Absorption Promoters Research Articles

The influence of phenolic and phytic acid food matrix factors on iron bioavailability potential in 10 commercial lentil genotypes (Lens culinaris L.)

This study aimed to identify lentil (Lens culinaris L.) genotypes with superior Fe concentrations and phenolic and phytic acid profiles for enhanced Fe bioavailability. Ten commercial lentil cultivars were analyzed for concentrations of Fe, phytic acid (PA; Fe absorption inhibitor), ascorbic acid (AA; Fe absorption promoter), gallic acid (GA; Fe absorption inhibitor), and chlorogenic acid (CLA; Fe absorption inhibitor). Fe concentrations were measured using inductively coupled plasma-emission spectroscopy. Phytic acid and phenolic compounds were determined using high performance liquid chromatography. Fe concentration across genotypes was 56–70mgkg−1. Phytic acid was observed at concentrations between 6.3 and 8.7mgg−1. Mean concentrations of other food matrix factors were as follows: AA=72.4mgkg−1; GA=25.0mgkg−1; and CLA=17.4mgkg−1. Phytic acid to Fe molar ratios in lentil ranged from 8.6 to 13.0, indicating moderate Fe bioavailability. Overall, lentil appears to have considerable potential for Fe biofortification with proper genetic and environmental sourcing. In addition, measurements of food matrix factors (promoters and inhibitors) in conjunction with in vitro digestion/Caco-2 cell cultures are suggested to determine lentil genotypes with superior Fe bioavailability.

New polyfluorothiopropanoyloxy derivatives of 5β-cholan-24-oic acid designed as drug absorption modifiers

A series of final six propanoyloxy derivatives of 5β-cholan-24-oic acid (tridecafluoroctylsulfanyl- and tridecafluoroctylsulfinylethoxycarbonylpropanoyloxy derivatives) as potential drug absorption promoters (skin penetration enhancers, intestinal absorption promoters) was generated by multistep synthesis. Structure confirmation of all generated compounds was accomplished by 1H NMR, 13C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (RM) was determined. The hydrophobicity (log P), solubility (logS), polar surface area (PSA) and molar volume (MV) of the studied compounds were also calculated. All the target compounds were tested for their in vitro transdermal penetration effect and as potential intestinal absorption enhancers. The cytotoxicity of all the evaluated compounds was evaluated against normal human skin fibroblast cells. Their anti-proliferative activity was also assessed against human cancer cell lines: T-lymphoblastic leukaemia cell line and breast adenocarcinoma cell line. One compound showed high selective cytotoxicity against human skin fibroblast cells and another compound possessed high cytotoxicity against breast adenocarcinoma cell line and skin fibroblast cells. Only one compound expressed anti-proliferative effect on leukaemia and breast adenocarcinoma cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC50>37μM), indicating they would have moderate cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity/polarity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and penetration enhancement effect are discussed in this article.

New propanoyloxy derivatives of 5β-cholan-24-oic acid as drug absorption modifiers

A series of final twelve propanoyloxy derivatives of 5β-cholan-24-oic acid (O-propanoyl derivatives of cholic acid) as potential drug absorption modifiers (skin penetration enhancers, intestinal absorption promoters) was generated by multistep synthesis. Structure confirmation of all generated compounds was accomplished by 1H NMR, 13C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (RM) was determined. The hydrophobicity (log P), solubility (log S), polar surface area (PSA) and molar volume (MV) of the studied compounds were also calculated. All the target compounds were tested for their in vitro transdermal penetration effect and as potential intestinal absorption enhancers. The cytotoxicity of all the evaluated compounds was evaluated against normal human skin fibroblast cells. Their anti-proliferative activity was also assessed against human cancer cell lines: T-lymphoblastic leukemia cell line and breast adenocarcinoma cell line. One compound showed selective cytotoxicity against human skin fibroblast cells and another compound possessed the highest cytotoxicity against all the tested cell lines. Only one compound expressed anti-proliferative effect on leukemia cancer cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC50>37μM), indicating they would have moderate cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity/polarity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and enhancement effect are discussed in this article.

Nasal drug delivery.

The nasal cavity has for more than three decades been widely explored as a potential alternative route to oral or parenteral administration for systemically active drugs. The nasal route has shown remarkable advantages that include a rapid and high systemic availability, avoidance of first pass metabolism by the liver, and the possibility of targeting drugs directly from the nasal cavity to the brain [1, 2]. Considerable knowhow and data have been accumulated over the years from investigational work carried out by various excellent research groups in academia and industry. New nasal delivery carriers and emerging technologies have been used for product design and efficient clinical translation to nasal medicines. The nasal route for systemic administration is attractive in many therapeutic areas where a rapid onset of action is required, e.g., pain, erectile dysfunction, frigidity, migraine, seizures, insomnia, panic attacks, Parkinson rigidity, hot flushes, emesis, Alzheimer or MS attacks, and cardiovascular events. An increasing number of small molecules are being marketed as nasal products such as Zomig® (zolmitriptan), Imitrex® (sumatriptan), and Stadol NS (butorphanol tartrate) for migraine treatment, Aerodiol® (estradiol hemihydrate) for menopausal syndrome treatment, PecFent® and Instanyl® (fentanyl) for severe pain treatment, and Nicorette® (nicotine) for smoking cessation [3]. With this growing number of applications, the US market of intranasal drug products is expected to reach US$5.2 billion by 2017 [4]. It is noteworthy that most of the marketed products are based on molecules sufficiently lipophilic to enable therapeutic levels of the drug to reach the systemic circulation, thus requiring no nasal absorption enhancers. Despite the obvious advantages of intranasal drug delivery, the nasal cavity presents a number of limitations for drug absorption, including low intrinsic permeability for some drugs, such as hydrophilic molecules, peptides, proteins, and nucleotides, rapid mucociliary clearance, and enzymatic degradation [1, 2]. In order to achieve efficient and safe intranasal drug products, a number of strategies for overcoming nasal delivery barriers can be applied. In the design of a nasal product, three main cooperative entities should be taken in consideration: the drug, the delivery carrier, and the administration device. The factors to be considered in the design and development of an efficient nasal product, related to these three components, are schematically presented as a three-lobe fleur-de-lys in Fig. 1. Several important morphological and physiological constraints on nasal drug delivery including limited volume of administration requiring high drug potency or mucosal enzymatic drug degradation should be kept in mind when formulating new nasal products. Also, the key properties required from drug candidates for development of successful intranasal products would be potency, lipophilicity, and water solubility. The nasal delivery of hydrophilic or high molecular weight drugs would be in need of a nasal absorption promoter in order for the drug to be transported across the nasal membrane in sufficient quantity for therapeutic use. Innovative strategy approaches to design efficient nasal delivery systems for specific drugs are currently in various stages of research and development. These include new nasal enhanced delivery technologies, design of carriers that impede drug degradation by mucosal enzymes, modulation E. Touitou (*) Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel e-mail: touitou@cc.huji.ac.il

Analysis of daidzein in nanoparticles after oral co-administration with sodium caprate to rats by ultra-performance liquid chromatography–quadrupole-time-of-flight mass spectrometry

An ultra-performance-liquid-chromatography–quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS) method was developed and validated for the quantitation of daidzein (DZ) in rat plasma. Ethylparaben was chosen as internal standards (IS). DZ was linear over the range of 0.001–5μg/mL. The lower limit of quantification (LLOQ) was 0.001μg/mL and the limit of detection (LOD) was 0.0005μg/mL. The intra-day and inter-day relative standard deviations (RSDs) were ranged from 3.59% to 6.43% and 5.35% to 7.25%, respectively. This UPLC/Q-TOF-MS method provided good specifity, highly sensitivity, accurate and high-speed detection (6min), applicable to the pharmacokinetics study in rats in vivo after oral administration of free daidzein solution, daidzein-loaded poly (lactide-co-glycolide) (PLGA) nanoparticles (D-NPs) suspension and D-NPs co-administered with sodium caprate (C10) which as the oral absorption promoter. It was shown that the pharmacokinetics behavior was significantly improved after the oral administration of D-NPs suspension co-administered with absorption promoter C10 by the fact that the relative bioavailability were enhanced about 4.24-fold, compared to that of DZ suspension.

A new manganese-based oral contrast agent (CMC-001) for liver MRI: pharmacological and pharmaceutical aspects

Manganese is one of the most abundant metals on earth and is found as a component of more than 100 different minerals. Besides being an essential trace element in relation to the metabolic processes in the body, manganese is also a paramagnetic metal that possesses similar characteristics to gadolinium with regards to T1-weighted (T1-w) magnetic resonance imaging (MRI). Manganese, in the form of manganese (II) chloride tetrahydrate, is the active substance in a new targeted oral contrast agent, currently known as CMC-001, indicated for hepatobiliary MRI. Under physiological circumstances manganese is poorly absorbed from the intestine after oral intake, but by the use of specific absorption promoters, L-alanine and vitamin D(3), it is possible to obtain a sufficiently high concentration in the liver in order to achieve a significant signal enhancing effect. In the liver manganese is exposed to a very high first-pass effect, up to 98%, which prevents the metal from reaching the systemic circulation, thereby reducing the number of systemic side-effects. Manganese is one of the least toxic trace elements, and due to its favorable safety profile it may be an attractive alternative to gadolinium-based contrast agents for patients undergoing an MRI evaluation for liver metastases in the future. In this review the basic pharmacological and pharmaceutical aspects of this new targeted oral hepatobiliary specific contrast agent will be discussed.

Lipoamino Acids as Major Components of Absorption Promoters in Drug Delivery

Many biologically active compounds are unsuitable for development as drugs due to their poor bioavailability. For hydrophilic compounds, modifications to increase lipophilicity can increase passive diffusion or increase uptake into the lymphatic system. Alternatively, improved bioavailability of hydrophilic drug candidates may be achieved by formulation with absorption promoters such as surfactants, penetration enhancers, or ion pairing agents. This approach to enhancing bioavailability also has the potential to widen the range of compound categories that can be used as chemical probes to study biological systems in cells and in vivo where membrane permeability would otherwise be a significant limitation. Lipidic amino acids, which combine the structural properties of lipids with those of α-amino acids, represent a relatively unexplored class of agents that can improve drug adsorption. This review discusses the potential of absorption promoters possessing lipoamino acids for improving drug bioavailability.

Novel intraocular and systemic absorption drug delivery and efficacy of N‐acetylcarnosine lubricant eye drops or carcinine biologics in pharmaceutical usage and therapeutic vision care

The latest estimates of the World Health Organization indicate that there are 161 million visually impaired individuals worldwide, 37 million of whom are blind, with a yearly increase of 1-2 million. The scientists developed and patented the lubricant eye drops formulated as 1%N-acetylcarnosine prodrug of l-carnosine containing a mucoadhesive cellulose-based compound combined with corneal absorption promoters in an ocular drug delivery system. Carcinine is suitable for the systemic administration (per oral) for ophthalmic therapeutic indications. The HPLC analysis was developed to search the pathways of ocular metabolic activities of 1%N-acetylcarnosine and the bioactivation of this drug molecule promoting transcorneal uptake of l-carnosine in the aqueous humor. A meta-analysis of phase 2 randomized double-blind placebo-controlled clinical trial data was conducted. The intraocular absorbed l-carnosine demonstrated a number of pharmacological mechanisms of prevention and reversal of cataracts. Results of systemic absorption of l-carnosine provide tuberomammillary activation that regulates neuronal functions such as hypothalamic control promoting sensory input in the primary vision perceptual pathway. The parabulbar, subconjunctival, and intravitreal injection of carcinine with most of the vehicle removed is not toxic to intraocular structures, reduces postoperative intraocular inflammation, is a potentially useful tool in the treatment of proliferative vitreoretinopathy as well as considered as the antiapoptotic drug for the protection of photoreceptor cells from oxidative light-induced stress. The discovery of naturally occurring carnosine derivatives introduces N-acetylcarnosine and carcinine as effective medical treatment for sight-threatening eye disorders.

Pharmaceutical study of suppository formulations for improved in vivo kinetics of rifampicin.

To study rifampicin (RFP) suppository formulations that were prepared by adding an absorption promoter and a holding agent to conventional rifampicin suppositories in order to achieve higher blood drug levels. The subjects were 3 healthy volunteers who gave consent to participate in this study. Suppository formulations were prepared by adding sodium caprinate (the absorption promoter) to 600 mg, 750 mg, or 900 mg of RFP at about 3% of the suppository weight and sodium alginate (the holding agent) at 25% of the RFP content. Serum samples collected at 2, 6, and 10 hours after insertion of a suppository were subjected to RFP concentration analysis. In subject no. 1, the maximum concentration was 0.807 Lg/ml, 1.093 microg/ml, and 1.291 microg/ml after administration of a suppository containing 600 mg, 750 mg, or 900 mg of RFP, respectively. Since an injectable RFP formulation has not been approved in Japan, formulation studies of RFP suppositories are important to achieve a better clinical response and to prevent the development of resistance. The present formulation that delivered a blood concentration of RFP considerably higher than 1 microg/ml was considered to have therapeutic potential. Its clinical utility will be examined in further formulation studies.

Effect of preservatives on systemic delivery of insulin by ocular instillation in rabbits.

The effects of absorption promoters and ophthalmic preservatives on the systemic absorption of insulin through the ocular route were investigated in albino rabbits. Insulin absorption was evaluated by its hypoglycaemic response. Although ocular instillation of insulin alone did not decrease the serum glucose concentration, instillation of insulin with absorption promoters such as EDTA and saponin decreased it. The promoting effect depended on the concentration of the absorption promoters. Of ophthalmic preservatives investigated (benzalkonium chloride, paraben, 2-phenylethanol, benzyl alcohol and sorbic acid), benzalkonium, chloride and paraben showed promoting effects. The promoting effect for benzalkonium chloride was reversible and dependent on concentration of both benzalkonium chloride and insulin in the formulation.

The influence of concentration of two salicylate derivatives on rectal insulin absorption enhancement.

3,5-Diiodosalicylate sodium (DIS), a highly lipophilic salicylate, was evaluated against 5-methoxysalicylate sodium (MS) as a potential adjuvant absorption promoter for rectal insulin delivery. Comparative blood glucose measurements were made using the two adjuvants under identical conditions as promoters of rectal insulin absorption in rats. Concentrations of DIS greater than and including 0.1 M produced an unexpected, progressive decrease in adjuvant activity as determined by a decline in observed hypoglycaemic response. This was not due to formation of an insulin-DIS complex. The adjuvant MS produced a classical, sigmoidal log-dose response curve. Possible reasons for the occurrence of the DIS optimum phenomenon are discussed as well as are the observed differences in adjuvant potency of these agents in a propylene glycol-containing vehicle.

Ophthalmic preservatives as absorption promoters for ocular drug delivery.

The effects of ophthalmic preservatives on the drug permeability through isolated ocular membranes of albino rabbits were investigated using a two-chamber glass diffusion cell. Tilisolol and fluorescein isothiocyanate (FITC)-dextrans (average molecular weights 4400 and 9400 Da; FD-4 and FD-10, respectively) were used as model penetrants of ophthalmic beta-blockers and peptide drugs. Preservatives significantly enhanced the corneal penetration of not only tilisolol but also FITC-dextrans. Especially, benzalkonium chloride increased the corneal permeability of FD-4 and FD-10 by 28.8 and 37.1 times, respectively. These results indicate the usefulness of ophthalmic preservatives as absorption promoters for the ocular delivery of beta-blockers and hydrophilic macromolecules. Preservatives also enhanced the conjunctival permeability of tilisolol, FD-4 and FD-10. The promoting effect of preservatives on the conjunctival drug penetration was smaller than that on the corneal one. Preservative increased the ratio of corneal to conjunctival permeability of tilisolol, FD-4 and FD-10. The different responses of corneal and conjunctival drug penetrations to ophthalmic preservatives may be useful to control the extent and pathway for the ocular and systemic absorptions of instilled drugs.

Non-ionic surfactants and gastric mucosal transport of paraquat.

The influence of a range of polyoxyethylated non-ionic surfactants upon the transport of [14C]-paraquat dichloride across rabbit isolated gastric mucosa was investigated. Paraquat was shown to cross the mucosal epithelium by passive diffusion. Certain members of the surfactant series enhanced transmucosal paraquat transfer at low surfactant concentrations (e.g. 0.001%) but the occurrence and magnitude of this effect was not dependent in a simple manner upon surfactant structure of physiochemical properties. At micellar concentrations the increase in paraquat transport was greatest with those surfactants possessing both ethylene oxide chains of 10-20 units and alkyl chains longer than C7-C9. The most effective absorption promoter was found to be Brij 36T (C12E10). At micellar surfactant concentrations the enhancement of paraquat transfer appeared, from histological evidence, to be related to the ability of the surfactants to solubilize membrane components and disrupt epithelial cells.

Telomere‐dependent senescent phenotype of lens epithelial cells as a biological marker of aging and cataractogenesis: the role of oxidative stress intensity and specific mechanism of phospholipid hydroperoxide toxicity in lens and aqueous

Cataract formation represents a serious problem in the elderly and has a large impact on healthcare budget. Aging and cataract formation are relatively complex phenomena, both in vivo and in vitro. Telomeres are special structures at the end of chromosomes. They shorten during each round of replication, and this has been characterized as a mitotic counting mechanism. Our review analysis in this work shows that the rate of telomere shortening in human lens epithelial cells during aging and cataract formation is modulated by oxidative stress as well as by differences in antioxidative defense capacity of the normal and cataractous crystalline lenses. Presented in this review studies suggest that telomere shortening in human lens cells and increased oxidative stress are the result of the peroxidative damage to the lens cell membranes and biomolecules induced in the lack of reductive detoxification of phospholipid hydroperoxides as the triggering mechanism of cataractogenesis. Lipid peroxidation (LPO) is a causative factor of cataract. The increased concentrations of primary molecular LPO products (diene conjugates, lipid hydroperoxides) and end fluorescent LPO products were detected in the lipid moieties of the aqueous humor samples obtained from patients with senile and complicated cataracts when compared to normal donors. The progressive accumulation of oxidative damage may act as an important mechanism for organism aging and cataractogenesis. The oxidative stress form and intensity might determine the lens senescence rate and cataract type, making efforts in the cataract prevention challenge more complex. The analyzed challenge in this work is that the reduction in telomere shortening rate and damages in telomeric DNA make an important contribution to the anticataract and life-extension effect of carnosine administered systemically in the formulations stabilizing a dipeptide from the enzymatic hydrolysis with carnosinase, or topically administered to the eye with carnosine ophthalmic prodrug N-acetylcarnosine and lubricant formulations thereof including corneal absorption promoters. Telomere length in the human crystalline lens cells is a reflection of aging, cataractogenesis, and lifespan in biogerontological studies.

Restoration of Rat Colonic Epithelium After In Situ Intestinal Instillation of the Absorption promoter, Sodium Caprate

Sodium caprate (C10) is an oral absorption promoter that is currently in clinical trials as a component of solid dosage forms for poorly permeable small molecules and peptides. Clinical data with zoledronic acid tablets suggest that significant delivery along with acceptable safety can be achieved from a once-a-week dosing regime. C10 has surfactant-like properties at the high doses used in vivo and therefore we examined its effects on rat intestinal epithelium following intestinal instillation. Addition of 100 mM concentrations of C10 with the paracellular flux marker, fluorescein isothiocyanate-dextran 4 kDa, permitted a bioavailability of 33% to be achieved. When C10 was added 10, 30 and 60 min in advance of fluorescein isothiocyanate-dextran 4 kDa, enhancement still occurred, but was progressively reduced. Histology revealed that the permeability increase was likely related in part to superficial epithelial damage caused in the first few minutes of exposure, which was rapidly repaired within 30-60 min. Design of optimized dosage forms containing C10 should corelease the payload and promoter close to the epithelium in high concentrations. While C10 induces some epithelial damage, its remarkable capacity for epithelial repair may render this effect insignificant in vivo.

Potential of Nanoparticulate Drug Delivery Systems by Intranasal Administration

Due to number of problems related with oral, parenteral, rectal and other routes of drug administration, the interest of pharmaceutical scientists has increased towards exploring the possibilities of intranasal delivery of various drugs. Nasal drug delivery system is commonly known for the treatment of local ailments like cold, cough, rhinitis, etc. Efforts have been made to deliver various drugs, especially peptides and proteins, through nasal route for systemic use; utilizing the principles and concepts of various nanoparticulate drug delivery systems using various polymers and absorption promoters. The incorporation of drugs into nanoparticles might be a promising approach, since colloidal formulations have been shown to protect them from the degrading milieu in the nasal cavity and facilitate their transport across the mucosal barriers. The use of nanoparticles for vaccine delivery provides beneficial effect, by achieving good immune responses. This could be due to the fact that small particles can be transported preferentially by the lymphoid tissue of the nasal cavity (NALT). The brain gets benefited through the intranasal delivery as direct olfactory transport bypasses the blood brain barrier and nanoparticles are taken up and conveyed along cell processes of olfactory neurons through the cribriform plate to synaptic junctions with neurons of the olfactory bulb. The intranasal delivery is aimed at optimizing drug bioavailability for systemic drugs, as absorption decreases with increasing molecular weight, and for drugs, which are susceptible to enzymatic degradation such as proteins and polypeptides. This review discusses the potential benefits of using nanoparticles for nasal delivery of drugs and vaccines for brain, systemic and topical delivery. The article aims at giving an insight into nasal cavity, consideration of factors affecting and strategies to improve drug absorption through nasal route, pharmaceutical dosage forms and delivery systems with examples of some patents for intranasal delivery, its advantages and limitations.

Enhancement of intestinal absorption of 2-methyl cytidine prodrugs

The purpose of this study was to investigate the in vivo absorption enhancement of a nucleoside (phosphoramidate prodrug of 2′-methyl-cytidine) anti-viral agent of proven efficacy by means of intestinal permeation enhancers. Natural nucleosides are hydrophilic molecules that do not rapidly penetrate cell membranes by diffusion and their absorption relies on specialized transporters. Therefore, the oral absorption of nucleoside prodrugs and the target organ concentration of the biologically active nucleotide can be limited due to poor permeation across the intestinal epithelium. In the present study, the specificity, concentration dependence, and effect of four classes of absorption promoters, i.e. fatty acids, steroidal detergents, mucoadhesive polymers, and secretory transport inhibitors, were evaluated in a rat in vivo model. Sodium caprate and α-tocopheryl-polyethyleneglycol-1000-succinate (TPGS) showed a significant effect in increasing liver concentration of nucleotide (5-fold). These results suggested that both excipients might be suited in a controlled release matrix for the synchronous release of the drug and absorption promoter directly to the site of absorption and highlights that the effect is strictly dependent on the absorption promoter dose. The feasibility of such a formulation approach in humans was evaluated with the aim of developing a solid dosage form for the peroral delivery of nucleosides and showed that these excipients do provide a potential valuable tool in pre-clinical efficacy studies to drive discovery programs forward.

Enhancement of intestinal absorption of akebia saponin D by borneol and probenecid in situ and in vitro

Akebia saponin D is a typical bioactive triterpenoid saponin isolated the rhizome of Dipsacus asper Wall. Our previous studies demonstrated that the oral bioavailability of akebia saponin D was very low, but the underlying mechanisms remained unknown. The present study aims to investigate the intestinal absorptive characteristics of akebia saponin D as well as the absorptive transport behavior influenced by co-administration of three absorption-enhancing agents and three efflux protein inhibitors using an in vitro everted gut sac method and an in situ intestinal perfusion model. The results showed that akebia saponin D had a quite limited intestinal permeability, and there was a non-linear increase in transepithelial transportation with increasing concentrations of akebia saponin D. The absorption of akebia saponin D was intestinal segment selective and the small intestine was the best absorptive site. Among three absorption promoters, borneol could significantly improve the permeability of akebia saponin D across ileum, while Tween-80 and DMSO had almost no absorption-enhancing effect. In addition, verapamil, probenecid and pantoprazole in the perfusates were used in this study as modulators of transporters such as P-glycoprotein, MRPs and BCRP in the intestinal mucosa, respectively. The results exhibited that the ileal permeability of akebia saponin D was markedly elevated by the co-administration of probenecid, indicating that akebia saponin D may be likely a substrate of MRPs. The above-mentioned results suggest that akebia saponin D has a poor intestinal absorption not only due to its poor transepithelial permeability but also owing to the contribution of efflux transporters such as MRPs in the intestine.

Chemical permeation enhancers for transbuccal drug delivery

Importance of the field: The buccal drug delivery system has been accepted as a potential non-invasive route of drug administration, with the advantages of avoidance of the first-pass metabolism, sustained therapeutic action and better patient compliance. However, transmucosal delivery of drugs by means of the buccal route is still very challenging. The main obstacles derive from the limited absorption area and from the barrier properties of the mucosa that have to be overcome for successful delivery drug molecules to the systemic circulation by this route.Areas covered in this review: One long-standing approach for improving buccal drug delivery uses buccal absorption promoters, also called permeation enhancers. This requisite has fostered the study of permeation enhancers that will safely alter the permeability restrictions of the buccal mucosa. This review includes various classes of transmucosal chemical permeation enhancers and their mechanism of action. As enhancers influence drug delivery, further exploration of these compounds is required to understand their modifying action on the properties of buccal mucosa.What the reader will gain: This review will help the readers in the selection of a suitable enhancer(s) for improving the buccal drug delivery for future endeavor.Take home message: The authors imagine new buccal formulations bearing permeation enhancer(s) being commercialized in the coming years.

Impact of amino acid replacements on in vitro permeation enhancement and cytotoxicity of the intestinal absorption promoter, melittin

Melittin is an amphipathic α-helical peptide known to cause the non-cell selective perturbation of cell membranes, especially erythrocytes. The well characterised interaction of the peptide with phospholipid bilayers has led to its use as a model to study lipid-peptide interactions. In recent years, melittin has emerged as a potential intestinal absorption promoter that increases paracellular marker permeability across both in vitro and in situ intestinal drug delivery models. Like many other promoters, inherent toxicity limits the drug delivery potential of melittin. The purpose of this study was to examine the effect of amino acid modifications of melittin on viability and drug permeation in human intestinal epithelial cell monolayers (Caco-2), where each structural change made to the peptide is known to reduce the cytolytic action of the peptide on cell membranes composed of zwitterionic phospholipids. Each of the 4 peptide analogues (PA) demonstrated reduced cytotoxicity in the methylthiazolyldiphenyl-tetrazolium bromide (MTT) conversion assay and lactate dehydrogenase (LDH) membrane integrity assay, which was correlated with a reduction in amphipathicity and hydrophobicity, as measured by RP-HPLC. The selected amino acid changes however, also attenuated the epithelial permeation enhancement activity of melittin, as measured by transepithelial electrical resistance (TEER) and flux of FITC-dextran-4 kDa across Caco-2 monolayers. This data suggests that the cytolytic action of melittin is responsible in part for permeation enhancement and that these effects are related to transcellular perturbation in addition to effects on tight junctions.