The contemplation of amylose for the delivery of ulcerogenic nonsteroidal anti-inflammatory drugs

Abstract

This manuscript proposes an innovative approach to mitigate the gastrointestinal adversities linked with nonsteroidal anti-inflammatory drugs (NSAIDs) by exploiting amylose as a novel drug delivery carrier. The intrinsic attributes of V-amylose, such as its structural uniqueness, biocompatibility and biodegradability, as well as its capacity to form inclusion complexes with diverse drug molecules, are meticulously explored. Through a comprehensive physicochemical analysis of V-amylose and ulcerogenic NSAIDs, the plausibility of amylose as a protective carrier for ulcerogenic NSAIDs to gastrointestinal regions is elucidated. This review further discusses the potential therapeutic advantages of amylose-based drug delivery systems in the management of gastric ulcers. By providing controlled release kinetics and enhanced bioavailability, these systems offer promising prospects for the development of more effective ulcer therapies.

GRAPHICAL ABSTRACT

Plain language summary

Executive summary.

Challenges associated with nonsteroidal anti-inflammatory drugs (NSAIDs)

• The primary cause of NSAID toxicity stems from its nonselective inhibition of cyclooxygenase enzymes, leading to disruptions in the gastric mucosa's defense mechanism and the formation of ulcers.

• Polysaccharides show promise as advanced drug delivery systems due to their biodegradability, biocompatibility and ability to provide controlled release kinetics, thereby enhancing pharmacokinetics and maintaining optimal drug concentrations across physiological barriers.

Structural uniqueness of V-amylose

• The tightly packed helical structure, hydrophobic interior and hydrophilic exterior with the 6-glucose unit per turn and a pitch height of 7.91–8.17 Å renders V-amylose a privileged delivery system for ulcerogenic NSAIDs.

Potential therapeutic advantages of V-amylose & NSAIDs conjugates

• Emperical findings of V-amylose NSAID complexes demonstrated potential attributes of innovative drug delivery systems such as biodegradability, biocompatibility and controlled release kinetics for enhancing pharmacokinetics and maintaining optimal NSAID concentration in patients.

• Amylose-based delivery platforms such as hydrogels, solid dosage formulation, enteric coated tablets and conjugates have proven effective in precisely targeting and delivering fenamic acid NSAIDs to the mucosal regions and gastrointestinal tract, minimizing ulcer development and maximizing therapeutic efficacy.

• Incorporating V-amylose into drug delivery not only addresses ulcerogenicity concerns but also enhances the pharmacokinetics and bioavailability of NSAIDs.

• Further research and advancement are imperative to translate these findings into practical applications.

Polysaccharides, composed of repetitive mono- or di-saccharide units, are ideal for controlled drug delivery due to their biodegradability, biocompatibility, low toxicity and low immunogenicity. They are available in plants, animals and microbes, and offer a wide range of physicochemical properties relevant to drug delivery. Polysaccharides can adhere to the physiological mucus layer, increasing drug residence times across various morbid mucosal tissues. Cationic polysaccharides such as chitosan can cleave epithelial cell junctions, enhance drug permeability and promote targeted delivery of crucial therapeutic agents. Natural and environmentally viable polymers, such as starch, pectin, dextran, chitosan, hyaluronic acid, guar gum, alginate and cellulose, have substantial promise for therapeutic cargo transport. By modifying the hydroxyl (OH), amine (NH₂) and carboxyl (COOH) functional groups, new polysaccharide derivatives can be generated for various biomedical applications. Oral administration of proteins and drugs face challenges due to susceptibility to enzymatic degradation in the stomach and small intestine [1]. Drug design has therefore leaned towards a prodrug strategy to overcome obstacles such as limited water solubility, potential tissue damage and pharmacological complexities. Prodrugs are inert derivatives of drugs that can convert into active parent compounds through enzymatic or chemical transformations [2]. An optimal drug delivery system should have resistance to unintended release, inertness, biocompatibility, mechanical resilience, patient acceptability, capacity for high drug loading, and streamlined manufacture and sterilization protocols. Traditional drug delivery systems have rapid systemic drug elimination, while controlled drug delivery systems ensure sustained maintenance of drug plasma levels by precisely delivering the appropriate drug dose within defined intervals. These systems also offer stable plasma concentration profiles and tailor release kinetics to accommodate diverse pharmacokinetic profiles. Prodrug strategy is also highly responsive to diverse pH levels and promotes suboptimal absorption in the upper gastrointestinal (GI) tract, along with time-dependent multicoating systems, pH-sensitive polymer coatings and biodegradable polymers [3]. Research on polysaccharide-centric, colon-specific drug delivery systems is therefore crucial for simplified formulation processes and improved patient compliance.

Need for modified polysaccharides in drug delivery

Chemical modification of polysaccharides offers a distinctive benefit owing to their ability to form inclusion complexes with numerous organic and inorganic compounds, improve drug solubility and promote efficient drug delivery to various cancer cells with minimal cytotoxicity. Chemical modifications are known to enhance the inherent properties of polysaccharides such as antioxidation and immune regulation, and antimicrobial and anti-tumor features [4]. Various modified polysaccharide-based drug delivery systems demonstrate a range of benefits, such as improved drug release, targeted delivery and enhanced therapeutic outcomes. Notable examples include alginate-based carriers and nanoparticles for doxorubicin and ciprofloxacin hydrogel beads for controlled drug delivery in cancer [5]. The emerging applications of modified polysaccharides have the potential to revamp the realm of contemporary drug delivery, biomedicine, cell culture technology and tissue engineering.

In the domain of advanced drug delivery systems, the utilization of modified polysaccharides has yielded intricate formulations with reinforced therapeutic efficacy. The integration of dual-responsive alginate with sulfhydryl dendrimers resulted in a sophisticated smart stimuli-responsive controlled drug delivery system for doxorubicin, leading to a notable augmentation in antitumor activity as observed in HepG2 cells, coupled with a substantial 76% drug release [6]. Carboxylated graphene oxide impregnated in alginate, in conjunction with aminated chitosan, produced microbeads characterized by increased drug release, targeted drug delivery and an enhanced swelling behavior, which is particularly advantageous for pH-responsive antibiotic delivery [7]. Hydrogel beads fashioned from psyllium moringa gum alginate demonstrate commendable antiulcer potential, antioxidative prowess and a proclivity for slow and sustained drug delivery [8]. In parallel, calcium alginate-based microspheres, incorporating bovine serum albumin and ranitidine hydrochloride, manifest an elevated drug encapsulation rate, with 95% ranitidine release in simulated gastric fluid and 73% bovine serum albumin release in simulated intestinal fluid, underscoring their utility as a gastroretentive drug delivery system [9]. These innovative formulations, spanning various nano- and micro-scale carriers, exhibit promising attributes such as targeted drug delivery, prolonged drug release kinetics and enhanced therapeutic efficacy, portraying their potential across diverse biomedical applications.

The pharmaceutical industry has a long history of using starch and its derivatives for drug delivery and tablet formulations. Starch is a plant carbohydrate that is produced by plants through photosynthesis. The physiological benevolence, biodegradability and vulnerability to enzymatic breakdown based on its amylose:amylopectin ratio, biocompatibility and extraordinary swelling behavior make it a desirable candidate for the development of advanced drug delivery systems [10]. Furthermore, amylose has recently garnered great attention due to its tightly packed helical structure, biocompatibility and hydrophobic interior and hydrophilic exterior for delivering various nonsteroidal anti-inflammatory drugs (NSAIDs) [11]. The multiple advantages of combinational chemotherapy using amylose such as tumor shrinkage, less toxicity, increased response rate and targeted treatment has been extensively studied using anticancer drugs. The synergistic action of curcumin and doxorubicin inclusion complexes inside the hydrophobic cavity of amylose demonstrated enhanced therapeutic effects, trivial enzymatic degradation and minimal drug resistance [12]. Amylose, when modified with ethylene diamine and poly(methyl methacrylate) via the atom transfer radical polymerization technique, induced switchable hydrophilicity and enhanced drug complexing ability [13]. Furthermore polysaccharide-capped metal nanoparticles with special reference to amylose have been reported by Prasher et al. [14] for delivery of antibiotics and anticancer drugs that possess poor availability and degrade easily due to cellular microbial efflux. Acetylation adds ester groups to starch, making it more functional, less toxic and more stable, and produces low, medium and high degrees of substitution starch relevant to controlled drug delivery systems [15]. Several studies have reported the acetylation of starch and amylose to be more beneficial than other chemical modification techniques as it improves starch retrogradability and water solubility. Najafi et al. synthesized in vitro-acetylated corn starch by varying the degree of substitution to deliver the antibiotic ciprofloxacin for treating respiratory, urinary, corneal and gonococcal infections, and demonstrated enhanced drug entrapment efficiency from 67.7 to 89.1%, thus preventing premature drug release with reduced toxicity [16]. Acetylation and oxidation processes are known to impart stability to high-amylose starch and ascorbyl palmitate complexes in aqueous solutions, which have immense application in oral formulations and targeted delivery [17]. Moreover, where ethylation reports OH group substitution with carboxymethyl, hydroxypropyl or hydroxyethyl groups, COOH-methylated starches are extensively used as disintegrants in drug delivery due to their increased sensitivity to pH.

Chemically modified starch has also been investigated to modulate molecular pathways in cells depending on the type and degree of modification, as well as the cell or tissue type involved. These pathways are involved in various cellular processes and have been linked to several diseases, including metabolic disorders, inflammation and cancer. Dialdehyde starch and its derivatives have been known for their inherent antiviral, anti-inflammatory and antineoplastic properties. Dialdehyde starch nanoparticle drugs, in conjunction with 5-flurouracil, reported significant inhibition of MCF-7 cell proliferation and reduced tumour weight in vivo [18]. This complex arrested various phases of the cell cycle and induced necrosis in cultured cells owing to the presence of two aldehyde groups that conjugated with the imine groups in 5-flurouracil, making it a versatile and nontoxic carrier.

Necessity of mucoadhesive drug delivery vehicles

Mucus acts as a physiological barrier for the underlying organs and tissues against foreign agents. Essentially, the permeability of the mucus mesh is controlled by interaction-filtering and size-filtering mechanisms, and its varied spacing spans from 20 to 1800 nm across various organs [19]. Smaller particles can pass through the mesh while the larger molecules are retained by the size-filtering effect. Positively charged molecules stick to the negatively charged mucus layer, whereas similarly charged molecules neither stick to nor penetrate the mucus layer; this is why the interaction-filtering mechanisms enable neutral molecules get through. The mucus layer, which is generally negatively charged due to COOH and SO4^2- functional groups on mucin, govern the mucoadhesive/mucopenetration capacity of logically constructed drug delivery systems [20]. The fact that drug distribution across the alveolar mucosa resists mucociliary clearance further posits a challenge to drug pharmacokinetics, necessitating the maintenance of an optimum therapeutic dosage. In addition, in order to retain the best possible therapeutic impact, these elements require higher dosage frequencies, which may make patient compliance more difficult. The primary function of cationic polysaccharides such as chitosan is to increase the bioadherence of the parent polymer to the physiological mucus barrier by either quaternizing NH₂ groups or chemically modifying OH groups to NH₂ and NH functionalities. Through their ability to stick to the mucus mesh and interact with its components mostly through hydrogen bonding and electrostatic forces, the cationic polysaccharides primarily aid in mucoadhesive drug delivery to the morbid cells beneath the mucus layer [21]. Delivery of therapeutics to mucosal tissue such as sublingual, buccal, nasal, vaginal, ocular and rectal mainly result in bypassing the first-pass metabolism to successfully deliver the drugs. To enhance mucoadhesion to cellular membranes of such sites and to extend the residence time of most drugs, the local cationic charge on the surface of starches can be altered. There have been very few studies that have used diaminated or cationic starch to achieve a sustained drug-release effect. In this regard, Nouri et al. developed a cationic polysaccharide-based drug delivery system in which primary and secondary amines were introduced into the backbone of starch, resulting in an increased solubility and mucoadhesiveness [22]. Moreover, Jelkmann et al. demonstrated an improved mucoadhesion delivery system using starch as an alternative to chitosan, where amino groups, when added to starch, resulted in enhanced intestinal residence time over native starch or chitosan [23]. The incorporation of amine linkages onto polysaccharides imparts versatility, significantly expanding their applicability in pharmaceutical domains while their modification facilitated drug delivery systems to meet specific therapeutic requirements, including tumor-targeted or stimuli-responsive drug release. Naturally occurring polysaccharides possessing amine linkages, such as hyaluronic acid or chitosan, demonstrated outstanding biocompatibility and biodegradability for diverse biomedical applications [24].

Comparing chemically modified high-amylose corn starch to chitosan, the addition of NH₂ and NH groups at its OH group demonstrate significant diamination and enhanced hydrophilicity and mucoadhesion. 4-toluenesulfonyl chloride and triethylamine for 12 h at 5°C generates diaminated starch. When starch's OH groups were chemically modified to create diaminated starch, which has both NH₂ and NH groups, the observed retention time on mucosa was ten times longer than it was with chitosan and it had better water solubility and mucoadhesion at physiological pH [22]. Compared with chitosan, which protonates only at the NH₂ group at the same pH, the diaminated starch's mucoadhesive potential is further mitigated by the protonation of both the NH₂ and NH groups at an acidic pH. On the other hand, diaminated starch is protonated at the NH₂ group at neutral pH, which enables pH-responsiveness of the cationic starch's surface charge, resulting in a noticeable mucoadhesive pH-responsive smart drug delivery system. Unlike chitosan, which only shows solubility at acidic pH, diaminated starch demonstrates solubility over acidic, neutral and basic pH. Due to the protonation of the NH₂ and NH groups, diaminated starch shows a characteristic swelling behavior and water permeability at acidic pH 1.2, resulting in a 53-fold increase in the initial weight. A 30-fold increase in weight has been seen at pH 3, and an 18-fold increase has been seen at pH 5. A slight swelling of diaminated starch occurs as the pH gets closer to the neutral values of 6.8 and 7.4, suggesting that diaminated starch degrades gradually and retains water. In addition, the maximum detachment force and total work of adhesion exhibits higher tensile strength and elasticity, further validating its use as a mucoadhesive material. Comparing the monoaminated counterpart with NH₂ to chitosan, it shows better mucoadhesion and water solubility, similar to diaminated starch [23].

Limitations of NSAIDs

NSAIDs serve as extensively prescribed therapeutic agents for the chronic management of rheumatic and arthritic conditions. These compounds act as inhibitors of cyclooxygenase 1/2 (COX-1/2) and include salicylates, oxicams, sulfonanilides, acid derivatives and selective COX-2 inhibitors [25]. It is imperative to realize that the utilization of NSAIDs is associated with potential upper gastrointestinal (GI) complications, ranging from mild dyspepsia to more severe outcomes such as hemorrhage, ulceration and even perforation of the gastric or intestinal walls. The ulcerogenicity of representative NSAIDs and analgesics arises from mucosal layer erosion, a significant side effect associated with conventional anti-inflammatory therapies for numerous rheumatic disorders. Acute toxicity studies of NSAIDs have revealed hepatocyte necrosis and liver sample degeneration, accompanied by alterations in various molecular pathways, ultimately leading to suboptimal pharmacokinetics and reduced patient compliance (Table 1). Fenamates are a subgroup of NSAIDs derived from a fenamic acid core structure and share intrinsic pharmacological traits as organic acids, predominantly characterized by a pKa value typically falling within the pH range of 3–5 and include mefenamic acid, tolfenamic acid, meclofenamic acid and flufenamic acid (Figure 1). Generally, fenamates include an acidic functional group, notably carboxylic acid or enol, and are attached to an aromatic, planar moiety covalently linked to a lipophilic segment through a polar moiety, playing a crucial role in mediating their cyclooxygenase inhibitory activity [26]. Anthranilic acid serves in several NSAIDs and fenamates, present a privileged profile as pharmacophores for the rational development of commercial drugs and pharmaceuticals deliberated for managing the pathophysiology and pathogenesis of various diseases. The presence of free carboxylic acid (-COOH) and amino (-NH₂) functionalities allows for covalent attachment to various substituents, linkers and functional head groups, thereby broadening the scope of structure–activity relationship analysis for the resulting compounds [27]. Fenamates exhibit robust analgesic, antipyeretic and anti-inflammatory properties, making them valuable in treating rheumatic disorders [28]. At physiological pH levels, fenamates are >99% ionized and are primarily removed in the urine through hydroxylation and glutamate conjugation within 3–4 h. To enhance the systemic bioavailability of fenamates, it is often desirable to escalate the dosage and dosing frequency, potentiating the incidence of GI ulcers and bleeding. To mitigate these complications, fenamates are frequently administered in the form of enteric coatings or as solid dosage formulations. This strategy facilitates the achievement of therapeutic objectives with a single dose, ensuring controlled and sustained release of the therapeutic compound, while circumventing the need for multiple administrations.

Table 1.

Toxicity biomarkers and molecular pathways affected with nonsteroidal anti-inflammatory drugs.

NSAID	Brand name	Cell line/animal used	Adverse effect/toxicity	Biomarker affected	Ref.
Mefanamic acid	Ponstel	HepG2	Oxidative stress	↑ SOD, ↑ H2O2, ↑ PC, ↑ AOPP	[29]
Indomethacin	Tivorbex	Rats	Hemorrhagic lesion on small intestine	↑ COX-2, ↓ PGE2	[30]
Mefanamic acid	Ponstel	HepG2	Oxidative stress	↑ SQSTM1, ↑ Nrf2, Keap1	[31]
Celecoxib, ibuprofen, diclofenac, flufenamic acid, maclofenamic acid, mefanamic acid	Celebrex, Advil, Arlef, Meclomen, Ponstel	Immortalized mouse bone marrow-derived macrophages	Inhibition of Cl- channels in macrophages	↓ NLRP3 inflammasome, ↓ VRAC, ↓ IL-1b, ↓ TRPM2, ↓ ASC protein, ↑ caspase 1	[32]
Mefanamic acid, maclofenamic acid, niflumic acid, flufenamic acid	Ponstel, Meclomen, Donalgin, Arlef	Cultured embryonic rat hippocampal neurons	Neuroprotective efficacy against gluatamate induced excitotoxicity	↓ ROS, ↓ NO accumulation, ↓ mitochondrial cytochrome C, ↑ BCL Xl, minimal cell death	[33]
Indomethacin	Tivorbex	RGM 1 cells	Enhance surviving degradation by ubiquitin proteasome machinery in gastric epithelial cell injury	↓ Survivin, ↑ TNF-α, ↑ cell injury and apoptosis	[34]
Aspirin along with TRAIL	Bayer	Human prostate adenocarcinoma LNCaP and DU-145 cell lines, human colorectal carcinoma CX-1 cell line	Activation of effector caspases related to mitochondrial apoptosis	↓ AKT NF-κB, ↓ IKK-B, ↑ caspase 3, 6, 7, ↓ BCL-2	[35]
Aspirin	Bayer	Human gastric epithelial cell line (AGS)	Cytochrome C release and activation of caspases 9	↑ Caspase 8, 9, ↑ Bax, Bid, SMAC, ↑ cytochrome C	[36]
Celecoxib along with dimethyl celexib	Celebrex	LN229, U251, T98G, U87 (glioblastoma), HCT116, DLD1 (colorectal carcinoma), Raji (Burkitt lymphoma), T47D, MCF7 (breast carcinoma), Mia Pa Ca 2, BxPc 3 (pancreatic carcinoma), A549 (lung carcinoma)		↓ Survivin, induce apoptosis, ↑ caspases	[37]
Tolfenamic acid	Clotam	Hep G2, HeLa cells, PC	Inhibition of VEGFR-2 tyrosine kinase in solid tumors, high docking score (ΔG) in VEGFR-2	↑ Caspase 4, 8, ↓ VEGFR 2, ↓ cell cycle progression via inhibition at G2/M phase	[38]

AOPP: Advanced oxidation protein products; COX-2: Cyclooxygenase 2; H₂O₂: Hydrogen peroxide; NO: Nitric oxide; NSAID: Nonsteroidal anti-inflammatory drug; PC: Pancreatic carcinoma; PGE₂: Prostaglandin E2; ROS: Reactive oxygen species; SO: Superoxide dismutase.

Figure 1.

Chemical structures and names of nonsteroidal anti-inflammatory drugs.

Flufenamic acid (also known as 2-[3-(trifluoromethyl)anilino]benzoic acid) is an aromatic amino acid comprising anthranilic acid with an N-(trifluoromethyl)phenyl substituent exhibiting IC₅₀ values of 3 and 9.3 μM for human COX-1 and COX-2, respectively [39]. Its anti-inflammatory and analgesic properties were acknowledged in the 1960; however, the high incidence of GI side effects such as ulceration and bleeding associated with its chronic pathological use restricts its usage in humans [40]. In human polymorphonuclear leukocytes, flufenamic acid demonstrated inhibition of calcium influx induced by formyl-methionyl-leucyl-phenylalanine, with IC₅₀ values of 29 and 14 μM, respectively [41]. Furthermore, flufenamic acid inhibited the activity of cystic fibrosis transmembrane conductance regulator and activated a number of ion channels, including large-conductance calcium-activated potassium channel and transient receptor potential canonical 6. This compound also effectively hindered TNF-α-induced elevation in COX-2 levels and NF-κB activation in HT-29 colon cancer cells in a concentration-dependent manner [42].

The enzyme cyclooxygenase exists in two isoforms, COX-1 and COX-2, each fulfilling discrete roles. COX-1 is constitutively expressed and assumes a pivotal function in safeguarding the gastric mucosa through the synthesis of prostaglandins. In addition to being involved in the synthesis of prostaglandins, COX-1 is essential for physiological platelet activation, GI tract mucosal protection and renal function maintenance. On the other hand, the inflammatory response triggers the production of COX-2, inhibiting smooth cell growth, platelet suppression and vasodilation. NSAIDs exert their anti-inflammatory effects by binding to and inhibiting COX, thereby hindering the production of proinflammatory prostaglandins. By inhibiting COX enzymes, NSAIDs block the synthesis of prostaglandins, which are lipid mediators that play a crucial role in inflammation, pain and fever. Prostaglandins sensitize pain receptors and contribute to the perception of pain. Inhibition of prostaglandin synthesis by NSAIDs helps alleviate pain. NSAIDs can inhibit the synthesis of thromboxane, thereby reducing platelet aggregation and potentially lowering the risk of thrombotic events [43]. Traditionally, most NSAIDs exhibit nonselective inhibition of both COX-1 and COX-2. While COX-2 is primarily induced during inflammation and contributes to its pathogenesis, COX-1 is constitutively expressed and plays physiological roles in various tissues, including protecting the gastric mucosa and maintaining renal blood flow.

The primary cause of NSAID-induced gastropathy is the suppression of COX-1, which perturbs the regular defence mechanism of gastric mucosa [44]. GI complications attributed to NSAID use stem primarily from three distinct mechanisms: the inhibition of COX-1 enzyme and gastroprotective prostaglandins, alterations in membrane permeability and the generation of supplementary proinflammatory mediators. To ameliorate the GI disturbances associated with COX-1 inhibition, COX-2-selective NSAIDs were developed manifesting adverse cardiovascular events [45]. The prevailing trend in NSAID development primarily focuses on enhancing therapeutic efficacy and mitigating upper GI side effects by modifying dosage forms to optimize drug delivery. These formulations are engineered to improve patient compliance through prolonged therapeutic effect and reduce adverse effects by lowering peak plasma concentrations. Polysaccharides exhibit notable potential as a prospective advanced drug delivery system, attributed to their biodegradability, biocompatibility and controlled/sustained release kinetics, which further endorse the pharmacokinetics and maintain an optimal drug concentration across the physiological mucus barrier.

V-amylose characteristics

Amylose has widespread application as a pharmaceutical disintegrant and adhesive owing to its favorable attributes such as biocompatibility, biodegradability and nontoxicity. It has been observed that amylose undergoes hydrolysis by α-amylase from pancreatin in the small intestine and is subject to potential metabolism by bacterial amylase enzymes in the colon. Consequently, amylose is regarded as a promising carrier for targeted and controlled drug release of therapeutically relevant molecules within the intestines. Amylose is recognized for its capacity to establish inclusion complexes with hydrophobic ligands (guest molecules) and can adopt either a disordered amorphous conformation or two distinct helical forms: the double helix of the amylose chains (A or B form) or a single-helix structure (V-form) [46]. The V-form is induced in the presence of hydrophobic guest molecules. The prevalent form within the V-amylose family is the typical V6 amylose, distinguished by six glucose units per turn. However, certain guest molecules induce a variation in the helical structure, resulting in what is termed the V8 structure. The V8 structure features a larger cavity within the helical arrangement, accommodating eight glucose residues per turn, thereby enabling the inclusion of larger molecules [47]. V-amylose demonstrates a unique structural composition consisting of a hydrophobic helical core and a hydrophilic exterior, making it an attractive option for the targeted delivery of various pharmaceutical molecules [48]. Specifically, in oral drug delivery, encapsulating the drug within the V-amylose helix enhanced its resistance to acidic hydrolysis, leading to controlled release in the colon through enzymatic stimulation, improving the tolerability of drug molecules that may have toxic effects during burst release. The drug molecules and amylose combine to form inclusion complexes in which the former caused the latter to undergo a conformational change, resulting in a compact helical shape with a hydrophobic interior and a hydrophilic outside. A single-chain helix of amylose is stabilized by Van der Waals interactions and intramolecular hydrogen bonding between the helical turns, whereas the bonds between the amylose and drug are stabilized by intramolecular forces. The hydrophilic exterior of helical amylose is formed by glycosyl OH groups, while the hydrophobic cavity of the polymer is made up of 1,4-glycosidic linkages and methylene groups, broadening its ability to wrap different therapeutic molecules. The small intestine's α-amylase further acts as a catalyst for the breakdown of drug amylose conjugate and releases the encapsulated drug subsequently. The rate at which amylose hydrolyzes determines the drug release and can be controlled or sustained over an extended period. But unlike amylopectin, which has additional 1,6-glycosidic linkages with highly branched structures and a greater surface area for the activity of enzymes, helical amylose has a limited rate of enzymatic hydrolysis in the small intestine due to its linear 1,4-glycosidic linkages. The amylose-to-amylopectin ratios of starch vary depending on the biological sources from which it is derived. Its processing simplicity and efficacy as an oral drug delivery vehicle are constrained by low shear stress resistance, poor aqueous/organic solubility and poor GI digestion. Amylose-to-amylopectin ratio is the primary factor that is changed when starch composition is modified by genetic engineering. Acetylation reduces the ability of starch to be digested by enzymes and to dissolve in water but at low pHs, carboxymethylation renders starch acid-insoluble and aggregative. The overall effects sustain drug release in the upper intestine. The drug release from carboxymethylated starch that is acid insoluble can be further decreased by aminating it to give it the ionic character needed to create hydrogels. Ionic starch indeed manifestes insoluble, controlled-release complexes with drugs, nonstarch polyelectrolytes and oppositely charged starches [49].

V-amylose is naturally synthesized in plants and hence easily available and economically convenient compared with the synthetic polymers used to deliver NSAIDs and other drugs to GI system [50]. This also promotes nontoxicity and nonimmunogenicity to targeted cells and neighbouring cells. Owing to its unique helical structure, V-amylose resists degradation and hydrolysis in the withesence of gastric enzymes such as amylase compared to other counterparts that precipitate easily. This feature renders V-amylose distinct as it promotes sustained and controlled delivery of a variety of therapeutics to the colon for enhanced effects with reduced biodegradability and reduced occurrence of burst effects and ulcerogenicity in intestines (Figure 2) [51]. The ease of chemical modification to the backbone of V-amylose renders it cationic, making it an ideal mucoadhesive candidate for adhering to the negatively charged mucus layer due to the presence of primary and secondary amino groups [52]. This mucoadhesion promotes enhanced residence time of drugs to intestines and ensures controlled delivery of an active pharmaceutical agent to the bloodstream.

Figure 2.

Applicability of amylose in a contemporary drug delivery paradigm.

V-amylose drug complexes

The classical method of V-amylose preparation involves mixing a high-amylose corn starch or pure amylose with the drug or ligand under shear-free moisture or heating. This procedure is generally called acidification of an alkali solution and involves dissolution of amylose in either KOH or DMSO or water, and adding the drug gradually followed by a reduction in pH and finally incubating at varied temperatures to yield amorphous and crystalline complexes (Figure 3) [53]. Amorphous-type V-amylose complexes have been reported to form at 60°C, whereas incubation at >90°C results in semi-crystalline complexes [54,55]. In recent times, there has been considerable interest in the in situ synthesis of amylose-based inclusion complexes using enzymatic polymerization. This approach involves the enzymatic polymerization of α-d-glucose 1-phosphate monomer facilitated by phosphorylase in the presence of a guest molecule. Several factors seem to influence the formation of V-amylose, categorizable into reactant and experimental factors. Reactant factors include starch type, water content within the starch, degree of polymerization of starch, concentration ratio of starch/ligand, and the structure of the inclusion molecule. Experimental factors impacting V-amylose complex formation are discussed below and include complexation temperature, duration of complexation and pH of the medium [53].

Figure 3.

Preparation of amylose drug complexes.

Effect of starch type

V-amylose produced from starches derived from various wheat varieties exhibits varying levels of crystallinity, thermal melting temperatures and enthalpies during complex dissociation. The impact of wheat variety or starch type on the yield of amylose-lipid complexes is likely attributable to differences in the penetration rates of ligands (lipids) into starch granules [56]. These differences stem from variations in granule microstructure, including the presence or absence of surface pores/channels on the granule. Starches containing higher levels of amylopectin typically exhibit a reduced tendency to form complexes compared with those with lower amylopectin content. Consequently, high-amylose corn starches such as Hylon^®, Amylo-maize 70^® and Gelose^© are deemed suitable for achieving higher yields of V-amylose, as evidenced by several studies [57].

Degree of polymerization

V-amylose yield is more influenced by the molecular weight of amylose than by the number of carbons present in the fatty acids [58]. Below a degree of polymerization of 400, both the yield and crystallinity of the complex increase with the degree of amylose polymerization. However, the yield decreases at higher degrees of polymerization, specifically at a degree of polymerization of 950 [59]. The minimum size of amylose required for complexing with fatty acids is approximately 30–40 glucosyl residues to accommodate palmitic acid, and 20–30 glucosyl residues for lauric and caprylic acids. This corresponds to a chain length sufficient to accommodate two fatty acids per chain [58].

Moisture

V-amylose complexes are easily formed under low (25%) and moderate (40%) moisture conditions, while high moisture levels (66% w/w) appear to impede both complex formation and crystallization [60]. In conditions of lower moisture content (36–64%, wet basis), water is proposed to play a vital role as a plasticizer during V-amylose formation. The heating parameters (duration, temperature and potential shearing effects) might also influence outcomes, particularly at elevated moisture levels [61].

Drug concentration & structure

Variations in the acyl chain length (hydrophobic segment), degree of unsaturation, concentration and the polar head type of the drugs, as well as the presence of native starch lipids, have been demonstrated to have a considerable impact on the type, yield and structure of resulting V-amylose complexes [55,62–64]. Enhanced fatty acid unsaturation results in the generation of complexes with lower crystallinity compared with those formed with fully saturated fatty acids [55,65]. The ideal concentration for each fatty acid correlates with its water solubility and critical micellar concentration, whereby at concentrations surpassing a certain threshold, lipids tend to self-assemble instead of forming V-amylose complexes [66]. This phenomenon could elucidate the observed variability in complex formation with stearic acid across different studies, with some reporting limited complexation while others indicate significant interaction [67,68].

Heat

The type of V-amylose crystal structures formed during complex formation is influenced by the complexation temperature, duration of heating and cooling rate. The specific temperature conditions employed during V-amylose preparation via a particular method are critical factors in determining both the yield and structures of V complexes formed. V-amylose type I is achieved at lower heating temperatures (60°C) through rapid nucleation, leading to a random arrangement of helices without the formation of distinct crystallites [59]. The precipitation/crystallization temperature is considered optimal at temperatures exceeding 90°C, where type II complexes are formed [69,70]. Complexing agents induce metastable crystalline structures that are less perfected and prone to reorganization upon heating, potentially through mechanisms such as lamella thickening [70] or reorganization of amorphous and crystalline lamellae [53].

pH

The pH of the complexation medium significantly influences complex formation. Neutral lipids, such as monoglycerides, readily form insoluble precipitates in neutral aqueous environments. In contrast, insoluble complexes with ionizable fatty acids are only formed at pH levels below 7 and in the presence of electrolytes. The ionizable COOH group in fatty acid ligands renders the initial aggregation of complexes more responsive to changes in pH and salt concentration [55].

Advancement of V-amylose in the controlled delivery of various NSAIDs

V-amylose's enzymatic hydrolysis results in a delayed release, which is achieved by complexing it with ibuprofen to reduce the drug's GI side effects. When compared with the simulated gastric medium (pH 1.2) and the simulated small intestinal medium (pH 7.2), the ibuprofen V-amylose inclusion complexes showed remarkable stability, which eventually explained the gradual drug release in the test media [71]. Further reducing the drug's effective therapeutic dosage, potential toxicity was provided by the V-amylose–ibuprofen complex. The system demonstrated only 5.5% release of the drug present in the complexes in simulated gastric medium, according to the in vitro assay used to evaluate the drug-release behavior of the inclusion complex, indicating its remarkable stability. In a manner similar to the small intestine model, these complexes demonstrated a sustained and complete release of the drug cargo in order to attain the best possible therapeutic response. Moreover, the medium's amylase content caused the complex to biodegrade, which in turn caused the ibuprofen to release gradually over the course of 8–12 h [72]. Mainly, the ibuprofen molecules were encapsulated in the 5.4 Å diameter and 8 Å pitch height of internal hydrophobic cavity of V-amylose to create flexible helices and persistent inclusion complexes, preventing premature drug leakage from the hydrophobic cavity.

To enhance the therapeutic efficacy and mitigate the gastric side effects of indomethacin, amylose–indomethacin inclusion complexes were investigated by Yang et al. in 2013. Indomethacin's release profile was ameliorated at pH 12, where the solubility reached its peak, escalating the drug's hydrolysis and resulting in the loss of 5-methoxy-2-methylindole-3-acetic acid and p-chloro benzoic acid moieties, which degraded the molecule. An innovative drug delivery system that relies on enzymes was developed when indomethacin and amylose were chemically conjugated using ester linkages, a N,N-dicyclohexylcarbodiimide coupling agent and a 4-(N,N-dimethylamino) pyridine catalyst [73]. Better water absorption efficiency in the conjugates with lower indomethacin concentration triggered the activity and diffusion of hydrolyzing enzymes to the swollen conjugates. This characteristic promoted amylose–indomethacin conjugate biodegradation, resulting in prolonged release of the conjugated drug molecules in the simulated intestinal media. At the same time, the conjugation showed negligible drug release in the gastric fluid. Less than 2% of the drug was released by the conjugates in simulated gastric fluid after 90 min at 37°C. In contrast, the drug was gradually released during the 180-min incubation period in the simulated intestinal media. Principally, when incubated in the colonic fermenter, it produced a 65% release in 36 h, indicating a prolonged and sustained release for intestinal targeting. Indomethacin and V-amylose formed a trivial complex as the drug molecules physically trap in the matrix of amylose instead of the helical hydrophobic cavity. However, the absence of indomethacin within the helix of V-amylose limited the effectiveness of the drug's targeted release in the intestine and promoted early release in the stomach's acidic pH.

By physically fitting inside the helical cavity, bulkier nutraceuticals such as ‘genistein’ reported the formation of inclusion complexes with V-amylose. The complex aggregated as a result of hydrophobic interactions between V-amylose and genistein in the stomach's acidic environment and released less than 15% of the drug, suggesting a discernible stability in these circumstances. The regulated release of genistein molecules at the intended site in the digestive system in the presence of hydrolyzing gut enzymes was validated by its stability in acidic pH, which prevented the molecules from releasing prematurely in the gastric area. It is interesting to note that these compounds showed exceptional stability at 30 and 50°C across a pH range of 4–8 [74]. The releasing behavior was further enhanced by the additional pH rise, primarily as a result of their partial breakdown in alkaline environments. The partial charge that V-amylose and genistein acquire on their surfaces decreased the interactions between them and enhanced their interactions with the surrounding water molecules, accelerating free genistein in the solution.

An acceptable substitute for the controlled administration of quercetin is V-amylose. The B aromatic ring in the quercetin molecule changes its conformation to a more ordered state when it is encapsulated in V-amylose through hydrophobic and hydrogen-bonding with V-amylose via carbonyl (C=O) and OH groups. In simulated stomach settings, the V-amylose–quercetin complex showed a significant retention of the latter; however, in simulated small intestine conditions, the release rate gradually increased in the presence of pancreatin, reaching a maximum at 97% after 8 h [75]. The V-amylose inclusion complexes with ‘nimesulide’ and ‘praziquantel’ is an excellent rationale for accomplishing site-specific drug release. The drug molecules that were encapsulated were released in an enzyme-sensitive manner as a result of the system's pH-dependent behavior in absorbing nearby water molecules. At acidic pH levels, the protonation of polar head groups decreased electrostatic repulsion, which in turn decreased the absorption of water molecules [76]. On the other hand, at higher pH levels, the hydrophobic drug molecules that are present on the surface of these complexes were formed into crystalline structures by the ionisation of the polar head groups. These complexes' increased electrostatic repulsions encourage the absorption of nearby water molecules and promote delayed drug release [77]. Mainly, the V-amylose drug complexes conferred a modest release profile in phosphate buffer (6.9) and acidic pH (1.2); however, the drug-release rate improved when pancreatin enzyme was specifically included.

Amylose as an enteric-coated & sustained-release vehicle

The use of sustained-release vehicles and enteric coatings in NSAID dosages improve their physiological tolerance by facilitating a controlled drug release rather than burst release, preventing toxicity to gastric mucosa that may occur due to a rapid increase in drug concentration. The osmotically triggered slow-release version of indomethacin, which is no longer marketed, has been linked to distal side effects such as perforating colonic and ileal ulcers when used with sustained-release NSAIDs [78].

Under optimal conditions, the gelation of V-amylose yields films that exhibits remarkable resistance against pancreatic α-amylase, but gradually deteriorates when colonic microflora amylases are present. Enteric coatings made of amylose quickly swell in GI simulators, creating porosity and allowing drug molecules to be released from their capsules. By adding insoluble polymers such as ethylcellulose to the amylose film, V-amylose's swelling characteristics are improved, which in turn improves its drug-release profile [79]. The anti-inflammatory mesalazine, or 5-aminosalicylic acid, showed remarkable resistance to the simulated gastric and small intestinal conditions when V-amylose–ethylcellulose was coated in a 1:4 ratio, preventing any drug release for 24 h. It has been found that ethylcellulose inhibited V-amylose swelling, which ultimately delayed the drug release from the coating. However, after being added to the fermenter, the V-amylose–ethylcellulose-coated 5-aminosalicylic acid released more quickly between 2 and 5 h, and displayed 8 h for the complete release of mesalazine [80].

After 2 h at 37°C, mathematical modelling of the release kinetics of antibacterial and antineoplastic limonene molecules from V-amylose revealed exceptional resilience towards the acidic environment. In 6 h, the system demonstrated a controlled, delayed drug release, increasing gradually from 34 to 79% in small intestine-simulated medium. When compared with the Peppas model, the release pattern of limonene from V-amylose showed the highest determination coefficient, whereas fuzzy logical intelligent modelling showed a coefficient of determination larger than 0.99. With a greater success rate than traditional experimental methods, the mathematical simulations effectively stimulated the adoption of strategies for modelling the controlled release trend of encapsulated limonene molecule and comparable nutraceuticals from V-amylose [81].

The intestinal-specific release of flufenamic acid was accomplished through its encapsulation within the helical cavity of V-amylose, effectively preventing its burst release at the target site responsible for manifestation of gastric ulcers. The V-amylose–flufenamic acid complex exhibited sustained drug release over a 12-h period, demonstrating notable stability under simulated gastric pH conditions while concurrently demonstrating controlled drug release in simulated intestinal media. Moreover, the complex displayed significant stability across a range of pH levels and at elevated temperatures, further underscoring its potential for intestinal drug delivery applications. This targeted and sustained release mechanism provided by V-amylose presents a robust candidature for the safer delivery of NSAIDs, which are known to elicit gastric mucosal damage upon rapid release within the GI tract [82].

Colon-targeted drug delivery offers a multitude of advantages within pharmaceutical delivery systems. Various commercially available technologies such as Eudracol, CODES, microbial-triggered colon-targeted osmotic pump, multimatrix technology, pelletized tablet, PHLORAL and Colal-Pred systems have shown promising outcomes in delivering drugs specifically to the colon and subsequently initiating drug release in a controlled manner. The delivery of NSAIDs to the intestines using resistant starch further exhibits considerable potential by limiting early release in the acidic environment of the upper GI system to achieve a localized effect. Through the action of pancreatic amylase, resistant starch is only minimally broken down in the small intestine. Consequently, resistant starch containing a high percentage of amylose surpasses the small intestine's enzymatic hydrolysis and enables gut microbiota-based, colon-targeted drug release [83]. The trigger mechanisms for delayed drug release are conspicuous to contemporary innovations such as phloral coating technology and include the microbiota trigger based on resistant starch V-amylose and the pH trigger based on Eudragit S, which dissolves in intestinal fluid. Thus, this coating technology offers a fail-safe method for cargo drugs to be released colonically. It is noteworthy that the integrity of the coating in the upper GI tract and Eudragit S remain unaffected with the resistant starch coating [84]. Likewise, unique OPTICORE technology presented accelerated release, as the duocoat present in the inner layers, when combined with the Phloral-triggered mechanism in the outer layer, quickly released drug particularly due to the isolation layer separating the inner layer and the core. In essence, when the pH of the luminal fluid deviates from neutral, the presence of a Phloral outer coating facilitates enhanced drug release. Consequently, OPTICORE technology enables specific drug delivery to the colon region for patients suffering from ulcerative colitis [85].

Amylose-based solid dosage formulation for controlled drug delivery

Matrix tablets play a pivotal role in the realm of drug delivery by modulating controlled and sustained release of pharmaceutics. These tablets are meticulously designed with the drug uniformly dispersed within a matrix or polymer, a strategic arrangement that exercises dominion over the release kinetics of the drug across an extended temporal span [86]. The significance of matrix tablets is underscored by a constellation of cardinal attributes. First and foremost, matrix tablets exhibit the phenomenon of controlled release, resulting in the preservation of therapeutic drug concentrations within the body over an extended duration, which is particularly advantageous for drugs harboring a slender therapeutic window or those necessitating consistent dosing regimens. Furthermore, matrix tablets reduce dosing frequency, and augment patient compliance and convenience, particularly for drugs requiring frequent administration schedules [87].

In a matrix system, the active and inactive components are combined and uniformly distributed throughout the dosage form. By controlling the release of the drug dosage from solid forms, matrix tablets mitigate the undulations and potential undesirable side effects. For drugs characterized by short half-lives, matrix tablets based on amylose bestow a sustained release profile within the body, thus potentiating their therapeutic efficacy. Substantively, matrix tablets also curtail the fluctuations between drug peaks and troughs in plasma concentration, an aspect that holds promising clinical outcomes. By judiciously selecting polymers and formulations, amylose matrix tablets afford the luxury of tailoring drug release profiles to harmonize the idiosyncratic pharmacokinetic requisites of diverse therapeutic agents.

In the development of solid dosage formulations and enteric coated pills, high-amylose maize starch has been used as a disintegrant, binder and filler in matrix tablet preparation. Native starch can be chemically modified as primary and secondary OH groups are present for tailorable physicochemical properties. The complexation of diclofenac with high-amylose starch that has been combined with cross-linked polymers demonstrated additional control over the delivery vehicle's characteristics, resulting in a more regulated release profile and better therapeutic outcomes. When a drug is added to high-amylose starch (70% amylose), the system's strength, crystallinity and thermal stability are ameliorated. The amylose–diclofenac complex, with enhanced physicochemical features, serves as an important controlled delivery method for distribution to the colon, specifically improving the degradation profile of drug conjugated to amylose. Diclofenac sodium was released under regulated conditions using tableted microparticles made of pectin blend and high-amylose starch polymers, and significantly demonstrated prolonged and sustained GI-targeted release via Fickian diffusion in vitro (95% release in 30 min) [88].

Moreover, controlled delivery of fenamates (flufenamic acid, maclofenamic acid, tolfenamic acid and mefenamic acid) in the form of matrix tablets to intestines has been reported recently. Aminated high-amylose corn starch–fenamate tablets demonstrate a controlled release pattern in simulated intestinal media, both with and without the presence of pancrelipase enzyme. Following an initial rapid drug release, a controlled release profile was achieved by 10 h, owing to the stability of the imine linkage in aminated starch under weakly acidic conditions. In addition, primary amines undergo sufficient protonation at this pH, enhancing the swelling index and facilitating controlled drug release. Conversely, in simulated gastric media, initial drug release is rapid due to imine linkage degradation under strongly acidic conditions. However, the release profile mimicked that of simulated intestinal media up to 10 h, supported by primary amine group protonation at acidic pH, preventing premature and burst drug release. Complete drug release in simulated gastric media was observed due to carrier system degradation and loss of amine appendages from imine functionality hydrolysis at strongly acidic pH. The remarkable mucoadhesive potential of aminated high amylose corn starch–fenamate tablets is crucial for targeted drug delivery to the intestine. Furthermore, the controlled release profile achieved by aminated high-amylose corn starch for fenamate NSAIDs may provide useful insights in mitigating the ulcerogenicity induced by fenamates [89].

Amylose-based magnetically-guided drug delivery systems

Magnetic nanoparticles (MNPs) have emerged as versatile entities with multifaceted roles in advancing both targeted drug delivery and theranostics, combining therapeutic and diagnostic functionalities within a unified platform [90]. In the domain of targeted drug delivery, MNPs function as carriers for therapeutic agents for transporting drugs, peptides, nucleic acids and other cargoes to specific anatomical sites. Among several MNPs, iron oxide is the most preferred owing to its superparamagnetic nature at room temperature. But due to its hydrophobic nature, it tends to agglomerate and form large clusters with reduced colloidal stability [91]. Another hitch is the oxidation of the MNPs due to their large surface-to-volume ratio, necessitating coating of the iron oxide core with a functional shell containing long-chain molecules to enhance colloidal stability and minimize residual magnetization [92].

Owing to their low toxicity, ease of surface modification, biocompatibility and magnetic attributes, MNPs are considered as next-generation drug/gene carriers with immense utility in diagnostics, theranostic and clinical science. Their modifiable surface properties supplement functionalization with targeting ligands, enabling precise recognition and binding to particular cells or tissues. Following targeting, the nanoparticles can be effortlessly maneuvered and concentrated at the intended location through external magnetic field augmenting adequate drug accumulation while mitigating systemic exposure. This targeted strategy elevates the therapeutic efficacy of drugs and diminishes off-target effects, ultimately enhancing patient outcomes.

In the realm of drug delivery systems, V-amylose has exhibited promising potential; however, its comprehensive utilization as a drug carrier remains unrealized in the current era. Notably, its application as a carrier for ulcerogenic flufenamic acid, ibuprofen, indometacin and nimesulide has only undergone preliminary investigation. Furthermore, the evaluation of V-amylose's impact on the pharmacokinetics of NSAIDs is still in its nascent stages, with limited ongoing clinical trials.

Controlled drug release facilitated by V-amylose delivery systems holds the promise of potentially reducing the effective therapeutic dose and the frequency of drug administration. This could significantly enhance patient compliance and mitigate the adverse effects associated with NSAID use, particularly the development of GI ulcers (Table 2). Despite these initial strides, a conclusive determination of V-amylose's efficacy and safety in the context of NSAID delivery awaits further research and rigorous clinical validation. A comprehensive understanding of the long-term effects and potential side effects through extensive clinical trials will be pivotal in establishing V-amylose as a reliable and effective drug delivery system. Finally, the integration of cutting-edge technologies and innovative approaches in pharmaceutical research will likely contribute to unlocking the full potential of amylose, paving the way for its successful integration into contemporary therapeutic strategies for NSAID delivery.

Table 2.

Controlled delivery systems based on amylose for various nonsteroidal anti-inflammatory drugs.

Amylose	NSAID	Delivery system	Therapeutic response	Ref.
HACS pectin blend	Diclofenac	Tableted microparticles	Effective controlled release of drug initially followed by slow release by blended matrix	[88]
Amylose, dextran	Indomethacin, sulphomethoxazole	Hydrogel beads	Controlled release of drugs achieved with respect to the pH of the stomach and colon	[93]
High-amylose rice	Diclofenac	Mucoadhesive buccal films	Enhanced transparency and mucoadhesiveness for drug incorporation	[94]
Amylose ethylcellulose	Ketoprofen	Compression-coated tablet	Optimized colonic delivery achieved through factorial design of experiments	[95]
Hydroxyethyl amylose and methyl cellulose	Indomethacin	Micelle	Conjugates with low drug content were stable in in vitro-simulated medias of the intestine and stomach, and showed a sustained release pattern in a colonic fermenter	[96]
Amylose ethylcellulose	5-amino salicylic acid	Coated pellet film	Coated films deliver drugs in a slow and sustained manner to thee colon compared with uncoated	[97]
Native amylose	Ibuprofen	Matrices	Structural model for highly crystalline lamellar amylose complexes predicted release and degradation in simulated medias of intestines and stomach	[98]
Anionic and cationic amylose	Acetaminophen, mesalamine naproxen	Tablets	Enhanced drug loading and sustained release at higher concentrations by in vitro dissolution tests with stable swelling and erosion in simulated intestinal fluid	[99]
Amylose	Ibuprofen	Inclusion complexes	Enhanced yield and complexing efficiency, potential pH-responsive delivery system for targeted and controlled release of drug	[100]
Amylose ethyl cellulose	4-amino salicylic acid	Capsules	Robust formulation for the treatment of inflammatory disorders with slow and sustained release of drug in the colon	[101]
Amylose pectin	Diclofenac	Microparticle blends	Enhanced drug loading, thermal stability and degree of crystallinity	[102]
High-amylose corn starch	Paracetamol, zein	Films, tablets	Prevention of burst release and promotion of drug release only in a simulated colonic fermenter	[103]
High-amylose rice starch	Ibuprofen, naproxen and ketoprofen	Powder	Enhanced thermal stability, formulation and kinetics for novel pharmaceutical excipient use	[104]
Amylose	Diclofenac sodium	Core tablets	Optimized delivery and response surface plots confirmed the presence colonic drug release with respect to pH	[105]
Cycloamylose	Ibuprofen	Solid dispersion	14 fold improvement in drug solubility in vivo, with enhanced oral bioavailability based on dispersion without structural change	[106]

HACS: High-amylose corn starch; NSAID: Nonsteroidal anti-inflammatory drug.

Conclusion

In summary, the consideration of V-amylose as a potential carrier for delivering ulcerogenic NSAIDs offers a promising avenue for addressing the prevalent challenge of GI complications associated with these widely used medications. Through a comprehensive exploration of the physicochemical interactions between V-amylose and selected NSAIDs, this study has yielded valuable insights into amylose's potential as a protective and efficient carrier. Experimental results further indicate favorable attributes of V-amylose as a drug delivery vehicle such as biocompatibility, biodegradability and the ability to form stable inclusion complexes with ulcerogenic NSAIDs. Molecular-level insights derived from spectroscopic techniques and molecular modelling contribute to a deeper comprehension of the intricate interactions between V-amylose and NSAIDs, paving the way for the development of tailored drug delivery systems.

Furthermore, in vitro release studies suggest that formulations based on V-amylose have the potential to offer controlled release profiles, a feature that could contribute to minimizing the adverse effects associated with NSAID administration while preserving therapeutic efficacy. The contemplated use of V-amylose in drug delivery not only addresses the issue of ulcerogenicity, but also holds promise for improving the overall pharmacokinetics and bioavailability of NSAIDs. As we conclude, it is clear that further research and advancement is necessary in order to translate these outcomes in real-world settings. Leveraging amylose as a carrier for ulcerogenic NSAIDs represents a novel and innovative approach that could significantly impact the field of drug delivery, providing safer and more efficient therapeutic alternatives for patients requiring NSAID therapy. This review establishes a groundwork for future investigations and underscores the potential of V-amylose-based formulations as a transformative solution in NSAID delivery.

Future perspective

Enhancing drug delivery through V-amylose currently requires methodologies capable of expediting formulation development, accurately predicting in vivo performance and facilitating clinical trials [107]. This imperative stems from the need to optimize drug delivery systems for efficient therapeutic outcomes while minimizing adverse effects. Molecular dynamics has proven valuable in elucidating the formation process of polymer-coated nanoparticles generated via flow nanoprecipitation, demonstrating how atom-level insights can be leveraged to enhance the optimization of colon-targeted nano formulations [108]. Insights into machine learning and deep learning recently facilitated the release, permeation and dissolution profile of piroxicam when used with chitosan and xanthan gum [109]. In a recent study artificial intelligence aided in the design of experiments for optimized targeted delivery of an NSAID for the management of arthritis [110]. By modifying key absorption, distribution, metabolism and excretion parameters, physiologically based pharmacokinetic models have the potential to precisely forecast how variations in physiology impact pharmacokinetics across diverse patient populations when using amylose NSAIDs complexes in the formulation. Studies employing widely used physiologically based pharmacokinetic software such as GI-Sim and GastroPlus have demonstrated the prediction of colonic absorption of drugs and high performance levels in regional absorption studies in dogs during the preclinical stages of drug development [111]. It is crucial to emphasize the significance of conducting in vivo and ex vivo studies on different amylose drug conjugates. Specifically, the design of amylose-based hydrogels and self-assembled polymeric micelles with adjustable biodegradability under physiological conditions is important and highly dependent on the intended application. Indeed, this characteristic directly influences its in vivo biocompatibility. Microencapsulation techniques, such as nanoencapsulation with particle sizes smaller than 100 nm, offer promising avenues to improve the bioavailability, stability, controlled release and targeted delivery of NSAIDs while also mitigating their bitter taste, improving efficacy and mitigating side effects. Low-molecular-weight NSAIDs can be encapsulated using a variety of techniques including emulsion, coacervation, extrusion, spray drying, freeze-drying, molecular inclusion, microbubbles, fluidized bed coating, supercritical fluid encapsulation, electrospinning/spraying and polymerization [112]. By leveraging these scientific approaches, we can expedite the translation of V-amylose-based drug delivery systems from bench to bedside, ultimately improving patient outcome and advancing the field of pharmaceutical science.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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