Phytosomes: An Ideal way to Enhance Bioavailability of Mangiferin

 

Rana Zainuddin¹, Geeta P. Darekar²

¹Associate Professor, Department of Quality Assurance, Y. B. Chavan College of Pharmacy,

Rauza Bagh, Aurangabad - 431001, Maharashtra, India.

²Y. B. Chavan College of Pharmacy, Rauza Bagh, Aurangabad - 431001, Maharashtra, India.

 

ABSTRACT:

Today, one of the most challenging public health issues is diabetes mellitus. Despite the availability of therapeutic medications, they exhibit several limitations. Given the escalating prevalence and fatality rates, there is a pressing need for more potent therapeutic drugs in clinical treatment. Mangiferin, a polyphenol and natural substance, offers a wide array of beneficial pharmacological properties. However, its applicability in research and clinical settings is hampered by its membership in the BCS class IV due to weak water solubility, poor fat solubility, and low bioavailability. Addressing these limitations is crucial. Our comprehensive review delves into strategies for enhancing mangiferin's solubility by modifying its dosage form. Additionally, we highlight preliminary findings, aiming to provide a valuable roadmap for the future application of mangiferin in diabetes management. It is conceivable that in the near future, mangiferin could serve as an adjuvant medication for diabetes mellitus treatment and its associated complications.

 

 

 

INTRODUCTION:

Diabetes stands as a worldwide health concern characterized by elevated blood glucose levels resulting from insufficient insulin production. As a metabolic disorder, it lacks a definitive cure, yet effective management can empower diabetic patients to lead normal lives. Typically, individuals afflicted with diabetes rely on a daily regimen of anti-diabetic medications^1. However, such therapies often involve multiple drugs, potentially leading to additional health complications².

 

In this context, it becomes imperative to shift our focus towards herbal alternatives for diabetes management, aiming to mitigate the undesired effects associated with conventional anti-diabetic medications³. Hailing from the regions of South and Southeast Asia, Mangifera indica L., a noteworthy fruit, belongs to the Anacardiaceae family. Countries like India, Bangladesh, Indonesia, Thailand, Pakistan, China, Mexico, and the Philippines are prominent cultivators of mango, highlighting its significance. Within the mango species, a rich composition of compounds is found, including mangiferin, phenolic acids, benzophenones, as well as antioxidants like flavonoids, vitamin C, tocopherols, and carotenoids^4,5.

 

The therapeutic potential of mango leaf extracts has been explored extensively, revealing anti-diabetic, anti-oxidant, anti-microbial, anti-cancer, anti-obesity, lipid-lowering, anti-diarrheal, and hepatoprotective   properties^6,7. Among these, mangiferin, a naturally occurring yellow crystalline glucoxilxanthone, has been comprehensively investigated for its biological and therapeutic applications⁸. Research by Lum PT et al and Walia V et al has documented its distribution across 19 families, 28 genera, and 96 species of angiospermic plants^9,10. However, it is the Anacardiaceae family's Mangifera Indica (mango) plant that serves as the primary and original source of mangiferin, with nearly all parts of the mango plant containing significant levels of this compound¹¹.

 

Fig 1: Structure of mangifrerin

 

Mangiferin, classified as a C-glucoside, predominantly originates from various parts of the mango tree, with leaves being a prominent source (fig. 1.)¹⁰. Displaying a spectrum of therapeutic and preventive attributes, mangiferin exhibits antibacterial, antioxidative, antiallergic, anti-inflammatory, neuroprotective, and cognition-enhancing properties¹⁰. Its water solubility facilitates extraction into infusions and decoctions, thus prompting numerous investigations into its potential health advantages. Notably, recent findings highlight mangiferin's efficacy in addressing diabetes and its associated complications. Particularly for type 2 diabetes mellitus, mangiferin emerges as a beneficial phytochemical due to its capacity to normalize adipokine levels, enhance lipid profiles, and improve insulin sensitivity¹¹.

 

Some studies of mangiferin:

Mangifera indica L., a fruit of significant importance from South and Southeast Asia, belongs to the Anacardiaceae family¹⁰. Prominent mango cultivators include countries such as India, Bangladesh, Indonesia, Thailand, Pakistan, China, Mexico, and the Philippines¹⁰. The mango species contains diverse compounds, including mangiferin, phenolic acids, benzophenones, flavonoids, vitamin C, tocopherols, and carotenoids^4,5. This natural composition has led to the exploration of mangiferin's therapeutic applications, revealing its anti-diabetic, anti-oxidant, anti-microbial, anti-cancer, anti-obesity, lipid-lowering, anti-diarrheal, and hepatoprotective properties^6,7.

 

Efforts to enhance mangiferin's solubility have resulted in significant breakthroughs. Pleguezuelos-Villa M demonstrated an 80-fold increase in mangiferin solubility through the preparation of its nanoemulsion¹². Furthermore, microencapsulation techniques employing polymers through spray-drying were utilized, and the presence of polysaccharides in formulations was confirmed via FTIR, along with the characteristic absorption bands of bioactive mangiferin¹³. By encapsulating mangiferin within glycethosomes, a viscous vesicular form, its retention in the epidermis was optimized, offering a sustained release mechanism and efficacy against oxidative stress in fibroblasts¹⁴.

 

In the realm of ocular applications, a novel delivery system for mangiferin was introduced by Liu R et al. This nanostructured lipid carriers approach exhibited favorable characteristics including appropriate particle size, sustained release, stability during storage, improved corneal permeability, high ophthalmic tolerability, and prolonged retention, suggesting its potential to enhance mangiferin's ocular bioavailability and safety profile¹⁵.

 

Another innovative avenue explored the utilization of Box-Behnken design to develop a transdermal delivery system named Mangiferin loaded Nanotransethosomes. This formulation exhibited enhanced anti-rheumatic activity compared to traditional routes, indicating improved skin permeation and in-vitro release¹⁶.

 

Switching focus to diabetes, hyperglycemia, a hallmark of the condition, arises from various factors including excess carbohydrate intake, increased glucose synthesis, and insufficient glucose disposal. Mangiferin's potential in addressing diabetes lies in its ability to enhance GLUT4 levels, promoting glucose uptake in various cell types¹⁷. Notably, MGF's activation of AMPK contributes to GLUT4 expression and glucose uptake. Moreover, MGF activation extends to enzymes involved in glycogen production and glycolysis¹⁸. The intricate balance of these pathways can influence glucose homeostasis, making mangiferin an intriguing candidate for diabetes management.

 

Despite its therapeutic promise, mangiferin faces challenges due to its low solubility and bioavailability. This limitation is evident in its modest oral bioavailability of 1.2%²². Nonetheless, its multifaceted protective effects in diabetic conditions and related complications have been widely observed^20,21.

 

Collectively, the wide range of pharmacological actions displayed by mangiferin underscores its potential, despite current limitations that hinder its clinical application. This potential is further demonstrated by its protective effects against diabetic complications, as summarized in Table 1.

 

Sr. No.	Action of mangiferin	Reference
1	In a recent study, the efficacy of mangiferin medication was investigated in diabetic mice induced by streptozotocin (STZ). The experimental protocol involved administering a daily dose of 40 mg/kg mangiferin for a span of 30 days, during which observations were meticulously recorded. Notably, the diabetic mice subjected to the mangiferin treatment exhibited marked improvements. Specifically, their blood sugar levels, glycosylated hemoglobin levels, as well as markers of liver function including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), were significantly lower when compared to the diabetic control mice. These findings suggest a potential therapeutic benefit of mangiferin in mitigating various aspects of diabetic complications in this experimental model.	24,25
2	In a conducted study, mangiferin exhibited the capacity to address multiple aspects of diabetes-associated issues simultaneously. The research focused on a rat model induced with insulin resistance through a high fat, high fructose diet combined with streptozotocin (STZ). The outcomes of the study revealed that mangiferin intervention led to a reduction in insulin resistance, while also bolstering cellular functionality. Notably, there were substantial reductions observed in the levels of serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), along with an improvement in the atherogenic index. Furthermore, mangiferin exhibited its efficacy by lowering liver triglyceride (TG) and total cholesterol (TC) content, while simultaneously increasing liver glycogen content. These comprehensive findings suggest that mangiferin holds the potential to enhance insulin responsiveness, making it a promising candidate for the management of type 2 diabetes (T2D) alongside addressing gastrointestinal insufficiencies.	26,27
3	In a rat model of nephropathy induced by streptozotocin (STZ), mangiferin was administered as a treatment. The outcomes of this intervention demonstrated notable improvements. Specifically, there was a significant decrease in plasma glucose, uric acid, and creatinine levels. Additionally, indicators such as kidney-to-body weight ratio and blood urea nitrogen exhibited reductions as well. These findings collectively indicate the effectiveness of mangiferin in managing type 2 diabetes (T2D) and its associated complications, particularly in the context of nephropathy.	28
4	An animal experiment performed to observe effect of mangiferin. In this STZ‑induced diabetic nephropathy rat model taken by author. the model treated with mangiferin for 9 weeks orally targeting glyoxalase. It resulted in reduction in albuminuria, periodic acid‑Schiff stain positive mesangial matrix area, kidney weight index, BUN, glomerular extracellular matrix expansion and accumulation and glomerular basement membrane thickness. Blood glucose found to be unchanged in this study.	29
5	In a study, mangiferin demonstrated effective treatment of renal fibrosis by inhibiting excessive osteopontin production and inflammation in a rat diabetic model induced by streptozotocin (STZ).	30
6	A study revealed that the oxidative stress and inflammation induced by hyperglycemia, which are believed to be linked to cardiovascular disease, can be effectively managed by mangiferin.	31
7	According to a study chronic treatment with mangiferin20 mg/kg of weigh of body administered (16 weeks) found decrease in the creatine kinase‑MB and lactate dehydrogenase and tumor necrosis factor α and interleukin (IL)‑1β in the blood serum and left ventricular myocar­dium.	32
8	Mangiferin (dose of 60 mg/kg) by oral gavage for 12 weeks found to inhibit JNK, inositol required enzyme 1, apoptotic signal regulating kinase, and blood glucose levels in a STZ induced diabetic rat model.	33
9	The chronic treatment of mangiferin for 14 days in a streptozotocin (STZ) paradigm considerably and noticeably increased oral glucose tolerance in glucose-loaded normal rats, presenting its powerful glucoselowering effect.	34
10	In a study mangiferin (10 and 20 mg/kg, by intraperitoneal route.) in STZ-diabetic ratsshows the better in oral glucose tolerance. However, this experiment did not show the state of hypoglycemia.	35
11	As per a study mangiferin produces effect on insulin resistance by enhancing insulin sensitivity and glucose uptake, and the possible mechanism is that mangiferin promotes free fatty acid catabolism by promoting the enzymes forfree fatty acid utilization and oxidation by the PPARα signaling pathway.	36
12	Mangiferin showed protective effect in Gestational diabetes mellitusmice by reducing oxidative stress, inflammationand Endoplasmic Reticulumstress in GDM mice, signifyingthis phytochemical can be used to manage GDM.	37

 

Phytosomes:

This method involves the preparation of lipid-compatible phytochemicals utilizing specific phospholipids^38,39. Phytosomes, a patented technology, serve as encapsulation systems for phytochemicals, offering an avenue for enhanced absorption and bioavailability⁴⁰. Exhibiting a structure akin to liposomes, phytosomes represent cutting-edge lipid-based delivery mechanisms that have the capability to incorporate diverse phytoconstituents, particularly those with polyphenolic bases, thereby augmenting their absorption potential. In the late 1980s, Indena pioneered the formulation of the first phytosomes, leveraging phospholipids to achieve improved bioavailability^41,42.

 

The process involves integrating standardized polyphenolic plant extracts into phospholipids, predominantly phosphatidylcholine (PC), resulting in the formation of phytosome structures. In non-polar solvents, the phosphate group of the phospholipid matrix interacts with the polyphenolic moiety of the herbal extract through hydrogen bonding, giving rise to the lipid vesicles that constitute phytosomes. The lipophilic tail of phospholipids, such as phosphatidyl, exhibits an affinity for the water-soluble polyphenolic rings found in phytochemicals like flavonoids and terpenoids. These components chemically bond to create the core of phytosomes. The lipophobic portion of phospholipids, such as choline, forms a bond with the phytochemicals, incorporating them into the structure.^43,44,45.

 

Numerous studies have demonstrated the enhanced bioavailability of anti-diabetic compounds through phytosomes. For instance, phytosomes of berberine exhibited improved anti-diabetic efficacy⁴⁶ Similarly, the preparation of phytosomes of naringin with polymers like chitosan and casein led to a two to fivefold increase in absorption, resulting in heightened antidiabetic effects⁴⁷. Furthermore, the formulation of phytosomes using soy lecithin for M. koenigii extract showcased elevated bioavailability in animal studies, showcasing potential for both antidiabetic and hypolipidemic applications⁴⁸. Phytosomes of Rutin, developed with phospholipids, displayed significant antidiabetic activity in animal studies, with notable reductions in blood glucose levels and restoration of altered lipid parameters compared to Rutin alone⁴⁹. Additionally, successful formulation of phytosomes of Casuarinaequisetifolia extract with soy lecithin demonstrated promising results, exhibiting good entrapment efficiency and stable physico-chemical characteristics⁵⁰.

 

Phytosomes containing Syzygiumcumini extract, along with cholesterol and lecithin, demonstrated a notable reduction in blood glucose levels in a dose-dependent manner in streptozotocin (STZ) induced diabetic rats. This outcome underscores the efficacy of the phytosome formulation in rapidly reducing glucose levels, both in Oral Glucose Tolerance Tests and STZ-induced diabetic rat models⁵¹.

 

The emergence of phytosome nanotechnology holds the potential to overcome challenges stemming from limited lipid solubility, thereby enhancing the bioavailability of beneficial phytochemicals. This innovation is poised to influence medication administration positively. The following studies underscore the substantial role of phytosomes in elevating bioavailability and improving solubility, as outlined in Table 2.

 

Table 2: Comprehensive Investigations on Phytosomes for Augmented Bioavailability of Herbal and Other Drugs.

Sr No	Study outcome	Reference
1.	5.6-fold more AUC (26.7 μg×min/mL), 29-fold more absorption, and increase in curcumin accumulation in liver	52,53,54
2.	Curcuminnaringenin phytosomes showedmore antioxidant activity and more duration of action.	55,56,57
3.	According to a research of Islam et al the polyphenolicphyto-constituent silymarin's solubility, absorption, oral bioavailability, and in vivo hepatoprotective action may all be enhanced by amphiphilic phospholipid-based phytosomes. The results found increased systemic bioavailability of silymarin as compared to pure silymarin indicates better silymarin oral bioavailability.	58
4.	When compared to the pure drug solution, the designed phytosome formulations containing piperine significantly increased the oral bioavailability of domperidone (79.5%).	59
5.	According to a study phytosome of cardamomumshowed 71% capacity to get entrapped. This species showed improved antioxidant and antimicrobial activities as compared to it crude extract. Phytosomes had higher (46%) ACE inhibitory efficacy than crude extract (39%).	60
6.	A study shows that phytosomes gives enhancedtherapeutic activity of traditional herbal extracts of fruits of Citrulluscolocynthis (L.) Momordicabalsamina and Momordicadioica	61
7.	According to a study Phytosomes of Berberine demonstrated good drug entrapment effectiveness (85%), particle in nanometer range, and a negative surface charge. The bioavailability of the Phytosome-Berberinewas dramatically increased by three times when compared to the administered berberine in earlier pharmacokinetic investigations (orally).	62
8.	Ginsenoside's improved relative bioavailability (157.94%) was demonstrated in a study using phytosomes. Additionally, it demonstrated a stronger neuroprotective potential by significantly (p 0.05) raising the nociceptive threshold.	63
9.	In a study, the formulation of phytosomes boosted the intestinal absorption rate (Ka) of echinacoside to nearly about 3 folds and the effective permeability coefficient to 3.39 times.	64
10.	According to a study, luteolin and doxorubicin phytosomes increased the effectiveness of chemotherapy by reducing cancer cell resistance and increasing permeability to chemical agents. As a result, they may be thought of as a viable delivery mechanism to enhance treatment procedures for cancer patients.	65
11.	According to a study, a silybin and phosphatidylcholine phytosome combination significantly increases bioavailability in dogs.	66
12.	The oral bioavailability of the substance was enhanced by the lipid-coated nanocrystal formulation (phytosome) in research, which also showed higher area under the curve for trans-resveratrol.	67
13.	In a study, Hedyotiscorymbosa extract (HCE) phytosomes increased the bioavailability of the main chemical ingredient Hedycoryside -A (HCA), which improved the extract's therapeutic effectiveness in the management of neuropathic pain.	68
14.	In research, Tecomellaundulata phytosomes with unilemellar vesicles, high drug entrapment efficiency was effectively generated. The outcomes demonstrated that phytosomes can increase bioavailability without using pharmacological adjuvants or altering the structural properties of the components.	69
15.	Formononetin phytosome may significantly lower hepatic metabolism and improved free concentration, hence increasing bioavailability for medicinal application by oral route.	70
16.	In a study, Boswellic acid phytosomes showed increased anti-inflammatory efficacy and significantly improved skin absorption of the BA-phytosomes combination.	71
17.	A research found that Celastrol (CST)-phytosome oral bioavailability was higher than that of crude Celastrol by a factor of four and five (AUC0–8, Cmax, respectively). In conclusion, the findings supported the potential of phytosomalnanocarriers to enhance CST oral administration, opening door touse in the treatment of oral cancer.	72
18.	According to a research, Diosmin could be effectively adjusted for Phytosome (99% drug loading) with better dissolving and penetration properties, this is encouraging to reduce the effect of external variables and boosting delivery of drug.	73
19.	In order to increase apigenin's water dissolution, solubility, in vivo bioavailability, and antioxidant activity, the apigenin-phospholipid phytosome was created.	74

 

CONCLUSION:

In summation, while mangiferin exhibits anti-diabetic potential, its utility is constrained by its limited solubility and inadequate bioavailability. Existing literature highlights the role of phytosome formulations in addressing these challenges, effectively enhancing solubility and bioavailability. In the present landscape, phytosomes have emerged as a compelling focus for researchers engaged in formulation development. Consequently, there is a compelling opportunity to harness the power of phytosomes to unlock the full therapeutic potential of mangiferin. By formulating mangiferin within phytosomes, its bioavailability can be elevated to unprecedented levels, paving the way for its impactful integration in diabetic management strategies.

 

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

 

ACKNOWLEDGMENTS:

The authors would like to thank Principal, Faculty and Management of Y. B. Chavan College of Pharmacy Aurangabad for their kind support during studies.

 

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Received on 08.06.2024      Revised on 10.10.2024 Accepted on 21.01.2025      Published on 05.03.2025 Available online from March 11, 2025 Res. J. Pharmacognosy and Phytochem. 2025; 17(1):38-44. DOI: 10.52711/0975-4385.2025.00007 ©AandV Publications All right reserved
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