ultrasound, and interaction effects. Results Ultrasound significantly (P,<,0.05) accelerated tissue fluorescence development. Conclusions Low-frequency ultrasound can accelerate ALA-induced fluorescence development. Lasers Surg. Med. 32:185,188, 2003. © 2003 Wiley-Liss, Inc. [source] Permeation of Sumatriptan Through Human Vaginal and Buccal MucosaHEADACHE, Issue 2 2000P. Van Der Bijl DSc Continued interest in the various routes by which sumatriptan may be administered prompted us to investigate its passage through buccal mucosa. Because human buccal mucosa is scarce, we proposed using the relatively abundant vaginal mucosa, which has been shown to have comparable diffusion rates for a number of widely varying molecules, as a model of buccal mucosa. In addition, by comparing these two tissues with respect to their permeability to sumatriptan, the human vaginal/buccal mucosa model could be further evaluated. Clinically healthy human vaginal and buccal mucosa specimens were used in the permeability studies. Permeability to sumatriptan was determined using a continuous flow-through diffusion system in the presence and absence of permeation enhancers. No statistically significant differences in permeability could be demonstrated for both mucosae toward sumatriptan. Flux values obtained in the absence and presence of glycodeoxycholate and lauric acid (1:1 molar ratio) to sumatriptan of buccal and vaginal mucosa, respectively, were not significantly different. The results obtained further support the hypothesis of the vaginal/buccal mucosal in vitro permeability model and suggest that this model may be used in conjunction with various absorption enhancers. Further studies on the buccal route of absorption of sumatriptan are thus warranted. [source] Cytotoxicity evaluation of enzyme inhibitors and absorption enhancers in Caco-2 cells for oral delivery of salmon calcitoninJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2004Rakhi B. Shah Abstract The usefulness of enzyme inhibitors and absorption enhancers with least mucosal cell cytotoxicity was evaluated on Caco-2 cell monolayers. The temporal cytotoxicity of several protease inhibitors at 500 ,g/mL (e.g., turkey and chicken ovomucoids, aprotinin, and Protease Inhibitor Cocktail) and absorption enhancers [e.g., cholate (3%), glycocholate (3%), glycosursodeoxycholate (3%), ethylenediaminetetraacetic acid (EDTA, 0.1%), hydroxypropyl-,-cyclodextrin (HP-,-CD, 5%), hydroxypropyl-,-cylcodextrin (HP-,-CD, 5%), ,-cylcodextrin (,-CD, 5%), tetradecyl-,- D -maltoside (0.25%), octylglucoside (0.25%), citric acid (10%), glycyrrhetinic acid (0.34 mM), and Tween-80® (0.1%)] was measured by monitoring their effect on Caco-2 cell viability. Cell viability was measured by mannitol permeability measurements, transepithelial electrical resistance (TEER) measurements, DNA-propidium iodide staining assay, and WST-1 assay (tetrazolium salt based assay). Sodium dodecyl sulfate (0.1%), a potent surfactant, was used as a positive control. Chicken and turkey ovomucoids were nontoxic to cells as evaluated by all the methods used. Aprotinin decreased the TEER, whereas plasma membrane damage was seen with Protease Inhibitor Cocktail after a 24-h period. With respect to the absorption enhancers, the toxicity increased directly as a result of an increase in the time of incubation. The enhancers EDTA and HP-,-CD can be used safely for a short period of time, whereas glycosursodeoxycholate, glycyrrhetinic acid, octylglucoside, HP-,-CD, and ,-CD can be used for a longer period. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 1070,1082, 2004 [source] In-vitro and in-vivo studies of cefpirom using bile salts as absorption enhancersJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2003Yahya Mrestani ABSTRACT Cephalosporins have to be administered by injection because of the poor intestinal absorption of the orally delivered drugs. Because of the obvious drawbacks of drug delivery by injection, the development of alternatives with enhanced oral bioavailability is receiving much attention in pharmaceutical research. Cefpirom (Cp) is a new semi-synthetic amino-2-thiazolyl-methoxyimino cephalosporin that has been substituted in position 3 with a cyclopenteno-pyridinium group in order to create a zwitterionic compound. It exhibits highly hydrophilic properties, as shown from its extremely low partition coefficient, and therefore its lipophilicity was increased using bile salts. The effect of this on the partition coefficients determined in the n-octanol/buffer system was confirmed using an in-vitro transport model with artificial and biological membranes. The pharmacokinetic properties of Cp were investigated in rabbits after intraduodenal administration with and without bile salts. Furthermore, the physiological compatibility of the bile salts was investigated using active D-glucose transport. [source] Increased vigabatrin entry into the brain by polysorbate 80 and sodium caprateJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2001D. Dimitrijevic The effects of a non-ionic surfactant, polysorbate 80, and the sodium salt of the saturated fatty acid, sodium caprate (C10), as potential brain absorption enhancers for vigabatrin were studied. Vigabatrin is an enzyme-activated irreversible inhibitor of ,-aminobutyric acid (GABA) transaminase that increases brain and cerebrospinal GABA concentrations in animals and man. Before intravenous administration, a range of concentrations of the surfactants were tested using erythrocyte lysis or the red blood cell lysis test to establish the non-toxic concentration range. Vigabatrin was dissolved in 0.1% polysorbate 80 and 0.1% sodium caprate and administered intravenously in doses of 4 mL kg,1 to male Wistar rats (230,250 g; n = 3). Rats were killed 2 h after drug and surfactant administration and the brains were immediately removed and homogenized in 0.4m perchloric acid. Selected ion monitoring electrospray mass spectrometry was used to determine the concentration of vigabatrin and GABA directly from the perchloric acid extract of the rat brain. This method was developed to increase the speed and efficiency of the analysis by removing the need for complex extraction and derivatization procedures while retaining the specificity of the mass spectrometer as a detector. The stability of both vigabatrin and GABA in perchloric acid was established by monitoring their pseudo molecular ions in standard solutions at timed intervals over 24 h. Although the detection level for vigabatrin and GABA was at least 50 pg, only GABA was detected in rat brain. Vigabatrin caused a small increase in whole brain GABA. However, GABA levels were higher in the samples with vigabatrin + enhancer than in the samples where vigabatrin alone was administered. One-way analysis of variance indicated a significant effect of the surfactants on GABA levels (F (5,17) = 11.86, P < 0.01) and vigabatrin absorption was presumed. The rectal temperature of the rats is lowered by the presence of vigabatrin in the brain. Vigabatrin alone decreased rectal temperature by 6%. When given with either polysorbate 80 or sodium caprate, the extent of temperature lowering was significantly greater (P < 0.001). There was no significant difference after 2 h between polysorbate 80 + vigabatrin, and sodium caprate + vigabatrin. [source] | ||||||||||