Introduction
The most common practical method of medicine’s routes of administration is oral administration.1 Due too many reasons, such as high solubility and hence drug dosage dumping, it is difficult to manage The liberation of water-soluble medications from the matrix setup.2 Drug poisoning or drug toxicity might occur from this.3 The release behavior of matrix tablets can be predicted by performing the in-vitro evaluation study, and these dosage forms are inexpensive and simple to make.4 Optimizing pharmacological characteristics and delivery methods will help the pharmaceutical industry overcome a significant difficulty in drug development, producing safe and effective medications.5, 6 A formulation with controlled release that maintains a blood level that is almost constant or uniform is required since the traditional drug delivery method is marked by rapid release and frequent dosing of the medication, potentially elevating the risk of dosage inconsistency. Maintaining a nearly constant or uniform blood level of a medication frequently results in greater patient compliance and increased clinical effectiveness of the medication for its intended usage.7 Systems for delayed medication release over an extended duration of time are referred to as sustained release systems. The technique is referred to as a controlled-release system if it achieves success in upholding consistent medication concentrations in the bloodstream or specific tissue targets.8 If it falls short in achieving this, it's termed as an extended-release system, yet it extends the duration of action beyond conventional delivery methods.9 For sustained release, matrix methods are frequently employed. Howard Press in New Jersey created the first sustained-release tablets in the early 1950s. The first pills developed using his technique patent were known as "Nitroglyn" and were produced by Key Corp.10 In Florida under license, Aceclofenac is a kind of NSAID, or non-steroidal anti-inflammatory medicine,11, 12, 13 Aceclofenac is used to treat osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis-related pain and inflammation. This medication works by preventing the cyclooxygenase (COX) enzymes from producing the chemical prostaglandins that cause pain, edema, and inflammation when an injury occurs. Nephrotoxicity, vomiting, diarrhea, flatulence, constipation, dyspepsia, somnolence, disorientation, etc. are all possible side effects of this medication.14
Materials and Methods
Raw materials
Aceclofenac was procured from Yarrow Chem Products in Mumbai. Local Markets were visited to purchase fresh okra, and a neighborhood garden was visited to procure hibiscus leaves.11 We bought Ethylcellulose, talc, lactose, and magnesium stearate from Loba Chemicals in Mumbai.10 All are LR grades.
Removal or isolation okra gum
The local market provided 1 kilogram of unripe and delicate Okra fruits (Pods). The seeds were eliminated because they lacked mucilage. After washing, the fruits were thinly cut using a knife.15
To remove the mucilage, the cut mass was immersed in distilled water overnight After soaking, the viscous gum extract (mucilage) was filtered out using a white muslin cloth.15
To induce gum precipitation, acetone was added in a proportion of 3-1 part gum extract. The gum extract underwent drying at 60°C for 72 hours, and was store in a desiccator to maintain its reduced size.15
Isolation of Hibiscus Leaf Mucilage
The dried leaves were ground into a powder and sent through screen number 10.15 The powdered leaves were steeped in hot distilled water (60 °C) for 1 hour and mixed vigorously for 30 minutes, followed by a resting period of 1 hour. Permit the mucilage to completely discharge into the water. A multi-layered muslin cloth bag was employed to extract the mucilage while simultaneously eliminating the marc from the dispersion. To precipitate the mucilage, acetone was added in amounts three times as large as the filtrate's. In a laboratory oven set at 40 °C for 6 hours, precipitated mucilage was dried on stainless steel trays.15
Quality control of pre-compression parameters
Micromeritic properties
BD was determined by dividing the mass (M) of the powder by its BV. This allows us to quantify the density (D) of the powder based on its mass and volume (V).14
Tapped density (TD)
TD was determined by splitting the mass of the powder by its TV. This formula helps in determining the tap density (Dt) of the powder based on its mass (M) and volume after tapping (Vt).14
Preparation of Aceclofenac Tablet
The direct compression procedure was used to produces the various tablet (Table 1) batch formulations (F1-F9). In a motor and pestle, the polymers (okra, hibiscus leaf, and ethyl cellulose) and API were well mixed for 10 minutes. 11 This mixture had lactose, talc, and magnesium Stearate added, and it underwent mixing for 20 minutes. 4 The formulation utilizes Aceclofenac as the API, a combination of okra, hibiscus leaf, and ethyl cellulose as polymers, lactose as a diluent, Magnesium Stearate as a lubricant, and talc as a glidant.
Quality control of Post Compression parameters
Weight variation test
To analyze weight variation, 20 tablets from every formulation were weighed utilizing a digital balance, adhering to the prescribed official procedure.10
Thickness
The thickness of each tablet was assessed using Vernier calipers. Five tablets were randomly selected from each batch, and the average measurements were computed. 11
Hardness
The durability of tablets against shipping, breakage, and storage conditions before usage relies on their hardness. Hardness measurements of the tablets were conducted using MHT.11
Friability
Friability serves as an indicator of tablet strength, assessed using the Roche friabilator. It was determined by the formula: [(Primary weight - Final weight) / Primary weight] * 100.11
Drug content study
The mean weight of the three tablets was ascertained by weighing each one separately. All of the tablets were then crushed, and a quantity of powder equal to 50 mg of the medication was weighed. The powder was dissolved in PBS (pH 6.8), and the stock solution was created by adding more buffer to get the volume down to 50 milliliters. Using PBS (pH 6.8), 1 milliliter of this stock solution was suitably diluted, and the drug content was assessed spectrophotometrically at 275 nm.11
Swelling index
The swelling process of tablet excipient particles involves absorbing liquid, leading to increased weight and volume. This liquid absorption may stem from capillary saturation or macromolecule hydration. As liquid infiltrates the particles through pores, it binds to large molecules, disrupting hydrogen bonds and causing swelling. Swelling is measured by the tablet's weight gain. Tablets from all formulations were first weighed, and then left to soak in 100ml of water for 12 hours. Afterward, the tablets were removed, blotted dry, and reweighed. SI was determined using: % SI = [(W2 - W1)/W1] × 100, where W1 is the primary weight and W2 is the final weight.7
In-vitro release-kinetics
The dissolution studies for all formulated tablets were conducted using a USP type-II apparatus (Electro lab, paddle method) with 900 ml of PBS (pH 7.8) as the dissolution vehicle. The vehicle was allowed to reach a temperature of 37°C ± 0.5°C. Tablets were placed in the vessel, which was covered, and the apparatus was running for 12 hours in PBS (pH 7.8) at 50 rpm. At specific time intervals, 5 ml aliquots of the sample were withdrawn accordingly, and the volume was restored with an exact volume of fresh dissolution vehicle. The samples were then assessed spectrophotometrically at UV. Following dissolution data collection, we delved deeper into pharmacokinetic parameters and kinetics. Our analysis included Hixson-Crowell Rate Kinetic Model, Higuchi plot, Korsmeyer-Peppas model, zero-order, and first-order kinetics. This comprehensive study unveils the intricate dynamics of our formulations, paving the way for precision-driven pharmaceutical advancements.7
Stability studies
The chosen formulations, including the optimized batch F6, underwent a three-month stability study by ICH guidelines. The tablets were placed in their final packaging and exposed to a temperature of 40 ± 0.2°C and a relative humidity of 75 ± 5% in a stability chamber. 6 After one month, the tablets were assessed for alterations in appearance, physical properties, drug content, and in vitro dissolution performance.
Tablets F3 and F9 emerged as optimal formulations post in-vitro dissolution studies, meeting study criteria. Optimization selects formulations achieving desired release profiles,ensuring efficacy and safety. F6 and F9's selection signifies their ability to meet target release profiles, promising controlled drug delivery for enhanced therapeutic outcomes and reduced risks.
The results for the kinetic study were plotted by Hixson Crowell Rate Kinetic Model, Higuchi plot, Korsmeyer-Peppas, zero-order and first-order kinetics.
Table 1
Formulation table of tablets
Table 2
Micromeritic properties
Table 3
Result of Quality Control of Post Compression Parameters
Table 4
In-Vitro release profile of formulated tablets
Table 5
Stability studies of F9 formulation at 40 °C±2 °C/75% Relative Humidity ±5%
Table 6
Drug Release kinetics
Results
Micromeritic properties
Quality control of pre-compression parameters for the Swellable Matrix Tablets was conducted through hands-on experiments, following the procedure outlined in the methodology section above. Subsequently, the findings of the quality control assessment for pre-compression parameters, including BD, TD, HR, CI, and AOR were documented in a tabular format. 16, 17
Result of quality control of post compression parameters
Quality control of Post Compression parameters of the Swellable Matrix Tablets was determined by the hands-on experiments by following the above procedure written at the methodology section. 18 Then the result of Quality control of Post Compression parameters like Weight Variation test, Thickness, Hardness, Friability, and Drug content study reported in a tabular manner. 14
Discussion
In contemporary pharmaceutical research, concerns over the adverse effects of synthetic polymers and excipients have prompted a shift towards exploring natural alternatives. In the current study, we focused on harnessing the potentiality of two natural excipients: okra gum and hibiscus leaf mucilages, for formulating sustainable or extended-release tablets. Before formulation, extensive pre-formulation studies including micro-politics property analysis, IR spectroscopy, and organoleptic assessments were conducted. These studies yielded consistent and reliable results, affirming the compatibility and suitability of the selected natural excipients. Subsequently, formulation studies were initiated, involving the evaluation of various ratios of okra gum and hibiscus leaf mucilages using the dry granulation process. Post-formulation studies were then performed to assess crucial parameters like hardness, friability, DT, and dissolution characteristics. 21 Notably, formulations utilizing 75 mg per tablet of okra gum and 75 mg per tablet of hibiscus leaf mucilage demonstrated superior performance across all evaluated parameters. Specifically, formulations designated as F6 and F9 emerged as the optimal formulations, exhibiting optimal hardness, minimal friability, rapid disintegration times, and desirable dissolution profiles. These findings underscore the efficacy of the selected natural excipients in facilitating the development of robust and effective extended-release tablets. 22 Overall, the successful formulation of sustainable tablets using okra gum and hibiscus leaf mucilagesp 23, 24 highlights the potential of natural alternatives in pharmaceutical research and underscores the importance of prioritizing safety and sustainability in drug formulation practices 25, 26. Okra gum and hibiscus leaf mucilage both are intrinsic natural semicrystalline polysaccharide, which serves as an efficient retarding polymer to formulate sustained-release pharmaceutical preparations. Okra gum from Hibiscus esculentus is a polysaccharide recently being studied in pharmaceutical research as a hydrophilic polymer in different dosage forms, and also exists as binding material for tablets and shows adequate hardness, friability, and drug release kinetics, In the present study we were using okra gum (F7, F8 & F9) and hibiscus leaf mucilage (F4, F5 & F6) as the release modifier and both of these were showing optimized drug release as compare to ethylcellulose (F1, F2& F3). The tablets with these polymers show greater bioavailability for sustained release and steady-state concentration for a prolonged duration of time. In the rate kinetic study, it was found that among all these formulations (F4 to F9) F6 and F9 follows zero-order kinetics and exhibits greater R2 value. Furthermore, the dissolution study and kinetic study suggests the formulation with these natural polymer shows less frequency and less adverse toxic effects as compared to conventional Tablets.27, 28
Conclusion
The formulation development and evaluation of swellable matrix tablets were successfully conducted with a NSAID entrapped to block the COX pathway. The polymeric coating was achieved using two natural polymers: okra gum and hibiscus leaf mucilage, aiding extended-release properties. Aceclofenac was the chosen drug, along with excipients like lab-made okra gum and hibiscus leaf mucilage. Preformulation studies ensured parameters were acceptable before formulation. Quality control tests included weight variations, hardness, friability, drug contents, and in-vitro API release kinetics. Stability studies were also conducted. Dissolution studies for formulations F1-F9 were performed, with absorbance values collected to calculate the percentage of drug release. Formulations F3, F6, and F9 showed promising results, with cumulative percentage drug release values of 97.23%, 94.19%, and 98.83% respectively. The study concluded that replacing Ethyl Cellulose with natural polymers like okra gum and hibiscus leaf mucilage was beneficial due to lower toxicity and higher biodegradability. Our sustained release formulation adheres to the matrix type of drug release kinetics, ensuring controlled release characteristics. Specifically, controlled release formulations are ideally designed to exhibit zero-order drug release kinetics. Through meticulous optimization, formulations F6 and F9 have demonstrated impeccable adherence to this principle. The outstanding R2 values approaching 1 indicate that our tablets, F6 and F9, achieve zero-order rate kinetics with utmost precision. In our cutting-edge research on matrix tablets, Okra Gum and Hibiscus Mucilage shine as star ingredients in formulations F6 and F9, boasting the highest concentrations. These dynamic duos have propelled F6 and F9 to the forefront, showcasing remarkable results. Our groundbreaking study confirms that both F6 and F9 embrace the coveted zero-order rate kinetics, rendering them concentration-independent powerhouses. Furthermore, F6 and F9 go beyond conventional release mechanisms, orchestrating a controlled and sustained release profile that stands the test of time. Their unparalleled ability to maintain steady-state concentrations over prolonged periods sets a new standard in formulation excellence. In essence, F6 and F9 emerge as the pinnacle of optimization, offering not just efficacy but a promise of sustained therapeutic impact. Step into the future of pharmaceuticals with F6 and F9. Formulations F6 and F9 were identified as the best formulations for natural matrix-based coated tablets.
Limitation
Limited generalizability
The study's findings, based on specific laboratory conditions and the use of a particular drug and excipients (Aceclofenac), may not directly apply to other drugs or formulations without further validation.
Biological evaluation
While the study extensively assesses physicochemical assets and in-vitro API release kinetics, the absence of biological evaluation, including pharmacokinetic and pharmacodynamic studies, limits understanding of the formulation's performance in living organisms and predicting clinical efficacy.
Scale-up considerations
Conducted on a small scale, the study raises concerns about transition costs and the availability of natural polymers, particularly those from botanical sources, which may hinder large-scale production and commercialization. Economic feasibility studies and exploration of alternative sources are warranted to address these challenges.
Future Prospective
Exploration of other natural polymers
While okra gum and hibiscus leaf mucilage show promise, future research should investigate additional natural polymers for drug delivery purposes. The vast array of polysaccharides and proteins from botanical sources offer diverse properties that could be explored for drug delivery, including swelling, mucoadhesion, and controlled release.
Optimization of formulation parameters
Subsequent studies should concentrate on refining formulation parameters like polymer concentration, drug loading, coating thickness, and excipient composition to improve formulation performance and consistency. The utilization of Design of Experiments (DOE) methodologies can systematically assess and refine these parameters.
Biocompatibility and toxicity studies
Thorough evaluations of biocompatibility and toxicity for natural polymer-based formulations are crucial to ensure their safety and effectiveness in clinical settings. Future investigations should encompass comprehensive studies on cytotoxicity, genotoxicity, immunogenicity, and tissue compatibility to meet regulatory requirements and address safety concerns.
Incorporation of therapeutic agents
Beyond NSAIDs, exploration of natural polymer-coated matrix tablets for delivering various therapeutic agents such as antimicrobials, antioxidants, anti-cancer drugs, and peptides could enhance therapeutic outcomes and minimize adverse effects. Developing combination therapies or targeted delivery systems holds promise for improving treatment efficacy.
Advanced drug delivery strategies
Future research avenues may involve exploring advanced drug delivery strategies like stimuli-responsive systems, nanotechnology-based carriers, and personalized medicine approaches. Integration of stimuli-responsive polymers or nanocarriers could facilitate triggered drug release in response to specific physiological signals or external triggers, enhancing drug targeting and efficacy.
Clinical translation and validation
Further preclinical and clinical studies are necessary to validate the efficacy, safety, and pharmacokinetic profiles of natural polymer-coated matrix tablets in human subjects. Clinical trials can offer valuable insights into real-world performance and support regulatory approval for commercialization.
Author Contributions
Study conception and design: Bhupendra Prajapati, Biswajit Basu, Rajdip Goswami; data collection: Rajdip Goswami, Saikat Santa, Bhaskar Pal; analysis and interpretation of results: Biswajit Basu, Bhupendra Prajapati, Saikat Santra, Bhaskar Pal; draft manuscript preparation: Rajdip Goswami, Saikat Santa, Bhaskar Pal. All authors reviewed the results and approved the final version of the manuscript.
Data availability statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Consent for publication
We all authors are declared that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. It is also declared that no data from animal and human studies are there in the manuscript and no individuals’ data are present in the manuscript.
