Thus, there is also a possibility that the PMs might be excreted

Thus, there is also a possibility that the PMs might be excreted before complete drug release or drug might not be released close to its absorption window in the GI tract. Several PMs systems designed to increase the oral bioavailability of hydrophobic compounds exhibit release times which largely exceeded the transit time in the small intestine [83, 84]. This is also true for surfactant micelles which have been found in some cases

to impede the absorption of hydrophobic drugs due to excessive retention in the micellar phase [85]. Hence, when developing oral formulations for poorly water-soluble drugs, it is important to adequately control Inhibitors,research,lifescience,medical the release rate in order to avoid either precipitation upon dilution or sequestration within the micellar phase which may lead to incomplete absorption.

4.2.1. Inhibitors,research,lifescience,medical Introduction of pH-Sensitive PMs The potential disadvantage of normal PMs can be solved by application of additional stimuli that cause micelle destabilization in a specially controlled manner thus increasing the selectivity and efficiency of drug delivery to target sites. External factors such as heat [86, 87], light [88], and sound (ultrasound) [89, 90] have already been studied by many researchers. Inhibitors,research,lifescience,medical However, these external stimuli may only activate the carriers that are situated different closely underneath the skin but not those deeply distributed in the body. The intracellular signals also play an important role in regulating drug release which causes a great deal of interests, and here we focus our attention on pH-responsive systems. As is known, blood and normal tissues have a pH of 7.23 [91]. The mildly acidic pH encountered in a tumor (pH ~6.8) as well as endosomes and lysosomes (pH 5.0–5.5) provides Inhibitors,research,lifescience,medical a potential trigger to accelerate the degradation of pH-sensitive PMs and release of encapsulated drugs. Therefore, numerous pH-sensitive polymeric micellar systems have been employed for intravenous administration of anticancer drugs to tumors [92–94]. In the GI tract, the pH varies Inhibitors,research,lifescience,medical from high acidity in the stomach (pH 1.0–2.5) to a neutral or slightly alkaline pH in the small intestine (pH 5.1–7.8) [95]. Such wide variation of pH along Cilengitide the GI tract

has been utilized for controlled drug release from carriers [2]. Strategies to prevent GI degradation or to promote absorption in the intestine by making use of the pH gradient appear promising. 4.2.2. Mechanisms of pH-Sensitive PMs for Enhancement of Bioavailability Among the various polymers composed micelles, polyacids, or polybases may be used as building blocks that impart pH sensitivity to drug release [73, 96]. Basic core monomeric units such as amines are uncharged and thus hydrophobic at high pH condition while hydrophilic upon protonation at low pH (see Figure 3(a)). On the contrary, acidic core units such as carboxylic acids are uncharged when protonated at low pH and become negatively charged at a relatively high pH (see Figure 3(b)).

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