Highlights• Liposomes and their related constructs offer unique advantages in terms of drug and vaccine delivery.• However, current processes used for the manufacture of liposomes present a range of challenges, driving up cost, and limiting production.• New production methods can address these issues and support the cost-effective manufacture of current liposomal systems and facilitate the development of new liposomal products.

PTI-125 is a novel compound demonstrating a promising new approach to treating IntroductionAlzheimer's disease (AD) represents one of the greatest health care burdens, affecting 35 million persons worldwide and an estimated 115 million persons by 2050 (Wimo and Prince, 2010). AD is a devastating dementia that first presents as progressive memory loss and later can include neuropsychiatric symptoms. Diagnosis is confirmed at autopsy by amyloid deposits and neurofibrillary tangles (NFTs) containing the microtubuleassociated protein tau. This neuropathology is estimated to precede symptoms by 10 years (Trojanowski et al., 2010). Current AD treatment is limited to acetylcholinesterase inhibitors, with mild and short-lived cognitive enhancement, and memantine, an NMDAR antagonist that may delay some later stage symptoms.Amyloid-␤ (A␤), in particular A␤ 42 , is commonly recognized as the principal causative agent in AD, though its mechanism is debated. Cognitive impairment and the magnitude of synaptic deficit in the AD brain are more highly correlated with soluble A␤ than with the abundance of amyloid plaques, suggesting that soluble A␤ inflicts synaptic impairment (Naslund et al., 2000). Robust evidence demonstrates that soluble A␤ elicits a toxic signaling cascade by the ␣7-nicotinic acetylcholine receptor (␣7nAChR), leading to impaired synaptic activities, intraneuronal A␤ 42 aggregates, and cognitive deficits (Liu et al., 2001;Pettit et al., 2001;Chen et al., 2006;Dziewczapolski et al., 2009;Wang et al., 2009). This aberrant signaling activates the kinases ERK2 and JNK1, which phosphorylate tau, leading to the formation of NFTs .A␤ 42 binds ␣7nAChR with femtomolar affinity (Wang et al., 2000a,b); therefore, to prevent A␤ 42 -induced ␣7nAChR toxic signaling, anti-A␤ therapies must either compete with this extremely high-affinity interaction or essentially eliminate all A␤ 42 . After the initial femtomolar interaction, numerous A␤ 42 molecules bind the receptor, eventually causing internalization and amyloid plaques. These additional A␤ 42 molecules appear to bind at a lower (picomolar) affinity (Wang et al., 2009); hence, it is possible to remove sufficient amounts of A␤ 42 to prevent plaque formation without any impact on the toxic signaling by the highaffinity A␤ 42 -␣7nAChR interaction. Furthermore, pharmacotherapies aiming to prevent A␤ 42 binding to ␣7nAChRs by directly targeting the receptor could, unfortunately, alter ␣7nAChR sensitivity or cell surface expression, especially if they surpass subpicomolar affinity. Alternative strategies to reduce A␤ 42 signaling by ␣7nAChR are needed.We show here that A␤ 42 toxic signaling requires the recruitment of the scaffolding protein filamin A (FLNA), which otherwise has very low levels of association with ␣7nAChR. Filamins are large cytoplasmic proteins best known for crosslinking actin but increasingly implicated in cell signaling (Stossel et al., 2001 A␤-induced FLNA recruitment to ␣7nAChRs and to reduce A␤ 42 signaling. PTI-125 decreases A␤ 42 affinity for ␣7nAC...

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Taurine has neuroprotective capabilities against glutamate-induced excitotoxicity through several identified mechanisms including opening of the Cl(-)channel associated with GABA(A)and glycine receptors, or a distinct Cl(-)channel. No existing work has however shown a direct interaction of taurine with the glutamate NMDA receptor. Here we demonstrate such direct interactions using electrophysiological and receptor binding techniques on rat medial prefrontal cortical (mPFC) slices and well-washed rat cortical membrane. Electrically evoked field potential responses were recorded in layer 4/5 of mPFC in the presence of picrotoxin to prevent opening of Cl(-)channels gated by GABA or taurine. Applied taurine markedly diminished evoked-response amplitude at the peak and latter phases of the response. These phases were predominantly sensitive to the NMDA antagonist, MK-801, but not the AMPA/kainate receptor antagonist CNQX. Furthermore, this taurine effect was blocked by APV pretreatment. Taurine (0.1 mM) decreased spermine-induced enhancement of specific ((3)H) MK-801 binding to rat cortical membrane in the presence of glycine, though it was ineffective in the absence of spermine. Our preliminary work shows that taurine diminished the apparent affinity of NMDA receptor to glycine in the presence of spermine. These results indicate that taurine may directly interact with the NMDA receptor through multiple mechanisms.

Abstract. A lot of resources and efforts have been directed to synthesizing potentially useful new chemical entities (NCEs) by pharmaceutical scientists globally. Detailed physicochemical characterization of NCEs in an industrial setup begins almost simultaneously with preclinical testing. Most NCEs possess poor water solubility posing bioavailability issues during initial preclinical screening, sometimes resulting in dropping out of an NCE with promising therapeutic activity. Selection of right formulation approach for an NCE, based on its physicochemical properties, can aid in improving its solubility-related absorption and bioavailability issues. The review focuses on preclinical formulations stressing upon different preclinical formulation strategies and deciphers the understanding of formulation approaches that could be employed. It also provides detailed information related to a vast pool of excipients available today, which is of immense help in designing preclinical formulations. Few examples mentioned, throw light on key aspects of preclinical formulation development. The review will serve as an important guide for selecting the right strategy to improve bioavailability of NCEs for academic as well as industrial formulation scientists.