This represents an example of a hydrogel hybrid of natural polymer hydrogels and inorganic metal nanoparticles (the non-hydrogel). The release behavior of the loaded model drug, propranolol hydrochloride was studied and it was found that the swelling and drug release was maximum in SIF at pH 7.4 as compared to pH 1.2 in the gastric environment. This study also includes ZnO/NaCMC nanocomposite which showed more swelling and more controlled drug release than that of ZnO/CMC hybrid hydrogels which in turn showed better swelling and controlled drug release behavior than neat hydrogel .
For example, PEG-b-poly(ethyl glyoxylate)-b-PEG , polyacetal-b-Pluronic , and PEG-b-poly (2,4,6-trimethoxybenxylidenepentaerythritol carbonate) , have been used for forming drug-loaded polymeric micelles showing faster drug lease at acidic pH than at neutral pH. Protein-based vaccines have been synthesized by copolymerizing benzylidene acetal cross-linking monomers and acrylamide in the presence of the protein payloads [69,70]. Using ovalbumin as the model protein, ovalbumin-loaded polymeric particles with diameters of 35 nm to 3.5 Î¼m were generated. Moreover, the particles demonstrated faster hydrolysis at acidic pH than at neutral pH . Results from animal studies showed that, compared with free ovalbumin, ovalbumin-loaded polymeric particles stimulated T-cell proliferation and protected animal from tumor development more efficiently, indicating that the polymeric particles dissociated in the endosomes after cellular uptake due to acetal hydrolysis and released the protein intracellularly.
This hydrogel is considered successful for insulin delivery as it is also hydrolyzed within 6 h after the release of insulin . Demirdirek et al. developed pH sensitive poly(anhydride-ester) and poly(acrylic acid) based hydrogels for the controlled release of insulin and salicylic acid for diabetic patients. From the drug release profiles, it was observed that hydrogels released 4-8% insulin in acidic milieu (SGF, pH 1.2) and 70% salicylic acid and 90% insulin in SIF (slightly basic milieu).
The image shows the less porous structure having pore size ranging from 7-11 Î¼m. The enhanced crosslinking agent decreased the number of pores and pore size which might be due to significant formation of tightly packed network structure.
Different pH-sensitive chemical linkages, including hydrazone, acetal, ortho ester and vinyl ester, have been employed for constructing pH-responsive drug delivery vehicles (Table 3). Cell-penetrating peptides and cationic polymers responsive to intracellular pH are also discussed in this section. PEG-b-poly (Î²-amino ester), a synthetic, hydrolytically degradable polymer, has been reported to be used for preparation of a pH-sensitive PbAEM micelle DDS [53-55]. Camptothecin-loaded PbAEM micelles showed a sharp micellization/demicellization transition in a slightly acidic environment (pH 6.4 – 6.8) and approximately four times faster drug release at pH 6.4 compared with that at pH 7.4 . Camptothecin-encapsulated PbAEM micelles have been demonstrated to have higher ability in accumulating in tumors, suppression of tumor growth, and prolonging the survival of tumor-bearing mice than free camptothecin.
Drug release can be controlled not only by interaction of ion-exchange resins and drugs but also by polymer coating [97,98]. The drug release from ion-exchange resins is promoted by an equilibrium exchange reaction; however, some drugs should be released faster for fast or high systemic exposure. For example, some drugs against heart attack or diabetes should be exposed immediately after the attack or meal.
2.2 Polymers responsive to intestinal high pH
China Univ. Sci. Technol.
Acrylamide/methacrylamide monomer has been grafted onto many natural polymers to develop different properties such as mechanical strength, pH sensitivity, muco-adhesivity, and superabsorption property in the hydrogel matrix . Mukhopadhyay et al. reported pH sensitive poly(acrylamide) grafted N -succinyl chitosan (PAA/S-CS) hydrogels as a successful carrier for the oral drug delivery of insulin. They observed 38% insulin loading efficiency and 76% encapsulation efficiency whereas 26% insulin release was found at pH 1.2 (acidic stomach pH) and 98% release at pH 7.4 (intestinal pH). They found no toxicity in the reported hydrogels and 4.43% bioavailability. These hydrogels appeared to be successful carriers for insulin capable of lowering the blood sugar level in diabetic mice .
As a result, the ionized negatively charged pendant groups on the polymer chains cause repulsion leading to swelling. This property of hydrogels can be exploited for drug delivery at pH 7.4 in the intestine . Another novel approach which proves to be successful for drug delivery applications is use of the polyelectrolyte complex (PEC) hydrogels which dismisses the usage of toxic covalent cross linkers. PEC hydrogels are mainly comprised of two components, (i) a cationic polymer like chitosan, and (ii) an anionic polymer like carboxymethyl chitosan and are stabilized by electrostatic interaction between these opposite charges in the blend.