The starch modification associates the transformation of physicochemical properties of the native form to upgrade its functional properties and also to stabilize the starch granules during processing. Several methods including chemical, physical, enzymatical, genetical modifications have been implemented to facilitate its utilization for different purposes such as tablet excipients, drug carriers, wound dressing materials, transdermal patches and scaffolds [111, 112]. The chemical modifications basically imply the introduction of various functional groups to the structure of starch via esterification, etherification, crosslinking, oxidation and so on, while physical modifications conferred by physical reinforcement of starch molecules under different hydrothermal conditions, pressure, shear, micronization, irradiation and electric fields without the presence of any chemical or biological reagents [113, 114]. In contrast to enzymatical modification, suspension of starch is reacted with diverse enzymes mostly hydrolyzing enzymes which directly attack the amorphous regions and produce highly functional derivatives, while in the case of genetical modification, enzymes accountable for starch biosynthesis are genetically modified either by introducing new enzymes from other microorganisms or silencing the plant RNA [115, 116]. After the modification of native starch, it has resulted in enhancing the various properties like increased stability, digestibility, cold-water swellability, film formation, emulsifying capacity and finally upgraded the water binding power and gel characteristics due to which its applications in the pharmaceutical field have increased [117]. However, the most widely used modified starch in the pharmaceutical industry is pregelatinized starch, because this modification not only improves the flowability, disintegration and hardness properties but also represents the excellent swelling and wettability in the cold water of the starches and eventually the amount of pregelatinized starch required is much less than conventional starch for the tablet production [118].
In the design of drug carriers, some modified starches are used as excipients for controlling the delivery speed of drug molecules to the desired site because of their low cost, accessibility and good in vivo performance. For example, native starch modified with acetylation was used in the tablet preparation of lamivudine and it was observed that tablets containing a high concentration of acetylated sago starch released the drug in a controlled manner by reducing undesired swelling over time in an aqueous environment and drug release begins when the dissolution media diffuses through the porous matrix [119]. In another study, high-amylose content sodium carboxymethyl starch composites have been developed as excipients for the formulation of tablets with sustained release behavior for the oral delivery of Tramadol HCl. The results revealed that tablets containing modified starch sustained the Tramadol HCl release by preventing undesired disintegration of the tablets in the gastrointestinal tract with consequent dose dumping [120]. Some researchers have also designed two-release rate (2RR) monolithic tablets based on modified calcium carboxymethyl-starch (CaCMS) for controlled delivery of poorly soluble drugs and it was found that CaCMS based tablet formulations exhibited initial fast release of ibuprofen followed by slow release over a period of 12 hours. The reason behind this is that the CaCMS complex possesses a high hydration capacity (mainly favored by the swelling of disintegrant crospovidone) leading to a first release. As it’s 2RR tablets, there must be a partial release and even if there is an outer layer disintegrated, the integrity of the tablets is always maintained and subsequently grants controlled release [121]. Likewise, to improve the mucoadhesive features of native starch, its native structure was modified by thiol treatment and evaluated as a potential mucoadhesive excipient for the formulations with sustained release behavior. The results indicated that modified starch adhered longest to the goat intestinal mucosa, which might be due to covalent tie-up via disulfide bond construction of the modified starch with the mucus involving thiol exchange reaction and simultaneously sustaining the speed of Irinotecan delivery [122]. Furthermore, nanoparticulate carriers were developed by using novel starch composites or derivatives for topical delivery of flufenamic acid, testosterone, caffeine and obtained results revealed that hydrophobic flufenamic acid and testosterone were released from nanoparticles in a sustained manner without any outburst effect, while the hydrophilic drug caffeine displayed a much immediate release owing to its hydrophilic nature. The release pattern is mainly controlled by the hydrophobic interactions among the encapsulated macromolecule (hydrophobic propyl-starch derivatives) and the nanoparticle matrix and showed a remarkable permeation effect across the barriers of skin [123]. A similar controlled release pattern by polymeric nanoparticles has been formerly investigated by using novel crosslinked reduction-sensitive starch and the results suggested that nanoparticles with disulfide crosslinked starch accelerated the release behavior of 5-aminosalicylic acid in a controlled manner in the existence of reducing agents dithiothreitol due to reductive cleavages of disulfide linkages. Thus, modified starches expand the usefulness of the starches with indigenous form and have provided some outstanding results as matrix-forming excipients for the extended and controlled release dosage forms [124].
Apart from the other starch derivatives from diverse sources, modified cassava starches including acetylated, succinate, phthalate, acetate, phosphate, methacrylate, carboxymethyl and polyacrylic acid blends starch have found great use in the pharmaceutical sectors for the development of various novel and conventional drug delivery vehicles (Fig. 3).
Space for Fig. 3.
Cassava starch deserves particular attention because of its purity and lack of no starchy compounds like lipids, proteins and ash as distinguished from other origin starches. The modified versions of cassava starch are not only used as a good matrix for delivery systems but also can protect the bioactive compounds with a short half-life from degradation and carry the drug molecules to the desired site [125–127]. Notably, modified cassava starches allow the incorporation of various specific ligands particularly flavor compounds to obtain inclusion complexes, being a large number of hydroxyl groups present in their polysaccharide backbone and will provide protection during processing and storage since the complexes are resisting at elevated temperatures. Because free flavor compounds are very volatile and susceptible to degradation in the existence of moisture, air, light and high temperatures, hence by using inclusion complexes flavor compounds are suitably released in a controlled manner and eventually imparted light shed to develop a novel carrier for entrapment of flavor compounds in treating cardiovascular, liver and other chronic diseases [128–131]. However, the potential utilization of modified cassava starch in the design of novel drug carriers especially microparticles and nanoparticles, as well as various conventional drug carriers including tablets, buccal films and topical gels are discussed in the below Table 2 and Fig. 4.
Table 2
Pharmaceutical applications of newly developed modified cassava starches as an excipient.
Sl. No. | Modified Starch | Drug Carriers | Purpose |
01. | Pregelatinized cassava starch succinate | Mucoadhesive microspheres | pH-dependent controlled delivery of propranolol HCl [132] |
02. | Pregelatinized cassava starch | Floating microspheres | Gastroretention of metronidazole for peptic ulcer [133] |
03. | Cassava starch methacrylate | Crosslinked microspheres | Sustained release of curcumin for colonic cancer [134] |
04. | Cassava starch acetate | Crosslinked starch-PEG-gelatin nanocomposites | Controlled delivery of cisplatin for solid tumors treatment [135] |
05. | Acetylated cassava starch | Silver-starch nanocomposite | Extended release of Rifampicin for the multi-resistant tuberculosis [136] |
06. | Cassava starch acetate | Starch-polyvinyl alcohol nanocomposites | Controlled and sustained release of paclitaxel for breast cancer treatment [137] |
07. | Crosslinked cassava starch acetate | Starch-polyvinyl alcohol- Closite30b nanocomposites | Controlled release of curcumin for cancer treatment [138] |
| Halloysite cassava starch | Starch based bio-nanocomposites | Controlled delivery of silver sulfadiazine for wound infections [139] |
08. | Hexadecyl cassava starch-grafted PEG | Amphiphilic starch based nanomicelles | Sustained release of curcumin for cancer treatment [140] |
09. | Pregelatinized cassava starch phthalate | Mucoadhesive buccal films | Enhanced bioavailability of diltiazem HCl for hypertension [141] |
10. | Carboxymethyl cassava starch | Topical gel formulations | Controlled delivery of ibuprofen for inflammatory disease [142] |
11. | Poly(acrylic acid- cassava starch graft | Hydrogels based on starch-nanostructured hybrid systems | Controlled release of cysteamine for microbial and bacterial disease [143] |
12. | Octenyl succinate cassava starch | Starch based tablet formulations | Sustained release matrix for theophylline for respiratory diseases [144] |
13 | Pregelatinized cassava starch | Non-effervescent floating mini tablets | Controlled release of ranitidine HCl for acid reflux diseases [145] |
14. | Oxidized konjac glucomannan-cassava starch | Starch based matrix tablet formulations | Sustained release excipient for bovine serum albumin [146] |
15. | Pregelatinized cassava starch phosphate esters | Starch based matrix tablet formulations | Controlled delivery of theophylline for respiratory diseases [147] |
16. | Pregelatinized cassava starch | Starch based fast disintegrating tablets | Immediate delivery of famotidine for geriatric and pediatric patients [148] |
17. | Microcrystalline tapioca starch | Starch based directly compressed tablets | Delivery of poorly compressible API ascorbic acid and paracetamol [149] |
Apart from the pharmaceutical applications, some modified cassava starch and their derivatives like crosslinked cassava starch phosphate, hydroxypropyl cassava starch, citrate esterified cassava starch, dialdehyde cassava starch, cassava ethyl-O-starch, konjac glucomannan modified cassava starch, crosslinked cassava starch and enzyme hydrolyzed cassava starch has already been used for other industrial purposes including food, dairy beverage, textile, paper, dusting powder, bioplastic composites and agrochemical industries [150–157]. In the food industry modified cassava starch is used as a stabilizer, thickening agent, emulsifier, texturizer, packaging materials and ice cream formulations, while in the textile industry it can be used for sizing, finishing, cloth printing, coating of fabrics [158–165]. Another important purpose of the modified cassava starches is that they can use as coating material, adhesive or binder for paper or non-paper materials in the paper industry as well as the adhesive industry and as an adsorbent for evacuation of dye and heavy metals from water or other materials in chemical and engineering fields [166–169]. Moreover, in abundant industrial applications, there is competition not only among starches from diverse sources but also between starches and other products as a result development of novel materials has continuously grown and allowed the starch industry to persist in its expansion. In view of all these potentialities, it seems obvious that nowadays, practically every industry in existence uses starch and its derivatives in one form or another for precise applications. Hence, the growth of the starch industry in the future appears to be very promising, which can be predicted that new ventures in starch modifications and their diverse applications will endure being of great interest in applied research [170–171].
Space for Fig. 4.