Exploring Hibiscus rosa-sinensis Mucilage as a Natural Excipient for Sustained Metformin Release

Abstract

Diabetes mellitus affects millions of people around the globe. It occurs when the pancreas does not produce enough insulin or the cells in the body become resistant to the insulin produced. The result is elevated levels of glucose in the bloodstream (hyperglycemia). Untreated diabetes mellitus leads to serious complications such as cardiovascular disease, stroke, kidney failure, eye disease, neuropathy and amputation. Sustained-release drug delivery systems provide many benefits to patients, including: consistent therapeutic plasma levels, fewer doses per day, and increased compliance with medication regimens. Polymers derived from natural sources are becoming increasingly popular in sustained-release formulations because they have low toxicity, biocompatibility, and biodegradability, making them suitable for drug delivery. One example of a natural polymer is the mucilage (gum) from Hibiscus rosa-sinensis (H. rosa-sinensis). The mucilage has excellent swelling properties, can form a gel matrix, maintain its structural integrity and be compatible with synthetic drug delivery systems. The mucilage is easily extracted from the plant using environmentally friendly techniques, and results in a stable polymer that is hydrophilic and has a pH-tolerant capacity, making it suitable for developing controlled drug delivery systems. Drug delivery systems formed from H. rosa-sinensis will release drugs via diffusion and/or erosion, following zero-order or higuchi kinetics. Metformin was chosen as a model drug; however, the polymer has broader application potential. Studies are needed to establish standardization, develop microbial stability, and validate clinical efficacy through additional systematic studies.

1. Introduction

Being one of the most prevalent and fastest growing diseases in the world, diabetes mellitus (DM) is characterized by high blood sugar levels as a result of either not making enough insulin or not using it correctly. ¹ According to a global estimate, in 2021, approximately 537 million adults were diagnosed with diabetes and this number is expected to increase to approximately 643 million adults by the year 2030; More than half of these individuals will live in developing countries. In the case of India alone, there were over 77 million adults diagnosed with diabetes at this time, making it the second highest country in the world for diagnosed diabetes, with projections for continued increases over the next 10 years. Rapid urbanization, lifestyle changes, and limited access to preventive healthcare have all contributed to rising rates of diabetes among adults living in developing areas and suggest the need for affordable therapies that will allow patients to comply. ² The continued high blood sugar levels (hyperglycemia) observed in patients with diabetes are associated with several long-term health complications, including heart disease, kidney disease, nerve damage, eyesight loss, delayed wound healing, as well as an impaired quality of life and the economic burden these complications create; therefore, it is vital to find effective and convenient therapies that are patient orientated. ³ Figure 1. Systemic pathophysiology and multi-organ involvement in type 2 diabetes mellitus (T2DM), illustrating insulin resistance, β-cell dysfunction, chronic hyperglycemia, and their downstream effects on major organs including the pancreas, liver, skeletal muscle, adipose tissue, kidney, cardiovascular system, and nervous system.

Figure 1.

Systemic pathophysiology and organ involvement in type 2 diabetes mellitus

The first-line medication for type 2 diabetes (T2DM) is a biguanide antidiabetic drug known as metformin, which is the standard treatment for T2DM because it has shown to be effective and safe, is affordable and is a well-known drug in the medical community. ⁴ Metformin lowers blood glucose levels mainly by reducing the amount of glucose produced by the liver, increasing the sensitivity of the body’s cells to insulin, and helping to take up glucose from the bloodstream into the cells of other tissues. Even though metformin has many benefits, the way it works limits its clinical use because it has a short half-life and needs to be taken multiple times per day for a patient’s blood glucose levels to stay at therapeutic levels. ⁵ Taking a medication multiple times throughout the day can affect how patients take their medications correctly and lead to changes in blood glucose levels while managing their diabetes over a long time. ⁶

To address the limitations inherent in immediate release formulations, metformin has been investigated extensively through many years in the development and evaluation of sustained release (SR) formulations. ⁷ The primary purpose of an SR formulation is to allow for the extended release of the drug allowing for prolonged maintenance of plasma drug levels to remain within the therapeutic range of the drug over an extended period of time, thus eliminating the need to take more frequent doses of metformin during a 24 hour period. Other advantages of SR formulations include less frequent dosing, better patient adherence/compliance, less gastrointestinal adverse events associated with peak drug levels and a more stable pharmacokinetic profile than immediate release formulations. ⁸ On the other hand, the unique characteristics of SR formulations are especially useful in the treatment of chronic diseases such as diabetes mellitus that require maintenance of consistent therapeutic drug exposure for extended periods of time.

Natural polymers are receiving increased interest as excipients in the design of sustained-release formulations of drugs due to several reasons. ⁹ One is that they are renewable, biodegrade, are biocompatible (make it easier to see how they interact with the human body), and typically possess low toxicity (i.e., produce very little risk when administered). Natural polymers are well known for having the ability to hydrate, swell, and form gel-like matrices, which assist in controlling drug release via two mechanisms through diffusion and the breakdown of the matrix (erosion of the gel). Additionally, the favorable safety profile of these materials makes them particularly suitable for prolonged use in the treatment of chronic diseases. ¹⁰ An example of natural polymers may be plant-derived mucilages, which represent a robust and readily available source of pharmaceutical excipients for drug formulations, in addition to having excellent biodegradability and release-modulating characteristics.^11,12

H. rosa-sinensis often referred to as the chinese Hibiscus is a very good source of mucilage because of its favorable physical and chemical attributes for medicine including high swelling, the ability to form a film, and biocompatibility. ¹³ Mucilage from the flowers and leaves of H. rosa-sinensis has a large potential to act as a natural matrix-forming substance for prolonged drug release. Substituting non-toxic H. rosa-sinensis mucilage into metformin formulation will likely be an easier way to increase diabetes therapy results for the patient. ¹⁴

This review will critically analyse research on metformin sustained-release formulations using H. rosa-sinensis mucilage including formulation methods, release characteristics, and how natural polymeric excipients can enhance diabetes treatment in the larger context.

2. Role of Natural Polymers in Drug Delivery and Diabetes Care

Natural polymers are important components of the evolution of various drug delivery systems and diabetic patient care. They provide significant improvements over traditional and modern drug dosages by allowing for improved quality and quantity of drug release, better access to drugs through the body’s metabolic processes, and improved patient outcomes. ¹⁵ At the same time, natural polymers have been the subject of much attention, especially in terms of their benefits eco-friendliness, bio-sustainability, low risk of toxicity, renewal sources, and lower costs compared with synthetic polymers all combined make them a safer, more accessible option. ¹⁶ As a result of their many benefits, natural polymers are found in almost all sources of food we consume including; crops, animals, marine species, animal-based, plant-derived, and microorganisms such as fungi. ¹⁷

2.1. Functional Importance of Natural Polymers in Drug Delivery Systems

The many functional roles played by naturally occurring compounds (polymers) within pharmaceuticals is extensive; the main uses of these compounds include being binders, disintegrants, thickeners, stabilisers, coatings and matrix forming agents. ¹⁸ Naturally occurring polymers exhibit unique physical and chemical properties that make them especially suited to be used as controlled release (CR) delivery systems. They can regulate the release of medication from an oral dosage form by three distinct methods: diffusion, dissolution, and swelling. When polymers are used to formulate a CR delivery system for an oral dosage form, they provide a means of sustaining therapeutic levels of drug concentration in the bloodstream for an extended period of time. ¹⁹ The similarities of naturally occurring polymers to our own biological tissues leads to superior tolerability of formulations made using natural polymers and a decreased incidence of adverse drug reactions, both of which help to increase patient compliance.

Natural polymers represent a broad range of materials that have been evaluated as potential carriers for the controlled delivery of drugs, including polysaccharides obtained from plants (e.g., guar gum, xanthan gum, gum acacia, pectin, and various other plant-derived mucilages such as okra, fenugreek, plantago and hibiscus), alginate and carrageenan from algae, polysaccharides from animals (including chitosan and gelatin), and polysaccharides generated by bacteria (e.g., pullulan and dextran). ²⁰ These natural materials protect drugs from degradation in the gastrointestinal tract while promoting sustained release of the drug from the carrier during the course of treatment. As a result, they are appropriate for long-term use in a variety of chronic therapy treatments. ²¹

2.2. Role of Natural Polymers in Drug Delivery Systems for Diabetes

The treatment for diabetes mellitus involves ongoing pharmacotherapy for long periods of time; therefore, new formulations are needed to provide continuous therapeutic efficacy and to improve adherence to the medication by patients. Natural polymers are becoming increasingly important excipients for developing controlled and sustained release systems that can provide antidiabetic medicines at a specific rate for an extended period of time. ²² Because these systems decrease the number of times a drug must be taken each day, fluctuations in plasma drug concentration are reduced, which creates stable glycemic control.

Another important example of how natural polymers can help in drug delivery systems is through mucoadhesive drug delivery systems, which adhere to the gastrointestinal tract, which may increase the amount of time a drug stays within the gastrointestinal tract and, therefore, increase drug absorption. ²³ This type of drug delivery system is especially useful for drugs that have a short half-life and or a narrow absorption window. ²⁴ Furthermore, since natural polymers are both biodegradable and non-immunogenic, they are ideal candidates for long-term use, which aligns with the chronic treatment goals of diabetes, ²⁵ while also supporting the current trend towards environmentally friendly and sustainable formulation practices in the pharmaceutical industry.

2.3. Natural Polymers for Controlled Release Applications Are Mainstream to Research

Numerous (natural) polymers have been studied and determined to be candidates for sustained controlled release (of drugs) hormones. Guar gum (galactomannan) is considered, particularly for its high swelling capacity and viscosity, making it an excellent matrix former for orally formulated SR tablets. The microbial-derived polysaccharide, xanthan gum, is widely used because of its strong gel forming (and) thickening properties that make it ideal for use in controlled-release formulations. ²⁶ Pectin (from plants) has shown utility for both colon-targeted and sustained release formulations. Locust bean gum exhibits synergistic gelling with other polysaccharides, increasing the utility of this gum for oral formulations. ²⁷ Tragacanth gum has the ability to hold more water than other gums, and modified starches have multiple film forming and matrix forming characteristics appropriate to most dosage forms. ²⁸ In addition to their advantages, which are primarily from being renewable resources, regulatory approval (GRAS) as generally recognized as safe substances, and structural diversity of structure (natural polymers), they present certain hurdles to exploit their advantages due to variability in batch-to-batch (pharmaceutical products) due to environmental and geographical conditions during processing, as well as, susceptibility to microbial contamination during storage, all of which can affect their reproducibility and quality. Consequently, to provide adequate and consistent performance of these products, they must be rigorously standardized and functionally evaluated. ²⁹

2.4. Natural Polymers as Drug Carriers for Diabetes Management

In order to control blood glucose levels during diabetes treatment, it is essential for patients to keep their blood glucose stable to avoid creating dangerous spikes in blood glucose levels as well as preventing the progression of long term disorders caused by uncontrolled blood glucose levels. ³⁰ With many antidiabetic drugs, including, but not limited to, metformin, the current delivery systems of immediate release often create large fluctuations in plasma drug concentrations, leading to gastrointestinal side effects and inconsistent glycemic control in patients who take them. This variable plasma drug concentration can lead to issues with both the drug and its effects on controlling blood glucose levels. The incorporation of natural polymers in the construction of sustained-release systems will help to alleviate the problems associated with large peak/trough fluctuations by creating more consistent drug release profiles and allowing for better glycemic control. ³¹

In addition to their roles as inactive excipients, many of the natural polymers have been shown to provide additional therapeutic benefits. For example, guar gum and fenugreek mucilage have been shown to slow down glucose absorption from the intestines, to help control postprandial glycemia through a reduction in postprandial glucose levels and improved lipid metabolism. ³² In addition to the above, other natural polymers also exhibit antioxidant properties, as well as mild hypoglycemic actions that may work together with one another to enhance the effectiveness of their use in treating diabetes. ³³

The natural polymer, H. rosa-sinensis mucilage, appears to be a strong candidate as a natural polymer for the sustained release of metformin, as it appears to have high swelling capacity, good film-forming ability, and a favorable safety profile. These characteristics should allow it to act as a suitable sustained-release matrix for metformin formulations, with the potential to improve therapeutic efficacy and to enhance compliance with the use of metformin for the management of diabetes.

2.5. Literature Search Strategy

A comprehensive literature search was conducted to collect relevant studies related to the use of H. rosa-sinensis mucilage as a natural polymer in pharmaceutical formulations and sustained drug delivery systems. Scientific databases including pubmed, scopus, and web of science were systematically searched for publications from 2000 to 2024.

Relevant keywords and combinations were used, including H. rosa-sinensis mucilage, natural polymers, plant mucilage, sustained release drug delivery, metformin sustained release, and natural pharmaceutical excipients. Boolean operators such as AND and OR were applied to refine the search strategy.

Studies were included if they reported the extraction, characterization, pharmaceutical properties, or formulation applications of H. rosa-sinensis mucilage, particularly in sustained drug delivery systems. Articles focusing on natural polymers used in controlled release formulations and studies related to metformin delivery systems were also considered. Studies unrelated to pharmaceutical applications, lacking sufficient experimental or review data, or not published in English were excluded. Additionally, reference lists of selected articles were screened to identify further relevant publications.

3. Mucilage of the H. rosa-sinensis: Origins, Characteristics & Pharmaceutical Applications

3.1. Botanical and Ethnomedical Background

The Hibiscus rosa-sinensis, is a perennial shrub that belongs to the family Malvaceae. It is commonly known as the chinese Hibiscus, shoe flower & china rose. But though it’s native to Eastern Asia, it has been grown widely all over the world, primarily in the tropical and subtropical regions, as a decorative plant due to its large, stunningly colored flowers. ³⁴ In addition to its garden value, H. rosa-sinensis is utilized historically as part of ayurvedic, unani & chinese traditional medicine. Botanically, the plant comprises of dark glossy green leaves & huge trumpet like flowers, most often red the leaves & petals contain a high mucilaginous polysaccharide content giving them an excellent ability to hold moisture and form a gel-like consistency.^35,36 Traditionally, different parts of the plant have been used in medicine preparations made from the leaf and flower parts of the plant have been used on the skin for healing wounds and for alleviating the pain and irritation associated with minor burns and ulcers, because of their abilities as demulcents. ³⁷ These preparations appear to produce anti-inflammatory activity, & thus may be helpful in alleviating pain & inflammation associated with inflammatory disorders. ³⁸

Multiple research initiatives have shown that H. rosa-sinensis has the potential to anti-diabetes. Extracts from different sections of the plant reduce blood sugar levels through the blockade of enzymes which breakdown carbohydrates (including alpha amylase and alpha glucosidase), improve insulin’s ability to work, and enhance the utilization of glucose in tissues. ³⁹ Other uses for H. rosa-sinensis include: acting as an emollient, producing hair-care products, blocking the potential to conceive, and supporting treatments for hypertension and dyslipidemia. The extensive number of pharmaceutical activities of the plant (together with its high availability and cultivatable amount) make H. rosa-sinensis an appealing agent for preparing natural mucilage for pharmaceutical purposes. ⁴⁰ The functional properties of the mucilage derived from H. rosa-sinensis particularly the ability of the mucilage to expand, hold water, bind ingredients, and form films, encourage further research to use it as a natural excipient to enable controlled and long-lasting delivery of medications. Additionally, the historical uses of H. rosa-sinensis as an antidiabetic have provided a valid basis for exploring the mucilage as a potential release-modifying agent for metformin and other antidiabetic products. ⁴¹

3.2. Isolation of Mucilage From H. rosa-sinensis

Mucilage is primarily derived from H. rosa-sinensis (Hibiscus) leaves and flowers, which contain a large quantity of water-soluble polysaccharides. ⁴² Mucilage is extracted from hibiscus by means of aqueous extraction and subsequent precipitation using solvents to eliminate pigments, phenolic compounds, and other chemicals present in the plant.

3.2.1. Standard Extraction Procedure

In standard Hibiscus mucilage extraction, fresh samples of hibiscus leaves flowers are collected, cleaned to remove contaminants, and then shade-dried to maintain heat sensitive components of the plant. After drying, the leaves/flowers are ground to create a coarser powder. ⁴³ The powdered leaves flowers are placed into distilled water (e.g., by soaking or heating) to allow mucilage to separate from the plant. This is generally assisted by continuous mixing or mild heating. The mixture is filtered to remove any solid residue after extracting mucilage. Following concentration through evaporation or using a vacuum, mucilage can be obtained from a solution (called a filtrate) by dropping in enough of an alcohol (or alcohol mixed with water) into the solution that all the compositional parts of the mucilage remain in a solid form, but that most of the other materials still dissolve entirely within the liquid. After thorough washing and removal of impurities from the precipitate, drying at controlled temperatures (to avoid damaging the mucilage), and milling fine into powder form, the product should be sealed tightly in air-tight containers for use in future pharmacological studies. The method of extraction outlined by this proposal is environmentally friendly, inexpensive, and simple, making it scalable and consistent with the tenets of green pharmaceutical manufacturing.^44,45

3.3. Characteristics and Functions of Hibiscus Mucilage

The primary reason for the use of H. rosa-sinensis mucilage in the pharmaceutical industry is due to its many favorable physical, chemical and functional characteristics.

• High degree of hydrophilicity in mucilage: Due to its high content of hydroxyl groups and urine acid residues which create strong hydration and water retention capabilities, H. rosa-sinensis mucilage can absorb and retain high volumes of water.

• High viscosity at low concentrations: H. rosa-sinensis mucilage can produce very high levels of viscosity even at low concentrations. Therefore, it is used as a thickening, suspension and controlled release agent.

• pH stability: H. rosa-sinensis mucilage remains stable at a wide range of pH levels (from acidic to near neutral). This enables the use of this product in oral dosage forms, which are subjected to both gastric and intestinal environments.

• Mucilage is biocompatible and safe for delivery via chronic use based on its toxicological assessment results, showing it to be non-toxic, non-irritant, and biocompatible. Furthermore, mucilage is a naturally occurring polysaccharide that biodegrades through enzymatic and microbial action to create no toxic by-products, meeting the demands for sustainable excipients today.

• Additionally, mucilage’s ability to swell and create coherent film structures permits the modulation of both the rate of drug dispersion and eroding of matrices, which are the mechanisms for the controlled release of drugs. The ease with which mucilage from H. rosa-sinensis is obtained, extracted, and maintained chemically stable, as well as its ability to perform multiple functions creates an opportunity to design and develop a natural material that will provide sustained-release systems for a variety of drugs.

Additionally, mucilage has potential applications when incorporated as an excipient in matrix forming or release modifying formulations, for instance, metformin; improving therapeutic efficacy and providing a means to reduce frequencies of dose Overall, the combination of the unique properties of mucilage from H. rosa-sinensis presents an exciting opportunity to develop a natural material that will sustain release drug delivery systems; thus improving compliance and clinical efficiency for diabetic patients.^46,47 Mucilage from H. rosa-sinensis (HRS) leaves has many physical properties (flowability, compressibility) and chemical properties (chemical structure, molecular weight and intrinsic viscosity) appropriate for creating hydrophilic matrix polymeric (HMP) materials. HRS mucilage has a molecular weight of about 10 million daltons and an intrinsic viscosity of about 23.2 in solution. Therefore, mucilage from HRS creates very high molecular weight polymers that are expected to produce viscous hydrogels upon hydration. HRS mucilage consists of a backbone polysaccharide structure that has a relatively large number of different sugar units (L-rhamnose, D-galactose, D-galacturonic acid and D-glucuronic acid), with a molar ratio of approximately 5:8:3:2. The high content of these sugars in HRS provides HRS mucilage with a very high amount of water binding capability. The physical characteristics of the dried powdered form of HRS mucilage provide good properties for manufacturing direct compression tablets. The powdered form of HRS mucilage has good flow properties, as evidenced by the angle of repose (approx. 25), carr index (9-10%) and hausner ratio (approximately 1.1) (36) swelling study results shown that HRS mucilage produces excessive amounts of hydration in aqueous solution and demonstrates a swelling ratio of approximately 9 in water, 10 in simulated gastric fluid (0.1N HCl) and 9 in phosphate buffer (pH 6.8), indicating that it has very little variability in swelling behavior with changes in pH (37). The pH-independent swelling characteristics of HRS mucilage are advantageous in developing sustained release pharmacotherapeutic formulations based on a hydrophilic matrix-type technology. As a result, the matrix systems that utilize HRS mucilage will respond similarly to multiple dissolution events that take place in both the gastric and intestinal phases since they will allow for the moisture absorption and swelling needed for their sustained release characteristics. In laboratory investigations, HRS mucilage has been used as a matrix polymer for sustained release formulations containing three different drugs ketoprofen, gabapentin, and diclofenac with sustained drug release occurring over 12-24 hrs, with differing formulations and design approaches. The release kinetics associated with HRS mucilage have been shown to be non-fickian and are indicative of a novel biocompatible matrix polymer for the potential for drug delivery. Metformin, as a highly water-soluble drug, has been demonstrated to have the potential benefit of slowing the release of Metformin from HRS mucilage-based matrices. Sufficient physicochemical and formulation data exist to permit the design of an optimal sustained release matrix, e.g., ∼30-50% w/w of polymer and/or through direct compression or wet granulation approaches. The reduction of Metformin being delivered during a predetermined amount of time, e.g., 12-24 hrs, is one of the primary aims of this research.

The Figure 2, Illustrates the sequential steps involved in isolating mucilage from H. rosa-sinensis leaves, including collection, drying, powdering, extraction, filtration, and precipitation, followed by drying and storage of the purified mucilage.

Figure 2.

Schematic representation of the extraction process of H. rosa-sinensis mucilage

3.4. Formulation-Relevant Functional Attributes of H. rosa-sinensis Mucilage

The mucilage obtained from H. rosa-sinensis exhibits a combination of physicochemical and biopharmaceutical properties that make it a highly suitable natural excipient for controlled drug delivery applications. These attributes are largely attributed to its polysaccharide-rich composition, which enables effective modulation of hydration, viscosity, and matrix integrity in pharmaceutical formulations. ³⁸

3.4.1. Hydrophilic Properties of H. rosa-sinensis Mucilage (Swelling)

A key aspect of the hydrophilic properties of the H. rosa sinensis mucilage is its strong attraction to water. As a result, when immersed in water or any other aqueous environment, H. rosa sinensis mucilage rapidly absorbs significant quantities of water, thus swelling. As a result, when exposed to the fluids in the GI tract, H. rosa sinensis mucilage forms a hydrated polymer and acts as a barrier to block the influx of additional fluids, thereby prolonging the time required to diffuse into the body for the active ingredient in the drug formulation.^28,39 Therefore, through the use of the swelling-controlled drug delivery mechanism of the H. rosa sinensis mucilage, it is possible to create sustained plasma levels of drug and thus provide a therapeutic benefit. ⁴⁸ In the case of metformin, which has a very high aqueous solubility and quick rate of dissolution, the swelling response of H. rosa sinensis mucilage and the resulting extended and close to uniform release of the drug have resulted in the formation of stable and sustained plasma concentrations of metformin and improved therapeutic efficacy of this medication. ¹³

3.4.2. Formation of Gels and Rheological Modification of Formulations

Hydroxypropyl methylcellulose (HPMC) made from H. rosa-sinensis dispersed in water is capable of thickening formulations and providing the means through which rheologically modified formulations will release drug substances from hydrated matrices. The ability of HPMC to form gels enables the creation of viscous gel matrices, which increase the interaction between the gel and the drug compound, ultimately resulting in the release rate of the drug compound from the gel matrix being determined by the combined effect of the gel’s ability to swell, gel strength, and viscosity, all of which are favorably modified by the presence of HPMC. ⁴⁹

The ability of HPMC to create a viscous gel matrix also serves to reduce sedimentation in liquid formulations, and to enable the uniform distribution of the drug compound in solid dosage forms through improving the physical stability and content uniformity of the formulation, thus creating a stable and robust formulation. ⁵⁰

3.4.3. Maintaining the Integrity of the Drug-Releasing Matrix

The ability of H. rosa-sinensis mucilage to produce cohesive and mechanically stable drug releasing matrices is of significant benefit. When incorporated into a compressed tablet, H. rosa-sinensis mucilage allows for controlling tablet structure, providing a delay in tablet disintegration while simultaneously allowing for controlled swelling and surface erosion in the gastrointestinal environment. ⁵¹ In this manner, the tablet remains intact while allowing for the release of the drug over an extended period of time. The ability of H. rosa-sinensis mucilage to form a film like coating provides an additional method for altering drug release profiles. This ability to form filmlike coatings and drug-releasing matrices is especially advantageous for anti-diabetic drugs such as metformin, which benefit from extended exposure to the drug compound. ⁵²

3.4.4. Compatibility and Biodegradability of Polymers

The mucilage from H. rosa-sinensis is a polysaccharide obtained from nature, which means that after ingestion, it can be neutralized and excreted without creating toxic residues and that it can be used safely over long periods (such as in chronic diseases like diabetes). ⁵³ Additionally, the mucilage is very compatible with many types of synthetic polymers (e.g. hydroxypropyl methylcellulose, carbopol, polyethylene oxide), which allows the formulation of polymer hybrids that provide the advantages of both the natural excipients’ sustainability and safety, along with the mechanical strength and reproducibility of synthetic products. These hybrid designs can be engineered to create specific drug release profiles, increased product stability and enhanced performance when used with advanced drug delivery systems e.g. hydrogels, nanoparticles and matrix systems. ⁵⁴ In summary, the combination of hydrophilicity and water retention capacity, gelling properties, stability as a matrix material, biodegradability, and ability to be used in combination with other polymers allows H. rosa-sinensis mucilage to be a suitable candidate for use as a release-modifying excipient. The several functions and properties of H. rosa-sinensis mucilage support the development of sustained release formulations for metformin and other anti-diabetic drugs.

4. Rationale for Sustained-Release Delivery of Metformin

4.1. Limitations of Conventional Metformin Therapy

Metformin is widely prescribed as the first-line oral agent for the management of type 2 diabetes mellitus due to its established efficacy and favorable safety profile. There are several pharmacokinetic shortcomings that restrict the clinical performance of metformin and present potential barriers to achieving optimal therapeutic goals. The systemic elimination half-life for metformin is only approximately 4-6 hours and its gastrointestinal absorption is limited. The metformin currently has an oral bioavailability of between 50-60%. Because of metformin’s relatively short half-life and limited gastrointestinal absorption, metformin must be dosed as an immediate release formulation two to three times each day to achieve an effective concentration of drug in plasma at all times over the duration of therapy. This may have a negative impact on patient adherence to treatment over time, especially if used for extended periods. ⁵⁵

As a result of metformin’s pharmacokinetic characteristics, patients frequently experience adverse gastrointestinal reactions to metformin including nausea, abdominal pain/discomfort, bloating, and diarrhea. The adverse gastrointestinal reactions to metformin are primarily related to the high concentration of metformin in the gastrointestinal system as it is released and absorbed very rapidly. ⁵⁶ Gastrointestinal intolerance is one of the most common reasons for metformin to be decreased or discontinued altogether; without these adverse reactions to metformin there would be sustained glycemic management with metformin and improved glycemic management overall. Conventional metformin formulations are associated with tolerability issues; therefore, there are significant issues with metformin compliance due to the need to achieve consistently effective therapeutic concentrations from conventional metformin formulations. ⁵⁷

4.2. Benefits of a Sustained Release Formulation of Metformin

Sustained release (SR) formulations are an innovative approach to address certain limitations of Immediate release (IR) Metformin and offer a way to improve patient care by allowing for gradual and sustained release of medication for a longer period while keeping blood levels within the therapeutic range. By extending the therapeutic delivery profile, SR formulation reduces the frequency of doses to once per day, improving patient compliance, and is especially beneficial for patients with chronic diseases such as diabetes mellitus. ⁵⁸

Additionally, through the minimization of peak plasma levels associated with metformin, sustained release formulations also decrease gastrointestinal irritation, enhance overall tolerability, and maintain more consistent drug levels in the blood. A more stable glycemic environment will allow for fewer changes in blood glucose levels and reduce the risk of treatment failure. Therefore, SR metformin formulations offer a way to improve the management of diabetes and provide improved overall quality of life and satisfaction to patients. ⁵⁹

In conclusion, the benefits of sustained release metformin include an improved pharmacokinetic profile and tolerability compared to conventional IR metformin formulations. The ability of sustained release formulations to maintain therapeutic drug levels for prolonged time periods while minimizing undesirable or intolerable side effects emphasizes the importance of sustained release metformin formulations in maximizing the benefits of diabetes treatment.

5. Future Potential of H. rosa-sinensis Mucilage for sustained Metformin Delivery

5.1. Formulation Strategies Utilizing Hibiscus Mucilage

The mucilage derived from H. rosa-sinensis has unique physicochemical characteristics, including a high degree of swelling, the ability to form gels, and its compatibility with human tissue; thus, it has excellent potential for producing a natural polymer to develop sustained release formulations of metformin. The properties of H. rosa-sinensis mucilage will allow for flexibility in the design of sustained-release systems that can modulate the release profile of the drug across all delivery systems. H. rosa-sinensis mucilage as an HPMC based hydrophilic matrix system has been widely used for sustained release of metformin. ⁶⁰

5.1.1. Hydrophilic Matrix-Based Oral Dosage Forms

The hydrophilic matrix systems provide one of the simplest and most widely used methods of developing sustained-release formulations. H.rosa-sinensis mucilage can be used in the formulation of matrix tablets either through direct compression or wet granulation, whereby it acts as a slow-release agent; at the time of contact with the gastrointestinal fluids, it creates a hydrated gel barrier that prolongs the time of drug release.The simplicity of matrix tablets, along with their ease of scaling and their cost-effective manufacture, has encouraged the widespread use of these dosage forms for sustained release of metformin. ⁶¹

5.1.2. Hydrogel and Bead-Based Systems

The mucilage from H. rosa-sinensis can be utilized to make hydrogels through chemical cross-linking or by combining with another natural or artificial polymer. The resultant 3D polymeric networks created through these processes can absorb a lot of water and trap drugs within the matrix, thus providing controlled drug release via diffusion and polymer matrix degradation. ⁶² The hydrogel platforms may mitigate the effects of rapid drug dissolution on a drug’s performance in a given dose, and offer predictable, continuous drug release from the hydrogel over the duration of its life. The development of mucilage filled bead systems for creating topical or slow release drug delivery for the GI tract could provide additional control over the drug and its effect during use. ⁶³

5.1.3. Nanoscale Delivery Platforms

The mucilage of H. rosa-sinensis is also useful in the production of nanoparticles, where it can serve as a stabilizing or matrix-forming component. ⁶⁴ By using mucilage, the efficiency of drug trapping within the particle will increase, due to its increased surface area to volume ratio. In addition to enhancing drug trapping within the particles, the use of mucilage will also produce greater mucoadhesion to the intestinal wall and therefore improve the amount of time the drug will remain in the gut, as well as to aid in the absorption of the drug into the small intestine. All of these factors combined will ultimately reduce the number of doses required and increase the effectiveness of metformin. ⁶⁵

5.2. Controlled Drug Release Mechanisms

When H. rosa-sinensis mucilage is used are based on the ability of water to penetrate and enlarge the polymers of the mucilage, which then form a gel-type layer around the metformin formulation when placed into aqueous solutions of body fluids i.e., when the dosage forms are introduced into the stomach or intestines. Hydrophobic, gel-forming polysaccharides (the hydrophilic polysaccharide chains) form a viscous gel barrier that delays metformin diffusion into the surrounding medium and therefore provides sustained metformin release. Drug release is then prolonged, due to the presence of the gel barrier surrounding the metformin dosage form. ⁶⁶

Additionally, the gradual degradation of the hydrated mucilage matrix and polymer (and eventual erosion) contributes significantly to drug release through the continuous degradation of the polymer. Sustained metformin release can therefore be achieved for long periods by means of a combination of swelling-induced diffusion and gradual polymer erosion.

Controlled drug release can then be modified according to the characteristics of the polymeric material that is used for the metformin formulation and could include adjustments in the concentration of polymers, degree of cross-linking, and geometry of the drug dosage forms.^67,68

Figure 3, Schematic representation of H. rosa-sinensis mucilage–based matrix systems illustrating metformin release modulation through swelling, gel formation, and diffusion controlled mechanisms, highlighting its potential as a biodegradable polymer for controlled release and improved therapeutic performance.

Figure 3.

Schematic illustration of the release mechanism and potential applications of H. rosa-sinensis mucilage in sustained-release metformin delivery systems

5.3. Comparative Advantages of H. rosa-sinensis Mucilage as a Natural Polymer

Natural mucilage sourced from the flower of the H. rosa-sinensis plant has several advantages versus synthetic or polymer-based sustained release formulations. As a biodegradable and non-hazardous substance, it can be metabolized or expelled from the body without the risk of the long-term accumulation of synthetic polymers, therefore making it ideal for long-term treatment regimens such as diabetes management. ⁶⁷

The extraction of mucilage from plants is relatively inexpensive and occurs through the use of renewable plant sources, which is in agreement with today’s trend toward sustainable pharmaceutical development. In addition to these factors, the fact that this material is plant-derived may increase patient preference for its use, especially for individuals looking for natural or environmentally friendly market offerings.^69,70

The intrinsic antioxidant and anti-inflammatory qualities of H. rosa-sinensis mucilage contribute to its uses in managing oxidative stress and low-grade inflammation that are typically present in diabetic patients. These bio-activities may help to provide an adjunctive role to the pharmacological properties of metformin, as well as support its therapeutic effect.^71,72

These qualities make H. rosa-sinensis mucilage a potential functional excipient and value added component of metformin sustained-release formulations. The use of these advanced drug delivery systems may improve patient adherence, reduce the incidence of adverse gastrointestinal effects, and improve long-term glycemic control in patients with type 2 diabetes mellitus. ⁷³

5.4. Limitations and Challenges

There are many barriers present to the possible use of H. rosa-sinensis mucilage for sustained release forms. These include:

5.4.1. Inconsistent Batch Characteristics

There is a great deal of variability in the chemical composition and properties of the natural polymers being used, since the plants from which the polymers came were grown in different locations and during different seasons. If the methods used to cultivate and harvest the plants, extract the polymers from the plants and carry out physicochemical analysis on them were consistent, the level of batch-to-batch variability could be reduced significantly. ⁷⁴

5.4.2. Microbial Stability

Since the mucilage contains high amounts of polysaccharides, the risk for microbial growth, particularly bacteria, is increased. This can create safety issues concerning the use of the mucilage in formulations. The inclusion of natural preservatives (sodium benzoate), the use of sterilization techniques (i.e., autoclaving and gamma radiation) as well as the use of spray drying processes may help to improve the microbial stability of the mucilage, without negatively affecting its functional properties. ⁷⁵

5.4.3. Specifications and Guidelines for Purification and Standardization

The requirements for purifying, standardizing, and characterizing mucilage present a great deal of complexity in the manufacturing process for mucilage based dosage forms; therefore, mucilage must be extensively purified and standardized prior to producing therapeutically active dosage forms to ensure very consistent release profiles from mucilage-based dosage forms. Various methods of purifying mucilage include ethanol precipitation, ultrafiltration and dialysis; the purity, viscosity measurements, swelling index, and molecular weight of the mucilage should be evaluated using a variety of analytical methods in conjunction with the purification process, in order to achieve uniformity between batches of mucilage and to ensure that the performance of each batch or the same batch can be predicted. ⁷⁶

5.4.4. Absence of Clinical and Regulatory Information Compared to Synthetic Polymers

(HPMC or carbopol), the lack of clinical studies and regulatory agency standards has limited the ability to utilize Hibiscus mucilage as an appropriate pharmaceutical grade excipient. It is critical to perform a complete preclinical and clinical evaluation, as well as adhere to a regulatory standard to demonstrate Hibiscus mucilage’s safe usage as an excipient in pharmaceutical formulation. Utilizing the recommendations stated above, H. rosa-sinensis mucilage may be able to erase its present limitations on reliability and clinical applicability as a sustained-release formulation. ⁷⁷

6. Future Outlook and Research Directions

The increased interest in using natural polymers for sustained drug delivery has revealed H. rosa-sinensis mucilage to have potential as a pharmaceutical excipient for diabetes therapy. Therefore, future investigations should investigate formulation optimization and how to develop advanced delivery systems, as well as provide for the clinical validation of its therapeutic potential. ⁷⁸

6.1. Optimization Through Polymer Combinations

Multiple polymer combinations may enhance mechanical properties, improve formulation stability, allow for consistent drug release, and reduce the inconsistencies found with using natural excipients. A strategy for achieving these goals is to blend Hibiscus mucilage with established synthetic polymers such as hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), or carbopol. ⁷⁹

6.2. Expansion Into Advanced Drug Delivery Systems

In addition to developing standard matrix tablets, Hibiscus mucilage may also be utilized to formulate advanced delivery systems such as micro spheres, nano particles, and mucous adhering films. These systems can provide for better control over drug release, prolong the time that drugs remain in the gut, and improve the likelihood of patient compliance, particularly for drugs that have a narrow absorption window, like metformin. ⁸⁰

6.3. Therapeutic Synergy Potential of Hibiscus Mucilage

Hibiscus mucilage has been suggested to have additional therapeutic value other than functioning as an excipient. Research has documented the antidiabetic, antioxidant, and anti-inflammatory properties of Hibiscus extracts; thus it could be postulated that a synergistic effect exists between Hibiscus extracts and sustained release drug formulations when combined. ⁸¹

6.4. Clinical Translation Pathway of Hibiscus Mucilage

Although preclinical-data has provided a solid foundation for developing clinical applications of Hibiscus mucilage, there currently lacks significant clinical data on the safety and efficacy of Hibiscus mucilage as well as an ongoing investigation into its pharmacokinetics. ⁴⁷

6.5. Quality Control, Standardization, and Regulatory Considerations

To support commercialization of H. rosa-sinensis mucilage as pharmaceutical products, standardization of H. rosa-sinensis mucilage extraction and protein characterization is necessary and compliance with applicable regulations and development of pharmacopeial reference standards would provide for consistency in quality, safety, and reproducibility of H. rosa-sinensis mucilage when commercially available.^82-84

Ultimately, the ability of H. rosa-sinensis mucilage to be used successfully as a drug delivery vehicle will be determined by how it is formulated and created with the newest methods of medicine, development of new and complex dosage forms, as well as conducted with complete preclinical and clinical evaluation of both animal and human subjects. ⁸⁵ Through the use of the unique, functional attributes of this natural polymer, it may provide the opportunity to develop new, sustained-release therapies for managing diabetes safely, effectively and compassionately for patients.^86,87 A summary of Future directions and opportunities for pharmaceutical use of H. rosa-sinensis mucilage is displayed in Figure 4.

Figure 4.

Future perspectives of H. rosa-sinensis mucilage in sustained-release metformin delivery

7. Conclusion

H. rosa sinensis mucilage is a biodegradable, natural polymer that is inexpensive and non-toxic, therefore, it can be a good candidate for an excipient to deliver a medicine in a controlled manner. The mucilage has great swelling ability, ability to form gel-like substances, and the ability to stabilize polymers and enable the production of hydrated matrices to modulate the diffusion and erosion of metformin from the matrix as a result, it could potentially improve the bioavailability of metformin and maintain optimum plasma levels over the long term. It is possible to create many different types of formulations with mucilage, including matrix tablets, hydrogels, beads, and nanoparticles, and further enhancements can occur by combining mucilage with other excipients to increase the mechanical strength and improve the release profile of the product. Major challenges exist with the use of mucilage; however, issues such as variable batch quality, lack of pathogen stability, and limited numbers of preclinical studies and clinical investigations exist. Therefore, further characterization, standardization, and clinical evaluation are required to optimize the benefits of mucilage as a sustainable patient-friendly excipient for the chronic management of type 2 diabetes mellitus.