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Membrane permeability of copper complexes with potential anti-inflammatory activity were measured using an artificial membrane in a modified Franz cell. Using CuCl2 as the control, all the ligands tested enhanced the diffusion of copper, with enhancement factors ranging from 2 to 7. Octanol/water partition coefficients (log Ko/w) were measured and correlated with the permeability coefficients (Kp). In addition, chemical speciation was used to determine the predominant complex in solution at physiological pH. No correlation was found between the measured permeability coefficients and either molecular weight (MW) or log Ko/w. [ABSTRACT FROM AUTHOR]

Carthamus tinctorius L. (Safflower) is extensively used as a functional food and herbal medicine, with its application closely associated with hydroxysafflor yellow A (HSYA). However, the low oral bioavailability of HSYA in safflower extract (SFE) limits its health benefits and application. Our study found that co-administration of 250, 330, and 400 mg/kg peach kernel oil (PKO) increased the oral bioavailability of HSYA in SFE by 1.99-, 2.11-, and 2.49-fold, respectively. The enhanced bioavailability is attributed to improved lipid solubility and intestinal permeability of HSYA in SFE due to PKO. PKO is believed to modify membrane fluidity and tight junctions, increase paracellular penetration, and inhibit the expression and function of P-glycoprotein, enhancing the transcellular transport of substrates. These mechanisms suggest that PKO is an effective absorption enhancer. Our findings provide valuable insights for developing functional foods with improved bioavailability. [Display omitted] • Peach kernel oil (PKO) enhance the oral bioavailability of hydroxysafflor yellow A in safflower • PKO increase the lipid solubility and membrane fluidity • PKO can temporarily and reversibly open tight junctions • PKO can inhibit the expression and function of P-gp [ABSTRACT FROM AUTHOR]

Purpose: The poor permeability of new drug candidates across intestinal epithelial membranes complicates their development in oral form. This study investigated the potential of cell-penetrating peptides (CPPs) to improve the intestinal permeation and absorption of low-permeable low-molecular-weight (low-MW) drugs. Methods: The in vitro epithelial permeation of six different drugs (metformin, risedronate, zanamivir, methotrexate [MTX], tacrolimus, and vincristine [VCR]) across Caco-2 cell monolayers was examined in the presence and absence of L- or D-penetratin, and the correlation between permeation enhancement efficiency and the properties of tested drugs was analyzed. In addition, a rat closed ileal loop absorption study was conducted to determine the in vivo effects of penetratin. Results: MTX and VCR efficiently permeated Caco-2 monolayers in the presence of L- and D-penetratin, suggesting that CPPs enhanced the epithelial permeation of drugs with relatively high molecular weight and resultant limited intrinsic permeability. The in vivo rat closed ileal loop absorption study revealed the stimulatory effect of L- and D-penetratin on the intestinal absorption of MTX and VCR. Conclusions: CPPs are useful as oral absorption enhancers for low-permeable drugs. [ABSTRACT FROM AUTHOR]

This study intended to evaluate the effect of cyclodextrins on the apparent solubility and permeability of lipophilic drugs under physiological conditions and establish in silico model to choose the optimal amount of cyclodextrins for cyclodextrin-containing oral formulations. In order to study the effect of cyclodextrins under physiological conditions, bile salts and lecithin were added into the rat intestinal perfusion solution to simulate the fasted intestinal fluid. In addition, the in vivo oral absorption performances of cyclodextrin-containing formulations were simulated by gastrointestinal simulation technology based on the advanced compartmental absorption and transit model. The permeability of progesterone was not significantly different between 0.1 mM and 1 mM of 2-hydroxypropyl-β-cyclodextrins (HP-β-CD) under physiological conditions. When the concentration of HP-β-CD was 1 mM, the permeability of progesterone under physiological conditions was significantly higher than that in vitro . The in silico model established in this study was validated by in vivo studies of 4 formulations containing different dosage of cyclodextrin, proving that it was accurate and reliable. In conclusion, this work that demonstrates the permeability of lipophilic drugs could not decrease quickly among a certain range of dosage of HP-β-CD in vivo . Studying the solubility-permeability interplay under physiological conditions would be more meaningful. [ABSTRACT FROM AUTHOR]

Therapeutic peptides and protein are being used in several indications; however, their poor permeability still remains to be solved. This study focused on the pulmonary route of macromolecules. First, the effects of arachidonic acid (AA) as an absorption enhancer on drug serum concentration, after intratracheal administration, were investigated in rats. Second, the safety of AA was assessed in rats in an acute toxicity study for 7 days. AA enhanced the exposure of both interferon-α (IFN-α) and fluorescein isothiocyanate 4000 (FD-4). In addition, the histopathological analysis indicated that AA caused alveolitis and bronchitis in rats. In combination with Taurine (Tau), these lung injuries were prevented through the histopathological analysis. The combined use of Tau with AA did not show any changes in the pharmacokinetics of FD-4. From these results, we suggest the combined use of AA with Tau as a novel formulation on the pulmonary route of macromolecule drugs. This formulation could improve the bioavailability of macromolecule drugs without any serious local damage to the lungs. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO), an endogenous gas that plays a versatile role in the physiological system, has the ability to increase the intestinal absorption of water-soluble compounds through the paracellular route. However, it remains unclear whether NO can enhance the absorption of hydrophobic drugs through the transcellular route. In this study, we examined the absorption-enhancing effect of NO on intestinal permeability of hydrophobic drugs in rat intestine. The pretreatment of rat gastrointestinal sacs with NOC7, a NO-releasing reagent, significantly increased the permeation of griseofulvin from mucosa to serosa in the sacs prepared from the duodenum, but not in those prepared from the other regions such as jejunum, ileum, and colon. The absorption-enhancing effect of NOC7 on the duodenal permeation varied depending on the hydrophobicity of the drugs used. Furthermore, NOC7 treatment was found to be apparently ineffective on the griseofulvin permeation in the duodenum pretreated with dithiothreitol (DTT) that was used as a mucus remover, even though the permeation was increased by pretreatment with DTT alone. These results suggest that NO increases the absorption of hydrophobic drugs through the transcellular route in the duodenum by modulating the mucus layer function. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to gain quantitative mechanistic insight into the role cyclodextrin carriers may play in the intestinal absorption of highly lipophilic molecules. The physical model approach was employed to investigate capric acid absorption in the rat ileum using the in situ single-pass method with 2-hydroxypropyl-β-cyclodextrin ( HPB) present in the perfusate. Two physical models were examined: the flat surface model in which the intestinal wall was treated as a hollow, smooth, circular cylinder, and the villus model in which the intestinal surface allowed for the presence of villi. Capric acid absorption was found to be essentially 100% aqueous boundary layer controlled at low HPB concentrations and increasingly membrane controlled at the higher HPB concentrations. Theoretical calculations based on the experimental data and model parameters were found to be consistent with: at low HPB concentrations, capric acid was mainly absorbed at the villus tips and there was very little capric acid penetration into the intervillus space; in contrast, at 50 mM HPB, there was considerable capric acid penetration into the intervillus space, this corresponding to around a 4.5-fold increase in the accessible area for absorption when compared with 0 mM HPB. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2832-2844, 2015 [ABSTRACT FROM AUTHOR]

It is challenging to deliver molecules to the brain for diagnosis and treatment of brain diseases. This is primarily because of the presence of the blood-brain barrier ( BBB), which restricts the entry of many molecules into the brain. In this study, cyclic- ADT peptides ( ADTC1, ADTC5, and ADTC6) have been shown to modify the BBB to enhance the delivery of marker molecules [e.g., 14 C-mannitol, gadolinium-diethylenetriaminepentacetate ( Gd- DTPA)] to the brain via the paracellular pathways of the BBB. The hypothesis is that these peptides modulate cadherin interactions in the adherens junctions of the vascular endothelial cells forming the BBB to increase paracellular drug permeation. In vitro studies indicated that ADTC5 had the best profile to inhibit adherens junction resealing in Madin- Darby canine kidney cell monolayers in a concentration-dependent manner ( IC50 = 0.3 mM) with a maximal response at 0.4 mM. Under the current experimental conditions, ADTC5 improved the delivery of 14 C-mannitol to the brain about twofold compared with the negative control in the in situ rat brain perfusion model. Furthermore, ADTC5 peptide increased in vivo delivery of Gd- DTPA to the brain of Balb/c mice when administered intravenously. In conclusion, ADTC5 has the potential to improve delivery of diagnostic and therapeutic agents to the brain. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1065-1075, 2015 [ABSTRACT FROM AUTHOR]

Risedronate is widely used clinically to treat osteoporosis, Paget's disease, hypercalcemia, bone metastasis, and multiple myeloma. However, its oral efficacy is restricted due to its low bioavailability and severe gastrointestinal adverse effects. This study was designed to evaluate the effect of deoxycholic acid derivatives on the permeability and oral bioavailability of risedronate by increasing its lipophilicity and affinity to bile transporters. We synthesized two bile acid derivatives, N-deoxycholyl- l-lysyl-methylester (DCK) and N-deoxycholyl- l-lysyl-hydroxide (HDCK) as oral absorption enhancers. After ionic complex formation with the bile acid derivatives, the complexes were characterized by powder X-ray diffraction. Their artificial membrane permeabilities and bioavailabilities in rats were investigated in comparison with pure risedronate. Complex formation with DCK or HDCK demonstrated that risedronate existed in an amorphous form in the complex. A physical complex of risedronate with DCK enhanced the apparent membrane permeability of risedronate significantly but pure risedronate was not permeable. An in vivo study revealed that the C and AUC of risedronate/DCK (1:2) complex were 1.92- and 2.64-fold higher than those of pure risedronate, respectively. Thus, the risedronate/DCK complex can improve the oral absorption of risedronate and patient compliance by reducing dose frequency and adverse reactions. [ABSTRACT FROM AUTHOR]

This study compared transdermal aconitine delivery using solid lipid nanoparticles ( SLN) and microemulsion ( ME) vehicles. Aconitine-loaded SLN and ME were formulated with the same surfactant, cosurfactant, and water content, with an equal amount of oil matrix ( ATO 888 for SLN and ethyl oleate for ME). These nanosized formulations (70-90 nm) showed suitable p H values and satisfactory skin tissue biocompatibility. SLN contained a higher concentration of smaller nanoparticles, compared with that in ME. Neither of the nanocarriers penetrated across excised skin in their intact form. In vitro transdermal delivery studies found that transdermal aconitine flux was lower from SLN than from ME ( p < 0.05), but skin aconitine deposition was higher using SLN ( p < 0.05). Fluorescence-activated cell sorting indicated that in vitro uptake of fluorescently labeled SLN by human immortalized keratinocyte ( Ha Ca T) cells was greater than that of ME, indicating that a transcellular pathway may contribute to cutaneous drug absorption more effectively from SLN. In vivo studies found that these formulations could loosen stratum corneum layers and increase skin surface crannies, which may also enhance transdermal aconitine delivery. SLN produced a more sustained aconitine release, indicating that compared with ME, this transdermal delivery vehicle may reduce the toxicity of this drug. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3602-3610, 2014 [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine concentration-dependent effects of Azone® ( AZ) on the buccal absorption of diazepam ( DIAZ). Porcine buccal mucosa was placed in modified Ussing chambers and pretreated with 10 μL of 0%, 5%, 20%, and 50% (w/v) AZ in ethanol. DIAZ was administered to the donor chamber either in solution or a chitosan-based gel. The donor chamber disappearance, receptor chamber appearance, and tissue retention of DIAZ were monitored over 2 h by HPLC, with AZ tissue disposition also measured by liquid chromatography-mass spectrometry profiling of tissue cryosections. DIAZ steady-state flux values significantly ( p < 0.05) decreased 1.4- and 2.4-fold in 20% and 50% AZ-pretreated tissues, respectively. Only 20% and 50% AZ-pretreated tissues were also accompanied by an increased loss of DIAZ from the donor chamber, suggesting DIAZ was forming a reservoir in the buccal mucosa with higher AZ concentrations. Indeed, the percentage of the initial DIAZ dose remaining in the mucosa following a 2 h experiment was increased 3.0-fold with a 50% AZ pretreatment compared with control. AZ provided a concentration-dependent reservoir for DIAZ in buccal mucosa, resulting in retarded release into the receptor chamber, an approach that may be exploited for controlled release of DIAZ. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1133-1141, 2014 [ABSTRACT FROM AUTHOR]

Abstract: Aim: Total flavones of Hippophae rhamnoides L. (TFH) have a clinical use in the treatment of cardiac disease. The pharmacological effects of TFH are attributed to its major flavonoid components, isorhamnetin, kaempferol, and quercetin. However, poor oral bioavailability of these flavonoids limits the clinical applications of TFH. This study explores phytic acid (IP6) enhancement of the oral absorption in rats of isorhamnetin, kaempferol, and quercetin in TFH. Methods: In vitro Caco-2 cell experiments and in vivo pharmacokinetic studies were performed to investigate the effects of IP6. The aqueous solubility and lipophilicity of isorhamnetin, quercetin, and kaempferol were determined with and without IP6, and mucosal epithelial damage resulting from IP6 addition was evaluated by MTT assays and morphology observations. Results: The Papp of isorhamnetin, kaempferol, and quercetin was improved 2.03-, 1.69-, and 2.11-fold in the presence of 333μg/mL of IP6, respectively. Water solubility was increased 22.75-, 15.15-, and 12.86-fold for isorhamnetin, kaempferol, and quercetin, respectively, in the presence of 20mg/mL IP6. The lipophilicity of the three flavonoids was slightly decreased, but their hydrophilicity was increased after the addition of IP6 in the water phase as the logP values of isorhamnetin, kaempferol, and quercetin decreased from 2.38±0.12 to 1.64±0.02, from 2.57±0.20 to 2.01±0.04, and from 2.39±0.12 to 1.15±0.01, respectively. The absorption enhancement ratios were 3.21 for isorhamnetin, 2.98 for kaempferol, and 1.64 for quercetin with co-administration of IP6 (200mg/kg) in rats. In addition, IP6 (200mg/kg, oral) caused neither significant irritation to the rat intestines nor cytotoxicity (400μg/mL) in Caco-2 cells. Conclusions: The oral bioavailability of isorhamnetin, kaempferol, and quercetin in TFH was enhanced by the co-administration of IP6. The main mechanisms are related to their enhanced aqueous solubility and permeability in the presence of IP6. In summary, IP6 is a potential absorption enhancer for pharmaceutical formulations that is both effective and safe. [Copyright &y& Elsevier]

Distribution profiles of topically applied drugs can be influenced by the presence of excipients. This study investigated the effect of common topical excipients on the simultaneous lateral diffusion and stratum corneum ( SC) penetration of a model compound, ibuprofen ( IBU) in humans. IBU solutions with and without propylene glycol ( PG), polyethylene glycol 200 ( PEG 200), and/or octisalate ( OS) were dosed onto the forearm of participants. At various times, 10 'tape-strippings' were obtained with perforated concentric tapes and analyzed for IBU concentration and SC protein mass. Complimentary in vitro permeation studies assessed the effect of excipients on the percutaneous absorption of IBU across human skin. Following in vivo application, IBU displayed a greater tendency for lateral diffusion when applied with OS, whereas IBU resisted lateral diffusion when dosed with PG and PEG 200. After 24 h, 25.3 ± 8.0% and 55.5 ± 18.6% of IBU was recovered from the SC in vivo with and without excipients, respectively. There was a twofold-to threefold enhancement in IBU flux in vitro when applied with excipients. The lower IBU recovery from the SC when applied with excipients may be attributed to the permeation enhancement effects of these excipients. The ability of IBU to laterally diffuse appears to be dependent on formulation excipients. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:909-919, 2014 [ABSTRACT FROM AUTHOR]

The intestinal absorption and antiasthmatic efficacy of poorly water-soluble curcumin (CUR), which has low solubility and permeability, was increased by fabricating solid dispersion granules (SDGs). The SDG containing CUR (SDG-CUR) was prepared by dispersing CUR in excess Cremophor RH40 as a solubilizer and Ryoto sugar ester L-1695 as an absorption enhancer using fluid bed granulation. We evaluated the physicochemical properties such as crystallinity and dissolution, pharmacokinetics, and antiasthmatic efficacy of SDG-CUR. Our results showed that CUR was molecularly dispersed, and the dissolution of SDG-CUR was significantly higher than that of native CUR. In addition, the blood concentration of SDG-CUR in rats was much higher than that of native CUR. Compared to CUR, SDG-CUR showed a 9.1- and 13.1-fold increase in area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax), respectively. Further, SDG-CUR effectively alleviated airway hyperresponsiveness and levels of T-helper 2 cytokines (interleukin-4, interleukin-5, and interleukin-13) in a murine model of asthma. In conclusion, our results suggest that the SDGs could be considered as a potential oral formulation to enhance the absorption and efficacy of CUR. [ABSTRACT FROM AUTHOR]

Insertion behaviour of microneedle (MN) arrays depends upon the mechanical properties of the skin and, MN geometry and distribution in an array. In addressing this issue, this paper studies MN array insertion mechanism into skin and provides a simple quantitative basis to relate the insertion force with distance between two MNs. The presented framework is based on drawing an analogy between a beam on an elastic foundation and mechanism of needle insertion, where insertion force is separated into different components. A theoretical analysis indicates that insertion force decreases as interspacing increases. For a specified skin type, insertion force decreased from 0.029 to 0.028 N/MN when interspacing at MN tip was increased from 50 μm (350 μm at MN base) to 150 μm (450 μm at MN base). However, dependence of insertion force seems to decrease as the interspacing is increased beyond 150 μm. To assess the validity of the proposed model, a series of experiments was carried out to determine the force required for skin insertion of MN. Experiments performed at insertion speed of 0.5 and 1.0 mm/s yielded insertion force values of 0.030 and 0.0216 N, respectively, for 30 μm interspacing at MN base (330 μm interspacing at tip) and 0.028 and 0.0214 N, respectively, for 600 μm interspacing at MN base (900 μm interspacing at tip). Results from theoretical analysis and finite element modelling agree well with experimental results, which show MN interspacing only begins to affect insertion force at low interspacing (<150 μm interspacing at MN base). This model provides a framework for optimising MN devices, and should aid development of suitable application method and determination of force for reliable insertion into skin. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1209-1221, 2013 [ABSTRACT FROM AUTHOR]

Abstract: This work aimed to evaluate the applicability of rhamnolipids as permeation enhancers for oral drugs. In this study, rhamnolipids were found to effectively increase the paracellular and transcellular transport of Transwell®-cultured Caco-2 cells, an in vitro model of the human small intestinal epithelium, in a concentration-dependent manner. Rhamnolipids at 150mg/L increased the paracellular apparent permeability (P app) of phenol red almost 7- to 8-fold, the largest enhancement ever reported, while Tween-80 exhibited no such effect. Regarding the transcellular pathway, rhamnolipids at 150mg/L enhanced the P app of propranolol 2-fold, similar to the performance of Tween-80 at 400mg/L. Moreover, rhamnolipids like Tween-80, significantly inhibited P-glycoprotein (P-gp) activity reflected by the reduced efflux ratio (basolateral-to-apical/apical-to-basolateral) of rhodamine 123 (R123), a P-gp substrate, on Caco-2 cells. Inhibition of P-gp activity was confirmed on plate cultured Caco-2 monolayers by assaying accumulation/efflux of R123 and R110, a non-P-gp substrate. Finally, rhamnolipids were demonstrated to be safe by cell viability and hemolysis assays. In conclusion, rhamnolipids were highly effective regulators of all three transport pathways, suggesting their use as a safe absorption enhancer for oral drugs. [Copyright &y& Elsevier]

Bisphosphonates are recommended for the treatment of postmenopausal osteoporosis, Paget's disease, bone metastasis, and multiple myeloma. However, the efficacy of oral preparations is limited because of their low bioavailabilities and adverse effects from the gastrointestinal tract. This study was conducted to investigate whether Nα-deoxycholyl- l-lysyl-methylester (DCK), an absorption enhancer derived from deoxycholic acid, can increase the oral bioavailability of ibandronate. We prepared a physical complex of ibandronate with DCK, and evaluated its permeability across a parallel artificial membrane. Furthermore, pharmacokinetic profile and oral absorption of the optimized formulation were also studied in rats. DCK enhanced the apparent membrane permeability of ibandronate by 14.4-fold in a parallel artificial membrane permeability assay model, compared with when ibandronate was applied alone. When ibandronate-DCK complex was intrajejunally administered to rats, it resulted in a 2.8- and 4.3-fold increase in maximum plasma concentration and area under the concentration-time curve from time zero to the last measurable time point, respectively. These results demonstrate that the ibandronate-DCK formulation can improve the oral absorption of ibandronate, allowing less frequent dosing to avoid side effects as well to enhance patient compliance. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:341-346, 2013 [ABSTRACT FROM AUTHOR]

Abstract: Following epidural administration, cerebrospinal fluid bioavailability of local anesthetics is low, one major limiting factor being diffusion across the arachnoid mater barrier. The aim of this study was to evaluate the influence of absorption enhancers on the meningeal permeability of epidurally administered ropivacaine. Five enhancers known for their ability to increase drug permeability via transcellular and/or paracellular pathways, i.e. palmitoyl carnitine, ethylenediaminetetraacetic acid, sodium caprate, dodecylphosphocholine and pentylglycerol, were tested ex vivo on fresh specimen of meninges removed from cervical to lumbar level of rabbit spine following laminectomy and placed in diffusion chambers. Among them, sodium caprate lead to the best permeability improvement for both marker and drug (440% and 112% for mannitol and ropivacaine, respectively) and was therefore selected for in vivo study in a sheep model using microdialysis technique to evaluate epidural and intrathecal ropivacaine concentrations following epidural administration. Resulting dialysate and plasma concentrations were used to calculate pharmacokinetic parameters. Following sodium caprate pre-treatment, ropivacaine intrathecal maximal concentration (Cmax) was 1.6 times higher (78±16μgml−1 vs 129±26μgml−1, p <0.05) but the influence of the absorption enhancer was only effective the first 30min following ropivacaine injection, as seen with the significantly increase of intrathecal AUC0–30min (1629±437μgminml−1 vs 2477±559μgminml−1, p <0.05) resulting in a bioavailable fraction 130% higher 30min after ropivavaine administration. Co-administration of local anesthetics with sodium caprate seems to allow a transient and reversible improvement of transmeningeal passage into intrathecal space. [Copyright &y& Elsevier]

Abstract: The aim of this study was to investigate three kinds of methylated chitosan containing different aromatic moieties; methylated N-(4-N,N-dimethylaminobenzyl) chitosan (TM-Bz-CS), methylated N-(4-N,N-dimethylaminocinnamyl) chitosan (TM-CM-CS) and methylated N-(4-pyridylmethyl) chitosan (TM-Py-CS), on the paracellular permeability of Caco-2 cell monolayers and their toxicity towards the cell lines. The factors affecting epithelial permeability were evaluated in intestinal cell monolayers of Caco-2 cells using the transepithelial electrical resistance (TEER) and permeability of Caco-2 cell monolayers, with fluorescein isothiocyanate dextran 4400 (FD-4) as a model compound for paracellular tight junction transport. The results revealed that methylated chitosan containing different aromatic moieties showed the different absorption enhancing ability. The rank of enhancing paracellular permeability was TM65CM50CS>TM56Bz42CS>TM65CS>TM53Py40CS. The cytotoxicity of these modified chitosans on Caco-2 cells was also studied by MTT assay where the TM53Py40CS exhibited less toxicity than other derivatives. These studies demonstrated that the chemical structure and the positive charge location play an important role for absorption enhancement and cytotoxicity. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the potential of the buccal mucosa for the systemic delivery of risperidone (RISP), and to determine the impact of Azone® (AZ) on the transport of RISP via this route. The permeability of RISP through porcine buccal mucosa was assessed in modified Ussing chambers at various concentrations to determine the mechanisms involved in transport across the tissue. The effect of AZ was assessed by administering AZ 5% (w/w) to the tissue as a pretreatment or together with RISP in solution or in a mucoadhesive gel formulation. RISP permeated the buccal mucosa via a passive diffusion mechanism and pretreatment or coadministration of AZ 5% did not significantly modify the permeation of RISP. Application of a RISP mucoadhesive gel resulted in a steady state flux of 64.65 ± 8.0 µg/cm2/h, which when extrapolated to the in vivo setting, is predicted to result in RISP plasma concentrations of 11.2-56.1 µg/L for mucosal application areas between 2 and 10 cm2. Given that these predicted concentrations are within the therapeutic range of RISP required in humans, delivery of RISP via the buccal mucosa has the potential to result in therapeutically relevant plasma concentrations for the treatment of schizophrenia. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4584-4592, 2010 [ABSTRACT FROM AUTHOR]

Abstract: Levothyroxine sodium (T4), administered orally, is used for the treatment of hypothyroidism. T4 is a narrow therapeutic index drug with highly variable bioavailability (40–80%). The purpose of the present study was to increase the transepithelial transport of T4 using straight chain fatty acids across Madin-Darby Canine kidney (MDCK) cell line. Capric acid (C10), lauric acid (C12) and oleic acid (C18) were studied in molar ratios of 1:0.5, 1:1, 1:2 and 1:3 (T4:fatty acid). Transport of the hydrophilic marker, Lucifer yellow, was also studied. All three fatty acids proved to significantly increase T4 transport and the order of enhancement was to the effect of C12≈C18>C10. This Increase in transport was accompanied by reductions in transepithelial electrical resistance (TEER) values, which indicates an opening of tight junctions. Cytotoxic effects of the fatty acids were evaluated by TEER measurements, lactate dehydrogenase release, percent viability and propidium iodide staining of the cells. At the lower molar concentrations of 1:1, the fatty acids did not show any toxicity. However, C12 and C18 when added, to T4:fatty acid molar ratio of 1:2 and 1:3, respectively showed severe toxicity with irreversible damage to the cells. Hence, addition of fatty acids to T4 formulations at low concentrations can significantly improve intestinal permeability of T4 without any toxicity potentially leading to improved bioavailability. [Copyright &y& Elsevier]

The effect of methylated N-(4- N,N-dimethylaminocinnamyl) chitosan (TM-CM-CS) was investigated on paracellular permeability and its toxicity towards Caco-2 cells. Fluorescein isothiocyanate dextran 4,400 (FD-4) was used as the model compound for paracellular transport. The factors, i.e. the degree of quaternization (DQ) and the extent of N-substitution (ES) of the derivatives, were studied for the effect on transepithelial electrical resistance (TEER) and permeability. The results revealed that at pH 7.4, TM-CM-CS appeared to increase cell permeability in a dose-dependent manner, and the effect was relatively reversible at lower doses of 0.05–0.5 mM. The difference of the DQ and the ES of TM-CM-CS slightly affected the decrease of TEER values and the FD-4 permeability. The cytotoxicity of TM-CM-CS was concentration-dependent and did not cause an acute cytotoxic effect as analyzed by the MTT assay. These studies demonstrated that this novel modified chitosan has the potential to be used as an intestinal absorption enhancer of therapeutic macromolecules. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of a type of hydrophobic moiety, extent of N-substitution (ES), and degree of quaternization (DQ) of chitosan (CS) on the transepithelial electrical resistance and permeability of Caco-2 cells monolayer, using fluorescein isothiocyanate dextran 4,400 (FD-4) as the model compound for paracellular tight junction transport. CS was substituted with hydrophobic moiety, an aliphatic aldehyde ( n-octyl) or aromatic aldehyde (benzyl), for the improved hydrophobic interaction with cell membrane, and they were quaternized with Quat-188 to render CS soluble. The factors affecting the epithelial permeability have been evaluated in the intestinal cell monolayers, Caco-2 cells. Cytotoxicity was evaluated by using the trypan blue and MTT viability assay. The results revealed that at pH 7.4 CSQ appeared to increase cell permeability in dose-dependent manner, and this effect was relatively reversible at the lower doses of 0.05–1.25 mM. The higher DQ and ES caused the higher permeability of FD-4. Cytotoxicity of CSQ was concentration, %DQ, and %ES dependent. Substitution with hydrophobic moiety caused decreasing in permeability of FD-4 and cytotoxicity by benzyl group had more effect than octyl group. These studies demonstrated that these novel modified chitosan derivatives had potential for using as absorption enhancers. [ABSTRACT FROM AUTHOR]

Abstract: The current study aims to investigate the effect of sodium caprate on the intestinal absorption and bioavailabilities of danshensu and salvianolic acid B, the major active components in Salvia miltiorrhiza Bge (Danshen). Biopharmaceutics and pharmacokinetics properties of the two compounds have been characterized by in vitro, in situ models as well as in vivo in rats. Based on the identified biopharmaceutics characteristics of the two compounds, effect of sodium carparate as absorption enhancer on the intestinal absorption and pharmacokinetics of danshensu and salvianolic acid B in pure compound form as well as extract form were investigated both in vitro and in vivo. Both danshensu and salvianolic acid B demonstrated very limited intestinal permeabilities, leading to oral bioavailabilities of only 11.09% and 3.90% in rats, respectively. Results from both in vitro and in vivo studies consistently indicated that sodium caprate could significantly enhance intestinal permeabilities as well as the in vivo bioavailabilities of both danshensu and salvianolic acid B. The current findings not only identified the usefulness of sodium caprate for the improved delivery of Danshen product but also demonstrated the importance of biopharmaceutics characterization in the dosage form development of traditional Chinese medicine. [Copyright &y& Elsevier]

The aim of this study was to investigate the effect of methylated N-(4- N, N-dimethylaminobenzyl) chitosan, TM-Bz-CS, on the paracellular permeability of Caco-2 cell monolayers and its toxicity towards the cell lines. The factors affecting epithelial permeability, e.g., degree of quaternization (DQ) and extent of dimethylaminobenzyl substitution (ES), were evaluated in intestinal cell monolayers of Caco-2 cells using the transepithelial electrical resistance and permeability of Caco-2 cell monolayers, with fluorescein isothiocyanate dextran 4,400 (FD-4) as a model compound for paracellular tight-junction transport. Cytotoxicity was evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide viability assay. The results revealed that, at pH 7.4, TM-Bz-CS appeared to increase cell permeability in a concentration-dependent manner, and this effect was relatively reversible at lower doses of 0.05–0.5 mM. Higher DQ and the ES caused the permeability of FD-4 to be higher. The cytotoxicity of TM-Bz-CS depended on concentration, %DQ, and %ES. These studies demonstrated that this novel modified chitosan has potential as an absorption enhancer. [ABSTRACT FROM AUTHOR]

Epithelial cell monolayers are routinely used to evaluate efficacy of paracellular permeability enhancers (PPEs). The purpose of the present work was to investigate how biorelevant refinements to the Caco-2 cell model impact in vitro efficacy (decrease in transepithelial electrical resistance and increase in mannitol permeability) of PPEs. Standard transport buffer was replaced by fasted-state simulated intestinal fluid (FaSSIF) or serum; or stirring was performed to decrease the unstirred water layer thickness. Apical FaSSIF significantly reduced the efficacy of amphiphilic PPEs palmitoylcarnitine and hexadecylphosphocholine and reduced the amount of these PPEs associated with cells. In contrast, FaSSIF did not affect efficacy of nonamphiphilic PPEs, ethylenediaminetetraacetic acid or 3-nitrocoumarin. Basolateral serum increased the transepithelial flux of PPEs, but did not lessen their potency. Stirring increased the flux of all PPEs, and also enhanced the potency of the amphiphilic PPEs. These results show that inclusion of FaSSIF and agitation in the cellular models significantly alter the efficacy of amphiphilic PPEs but not of hydrophilic or lipophilic PPEs. Future studies should be directed at evaluating the ability to these refined in vitro systems to predict in vivo effects of PPEs. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 1977–1992, 2008 [ABSTRACT FROM AUTHOR]

The purpose of this investigation was to study the influences of absorption enhancers in increasing oral bioavailability of Ganciclovir (GAN) by assessing the transepithelial permeation across cell monolayers in vitro and bioavailability in rats in vivo. The permeation of GAN across Caco-2 and MDCK cell monolayers in the absence/presence of dimethyl-β-cyclodextrin (DMβCD), chitosan hydrochloride (CH), sodium lauryl sulphate (SLS), and their combinations was studied for a 2-h period. GAN was administered to rats in absence/presence of absorption enhancers and drug contents in plasma were estimated. We found that the apparent permeability coefficient (Papp) of GAN in absence of absorption enhancers (control) were 0.261 ± 0.072 × 10-6 and 0.486 ± 0.063 × 10-6 cm/s in Caco-2 and MDCK cell monolayers, respectively, whereas in the presence of DMβCD, CH, SLS, and their combinations, Papp of GAN increased by 5- to 25-fold and 7- to 33-fold as compared to control in Caco-2 and MDCK cell monolayers, respectively. However, in rats, the maximum enhancement in bioavailability of GAN during coadministration of these absorption enhancers was only fivefold compared to GAN control. To conclude, the absorption enhancers-DMβCD, CH, SLS, and their combinations demonstrated significant improvement in transepithelial permeation and bioavailability of GAN. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2710–2722, 2007 [ABSTRACT FROM AUTHOR]

In our previous studies, taurine (Tau) and L-glutamine protected intestinal epithelial cells from local toxicity caused by sodium laurate (C12), an absorption enhancer, while maintaining sufficient absorption-enhancing effect of C12, and it was suggested that one of the mechanisms behind cytoprotection by amino acids was to prevent intracellular Ca2+ concentration ([Ca2+]i) from increasing. In the present study, we focused on the elucidation of mechanisms by which C12 increases [Ca2+]i and by which amino acids suppress [Ca2+]i by utilizing Caco-2 cells. Removal of extracellular Ca2+ remarkably suppressed the increase of [Ca2+]i by C12. Compound 48/80, an inhibitor of phospholipase C, and verapamil, a Ca2+ channel inhibitor, also significantly prevented [Ca2+]i elevation. These results indicate that C12 augmented [Ca2+]i due to (a) influx of extracellular Ca2+ through Ca2+ channel, (b) release of Ca2+ from the endoplasmic reticulum. Cytoprotective action by amino acids was significantly attenuated by orthovanadate, an inhibitor of plasma membrane Ca2+-ATPase (PMCA), suggesting that amino acids activate PMCA to enhance the efflux of intracellular Ca2+. Furthermore, Tau enhanced the mitochondrial uptake of Ca2+, which could contribute to the decrease in [Ca2+]i. These results clearly show that amino acids protect intestinal epithelial cells from being damaged by modulating intracellular Ca2+ dynamics. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:2256–2265, 2006 [ABSTRACT FROM AUTHOR]

Cationized gelatins, candidate absorption enhancers, were prepared by addition of ethylenediamine or spermine to gelatin and the effects of the resulting ethylenediaminated gelatin (EG) and sperminated gelatin (SG) on the paracellular transport of 5(6)-carboxyfluorescein (CF), FITC-dextran-4 (FD4), and insulin through caco-2 cell monolayers were examined. The Renkin function was used for characterization of the paracellular pathway and changes in the pore radius (R) and pore occupancy/length ratio (ℇ/L) calculated from the apparent permeability coefficients (Papp) of CF and FD4 are discussed. Ethylenediaminetetraacetic acid (EDTA) increased the R of the caco-2 cell monolayer and the Papp of all compounds examined was markedly increased by the addition of EDTA. On the other hand, EG and SG did not increase R and their enhancing effects were not as strong as those of EDTA. The increase in ℇ/L could be the enhancing mechanism for the cationized gelatins. The number of pathways for water-soluble drugs, such as CF and FD4, in the caco-2 monolayers could be increased by the addition of the cationized gelatins. The ratios of the permeability coefficients of insulin (observed/calculated based on the Renkin function) suggest that insulin undergoes enzymatic degradation during transport which is not inhibited by enhancers. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:1393–1401, 2006 [ABSTRACT FROM AUTHOR]

Objective: Many therapeutically active agents experience low bioavailability upon oral administration due to low permeability, low solubility, interaction with efflux transporters or first pass metabolism. In general, absorption enhancers are agents that can modulate the paracellular permeability of drugs, thus, potentially increasing oral bioavailability. The objective of this study was to examine the effect of the active fragment of Zonula occludens toxin (Zot), ΔG, on the transport of a paracellular marker, mannitol, using in vitro (Caco-2 cell monolayers) and in vivo (intraduodenal administration in rats) experimental methods. Methods: The transport of [14C]mannitol with ΔG (0, 50, 80, or 100 μg/ml) was determined across Caco-2 cells. Male Sprague–Dawley rats were assigned to receive one of the following treatments: [14C] mannitol (40 μCi/kg), [14C]mannitol/ΔG (417 μg/kg), or [14C] mannitol/ΔG/Protease inhibitors (PI). Results: The mean (±S.E.M.) apparent mannitol permeability coefficients (Papp) observed after incubation with 0, 50, 80, and 100 μg/ml ΔG were 3.5 (±0.4), 4.17 (±0.27), 4.33 (±0.61), and 9.94 (±0.24)×10−6 cm/s. After oral administration, Cmax (3.8×10−4 vs. 4.4×10−4 mM) and AUC0–6 h (0.096 vs. 0.088 mM min), obtained for [14C]mannitol and [14C]mannitol/ΔG, respectively, were not statistically different. However, both Cmax (7.6×10−4 mM) and AUC0–6 h (0.25 mM min) were significantly higher for the [14C]mannitol/ΔG/PI treatment. Conclusions: The 12 kDa fragment of Zot, ΔG, enhanced the in vitro transport and oral absorption of the paracellular marker, mannitol, in the presence of protease inhibitors (PI). [Copyright &y& Elsevier]