1. INTRODUCTION:

Oral drug administration faces absorption challenges due to physiological limitations such as inconsistent gastrointestinal movement, incomplete drug discharge, and limited drug action duration. Gastro retentive drug delivery systems (GRDDS) address these issues by retaining formulations in the stomach for prolonged periods, ensuring a sustained release of active components. In situ systems, among other methods, are increasingly researched to extend gastric residence time and regulate drug levels in the bloodstream^1,2. Among GRDDS, in situ, floating gelation systems, particularly rafting systems, show promise³. These systems form a gel matrix in the stomach, prolonging residence time and drug discharge. This extended retention enhances absorption and therapeutic outcomes, potentially optimizing efficacy, reducing dosing frequency, and improving patient compliance.

Raft-forming in situ gelation involves liquid transforming into a cohesive gel upon contact with gastric fluids, ensuring buoyancy and sustained drug discharge⁴.

Targeted drug delivery is a key focus in modern pharmaceutical research. Type 2 diabetes mellitus (T2DM) is a widespread disease with severe complications including blindness, limb amputation, kidney failure, and cardiovascular events. The global prevalence of diabetes in adults has quadrupled since 1980. To tackle this, Vildagliptin (VGN), a novel antidiabetic drug in the dipeptidyl peptidase IV (DPP-4) inhibitors class, targets the incretin system⁵.

VGN operates through the modulation of the incretin hormone glucagon-like peptide 1 (GLP-1), discharged in the intestinal wall post-food intake⁶. GLP-1 stimulates insulin secretion, inhibits glucagon, and is degraded by DPP-4. VGN, a potent DPP-4 inhibitor, raises GLP-1 levels, lowering glucose and enhancing glycemic control in T2DM by improving pancreatic islet function. Used alone, it suppresses inappropriate glucagon, stimulates insulin and reduces glycated hemoglobin with minimal hypoglycemia and no weight gain. Combined with other oral antidiabetic agents, VGN shows synergistic effects⁷.

Orally administered VGN showcases rapid absorption, with 85% eliminated via renal excretion. About 70% undergo metabolism through hydrolysis, with 23% excreted unchanged in urine. Importantly, food digestion does not alter the drug's pharmacokinetics⁸.

In the early stages, VGN and DPP-728 underwent preclinical studies with promising safety profiles. Minimal species-specific safety signals were observed. The in situ gel formulation for VGN offers benefits like enhanced gastric retention and improved bioavailability, addressing challenges associated with oral dosing and drug toxicity to enhance therapeutic performance for better patient outcomes⁹.

The study presented here concentrates on developing and evaluating a gastro-retentive gel designed for the precise delivery of Vildagliptin to the stomach. The main goal is to extend the residence time and improve the delivery of the drug at the intended location. The in situ synthesis of these gels employed a gelation method controlled by cations, incorporating different combinations and concentrations of pectin and HPMCK4M.

2. MATERIALS AND METHODS:

Vildagliptin was procured from Yarrow Chemicals, Mumbai. Calcium carbonate, calcium chloride, HPMC K4M, pectin, sodium alginate, and sodium citrate were sourced from Fischer Scientific, Bangalore. All utilized ingredients were of AR grade, and the experiments were conducted using double-distilled water.

2.1. Preparation of in situ gels:

A formula was generated using Design Expert software (Stat ease. Version 12) using pectin and HPMC K4M as independent variables to find the responses (CDR at 13, 30, 60, 120, and 240 min¹⁰. To create an in situ floating gel for VGN, a cation-controlled gelation method was used. Distilled water, sodium citrate, and calcium chloride dissolved at different polymer levels under continuous stirring at 800 rpm. The solutions were heated to 70°C, stirred continuously, and then cooled below 40°C. VGN and calcium carbonate were added, and the gel was stirred until uniformly dispersed. Preservatives and sweeteners were added, and the resulting gel was stored in an amber bottle for later use (Table 1).

2.2 Evaluation:

2.2.1. Appearance and pH:

The visual attributes of the gels were meticulously scrutinized, and the pH values of the in situ gel solutions containing VGN were assessed at a temperature of 25°C using a precise digital pH meter¹¹. Thorough characterization was achieved by subjecting each formulation to three distinct pH measurements and diligently recording the average value obtained, thereby ensuring the precision of the analysis^12-14.

2.2.2. In vitro gelation:

To assess the in vitro gelling capacity, a gelling solution was created using an HCl solution (0.1 N, pH 1.2). Subsequently, 1 ml of each formulation was introduced into a 10 ml gelling solution while maintaining a consistent temperature of 37±1°C. The gelation process commenced as the formulation interacted with the gelling solution¹⁵. The evaluation of gelation capacity took into consideration both the time taken for gelation and the duration of gel formation. The assessment utilized the following scoring system^16-18:

- "+": Gelling in few seconds and disperses rapidly

- "++": Gels instantly and float for 12 h

- "+++": Gels instantaneously and float for > 12 h

Table 1: Various trials of VGN in-situ gel formulations

Trials	VGN (mg)	Pectin (mg)	HPMC K4M (mg)	SA (mg)	SC (mg)	CaCl₂ (mg)	CaCO₃ (mg)	MP (mg)	PP (mg)	SP (mg)	DW (q.s) (ml)
T-1	100	0.50	0.40	1	0.25	0.15	0.75	0.15	0.05	0.1	100
T-2	100	1.00	0.40	1	0.25	0.15	0.75	0.15	0.05	0.1	100
T-3	100	0.50	0.80	1	0.25	0.15	0.75	0.15	0.05	0.1	100
T-4	100	1.00	0.80	1	0.25	0.15	0.75	0.15	0.05	0.1	100
T-5	100	0.39	0.60	1	0.25	0.15	0.75	0.15	0.05	0.1	100
T-6	100	1.10	0.60	1	0.25	0.15	0.75	0.15	0.05	0.1	100
T-7	100	0.75	0.32	1	0.25	0.15	0.75	0.15	0.05	0.1	100
T-8	100	0.75	0.88	1	0.25	0.15	0.75	0.15	0.05	0.1	100
T-9	100	0.75	0.60	1	0.25	0.15	0.75	0.15	0.05	0.1	100

SA: Sodium alginate; SC: sodium citrate; CaCl₂: calcium chloride; CaCO₃: calcium carbonate; MP: Methyl paraben; PP: Propyl paraben; SP: Stevia powder; DW: Distilled water

2.2.3. Viscosity:

The viscosities of various in situ gels were assessed using a Brookfield viscometer (DV-II+Pro digital) by placing 20 ml of sample in a beaker. The T-shaped shaft was meticulously lowered vertically to the center of the cup, ensuring it did not make contact with the bottom¹⁹. Viscosities were measured at 50 rpm, and the temperature was carefully kept throughout the procedure. To enhance precision, the average of three measurements was considered for each viscosity assessment^20,21.

2.2.4. Buoyancy:

An in vitro buoyancy study was performed with the USP-II dissolution device (Electrolab, India). For this study, 10 ml of the VGN in situ gel was introduced into the container, which was filled with simulated gastric fluid (0.1 N HCl, pH 1.2) at 37±0.5°C to mimic physiological conditions²². The study observed and recorded two critical parameters: the float delay time, representing the duration for the formulation to achieve buoyancy, and the total float time, indicating the overall duration the formulation remained afloat^23-25. These measurements provided insights into the buoyancy characteristics of the in situ gel and its behaviour in simulated gastric environments^1,26,27.

2.2.5. Density:

The density of the formulation was ascertained through the water displacement method. To execute this, 10 ml of the formulation solution was poured into 50 ml of 0.1 N HCl, initiating the gelation process. Subsequently, the resulting gel was meticulously transferred into a graduated cylinder to facilitate sedimentation. Both the volume and weight of the formed gel were then carefully measured^28,29. By combining these precise measurements of volume and weight, the density of the gel was estimated using the water displacement method. This method provides an accurate means to determine the density of the gel by considering the volume of water exiled when the gel is introduced³⁰.

2.2.6. Gel strength:

In the conducted study, a specific gravity of 30 g was applied to the formed gel. A 50g weight was centrally placed on the surface of the gel and allowed to pass through it. The duration taken for the weight to descend 5 cm through the prepared gel was considered an indicator of its strength^27,31. To ensure accuracy and reliability, three readings were recorded for each test, and the average of these readings was calculated. This approach was adopted to thoroughly evaluate the gel strength, providing a representative measure of its resistance to the applied force ^32,33.

2.2.7. VGN content:

A Shimadzu double-beam UV–visible spectrophotometer quantitatively analyzed VGN content in the in situ gel. 10 ml of the formulation, containing 100 mg of VGN, dissolved in 80 ml of 0.1 N HCl, underwent one-hour continuous stirring. The resulting solution was filtered and diluted with 0.1 N HCl to reach a total volume of 100 ml. Absorption was measured at 245 nm, providing crucial information for comprehensive characterization^34,35.

2.2.8. Water uptake:

The formulation was immersed in 40 ml of 0.1 N HCl (pH 1.2), and then gelled under controlled temperature. After separating and drying the gel, its initial weight was recorded. Subsequent weight measurements were taken at 30-minute intervals after adding 10 ml of distilled water, providing a systematic evaluation of weight changes over time^36,37.

2.2.9. In vitro VGN discharge:

VGN discharge was conducted using a USP Type II apparatus with a paddle stirrer at 50 rpm and a temperature of 37±0.5°C. The dissolution medium comprised 900 ml of 0.1 N HCl (pH 1.2). A 10 ml in situ gel equivalent to 100 mg of VGN was introduced into the medium at 37°C ± 0.5°C. Samples were collected at designated intervals, and the withdrawn volume was replaced with fresh medium. Filtered samples were diluted with the dissolution medium and analyzed using UV spectrophotometry at 245 nm to assess the VGN discharge profile over specified time intervals³⁸.

2.2.10. Optimization of in-situ gel by factorial design:

The evaluation results were analyzed through multiple regression analysis to formulate equations describing the influence of independent variables on selected responses, aiming to streamline and optimize the formulation process cost-effectively³⁹. The dependent variables included the percentage of cumulative drug discharge at various time points (15, 30, 60, 120, and 240 min). Two independent factors, namely pectin level (X₁) and HPMC level (X₂), were considered. High and low values for each factor were coded as +1 and -1, respectively, with the mean coded as zero. The chosen ranges for each factor were based on preliminary studies⁴⁰. This design was selected for its ability to provide sufficient degrees of freedom to evaluate the main effects and interactions between factors^41-43.

2.2.11. Accelerated stability studies:

The selected gels were stored in light-resistant bottles and subjected to stability studies following ICH guidelines, at 40±2°C and 75±5% RH for 6 months. Regular examinations assessed changes in appearance, active ingredient content, pH, in vitro buoyancy, and drug discharge. These evaluations aimed to determine the formulations' stability under varied storage conditions, offering vital insights into their resilience over time^44,45.

3. RESULTS AND DISCUSSION:

3.1. Appearance and pH:

The visual presentation of a pharmaceutical formulation is crucial for patient adherence to oral drug intake. In our investigation, we examined the visual attributes and pH of all gels, with results summarized in Table 2. Formulations T-1 to T-9 had a greenish-yellow appearance. The pH values ranged from 6.95±0.05 (T-8) to 7.81±0.64 (T-2), within the orally acceptable range, suggesting these formulations are unlikely to cause oral irritation. Moreover, the solutions exhibited a fluid consistency at room temperature, devoid of any signs of gelation⁴⁶. This attribute represents that the formulations maintain a liquid state until they encounter gastric fluid in the stomach. The visual presentation and pH measurements of the formulations validate their aesthetic appeal and indicate pH values were found to be as specified for orally given drugs⁴⁷.

3.2. In vitro gelation:

The evaluation of gelation capacity holds significant importance in assessing in situ gelation systems, as it measures the system's efficacy in swiftly transitioning from a sol to a gel state through ionic cross-interactions. This transition is crucial for converting a liquid formulation into a gel post-ingestion. In our study, all formulations underwent in vitro gelation analysis, and their gelation properties were evaluated on a standardized scale from ++ to +++ (Table 2). Remarkably, all formulations established effective gelation, trial T-4 and T-6 exhibiting immediate gelation and maintaining the gel beyond 12h⁴⁷. In contrast, reaming formulations showed good gelation with sustainability for 12 h⁴⁸.

3.3. Viscosity:

Viscosity is crucial in developing oral drug delivery systems as it affects ease of administration. Our study measured viscosities ranging from 245.2±3.6 to 322.9±7.1 cps, as detailed in Table 2. Optimal viscosity balances fluidity for easy administration with sufficient thickness to adhere to the target site. The range of viscosities in our formulations suggests a tailored approach for effective oral delivery⁴⁹. Viscosity is crucial for ensuring patient compliance, as appropriate viscosity aids in easy swallowing and consistent dosing⁵⁰.

The viscosity trend shows a direct correlation between increasing levels of gelling polymers and rising viscosity, due to heightened cross-linking and a more intricate network structure^51,52. This aspect of the study highlights the formulation's tunability, allowing viscosity adjustments for optimal oral drug delivery⁵³.

3.4. In vitro buoyancy:

The objective of this study was to evaluate the float delay time and total float time of the generated gel, and the results are succinctly presented in Table 2. From the findings, it can be deduced that trial (T-4) displayed superior buoyancy properties in comparison to the other in situ gels. These formulations exhibited rapid gel formation (within 30 sec), which was notably faster than the remaining formulations. All the gels remained buoyant for >12 h, indicating a prolonged duration of buoyancy⁵⁴.

3.5. VGN content:

The findings in Table 3 show the percentage content of the active ingredient across various formulations, ranging from 79.29±6.95% to 97.36±2.56%. This indicates a uniform distribution of the active ingredient, meeting monograph standards. Trial T-4 was particularly notable, with the highest VGN content at 97.36±2.56%. This high and consistent active ingredient content in T-4 underscores its potential effectiveness in delivering the intended therapeutic dose.

Table 2: Physical assets of prepared in situ gels

Trials	Physical appearance	pH	Gelling capacity	Viscosity (cps)	Buoyant lag time (s)	Total buoyant time (h)
T-1	Greenish yellow	7.52±0.05	++	245.2±3.6	58±1	>12
T-2	Greenish yellow	7.81±0.64	++	306.3±2.9	56±2	>12
T-3	Greenish yellow	7.05±0.27	++	245.9±1.5	48±3	>12
T-4	Greenish yellow	7.62±0.08	+++	282.3±6.3	68±4	>12
T-5	Greenish yellow	6.98±0.35	++	294.7±8.9	65±3	>12
T-6	Greenish yellow	7.27±0.29	+++	322.9±7.1	62±6	>12
T-7	Greenish yellow	7.34±0.68	++	278.8±1.9	59±4	>12
T-8	Greenish yellow	6.95±0.05	++	269.7±7.8	54±6	>12
T-9	Greenish yellow	7.17±0.14	++	282.3±9.5	61±2	>12

Values in mean ±SD; n = 3; ++: immediate gel formation with buoyancy for 12 h;

+++: immediate gel formation with buoyancy >12 h

3.6. Water uptake:

The percentage of water content in a drug delivery system critically influences drug discharge by affecting water penetration into the polymer matrix. In this study, % water absorption by the gels over 2 h ranged from 12.36±0.11% to 21.74±0.09%. The T-4 trial demonstrated superior water absorption, attributed to higher levels of pectin and HPMC K4M. This increased absorption enhances drug delivery by facilitating deeper penetration into the polymer matrix, leading to a faster and more efficient drug discharge process. T-4's greater water absorption suggests it is a promising candidate for optimizing drug delivery in situ gel formulations.

3.7. Density:

The low density of gastroretentive in situ floating gels is crucial for buoyancy in gastric fluid. The study measured densities (0.626±0.05 to 0.748±0.01 g/cm³), affirming they are lower than stomach contents (1.004 g/cm³). This buoyancy ensures prolonged gastric retention, facilitating sustained drug discharge and enhancing therapeutic efficacy.

3.8. Gel strength:

Gel strength, crucial for resisting peristaltic movements in vivo, was measured in this study (49.16±8.95 to 69.25±6.38 sec). Trial T-4, with a value of 69.25±6.38 sec, exhibited notable gel resistance. Enhanced gel strength in T-3 can be attributed to elevated levels of pectin and HPMC K100M, fostering stronger gel structures. These polymers contribute to increased cross-linking and gelation capacity. T-4's robust gel strength ensures integrity during transportation in the gut, vital for GRDDS and facilitating sustained drug discharge. The observed strength position of T-4 favour drug delivery, promising prolonged discharge and improved therapeutic outcomes. (Table-3).

3.9. In vitro drug discharge:

The 12-hour VGN discharge study using 0.1 N HCl revealed that higher polymer levels (pectin and HPMC K4M) enhanced sustained drug discharge. T-4 exhibited the highest drug discharge, indicating effective control and prolonged release due to its robust gel matrix. This finding suggests the potential for prolonged therapeutic effects and improved patient compliance with reduced dosing frequency. (Figure-1).

Table 3: VGN content, water uptake, gel strength, and density of the in situ gels

Trials	Drug content (%)	Water uptake (%)	Gel strength (sec)	Density (g/cm³)
T-1	85.26±4.82	12.36±0.11	52.21±2.62	0.659±0.05
T-2	84.37±4.64	14.68±0.06	55.36±1.64	0.698±0.04
T-3	79.29±6.95	17.86±0.11	51.29±3.96	0.696±0.05
T-4	97.36±2.56	21.74±0.09	69.25±6.38	0.748±0.01
T-5	80.26±5.92	19.65±0.14	53.95±4.92	0.701±0.03
T-6	95.69±3.87	14.65±0.07	66.92±2.65	0.711±0.04
T-7	82.33±7.02	18.65±0.06	49.16±8.95	0.629±0.03
T-8	86.31±1.08	17.25±0.07	51.22±8.02	0.647±0.02
T-9	91.07±3.69	18.65±0.08	58.26±7.05	0.626±0.05

Values in mean ±SD; n = 3

Fig. 1. Drug discharge from the in-situ gel formulations

3.10. Factorial design:

The percentage of cumulative drug discharge at different time points (15, 30, 60, 120, and 240 min) was the dependent variable analyzed using Design Expert software. The final equations in terms of coded factors were enlisted below:

CDR-15 min

=+44.60+1.28A-2.17B-0.7250AB-0.6813A²-1.83B²

CDR-30 min

=+48.95+1.17A-2.00B-0.6625AB-0.8431A²-2.02B²

CDR-60 min

=+86.95+1.38A-2.54B-1.0800AB-0.7938A²-2.22B²

CDR-120 min

=+94.15+1.38A-1.59B-0.6950AB-0.1281A²-1.38B²

CDR-240 min

=+95.10+1.50A-1.70B-1.1300AB-0.3787A²-1.45B²

Table 4: BBD layout with results of responses

Trials	Factors		Responses (% CDR at different intervals)
Trials	A:Pectin (mg)	B:HPMC K4M (mg)	CDR-15 (%)	CDR-30 (%)	CDR-60 (%)	CDR-120 (%)	CDR-240 (%)
T-1	0.50	0.40	42.60	46.95	84.59	92.64	92.80
T-2	1.00	0.40	46.50	50.00	89.25	96.52	97.85
T-3	0.50	0.80	39.20	43.60	80.74	90.70	91.51
T-4	1.00	0.80	40.20	44.00	81.08	91.80	92.04
T-5	0.39	0.60	41.30	45.12	83.26	91.47	91.80
T-6	1.10	0.60	45.10	49.30	87.51	95.78	96.32
T-7	0.75	0.32	43.60	47.20	85.47	93.26	94.20
T-8	0.75	0.88	38.20	42.50	79.60	89.00	89.62
T-9	0.75	0.60	44.60	48.95	86.95	94.15	95.10

Contour plots illustrate the impact of pectin and HPMCK4M amounts on the % cumulative drug discharge (CDR) at various time points (Figure 2). The optimal amounts, 0.7975 mg of pectin and 0.5476 mg of HPMC K4M aim to achieve desired % CDR values: 45.29% at 15 min, 49.55% at 30 min, 87.74% at 60 min, 94.76% at 120 min, and 95.77% at 240 min. Each contour plot indicates how changes in these components affect the % CDR at the respective time points, guiding towards regions that meet the desired outcomes (Figure 3).

Fig.2. Contour plots of inputs on the responses

Fig.3. Desirable values of the responses

3.11. Accelerated stability studies:

The formulation (T-4) exhibited no significant changes in form and buoyancy percentage during the accelerated stability study. The VGN content of these formulations remained stable, even after stressed storage conditions for 6 months. No significant differences in drug discharge were observed during this period.

4. CONCLUSION:

In conclusion, the research successfully developed an in situ floating gelation system, offering a promising alternative to conventional drug delivery methods. Key findings include immediate gelation, prolonged flotation, consistent active ingredient content, and favorable gel strength in T-4 trials. These formulations showed superior water absorption, controlled and sustained drug release, and extended gastric retention. The study affirms the effectiveness of gastro-retentive in situ gelation systems in enhancing drug delivery and bioavailability, paving the way for advancements in drug delivery technologies and therapeutic applications.

5. ACKNOWLEDGEMENTS:

The authors are thankful to Rajiv Gandhi University of Health Sciences, Bangalore for providing a UG research grant for performing the work.

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Received on 31.12.2023 Revised on 10.04.2024

Accepted on 21.06.2024 Published on 24.12.2024

Available online from December 27, 2024

Research J. Pharmacy and Technology. 2024;17(12):5923-5930.

DOI: 10.52711/0974-360X.2024.00898