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Thermosensitive hydrogels are in situ gelling systems composed of hydrophilic homopolymers or block copolymers which remain as solutions at room temperature and form gels after administration into the body. Its application in advanced drug delivery has gained significant attention in recent years. The tunable characteristics of thermosensitive hydrogels make them versatile and capable of incorporating both hydrophilic and lipophilic compounds and macromolecules. The drug molecules can be included as free molecules or preformulated into nano- or micro-particles or liposomes. Although there were several reviews on the materials of thermosensitive hydrogels, the compatibility between the drug and thermosensitive material as well as its in vitro release mechanisms and in vivo performance have barely been investigated. The current review is proposed aiming to not only provide an update on the recent development in thermosensitive hydrogel formulations for nasal, ocular and cutaneous deliveries, but also identify the relationship between the drug characteristics and the loading strategies, and their impacts on the release mechanisms and the in vivo performance. Our current update for the first time highlights the essential features for successful development of in situ thermosensitive hydrogels to facilitate nasal, ocular or cutaneous drug deliveries.

Tacrine (THA), as the first approved acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD), has been extensively investigated in last seven decades. After dimerization of THA via a 7-carbon alkyl spacer, bis(7)-tacrine (B7T) showed much potent anti-AChE activity than THA. We here report synthesis, biological evaluation and biopharmaceutical characterization of six THA dimers referable to B7T. According to IC50 values, the in vitro anti-AChE activities of THA dimers were up to 300-fold more potent and 200-fold more selective than that of THA. In addition, the anti-AChE activities of THA dimers were found to be associated with the type and length of the linkage. All studied THA dimers showed much lower cytotoxicity than B7T, but like B7T, they demonstrated much lower absorptive permeabilities than that of THA on Caco-2 monolayer model. In addition, all THA dimers demonstrated significant efflux transport (efflux ratio >4), indicating that the limited permeability could be associated with the efflux transport during absorption process. Moreover, the dimer with higher Log P value was accompanied with higher permeability but lower aqueous solubility. A balanced consideration of activity, solubility, cytotoxicity and permeability should be conducted in selection of the potential candidates for further in vivo investigation.

DB213 is an HIV-1 replication inhibitor targeting the Central Nervous System for the treatment of HIV-associated neurocognitive disorders. Current study aims to develop an in situ thermosensitive gelling system for intranasal delivery of DB213 facilitated by Statistical Design of Experiment (DoE) to conduct a more efficient experimentation by extracting the maximum amount of information from limited experiments. In our current study, information was extracted from twenty-five experimental designs from MODDE® Software and a mathematical model was successfully developed to predict formulations to achieve desired performance as well as to analyze relationships between the amount of Pluronic F-127, Pluronic F-68, Chitosan, DB213 and the performances of in situ thermosensitive gels. Based on DoE, in situ thermosensitive gels of 1% DB213 (F1) and 5% DB213 (F2) were developed for further in vivo bioavailability and brain uptake evaluations in Sprague-Dawley rats and C57BL/6 mice, respectively. In comparison to DB213 water solution, intranasal administrations of F1 at 1 mg/kg in rats and F2 at 25 mg/kg in mice demonstrated relative bioavailabilities of 145% and 165% with significant increase in brain uptake.

The present study aimed to develop an in situ gel formulation for intranasal delivery of tacrine (THA), an anti-Alzheimer's drug. Thermosensitive polymer Pluronic F-127 was used to prepare THA in situ gels. Sol-gel transition temperature (Tsol-gel), rheological properties, in vitro release, and in vivo nasal mucociliary transport time were optimized. The pharmacokinetics and brain dispositions of in situ gel were compared with that from THA oral solution in rats. The in situ gel demonstrated a liquid state with Newtonian fluid behavior under 20 °C, while it exhibited as non-flowing gel with pseudoplastic fluid behavior beyond its Tsol-gel of 28.5 °C. Based on nasal mucociliary transport time, the in situ gel significantly prolonged its retention in nasal cavity compared to solution form. Moreover, the in situ gel achieved 2-3 fold higher peak plasma concentration (Cmax) and area under the curve (AUC) of THA in plasma and brain tissue, but lowered Cmax and AUC of the THA metabolites compared to that of oral solution. The enhanced nasal residence time, improved bioavailability, increased brain uptake of parent drug and decreased exposure of metabolites suggested that the in situ gel could be an effective intranasal formulation for THA.

Drug delivery via the nasal route is gaining increasing interest over the last two decades as an alternative to oral or parenteral drug administration. In the current study an approach for rapid identification of relevant features, screening and in vivo verification of potential therapeutic agents for nasal delivery was carried out using "analgesic agents" as an example. Four such drug candidates (rizatriptan, meloxicam, lornoxicam and nebivolol) were initially identified as potentially viable agents based on their therapeutic use and physicochemical characteristics. An in vitro screening was then carried out using the Calu-3 cell line model. Based on the in vitro screening results and the reported pharmacokinetic and the stability data, meloxicam was predicted to be the most promising drug candidate and was subsequently verified using an in vivo animal model. The in vivo results showed that nasal administration of meloxicam was comparable to its intravenous administration, with respect to plasma drug concentration and AUC(0-2h). In addition, nasal absorption of meloxicam was much more rapid with higher plasma drug concentration and AUC(0-2h) than that of oral administration. The current approach appears to be capable of developing "analgesic agents" suitable for nasal delivery. Further studies are needed to prove the clinical advantage of the specific selected agent, meloxicam, by nasal administration in patients.

The present study aims to investigate the preclinical intestinal absorption of bis(7)-tacrine (B7T) using different absorption models. In addition, potential intestinal and liver first-pass metabolism was evaluated by in vitro incubation of B7T with rat intestine and liver microsome. Results showed that the permeability of B7T across artificial membrane was pH dependent with rapid diffusion achieved at both pH 6.8 and 7.4. However, the absorptive permeability of B7T in Caco-2 cell model was substantially lower than that in the artificial membrane accompanied with over 56% of B7T being trapped within Caco-2 cells. In the rat in situ intestinal perfusion model, B7T was subject to an extensive intestinal extraction (>90%) with extremely low concentration of B7T detected in mesenteric blood, which was further found to be associated with the high tissue binding (99.9%) of B7T. In vitro incubation of B7T with rat liver and intestinal microsomes revealed that hydroxylation of B7T might mainly occur in rat liver rather than intestine. In conclusion, B7T is expected to have a low oral bioavailability in vivo, which may be due to its poor intestinal permeability, significant tissue binding and hepatic hydroxylation metabolism.

This study was aimed at investigating the pH-dependent solubility and in vitro transmucosal permeability of sildenafil, an amphoteric compound with limited aqueous solubility, across parallel artificial membrane. The aqueous solubility and permeability of sildenafil as a function of solution pH were theoretically derived from the individual contributions of all species (cationic, neutral and anionic). The stability, octanol-water distribution coefficient (log D), and solubility of sildenafil were then determined at various pHs, the permeability study was also performed at different pHs using parallel artificial membrane. The pH-solubility and -permeability profiles were then fitted to theoretical equations using non-linear regression. The experimental pH-solubility profile was fitted very well to the theoretical equations (R(2)=0.9996). The in vitro permeability of saturated sildenafil solution at different pH values also showed similar trend as the predicted one (R(2)=0.7829). The two optimum pH (pH(max)) values were found to be 4.50 and 10.24, where the maximum solubility of either cationic or neutral species, or anionic and neutral species is simultaneously obtained, and the maximal transmucosal fluxes (J(ss)) are achieved. The above method can be applied to optimize the transmucosal delivery of other amphoteric drugs with low aqueous solubility.

The aim of this study was to provide preliminary validation of a new sublingual mucosal cell line (HO-1-u-1) for use as in vitro sublingual drug delivery screening of compounds involving passive diffusion. HO-1-u-1 cells were seeded on cell culture inserts. The ultrastructure and integrity of cell layers, inter-passage variation and directionality of drug transport, and apparent permeability coefficient (P(app)) of eight beta-blockers (representing compounds involving passive diffusion) were determined. HO-1-u-1 cells grown on inserts formed stratified and epithelial-like structure and maintained the typical histological features of normal human sublingual epithelium. The maximal integrity of the cell layer was reached in 23 days. No significant inter-passage variation was found at the passages ranging from 2 to 11 when measured by radiolabeled transcellular and paracellular markers (testosterone and mannitol, respectively). Bidirectional transport studies confirmed the passive diffusion as the mechanism of transport for these markers. The P(app) of eight beta-blockers across HO-1-u-1 cell culture ranged from 2.89+/-0.17 to 6.37+/-0.37x10(-6)cm/s and correlated well to the P(app) obtained from porcine sublingual mucosa (r(2)=0.647 and 0.83 when excluding propranolol). The above results indicate that the HO-1-u-1 cells grown on inserts may offer as a potentially in vitro model for screening sublingual drug permeation involving passive diffusion.

The present study aimed to investigate whether beta-cyclodetxrin (beta-CD) and its water-soluble derivatives, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and sulfobutyl ether beta-cyclodextrin (SBE-beta-CD), exert any effects on the permeation of two drug transport markers (propranolol and lucifer yellow) across rat intestinal epithelium. Rat ileum was stripped of its serosa and mounted inside an Ussing Chamber. Apparent permeability coefficients (P(app)) of the markers from the mucosal to serosal side of the tissue were determined at 37 degrees C in the presence and absence of the beta-cyclodextrins on the mucosal side. Potential difference (PD) was constantly monitored during each experiment to ensure maintenance of the viability and integrity of the tissue. Pre-incubation with 1% beta-CD, 1% HP-beta-CD or 1.48% SBE-beta-CD on the mucosal side for 30 min did not significantly alter the PD and the propranolol permeability (p0.05). Co-incubation with 1% beta-CD or 1% HP-beta-CD exerted no significant effect on the P(app) of both propranolol and lucifer yellow (p0.05), but co-incubation with 1.48% SBE-beta-CD lowered the P(app) of propranolol from (1.71+/-0.44)x10(-5) to (0.19+/-0.04)x10(-5)cm/s, which may be ascribed to the molecular complexation of propranolol with SBE-beta-CD. All three beta-cyclodextrins exert no apparent impact on both (passive) transcellar and paracellular drug transports.

Glucosamine, as a dietary supplement for management of osteoarthritis, has a low and erratic oral bioavailability due to its transport-mediated absorption and presystemic loss in liver and GI tract. The present study described an effective approach to improve glucosamine intestinal absorption and hence its bioavailability using chitosan. Effects of chitosan on intestinal permeability and pharmacokinetics of glucosamine were evaluated in Caco-2 cell monolayer and rats, respectively. In addition, randomized crossover pharmacokinetic studies in beagle dogs were performed to evaluate the oral bioavailabilities of the developed glucosamine oral formulations containing chitosan (QD-Glu solution and QD-Glu tablet) in comparison to its commercial products. Caco-2 permeability studies demonstrated that chitosan could enhance the absorptive transport of glucosamine by 1.9-4.0-fold via the reversible opening of the cell tight junction. After oral administration of glucosamine solutions containing chitosan in rats, it was found that 0.5% (w/v) chitosan exhibited the highest enhancement in Cmax (2.8-fold) and AUC0-∞ (2.5-fold) of glucosamine. Further pharmacokinetic studies in beagle dogs demonstrated that QD-Glu solution and QD-Glu tablet showed much higher relative bioavailabilities of 313% and 186%, when comparing with Wellesse™ solution and Voltaflex™ tablet, respectively. In conclusion, chitosan could serve as a promising oral absorption enhancer for glucosamine.

The purpose of this study was to demonstrate the feasibility of using a bio-activity guided in vitro pharmacokinetic (BAPK) method in identifying relevant (absorbable and bioactive) markers for quality control (QC) of Chinese medicines (CM), using Si Wu Tang (SWT), a popular CM for women's health, as an example. A stepwise BAPK approach was utilized for relevant marker determination and evaluating of six SWT products: (1) data mining to identify active components of SWT, (2) quantification of the identified active components in each SWT product, (3) determination of in vitro dissolution and metabolism of the components under simulated gastrointestinal conditions, (4) identification of absorbable components or marker(s) via in vitro Caco-2 cell model, (5) stability testing of the permeable marker(s). Our results showed considerable variations in the amount of active components in different SWT products. Of the nine active components identified from data mining, three (ferulic acid, ligustilide, senkyunolide A) were found to be well permeated and stable over three months. Paeoniflorin, the marker designated by Chinese Pharmacopoeia, was poorly permeable and thus could not be considered a relevant marker for SWT. Our preliminary evaluation of the BAPK method appears to be feasible and may offer as a useful approach for identifying relevant markers of other TCM products in the future.

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.

Flavonoids have low bioavailabilities due to extensive intestinal first-pass metabolisms, especially glucuronidation. The present study aimed to evaluate the intestinal glucuronidation of dihydroxyflavones and provide more information on their structure-activity relationships. Seven dihydroxyflavones, namely 3,7-, 5,7-, 6,7-, 7,8-, 2',7-, 3',7-, and 4',7-dihydroxyflavone and a monohydroxyflavone, 7-hydroxyflavone, were investigated by incubating each hydroxyflavone at various concentrations with either human jejunum microsome or rat intestinal microsome. Two mono-glucuronides were identified for each dihydroxyflavone. For human jejunum microsome, most of the studied dihydroxyflavones demonstrated greater glucuronidation activities than that of 7-hydroxyflavone except for 3,7-dihydroxyflavone and 4',7-dihydroxyflavone. 3',7-dihydroxyflavone had the greatest intrinsic clearance which was at least seven times greater than that of all other dihydroxyflavones. In addition, species difference in glucuronidation activity was observed with human jejunum microsome higher than rat intestinal microsome for all hydroxyflavones except for 3,7-dihydroxyflavone. The results further demonstrated that the hydroxyl group positions do affect the intestinal glucuronidation activity of hydroxyflavones. Increasing the number of hydroxyl groups on A- or B-ring (except for 4'-OH) would enhance the glucuronidation activity of flavones, whereas adding a 3-OH on C-ring might not. Furthermore, existence of hydroxyl group at 3' position may enhance the glucuronidation activity of flavonoids.

The current study was designed to investigate the absorption mechanism and identify the possible disposition pathways of green tea catechins (GTC), including epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), during their absorption across small intestine by Caco-2 monolayer model. The transport of each GTC from both apical to basolateral and basolateral to apical directions was measured in the absence and the presence of MK571, an MRP inhibitor. HPLC and LC/MS were employed to identify the possible metabolites of the four GTC formed during their bidirectional transport processes. The results indicated that the four GTC showed limited transepithelial absorption with relatively small P(app) values. However, significant efflux mediated by MRP was observed during the secretion of GTC, especially the non-gallated catechins. Methylation and sulfation were the main biotransformation pathways of GTC during their secretion transport and the efflux of the related metabolites seem to be mediated by MRP.