INTRODUCTION:

Diabetes mellitus is a metabolic disease characterized by excessive blood glucose levels, which can lead to complications and other conditions if left uncontrolled and untreated in the long term^1-4. According to a report by the International Diabetes Federation⁵, the global incidence of diabetes was 9.3% in 2019, estimated to increase by 0.9% and 1.6% in 2030 and 2045, respectively.

In addition, the lifetime incidence of diabetes complications, including diabetic foot ulcers (DFUs), is reportedly 15% to 25%⁶.

A non-healing foot ulcer can progress to tissue and bone damage requiring amputation, which negatively impacts the patient’s self-esteem and quality of life, highlighting the importance of appropriate wound care by minimizing the risk of infection^7-8. The goals of wound dressings for a DFU include maintaining a favorable moist environment, removing dead tissue and debris from the wound site, controlling and absorbing exudate, and preventing wound progression.

The healing of other types of wounds, such as cuts, abrasions, and burns, are also impaired in diabetes patients. A non-healing wound can cause severe chronic pain, minimize the ability to perform regular physical daily activities, and increase the risk of infection. Therefore, a wound dressing should provide symptom control, give comfort to the patient, and manage exudate from the wound.

A polysaccharide is a carbohydrate composed of polymeric chains of monosaccharides linked by glycosidic bonds. Polysaccharides have been shown to effectively facilitate every stage of the wound healing process to regenerate new tissue and replace damaged skin. They are used for fabricating various wound dressings, including electrospun fibers, hydrogels, films, sponges, and foams^9–11. Polysaccharide-based formulations can maintain skin hydration to provide an optimal wound healing environment¹². Furthermore, polysaccharides can be used as carriers to deliver controlled-release active ingredients to the wound site.

Effects of Diabetes on the Wound Healing Process:

Diabetes is associated with a greater risk for breaks in the foot skin that can develop into a DFU, thereby increasing the risk for amputation. Hyperglycaemia impairs normal physiological responses against infection by delaying adequate accumulation of inflammatory factors that promote wound healing. A DFU presents a pathway for microbial entry and subsequent foot infection, which can lead to sepsis. Common pathogenic causes of diabetic wound infections include Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter aerogenes, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, Staphylococcus epidermidis, and Staphylococcus haemolyticus¹³. However, several other factors that contribute to impaired wound healing in patients with diabetes include low growth factor production, impaired angiogenic responses, macrophage dysfunction, decreased collagen accumulation, and reduced fibroblast migration and proliferation^10,14,15.

Generally, wound healing process consists of four stages: homeostasis, inflammation, proliferation, and remodeling^16-19. The wound healing is influenced by both local and systemic factors, such as venous sufficiency, infection, and ischemia^20-22. In diabetes patients, the wound healing process is delayed by three mechanisms, namely neuropathy, vasculopathy, and impaired immunity (Figure 1). These conditions are associated with chronic foot ulceration through the hexosamine biosynthesis, glycosylation, and polyol pathways, which induce the mitochondria to overproduce reactive oxygen species²³, resulting in cellular damage due to oxidative stress and subsequent delayed tissue repair.

Figure 1: Wound healing process in diabetic patients.

Hyperglycemia disrupts glycolysis intermediates and activates the hexosamine biosynthesis pathway to metabolize glucose and the end product N-acetylglucosamine²⁴, which can modulate transcription by binding to the serine and threonine residues of transcription factors via O-linkages. This mechanism reduces the production of nicotinamide adenine dinucleotide phosphate and increases the production of reactive oxygen species²⁵. Moreover, hyperglycaemia induces glycosylation and increased production of end products, which cause cytogenic dysfunction and inflammation by crosslinking to proteins and binding to cellular receptors²⁶. In addition, hyperglycaemia-induced activation of the polyol pathway stimulates aldose reductase to convert glucose into sorbitol, which indirectly elevates the production of sorbitol dehydrogenase²⁷, an enzyme that converts sorbitol into fructose. The deposition of sorbitol and fructose in nerve cells will interfere with myo-inositol transport, leading to neuropathy^28-29. Reductions in nerve growth factors associated with neuropathy delay wound healing by impairing vasodilation via axon reflexes³⁰.

Besides, hyperglycaemia induces oxidative stress, which has been proposed to regulate inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity³¹. DDAH promotes cell migration through protein kinase A and maintains nitric oxide (NO) production, which can increase blood flow to sites of injury during the inflammation and proliferation phases^32-33. Inhibition of DDAH activity will elevate asymmetric dimethylarginine, an inhibitor of nitric oxide synthase. Low levels of NO delay vasodilation, angiogenesis, and functioning of platelets and immune cells³⁴. Hyperglycaemia also promotes ischemia by enhancing protein kinase C activity³⁵, which can influence the thickening of the arterial wall. Therefore, oxidative stress and ischemia can lead to peripheral vascular disease, neuropathy, and DFU development²⁴.

Polysaccharide-Based Formulations in Promoting Diabetic Wound Healing:

Polysaccharides are obtained from animal, plant, and microbial sources. There are two types of polysaccharides, which are homoglycans and heteroglycans. Homoglycans are composed of repeating units of monosaccharides connected by glycosidic bonds. Cellulose and dextrin are homopolysaccharides that consist of linear chains of repeating D-glucopyranose units connected by different glycosidic bonds. In contrast, heteroglycans are polysaccharides composed of more than one type of monosaccharide unit. For example, hyaluronic acid (HA) is a heteroglycan composed of repeating units of N-acetyl glucosamine and glucuronic acid. Figure 2 summarizes the strategies used in polysaccharide-based formulations for treating diabetic wounds.

Figure 2: Strategies using polysaccharide-based formulations for the treatment of diabetic wounds.

Cellulose-based formulations:

Cellulose is synthesized by plants and produced by some bacteria, including Acetobacter xylinum. The derivatives of cellulose, which include hydroxylpropyl methylcellulose, microcrystalline cellulose, and carboxymethyl cellulose (CMC), are widely applied in the pharmaceutical field as biocompatible, minimally toxic, and cost-effective materials^36-37.

Cellulose-based hydrogels are prepared by crosslinking of polymeric networks with citric acid. These formulations have high water-holding capacities to absorb excess exudates and maintain a moist environment around the wound to promote healing³⁸. In addition, cellulose-based hydrogels can increase the proliferation and migration of inflammatory immune cells, such as neutrophils and macrophages, which adhere to fibrin scaffolds^39–41. Neutrophils phagocytize cellular debris and promote wound decontamination to minimize the risk of infection³⁹. Besides, cellulose-based wound dressings can promote recovery of mechanical properties due to the unique supramolecular structure cellulose microfibrils, which are held together by hydrogen bonds that act as auxiliary crosslinking points that strengthen the polymer matrix^37,42. Good mechanical properties are essential for wound healing devices used to promote physical protection of the wound.

Koivuniemi et al.⁴³ conducted a prospective, single-center, clinical trial to evaluate the effectiveness of a nanofibrillar cellulose (NFC) hydrogel against polylactide-based copolymer dressings (Figure 3). The outcomes of skin grafts were evaluated at 1 and 6 months after surgery. The study concluded that the wound healing performance of the NFC hydrogel was comparable to that of the polylactide-based copolymer dressings, while skin elasticity and scar appearance were improved with a lower degree of pain reported by the patients.

Figure 3: The NFC dressing detachment from donor site. (A) It was removed without breaking the newly formed skin. (B) The epithelialized skin graft donor site after NFC dressing. (Adapted from Koivuniemi et al. ⁴³)

Nanotechnology-based formulations are promising systems for topical and transdermal drug delivery. Singla et al.⁴⁴ developed a nanobiocomposite hydrogel from bamboo cellulose nanocrystals impregnated with silver nanoparticles, which was formulated as an ointment and tested for the ability to accelerate the healing of full-thickness circular cutaneous wounds using a Swiss albino mouse model of streptozotocin-induced diabetes. The treated mice exhibited a greater degree of diabetic wound closure within 18 days as compared to the control groups, with significant decreases in the expression levels of several pro-inflammatory cytokines. In addition, they increased collagen production and various growth factors, which resulted in reduced inflammation plus enhanced re-epithelialization, vasculogenesis, and collagen deposition compared to the control groups.

Cellulose-based formulations are effective for DFU treatment. Piaggesi et al.⁴⁵ reported that as compared to conventional saline gauze dressings, sodium CMC was more effective for healing a DFU deeper than 1 cm within 3 weeks and shortened the healing time, increased the reduction of lesion volume, and increased the granulation tissue rate at 8 weeks. CMC films are pH-sensitive, allowing for the incorporation of controlled-release systems with wound dressings. The carboxyl group of sodium CMC is ionized at alkaline pH, which increases the pressure of a polymeric system and accelerates the swelling rate⁴⁶. A controlled-release formulation can enhance patient compliance with medication regimens by minimizing the frequency of transdermal administration to the wound. CMC-based films also maintain a moist environment around the wound, promoting tissue granulation growth, absorbing wound exudate through ion exchange⁴⁷, and accelerating inflammatory cell aggregation, re-epithelization, and wound closure.

Furthermore, cellulose can be crosslinked with alginate as an alternative wound dressing for the treatment of chronic DFU. El-Ghoul and Alminderej⁴⁸ designed a plant polysaccharide-based formulation by crosslinking alginate and a bioactive polysaccharide extracted from Carthamus tinctorius. The polymer was then grafted into a cellulose dressing, producing a woven cellulosic textile, which was evaluated by a damping and tensile strength study. This formulation was also tested against bacterial suspensions of the Gram-positive species Micrococcus luteus and S. aureus, and the Gram-negative species P. aeruginosa and E. coli. The woven alginate/bioactive polysaccharide textile had a good antibacterial effect, great hydrophilicity, and relatively high tensile strength. Hydrophilicity is vital to absorb exudate while promoting rapid tissue regeneration for wound healing. In addition, cellulose fibers are effective against Gram-negative and -positive bacteria. The anti-microbial effect of cellulose fibers minimizes the risk of infection, which can aggravate a DFU and lead to amputation. Furthermore, this grafting method provided better cell viability with no toxicity induced to the living cells.

Cellulose can be crosslinked with chitosan to produce a hybrid sponge formulation with a porous structure to absorb wound exudate. The hybrid sponge is non-toxic and promotes blood coagulation, which is essential in wound healing to protect against excessive blood loss. The cellulose-chitosan hybrid sponge had a lower blood clotting index than cellulose alone, indicating better clotting efficiency. However, diabetes mellitus is associated with plaque formation within blood vessels. Therefore, this treatment strategy must be continuously assessed to monitor the adverse effects.

HA-based formulations:

HA is a linear hydrophilic polysaccharide composed of disaccharide repeats of glucuronic acid and acetyl glucosamine, which help in the formation of direct continuous disaccharide structures called glycosaminoglycans. HA obtained from both animal and microbial sources interact with components essential to wound healing and undergo stretched random coil transformation as it has a high density of negative charges along the polymer chain that facilitates cell migration⁴⁹. Moreover, HA is highly hydrophilic due to the abundance of carboxyl and hydroxyl groups. These features allow HA to absorb exudate and enhance cell adhesion⁵⁰.

Ferraro et al.⁵¹ engineered a naked plasmid injection system for intradermal delivery of vascular endothelial growth factor (VEGF), which plays an important role in initiating angiogenesis. This formulation improved the healing of skin flaps through electroporation using a rat model of diabetes. VEGF improves skin regeneration locally and systemically by promoting the up-regulation of growth factors involved in tissue repair and enhances the mobilization of bone marrow-derived progenitor cells that contribute to the formation of new blood vessels in diabetic wounds⁵². Tokatlian et al.⁵³ produced a porous hydrogel using acrylated HA for local delivery of VEGF-carrying plasmids that were tested for healing of full-thickness wounds in diabetic rats. The pores allow the hydrogel system to increase the cell infiltration rate to promote the wound healing process. The infiltration of neutrophils and macrophages is essential to the inflammation phase of the tissue repair process. Neutrophils tend to produce proteases that disrupt the damaged extracellular matrix (ECM), thereby promoting the formation of new tissue to accelerate wound closure. However, excessive protease activities can interfere with the balance between tissue disruption and tissue regeneration⁵⁴, which favors degradation of the newly formed ECM, resulting in impaired wound healing. Macrophages are inflammatory cells that produce high amounts of cytokine mediators, such as interleukin (IL)-2 and tumor necrosis factor-α⁴⁰. IL-2 plays a major role in the secretion of growth factors and cytokines, such as interferon (IFN)-α. The combination of IL-2 and IFN-α accelerates the proliferation of endothelial cells and angiogenesis at the wound site⁵⁵. Macrophages produce chemo-attractants, such as monocyte chemoattractant protein 1, and chemokines, including IL-8, which promote angiogenesis via leucocyte migration from the intravascular compartment to sites of injury⁵⁶.

The phenotype of macrophages is influenced by the wound microenvironment. It evolves during the healing process from the pro-inflammatory (M1) phenotype in the early stages of wound repair to the less inflammatory pro-healing (M2) phenotype in the later stages. Liu et al.⁵⁷ produced a high-molecular-weight HA/polyvinyl alcohol hydrogel dressing by crosslinking high-molecular-weight HA (1400 kDa) with copper ions (Cu²⁺) associated with poly (vinyl alcohol) and tested the dressing on full-thickness wounds of diabetic C57BL/6 mice. Activated macrophages were incorporated into the hydrogel and directly delivered to the wound site. This hydrogel-based formulation had a synergistic effect on diabetic wound healing⁵⁷, as the high-molecular-weight HA stimulated an anti-inflammatory response⁵⁸ that can protect against reactive oxygen species⁵⁹.

In addition, Hsu et al.⁶⁰ developed biodegradable gelatin-based hydrogels with and without HA to evaluate the efficacy of sustained release of human recombinant thrombomodulin (rhTM) to treat diabetic wounds. The results showed that the rhTM-loaded hydrogel with 0.1% HA had significantly accelerated wound healing as compared to the rhTM hydrogel without 0.1% HA, demonstrating that the addition of HA to the hydrogel had a synergistic healing effect. The study concluded that the crosslinked gelatin/HA hydrogel was an effective system for topical delivery of rhTM to promote wound healing.

Alginate-based formulations:

Alginate is composed of guluronic acid and mannuronic acid linked by 1–4 glycosidic bonds. Alginate is a structural component of marine brown algae and a capsular polysaccharide of some bacteria, such as P. aeruginosa⁶¹ and Azotobacter vinelandii⁶². The gelling property of alginate, which is due to the interactions of divalent cations with the alginate structure, aids in the removal of wound dressings while avoiding injury and reducing pain intensity ¹³. Calcium ions assume an egg-box conformation when crosslinked with the carboxylate group of alginate, which elicits an excellent gelling effect⁶³. However, the presence of sodium ions in the wound exudate must be considered in the alginate gelling process.

The calcium ions of alginate fibers are displaced with sodium ions of the exudate through an ion-exchange mechanism. The release of active substances from a calcium alginate hydrogel is also affected by the replacement of sodium ions of physiological fluids with calcium ions of the hydrogel matrix⁶⁴. As the hydrogel interacts with water, the alginate becomes a soft gel that absorbs the wound exudate, which leads to the formation of a gel matrix within the formulation network. The addition of glycerol to an alginate-based wound dressing decreases the porosity of the hydrogel by enhancing the viscosity of the formulation⁶⁵. Alginate can also promote angiogenesis and cell migration while reducing the concentration of pro-inflammatory cytokines at the wound site, thereby facilitating the wound healing process⁶⁶.

Park et al.⁶⁷ prepared an alginate oligosaccharide formulation by treating sodium alginate with alginate lyase, which was shown to inhibit the synthesis of matrix metalloproteinase-1 (MMP-1) by Hs27 human dermal fibroblasts. This formulation also increased the expression of tissue inhibitors of metalloproteinase-1 (TIMP-1). MMP-1 degrades collagens I and III, which directly disrupts ECM formation⁶⁷, thereby impairing wound healing in diabetes patients. The MMP-1/TIMP-1 ratio is a predictor of tissue repair in DFU. An imbalance in the MMP-1/TIMP-1 ratio has been associated with impaired skin repair of diabetic wounds. Excessive MMP-1 and decreased TIMP-1 in diabetes lead to disorganization of the ECM and high exudate formation. High MMP-1 levels also interfere with the collagen I/III ratio.

Wang et al.⁶⁸ compared the effectiveness of calcium alginate dressing with a petroleum jelly (Vaseline) dressing for healing of full-thickness wounds of streptozotocin-induced diabetic Sprague Dawley rats. The calcium alginate dressing was found to accelerate wound closure by increasing the collagen I/III ratio. Lower collagen I/III ratio impairs wound healing as the amount of collagen III is greater than collagen I. Collagen III has been shown to give rise to an unorganized structure of the ECM and increase scar formation. Collagen I, as the major contributor to skin regeneration, plays an important role in the structural formation and tensile strength of the ECM to minimize the risk of tissue rupture⁶⁸. Hyperglycaemia alters glomerular filtration by hyperfiltration of glucose, which could induce diabetic nephropathy. Impaired glomerular filtration in diabetes patients also leads to excessive excretion of hydroxyproline, which is a major component of collagen that stabilizes the helical structure. Low hydroxyproline levels have been associated with inhibition of the wound healing process in diabetes mellitus. Calcium alginate was reported to increase hydroxyproline production in diabetic rats on treatment day 3 and produced high-quality ECM that promoted wound healing. Synthesis and deposition of collagen I are required for the formation of new skin tissue and can improve the organization of the ECM⁶⁸.

Xie et al.⁶⁹ developed composite sponges by crosslinking quaternized cellulose and sodium alginate with Zn⁺² to promote the healing of infected wounds. The composite sponges were produced at ratios of quaternized cellulose to sodium alginate of 1:0.3, 1:0.4, 1:0.5, 1:0.7, and 1:1 (QS-0.3, QS-0.4, QS-0.5, QS-0.7, and QS-1, respectively) with a constant proportion of alginate to ZnCl₂of 5:1 (w/w). The QS-1 composite had good water absorption capacities, excellent antibacterial properties, and remarkable biocompatibility. Thus, the QS-1 composite was chosen for in vivo evaluation of wound healing of three groups: an uninfected (control) group, an E. coli infection group, and an S. aureus infection group. The results demonstrated that the QS-1 composite achieved a smaller wound size than gauze dressings on treatment day 6 and accelerated wound closure on treatment day 12 in all groups. The wound healing process was evaluated by haematoxylin and eosin staining. Inflammatory cells were observed in all infected groups. On treatment day 6, the QS-1 group had fewer inflammatory cells, less tissue debris, and a higher content of fibroblasts than the gauze groups due to the antibacterial properties of the QS-1 composite. On treatment day 12, the QS-1 composite improved epithelial regeneration, with more ordered connective tissues and fibroblasts as compared to the gauze dressing in the infection and control groups. These results indicated the superior potential of quaternized cellulose/sodium alginate/Zn⁺² composite sponges for healing of infected wounds.

Miscellaneous:

Polysaccharides can also be obtained from Ganoderma lucidum mushrooms native to Japan and China, as well as other tropical countries. Cheng et al.⁷⁰ evaluated the wound healing effect of topical aqueous creams containing various concentrations of a hot aqueous extract of G. lucidum on streptozotocin-induced diabetic rats. The results showed that polysaccharide-rich (25.1%, w/w) hot aqueous extracts of G. lucidum enhanced the in vivo antioxidant levels and ameliorated oxidative damage during the wound healing process in diabetic rats. Lower amounts of antioxidants in diabetic wounds generally impair skin repair due to the presence of free radicals, which damage the cell membrane, DNA, and ECM. Additionally, the G. lucidum cream promoted the infiltration of macrophages into the wound site. Macrophages play an essential role in the wound healing process by promoting wound closure, phagocytosis of pathogens, and the production of proteolytic enzymes.

Prolonged inflammation and delayed cell proliferation in diabetic wounds impair collagen synthesis, which is needed for the formation of new ECM. Delayed production of collagen can promote the development of chronic diabetic wounds. A study of composite hydrogels containing polysaccharides derived from herbal residues of Periplaneta americana together with carbomer 940 and CMC prepared by a physical crosslinking method enhanced diabetic wound healing in rats by accelerating wound closure, re-epithelialization, collagen production and accumulation, angiogenesis, and macrophage polarization, while reducing inflammation³⁸.

Ponrasu et al.⁷¹ prepared hydrogel scaffolds formulated from a combination of psyllium seed husk-derived polysaccharides and human hair-derived keratin crosslinked with sodium trimetaphosphate loaded with morin, a flavonol with excellent antioxidant properties. An in vivo wound healing study using diabetic rats treated with the scaffold showed significant improvement in the rate of re-epithelialization and wound contraction by expediting collagen synthesis in diabetic rats as compared to the control groups. Table 1 summarizes the applications of polysaccharide-based formulations for the treatment of diabetic wounds.

Table 1. Utilization of polysaccharide-based formulations for the treatment of diabetic wounds

Dosage form	Active ingredient	Significant outcomes	Ref.
Nanofibrillar cellulose (NFC) hydrogel	-	i) Wound healing performance of the NFC hydrogel was comparable to polylactide-based copolymer dressings. ii) Skin elasticity and scar appearance improved with a lower degree of pain.	43
Nanobiocomposite hydrogel from bamboo cellulose nanocrystals	Silver nanoparticles	A greater degree of wound closure, reduced inflammation, and enhanced re-epithelialization, vasculogenesis, and collagen deposition when compared to control groups.	44
Carboxymethyl cellulose (CMC) films	-	Allows for the incorporation of controlled-release systems with wound dressings.	45
Cellulose dressing (crosslinking of alginate and bioactive polysaccharide extracted from Carthamus tinctorius)	-	Good antibacterial effect, great hydrophilicity, and relatively high tensile strength.	48
Acrylated hyaluronic acid (HA) hydrogel	Vascular endothelial growth factor (VEGF)	The pores allow the hydrogel system to increase the cell infiltration rate to promote the wound healing process.	53
High-molecular-weight HA/polyvinyl alcohol hydrogel	Activated macrophages	This hydrogel-based formulation had a synergistic effect on diabetic wound healing, as the high-molecular-weight HA stimulated an anti-inflammatory response that can protect against the effects of reactive oxygen species.	57
Crosslinked gelatin-based hydrogels with and without HA	Human recombinant thrombomodulin (rhTM)	rhTM-loaded hydrogel with 0.1% HA had significantly accelerated wound healing as compared to the rhTM hydrogel without 0.1% HA.	60
Alginate oligosaccharide	-	Inhibit the synthesis of matrix metalloproteinase-1 (MMP-1) by Hs27 human dermal fibroblasts.	67
Calcium alginate dressing	-	Increase hydroxyproline production in diabetic rats on treatment day 3 and produced high-quality extracellular matrix (ECM) that promoted wound healing.	68
Composite sponges of quaternized cellulose and sodium alginate	Zn⁺²	Improved epithelial regeneration, with more ordered connective tissues and fibroblasts as compared to the gauze dressing in the infection and control groups.	69
Aqueous creams containing various concentrations of a hot aqueous extract of G. lucidum	-	Polysaccharide-rich (25.1%, w/w) hot aqueous extracts of G. lucidum enhanced the in vivo antioxidant levels and ameliorated oxidative damage during the wound healing process in diabetic rats.	70
Composite hydrogels of polysaccharides derived from herbal residues of Periplaneta americana together with carbomer 940 and CMC	-	Enhanced diabetic wound healing in rats by accelerating wound closure, re-epithelialization, collagen production and accumulation, angiogenesis, and macrophage polarization, while reducing inflammation.	38
Hydrogel scaffolds formulated from a combination of psyllium seed husk-derived polysaccharides and human hair-derived keratin crosslinked with sodium trimetaphosphate	Morin	Significant improvement in the rate of re-epithelialization and wound contraction by expediting collagen synthesis in diabetic rats as compared to the control groups.	71

CONCLUSIONS:

Impaired wound healing is a common problem among individuals with diabetes, resulting in the development of chronic wounds and diabetic foot ulcers (DFU). Polysaccharide-based drug formulations have gained significant attention as wound dressings for promoting wound healing in recent years. Polysaccharides possess the capacity to be developed into diverse materials such as hydrogels, films, fibers, emulsions, and nanoparticles. Moist environments are known to facilitate re-epithelialization, cell infiltration to the wound site, and angiogenesis, while concurrently mitigating the risk of infection owing to the anti-microbial properties they possess. The development of polysaccharide-based formulations entails the incorporation of drugs, active constituents, and growth factors. These formulations present exciting possibilities for the management of wounds in individuals with diabetes, potentially leading to an improvement in the overall well-being of diabetic patients.

CONFLICTS OF INTEREST:

The authors declare no conflicts of interest.

ACKNOWLEDGEMENTS:

The authors would like to express gratitude to the Universiti Teknologi MARA, Malaysia for the financial support [600-RMC/GPK 5/3 (198/2020)].

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Received on 15.08.2022 Modified on 19.10.2022

Research J. Pharm. and Tech 2023; 16(6):2835-2842.

DOI: 10.52711/0974-360X.2023.00467