Formulation and Evaluation of Effervescent Anti-Diabetic Tablets Using Aegle marmelos Extract for the Management of Type 2 Diabetes Mellitus

Diabetes mellitus is a group of metabolic disorders characterized by elevated blood glucose levels due to abnormalities in insulin secretion, insulin action, or both. The disease has emerged as one of the most significant public health challenges worldwide. Persistent hyperglycemia leads to disturbances in carbohydrate, lipid, and protein metabolism and may result in severe complications affecting the cardiovascular system, kidneys, eyes, nerves, and blood vessels. Insulin, secreted by pancreatic β-cells, plays a crucial role in maintaining glucose homeostasis. Deficiency of insulin or resistance to its action results in impaired glucose utilization and accumulation of glucose in the bloodstream. The increasing prevalence of Type 2 diabetes has been attributed to sedentary lifestyles, unhealthy dietary habits, obesity, stress, and genetic factors. Although several synthetic anti-diabetic drugs are available, their long-term use may produce undesirable effects. Therefore, researchers are focusing on medicinal plants as alternative therapeutic agents. Among various medicinal plants, Aegle marmelos has attracted considerable attention because of its proven anti-diabetic, antioxidant, anti-inflammatory, and hepatoprotective activities. Incorporation of Aegle marmelos extract into an effervescent dosage form may provide rapid drug release, better absorption, improved patient compliance, and enhanced therapeutic effectiveness.

5. Diabetes Mellitus

Diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose levels resulting from impaired insulin secretion, insulin resistance, or both.

Classification

1. Type 1 Diabetes Mellitus (IDDM)

Type 1 diabetes mellitus is an autoimmune disorder characterized by destruction of pancreatic β-cells leading to complete insulin deficiency.

Causes

• Autoimmune destruction of β-cells
• Genetic predisposition
• Viral infections
• Environmental factors

Symptoms

• Polyuria
• Polydipsia
• Polyphagia
• Weight loss
• Fatigue
• Blurred vision

Treatment

• Insulin therapy
• Dietary management
• Physical exercise

2. Type 2 Diabetes Mellitus (NIDDM)

Type 2 diabetes mellitus is characterized by insulin resistance and gradual decline in insulin secretion.

Causes

• Obesity
• Sedentary lifestyle
• Genetic factors
• Unhealthy diet
• Stress
• Aging

Symptoms

• Frequent urination
• Excessive thirst
• Fatigue
• Delayed wound healing
• Obesity
• Recurrent infections

Treatment

• Oral anti-diabetic drugs
• Lifestyle modification
• Insulin therapy in severe cases

5. Symptoms and Complications of Diabetes Mellitus

Symptoms

1. Polyuria: Frequent urination due to osmotic diuresis caused by excess glucose in urine.
2. Polydipsia: Excessive thirst resulting from dehydration.
3. Polyphagia: Increased hunger because cells fail to utilize glucose effectively.
4. Fatigue: Reduced cellular energy production causes weakness and tiredness.
5. Weight Loss: Common in uncontrolled diabetes due to breakdown of fats and proteins.
6. Blurred Vision: High blood glucose affects the eye lens leading to visual disturbances.
7. Slow Wound Healing: Poor circulation delays tissue repair.
8. Recurrent Infections: Increased susceptibility to bacterial and fungal infections.

Complications

1. Microvascular Complications

• Diabetic neuropathy
• Diabetic nephropathy
• Diabetic retinopathy

2. Macrovascular Complications

• Hypertension
• Coronary artery disease
• Stroke
• Peripheral vascular disease

3. Other Complications

• Diabetic foot ulcers
• Delayed wound healing
• Diabetic ketoacidosis

5. Plant Profile

Fig no 1: Aegle marmelos

Botanical Description

Aegle marmelos (L.) Corr., commonly known as Bael or Belpatra, belongs to the Rutaceae family and is extensively used in traditional medicine.

Phytochemical Constituents

The leaves of Aegle marmelos contain several bioactive compounds including:

• Flavonoids
• Alkaloids
• Tannins
• Phenolic compounds
• Coumarins
• Marmelosin
• Essential oils

Pharmacological Activities of Aegle marmelos

1. Anti-Diabetic Activity: The anti-diabetic activity is attributed to:

• Stimulation of insulin secretion
• Enhancement of glucose utilization
• Reduction of oxidative stress
• Inhibition of α-amylase enzyme
• Inhibition of α-glucosidase enzyme

2. Antioxidant Activity: Phenolic compounds and flavonoids neutralize free radicals and protect pancreatic β-cells from oxidative damage.
3. Anti-Inflammatory Activity: The plant suppresses inflammatory mediators and reduces tissue inflammation.
4. Antimicrobial Activity: Effective against various bacterial and fungal pathogens.

5. Effervescent Tablets

Effervescent tablets are solid dosage forms that release carbon dioxide when dissolved in water due to reaction between acids and bicarbonates.

Effervescence Reaction

Citric Acid + Sodium Bicarbonate → Carbon Dioxide + Water + Sodium Citrate

The generated carbon dioxide promotes rapid disintegration and dissolution of the tablet.

Advantages of Effervescent Tablets

• Rapid dissolution
• Improved bioavailability
• Faster onset of action
• Better patient compliance
• Pleasant taste
• Suitable for geriatric and pediatric patients
• Easy administration

5. Objectives

1. To formulate and evaluate effervescent anti-diabetic tablets containing Aegle marmelos leaf extract for the management of Type 2 diabetes mellitus.
2. To collect, identify, and authenticate Aegle marmelos leaves.
3. To prepare and standardize the leaf extract using a suitable extraction method.
4. To formulate effervescent tablets using appropriate pharmaceutical excipients.
5. To improve drug dissolution and patient compliance through an effervescent dosage form.
6. To evaluate pre-compression parameters such as angle of repose, bulk density, tapped density, Carr’s index, and Hausner ratio.
7. To evaluate post-compression parameters including weight variation, hardness, thickness, friability, drug content, pH, and effervescence time.
8. To assess the in-vitro anti-diabetic activity of the formulation using the α-amylase inhibition assay.
9. To investigate the mechanism of anti-diabetic action of Aegle marmelos extract.
10. To perform stability studies according to ICH guidelines.
11. To develop a stable, safe, effective, and patient-friendly herbal anti-diabetic formulation with minimal side effects.

MATERIAL AND METHOD

MATERIALS:

Aegle marmelos leaf extract, sodium bicarbonate, citric acid, tartaric acid, mannitol, PVP K30, sodium saccharin, magnesium stearate, orange/lemon flavour, ethanol and distilled water.

Extraction Process (Soxhlet Method)

1. Fresh Aegle marmelos leaves were collected and authenticated.
2. Leaves were washed thoroughly with water to remove dirt and impurities.
3. The leaves were shade-dried for 7–10 days.
4. Dried leaves were powdered using a grinder.
5. The powder was passed through sieve No. 60 to obtain uniform particle size.
6. About 50 g of leaf powder was packed into a Soxhlet thimble.
7. Ethanol was added to the round-bottom flask.
8. Extraction was carried out for 6–8 hours using a Soxhlet apparatus.
9. The obtained extract was filtered.
10. The solvent was evaporated to obtain a concentrated extract.
11. The extract was dried and stored in a desiccator until further use.

Formulation Process (Direct Compression Method)

1. All ingredients were accurately weighed according to the formulation.
2. Sodium bicarbonate, citric acid, tartaric acid, mannitol, and Aegle marmelos extract were dried separately to remove moisture.
3. All dried ingredients were passed through sieve No. 60.
4. The ingredients were mixed uniformly in a mortar.
5. PVP K30 was added as a binder and blended thoroughly.
6. Sodium saccharin was added as a sweetener.
7. Orange/lemon flavour was added and mixed uniformly.
8. Magnesium stearate was added as a lubricant and blended gently.
9. The prepared powder blend was evaluated for pre-compression parameters.
10. The blend was compressed into tablets using a tablet compression machine.
11. The prepared effervescent tablets were stored in airtight containers to protect them from moisture.

EVALUATION PARAMETER

Pre-Compression evaluation

1. Repose

Angle of repose is the maximum angle formed between the surface of powder heap and horizontal plane. It indicates flow property of powder blend.

5. Procedure

1. Funnel was fixed at a suitable height.
2. Powder blend was allowed to flow through the funnel freely onto graph paper.
3. Powder formed a cone-shaped heap.
4. Height (h) and radius (r) of heap were measured.
5. Angle of repose was calculated.

5. Formula

Where:

• θ = Angle of repose
• h = Height of powder cone
• r = Radius of cone

5. Interpretation

2. Bulk Density

Bulk density is the ratio of mass of powder to bulk volume before tapping.

5. Procedure

1. Accurately weighed powder blend was transferred into graduated cylinder.
2. Initial volume occupied by powder was noted.
3. Bulk density was calculated.

5. Formula

Where:

• ρb = Bulk density
• M = Mass of powder
• V b = Bulk volume

3. Tapped Density

Tapped density is the ratio of mass of powder to tapped volume after mechanical tapping.

5. Procedure

1. Measuring cylinder containing powder was tapped mechanically for 100 taps.
2. Final volume was recorded.
3. Tapped density was calculated.

5. Formula

Where:

• ρt = Tapped density
• M = Mass of powder
• Vt = Tapped volume

4. Carr’s Compressibility Index

Carr’s index indicates compressibility and flow behavior of powder blend.

5. Procedure

Calculated using bulk density and tapped density values.

5. Formula

Where:

• TD = Tapped density
• BD = Bulk density

5. Interpretation

5. Hausner’s Ratio

Hausner’s ratio indicates interparticle friction and flowability of powder.

5. Formula

5. Interpretation