Development and Evaluation of a Floating Drug Delivery System for the Sustained Release of Vildagliptin and Metformin in Combination Therapy

Diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose levels (hyperglycaemia) due to problems with insulin production, its effectiveness, or a combination of both factors. This condition is primarily classified into two main types: Type 1 diabetes (T1D) and Type 2 diabetes (T2D). Type 1 diabetes typically manifests in children or young adults and results from the autoimmune destruction of the pancreatic beta cells responsible for insulin production. Conversely, Type 2 diabetes, which is more prevalent, usually occurs in adults and is associated with insulin resistance and a relative lack of insulin. The prevalence of diabetes has risen dramatically in recent years, raising significant public health concerns. Factors contributing to this trend include sedentary lifestyles, poor dietary choices, obesity, and an aging population. The World Health Organization (WHO) recognizes diabetes as a leading cause of morbidity and mortality worldwide, resulting in complications such as cardiovascular disease, neuropathy, renal disease, and vision impairment. Managing diabetes necessitates significant lifestyle adjustments, regular monitoring of blood glucose levels, and appropriate medical interventions. Floating matrix tablets represent an advanced drug delivery system aimed at improving the bioavailability and therapeutic effectiveness of medications, especially those that require extended gastric retention. This innovative method tackles prevalent issues in oral drug delivery, such as swift gastric emptying and inconsistent absorption rates, which can result in less-than-optimal therapeutic results. The fundamental concept behind floating drug delivery systems (FDDS) is their capacity to remain afloat. By integrating specific hydrophilic polymers into the tablet composition, these systems can maintain buoyancy in the gastric environment, facilitating a controlled release of the active pharmaceutical ingredients (APIs). This ability to float is essential for medications that are predominantly absorbed in the stomach or the upper sections of the gastrointestinal tract. Floating matrix dosage forms are specifically designed to uphold buoyancy within the gastrointestinal tract, thereby improving drug absorption and overall therapeutic efficacy. The following outlines the primary features of these dosage forms: Floating Mechanism: These formulations are crafted to remain on the surface of gastric fluids, which extends their retention time in the stomach and enhances drug absorption. Hydrophilic Polymers: These formulations often utilize polymers like hydroxypropyl methylcellulose (HPMC) or sodium alginate, which expand when exposed to gastric fluids. Gas-Generating Agents: This category may feature compounds such as sodium bicarbonate that produce gas, enhancing buoyancy.

MATERIALS AND METHOD:

MATERIALS:

Vildagliptin and Metformin were provided as complimentary samples by Fourrts India Pvt Ltd. The polymers, including Hydroxypropyl Methylcellulose K100M and K4M, were supplied by Coloron Asia Pvt Ltd, while Carbopol 940, Ethyl cellulose, HPC, Sodium bicarbonate, Citric acid, and Magnesium stearate were also received as gift samples from Fourrts India Pvt Ltd. The floating matrix tablets of vildagliptin and metformin represent an advanced drug delivery system aimed at improving the bioavailability and therapeutic effectiveness of medications, especially those designed for extended gastric retention.

METHODS:

In the direct compression technique, the initial weights of all active pharmaceutical ingredients (APIs) and excipients are determined. Begin by accurately weighing the APIs, Vildagliptin and Metformin, which should be passed through a #30 mesh sieve. Next, anhydrous lactose is measured, as it is essential for tablet formation due to its excellent compressibility. It also serves as a diluent for dry powder inhalations. Disintegrating agents, such as microcrystalline cellulose and anhydrous lactose, are precisely weighed and similarly passed through a #30 mesh. The polymers are weighed accurately to ascertain their concentrations and also passed through the #30 mesh. Introduce a gas-generating agent, such as sodium bicarbonate, which produces carbon dioxide when in contact with a dissolution medium (0.01 N HCl). The generated gas is encapsulated within the gel formed by polymer hydration, effectively reducing the tablet's density. Sodium bicarbonate should also be passed through a #30 mesh. Next, incorporate citric acid. When citric acid interacts with sodium bicarbonate in the presence of water, it produces carbon dioxide gas, creating bubbles that help gastric fluid rise. Prior to this, citric acid crystals should be crushed using a mortar and pestle and then passed through a #30 mesh. Mixing: All components are combined in a polyethylene bag for 5 to 10 minutes. After mixing, the blend is sieved using the same #30 mesh. Lubrication: Finally, magnesium stearate, which has been passed through a #60 mesh, is added as a lubricant. Compression: The lubricated granules are then subjected to compression using an 11.9 mm round punch, targeting a weight of 600 mg.

Drug Content Uniformity: To confirm that each tablet contains the correct amount of active ingredient. Randomly select 10 tablets and analyse each for drug content using an appropriate analytical method (HPLC). The active ingredient content should be within 85-115% of the labelled claim, with a relative standard deviation (RSD) of less than 6%.

In Vitro Dissolution Test: To assess the drug release profile from the tablets. Utilize a USP type I dissolution apparatus with a suitable dissolution medium (e.g., 0.1N HCl) at 37°C. Collect samples at specified intervals and analyse using UV spectroscopy or HPLC. The drug release should conform to the established release profile, typically indicating a specific percentage of drug released at designated time points. The assessment of post-compression parameters indicates that the tablets exhibit uniform weight, thickness, and size, as well as sufficient mechanical strength and minimal friability. The disintegration time and dissolution characteristics align with the established specifications, facilitating effective drug release. The uniformity of drug content falls within acceptable ranges, confirming that each tablet contains the appropriate dosage of the active ingredient. In summary, the evaluation of these parameters highlights the high quality of the tablets, affirming their suitability for the intended application.

Assay by HPLC Method:

Assay of vildagliptin and metformin by HPLC method:

METHOD OF ANALYSIS:

Table 1: Chromatographic conditions:

Preparation of Buffer Solution: Dissolve 1.7 g of Potassium dihydrogen phosphate in 1000 ml of water. Adjust the pH to 3.0 ± 0.1 using orthophosphoric acid. Incorporate 8.0 g of ammonium hexafluorophosphate and mix thoroughly.

Reference Solution (a): Accurately weigh 100 mg of Vildagliptin Working Standard and 40 mg of Metformin Hydrochloride Working Standard into a 100 ml volumetric flask. Shake the mixture well to ensure complete dissolution with the solvent mixture, then bring the volume up to the mark. Dilute 10 ml of this solution to 20 ml using the solvent mixture.

Test Solution (a): Weigh approximately 10 tablets and grind them using a mortar and pestle. Disperse the powdered tablets in the solvent mixture, utilizing a magnetic stirrer for 45 minutes. Dilute the resulting mixture to 500 ml with the solvent mixture, then centrifuge to obtain a clear supernatant and filter. Further dilute 10 ml of the filtrate to 20 ml with the solvent mixture.

Test Solution (b): Dilute 2 ml of Test Solution (a) to 50 ml with Solution A.

Procedure: Separately inject the reference Solution (a) (6 injections) into the chromatograph and record the major response. Ensure the following system suitability parameter.

Table 2: System stability parameter and acceptance criteria:

Inject Test solution (a) and Test Solution (b) (2 injections) into the chromatograph and calculate the content of Vildagliptin and Metformin Hydrochloride against the Reference Solution using the following expression.

Calculation:   

DISSOLUTION BY HPLC METHOD:

Table 3: Dissolution Condition:

Preparation of 0.01 M Hydrochloric acid: Dissolve 0.85 ml Hydrochloric acid in 1000 ml of water.

Table 4:  Chromatographic conditions:

Preparation of Buffer: Dissolve 1.7 g of Potassium dihydrogen phosphate in 1000 ml of water. Adjust to PH- 3.0 ± 0.1 with Orthophosphoric acid. Add 8.0 g of Hexafluorophosphate acid and mix.

Standard Solution: Weight accurately about 27.8 mg of Vildagliptin working standard and 27.8 mg Metformin Hydrochloride working Standard in a25 ml of volumetric flask. Add 15 ml of medium, sonicate to dissolve and make up to the volume with medium. Dilute 5 ml of this solution to 100 ml with medium.

Test Solution: Withdraw 15 ml of the sample of the medium from each bowl and filter through 0.45-µm membrane (Use Nylon Syringe Filter). Use the Filter for further analysis.

Sample for Vildagliptin: Use the filtrate.

Sample for Metformin Hydrochloride: Dilute 5 ml of the filtrate to 25 ml with medium.

Procedure: Separately inject the standard solution (6 injections) into the chromatograph and record the major response. Ensure the following system suitability parameter.

Table 5: System stability and acceptance criteria:

Calculation: Calculate the Percentage dissolution of Vildagliptin and Metformin Hydrochloride using the following expression.

Kinetic Studies of Vildagliptin And Metformin Matrix Tablet:

KINETICS MODEL OF DISSOLUTION:

Zero order kinetics: In this model, the drug release rate is constant over time, meaning that a constant amount of drug is released per unit of time, independent of its concentration.

Equation: 

First order kinetics: In first-order kinetics, the drug release rate is proportional to the amount of drug left in the dosage form, meaning that the rate decreases as the drug concentration decreases.

Equation

Equation:

Korsmeyer-Peppas Mode: This model accounts for the shrinking surface area during the dissolution process. As the drug dissolves, the surface area available for dissolution decreases, leading to a changing dissolution rate.

Equation:

Stability Studies: 

The assessment of a drug's stability within its dosage form under diverse environmental conditions is essential, as it directly impacts the formulation's shelf life. Any changes in physical attributes such as color, odor, taste, or texture may indicate potential instability of the drug. Among the various formulations evaluated, Formulation F2 was selected for stability testing due to its favorable physicochemical characteristics and release profile of the floating matrix tablet.  Stability evaluations were performed at 40 ± 2º C and 75 ± 5% relative humidity, as outlined in the accompanying table. The findings revealed no significant alterations in the physical appearance, average tablet weight, or hardness. Additionally, the initial drug content was consistent with that of samples analyzed after one month of storage. The release profile also showed no notable changes, indicating that both the physical and chemical properties of the formulation remained stable. Consequently, it can be concluded that the developed tablets preserved their stability and pharmaceutical effectiveness throughout the one-month duration.

Table 6: Formulation Table:

RESULT AND SISCUSSION:

Table 7: Organoleptic Properties of Vildagliptin and Metformin:

Solubility studies:

Table1 8: The solubility of Vildagliptin:

The solubility of Metformin was determined in different solvent such as water, HCL PH 1.2, ABS 4.5, PBS PH 5.8, 6.8 and 7.2 (ABS- Acetate Buffer solution, PBS- Phosphate buffer solution.

Table 9: The solubility of Metformin:

Drug Excipient Compatibility Study:

FTIR- (Fourier Transform infrared spectroscopy):

Figure 5: Compatibility of Vildagliptin and Metformin API

Figure 6: Compatibility study of Metformin and vildagliptin API

Figure 7: Compatibility study of HPMC K100M with Vildagliptin and Metformin API

9.5 Pre-Compression Parameters:

9.6 Flow Properties Of API:

Table 10: Flow properties of Vildagliptin and Metformin API: (Table 12)

Table 11: Flow properties of API with excipients in different formulation:

7 Post Compression Parameters:

Table 12:  Post compression parameter:

Figure 8: Buoyancy lag Time of Vildagliptin and Metformin Tablet Formulations

Figure 9:  Floating tablet image of various formulation F1, F2, F3, F4 and F5

9.8 Swelling Index:

Table 13: Swelling Index

Figure 10:  Swelling index of tablets

Assays of Vildagliptin And Metformin by Hplc:

Table 14: Standard Assay of Vildagliptin and Metformin API’S

Table 15: Sample Assay of Vildagliptin and Metformin Tablets:

Assay Chromatogram of Vildagliptin And Metformin:      

Sample chromatogram assay of vildagliptin in formulation (F2):

Figure 13: Sample Chromatogram assay of Vildagliptin in formulation (F1)

Sample Chromatogram assay of Metformin in formulation (F2):

Figure 14: Sample Chromatogram assay of Metformin in formulation (F2)

Dissolution Of Vildagliptin And Metformin:

Table 17: F2 -Dissolution of Vildagliptin and Metformin

Figure 15: F2 -Dissolution of Vildagliptin and Metformin

Kinetic studies of vildagliptin and metformin matrix tablet:

Kinetic studies of vildagliptin:

Table 18:  kinetic models of vildagliptin in various formulations:

Kinetic models of metformin:

Table: 19 Kinetic models of Metformin in various formulations:

Table 20: Stability study of Vildagliptin and Metformin: