*2.1.5 Microgels responsive to pH*

*Pharmaceutical Formulation Design - Recent Practices*

**2.1 Types of stimuli-responsive microgels**

*2.1.2 Microgels responsive to particular compounds*

*2.1.3 Microgels responsive to external fields*

configuration while faster for cis-configuration.

variations in temperature-responsive polymers [29–31].

*2.1.4 Microgels responsive to degradation*

*2.1.1 Microgels responsive to temperature*

the types of stimuli-responsive microgels is given below.

Stimuli-responsive properties can be incorporated into gels. Microgels may respond to a number of stimuli like pH, ionic strength, specific ions, external fields, and temperature [14–17]. Such DDSs are designed whether to target tissues, to reach specific intracellular locations, or to promote drug release [18]. Brief overview of

Several classes of polymers, including poly(N-isopropylacrylamide) and poly(ethylene glycol), demonstrate swelling/deswelling changes in response to temperature [19, 20]. With increase in temperature, these systems have reduced solvency and pronounced deswelling. Nolan et al. [21] demonstrated higher insulin release from poly (N-isopropyl acrylamide), with increasing temperature. Temperaturedependent aggregation property of such thermosensitive microgel systems may also be utilized in drug delivery, e.g., at elevated temperature; due to aggregation of PNIPAM microgels particle inside the cancerous cell, toxicity was observed [22].

Microgels can be designed to be triggered by the concentration of particular compounds, like insulin [23, 24]. For example, insulin containing poly (diethyl aminoethyl methacrylate) microgels conjugated with glucose oxidase [25]. The enzymatic conversion of glucose to gluconic acid causes pH-responsive swelling of the polymer network leading to release of insulin. In another study Sui et al. [26] reported trifluoperazine triggered volume transition in calmodulin-based hydrogels.

Microgel systems may also respond to external fields (ultrasound, light, and magnetic fields). Patnaik et al. [27] investigated photoresponsive drug release in azo-dextran nanogels based on (trans-cis) photoisomerization of an azobenzene present in the cross-linker. For this system, the release of drug was slower for trans-

Metal nanoparticles may be used for optical or magnetic heating. When temperature-responsive microgels are combined with metals, heat induced by the external fields may result in deswelling, leading to release of the absorbed drugs. Using this perspective, Wong et al. [28] explored Fe-containing PNIPAM microgels. The microgels showed ability to manifest local heating attributed to an oscillating magnetic field. With increasing temperature microgels deswelled. Similar kind of triggering was also manifested in other studies, where light-originated heating of absorbed metal nanoparticles was used to induce local heat, provoking permeability

Microgel degradation in response to stimuli offers another way of controlled

drug delivery [32, 33]. Such systems are commonly based on biodegradable microgels, occasionally surrounded by a shell impermeable to the drug. In later case, microgel degradation causes increased osmotic pressure, finally breaking the

**2. Stimuli-responsive microgels**

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pH-responsive microgels represent one of the major approaches for microgel-based delivery of biomacromolecular drugs. Of the many stimuli, alteration in pH is markedly fascinating because of the availability of pH gradients admissible for drug targeting. For example, pH gradients between normal tissues and some pathological sites, between the extracellular environment and some cellular compartments, and along the gastrointestinal (GI) tract are well characterized [38]. Orally administered drug encounters a pH gradient as it move from the stomach (pH 1–2, fasted state) to the duodenum (pH of about 6) and along the jejunum and ileum (pH 6–7.5) [39, 40]; therefore, attempts to avoid deterioration of drug and/or to promote intestinal absorption by exploiting this pH gradient is promising. pH-responsive polymeric networks, hence, have been extensively studied for the design of efficient carriers for drug delivery [41].

pH-responsive polymers are generally fabricated by inserting pendant acidic or basic functional groups to the backbone of the polymer. These functional groups either accept or release protons in response to appropriate pH and changes in the ionic strength of the surrounding aqueous media [42]. Polymers with acidic groups are unexpanded at low pH values, since the acidic groups are protonated and unionized. While increasing pH acidic groups are ionized, the resulting negatively charged polymer expands. The opposite behavior will be observed in the case of polybasic polymers [43, 44]. These systems can form polyelectrolytes with water, and microgels fabricated from weak polyelectrolytes demonstrate a pHresponsive volume phase changes. On the basis of the framework of polyelectrolyte, pH-responsive microgels can be classified as cationic, basic, or amphoteric. For instance, poly(acrylic acid) and polyethylenimine are weak polyacid and a polybase, respectively.
