Formulation and Evaluation of Glipizide-Loaded Mucoadhesive Microspheres Using Gum Karaya and HPMC K15M as a Novel Polymer Blend: A Sustained-Release Approach for Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus (T2DM) is a chronic, progressive metabolic disorder characterized by insulin secretory deficiency and peripheral insulin resistance. According to the IDF Diabetes Atlas (2021), approximately 537 million adults worldwide are currently living with diabetes, with projections exceeding 780 million by 2045 [1]. In India, the burden is particularly acute, with an estimated 74 million people affected, placing it among the countries with the highest absolute number of diabetic patients [1,2]. Effective pharmacological management of T2DM necessitates drug delivery strategies that maintain consistent therapeutic plasma drug concentrations and minimize inter-dose fluctuations.

 

Glipizide (C₂₁H₂₇N₅O₄S; MW = 445.54 g/mol) is a second-generation sulfonylurea oral hypoglycaemic agent classified as a BCS Class II drug (low solubility, high permeability). It acts by stimulating insulin secretion from pancreatic β-cells through selective closure of ATP-sensitive potassium channels (ABCC8), leading to membrane depolarization, calcium influx, and exocytosis of insulin granules [3]. Despite its well-established efficacy, Glipizide presents clinically significant pharmacokinetic challenges: a short biological half-life of 2–5 hours, oral bioavailability of approximately 80% (subject to food effect and absorption site dependency), and requirement for administration 30 minutes before meals, 1–3 times daily [4]. This frequent dosing schedule compromises patient adherence, particularly in the elderly T2DM population, and may contribute to erratic glycaemic control with associated risk of hypoglycaemic episodes [5].

 

Mucoadhesive drug delivery systems, particularly microspheres, have emerged as a clinically relevant strategy to address these pharmacokinetic limitations. By establishing intimate, prolonged contact with gastrointestinal mucosal surfaces, mucoadhesive microspheres extend drug residence time, enhance bioavailability, and enable controlled, sustained drug release, thereby reducing dosing frequency and improving therapeutic compliance [6,7]. Ionotropic gelation is a particularly advantageous fabrication technique for mucoadhesive microspheres, offering mild aqueous preparation conditions, avoidance of organic solvents, scalability, and preservation of drug integrity — attributes well-suited to BCS Class II drugs such as Glipizide [8].

 

Among natural polysaccharides explored as mucoadhesive polymers, Gum Karaya (GK) — a plant exudate obtained from Sterculia urens — has attracted considerable interest due to its anionic, partially acetylated galacturonic acid backbone that confers strong gel-forming capacity, high water-swelling ability, and mucoadhesive properties through ionic interactions with mucosal glycoproteins [9,10]. Hydroxypropyl Methylcellulose K15M (HPMC K15M), a semi-synthetic cellulose derivative, provides a well-characterized, hydrophilic sustained-release matrix with extensive hydrogen-bonding capacity via its hydroxypropyl groups, and is widely used in controlled-release pharmaceutical formulations [11,12]. While both polymers have individually been investigated in drug delivery systems, their combination as a binary blend in mucoadhesive microspheres for Glipizide delivery has not been previously reported, to the best of the authors' knowledge.

 

The scientific rationale for the GK–HPMC K15M combination is grounded in the expectation of synergistic mucoadhesion: GK provides ionic mucoadhesive interactions, while HPMC K15M contributes complementary hydrogen-bonding interactions, together creating a denser interpenetrating polymer network (IPN) with superior mucoadhesive and sustained-release properties compared to either polymer alone. The present study therefore aims to: (i) formulate Glipizide-loaded GK–HPMC K15M mucoadhesive microspheres by ionotropic gelation; (ii) systematically optimize the GK:HPMC K15M ratio; (iii) characterize the formulations for physicochemical and biopharmaceutical properties; and (iv) evaluate release kinetics and accelerated stability to establish proof-of-concept for a once-daily Glipizide dosage form.

2.1 Materials

Glipizide (gift sample, BP grade) was obtained from Sun Pharmaceutical Industries Ltd., Mumbai, India. Gum Karaya (pharmaceutical grade) was procured from Himedia Laboratories Pvt. Ltd., Mumbai. HPMC K15M (pharmaceutical grade, Methocel K15M Premium) was supplied by Colorcon Asia Pvt. Ltd., Goa. Calcium chloride (anhydrous, AR grade), hydrochloric acid (AR grade, 35–37%), potassium dihydrogen orthophosphate (AR grade), disodium hydrogen phosphate (AR grade), sodium hydroxide (AR grade), Tween 80, and methanol (HPLC grade) were obtained from SDFCL Fine-Chem Ltd., Mumbai. All materials were used as received without further purification. All aqueous solutions were prepared using freshly distilled water.

 

Table 1: Chemicals and reagents used in the study

2.2 Equipment

 

Table 2: Equipment used in the study

2.3 Drug Profile: Glipizide

 

Figure 1: Chemical structure of Glipizide (C₂₁H₂₇N₅O₄S; MW = 445.54 g/mol)

 

Table 3: Physicochemical and pharmacological profile of Glipizide

2.4 Preformulation Studies

2.4.1 Determination of λmax and Calibration Curve

A primary stock solution of Glipizide (1000 µg/mL) was prepared by dissolving 100 mg of the drug in HPLC-grade methanol in a 100 mL volumetric flask. Working standard solutions in the concentration range of 2–20 µg/mL were prepared by appropriate dilution with phosphate buffer saline (PBS, pH 6.8). The UV absorption spectrum was recorded between 200 and 400 nm using a double-beam UV-visible spectrophotometer (Systronics 117) against the respective blank solvent to determine the wavelength of maximum absorbance (λmax). Calibration curves were constructed in both 0.1 N HCl (pH 1.2) and PBS (pH 6.8), and linearity was confirmed by the coefficient of determination (R²). All measurements were performed in triplicate.

 

Figure 2: Standard calibration curve of Glipizide in PBS pH 6.8 at λmax = 272 nm (n=3, mean ± SD; R² = 0.9999; y = 0.0412x + 0.0062)

2.4.2 Solubility Studies

The saturation solubility of Glipizide was determined at 25 ± 2°C using the equilibrium method. An excess amount of drug (~50 mg) was added to individual screw-capped glass test tubes containing 10 mL of each solvent: distilled water, 0.1 N HCl (pH 1.2), PBS pH 6.8, methanol, and ethanol. Test tubes were sealed and agitated on an orbital shaker at 200 rpm for 24 hours. The resulting suspensions were centrifuged at 3000 rpm for 10 minutes, the supernatant filtered through 0.45 µm nylon membrane syringe filters, suitably diluted, and analysed spectrophotometrically at λmax. All experiments were conducted in triplicate.

 

Table 4: Solubility of Glipizide in various solvents at 25 ± 2°C (n=3, mean ± SD)

Glipizide exhibited practically insoluble behaviour in aqueous media, consistent with its BCS Class II classification. The markedly low solubility in acidic medium (pH 1.2) and the relatively higher — yet still limited — solubility at intestinal pH (6.8) confirm the formulation challenge and underscore the rationale for mucoadhesive microsphere development to enhance oral bioavailability through prolonged mucosal contact.

 

2.4.3 Melting Point Determination

The melting point of Glipizide was determined using the open capillary tube method in a Thiele's tube filled with liquid paraffin. A finely powdered sample was packed into three sealed capillary tubes and heated at a rate of approximately 1°C/minute near the expected melting point. The temperature at which the sample began to melt (onset) and completely melted (clear point) was recorded for each tube. The average of three determinations was reported and compared with the pharmacopoeial standard (B.P./USP: 205–209°C).

 

2.4.4 FTIR Spectroscopic Analysis

ATR-FTIR spectra of pure Glipizide, Gum Karaya, HPMC K15M, and the physical mixture of all three components (at the ratio corresponding to F5) were independently recorded using a Bruker Alpha ATR-FTIR spectrophotometer at ambient temperature (25.0 ± 0.5°C). Each spectrum was acquired by scanning the sample over the wavenumber range of 4000–400 cm⁻¹ at 4 cm⁻¹ resolution, accumulating 32 scans per spectrum. The spectra were analyzed for appearance, disappearance, or significant shifts (> 10 cm⁻¹) of characteristic functional group absorption bands as indicators of drug–excipient chemical interaction.

 

Figure 3: ATR-FTIR spectra of (A) pure Glipizide and (B) physical mixture of Glipizide + Gum Karaya + HPMC K15M. Characteristic peaks of Glipizide are retained in the physical mixture without significant shifts, confirming physicochemical compatibility.

 

Table 5: Interpretation of ATR-FTIR spectra of Glipizide and physical mixture

The characteristic N–H, C=O, and S=O absorption bands of Glipizide were present in the physical mixture spectrum with negligible wavenumber shifts (< 5 cm⁻¹), confirming the absence of significant chemical interaction between Glipizide and the selected excipients. The additional broad O–H stretching band (3412 cm⁻¹) and C–O–C glycosidic linkage band (1045 cm⁻¹) in the mixture spectrum are attributable to the polysaccharide backbones of GK and HPMC K15M and do not represent new bond formation. These findings validate the physicochemical compatibility of the GK–HPMC K15M binary system with Glipizide.

 

2.4.5 Differential Scanning Calorimetry (DSC)

DSC analysis was performed using a Shimadzu DSC-60 differential scanning calorimeter calibrated with indium standard (melting point 156.6°C). Precisely weighed samples (3–5 mg) of pure Glipizide and the physical mixture were placed in crimped aluminium pans with an empty aluminium pan used as reference. Samples were heated from 25°C to 300°C at a programmed heating rate of 10°C/min under a dry nitrogen purge at a flow rate of 50 mL/min. Thermograms were analyzed for characteristic endothermic/exothermic events, peak temperatures, onset temperatures, and enthalpies of fusion (ΔH).

 

Figure 4: DSC thermograms of pure Glipizide (peak: 207.8°C; ΔH = −98.64 J/g) and physical mixture (peak: 206.4°C). The retention of the drug's characteristic melting endotherm with only minor broadening confirms thermal compatibility and rules out solid-state interaction or eutectic formation.

 

2.5 Excipient Profiles

2.5.1 Gum Karaya (GK)

Gum Karaya is a dried exudate obtained from the stems and branches of Sterculia urens Roxb. (family Malvaceae). It is an anionic, high-molecular-weight (9.5 × 10⁶ Da) polysaccharide consisting of a partially acetylated galacturonic acid backbone with branches of galactose and rhamnose units. GK is practically insoluble in organic solvents but swells extensively in water to form viscous colloidal dispersions. It exhibits excellent mucoadhesive properties through anionic interactions with the positively charged sialic acid residues of mucin glycoproteins. GK is classified as GRAS (Generally Recognized As Safe) by the US FDA and finds application as a thickening agent, emulsifier, binder, and mucoadhesive excipient in pharmaceutical formulations [9,10].

 

2.5.2 Hydroxypropyl Methylcellulose K15M (HPMC K15M)

HPMC K15M (Methocel K15M Premium) is a semi-synthetic cellulose derivative with methoxy substitution of 19–24% and hydroxypropoxy substitution of 7–12%. It has a nominal viscosity of ~15,000 mPa·s (2% aqueous solution at 20°C). HPMC K15M is a hydrophilic matrix-forming polymer that swells extensively upon hydration to form a gel layer that controls drug diffusion. It is widely used in oral controlled-release tablets and multiparticulate systems. Its hydroxypropyl groups provide hydrogen-bonding mucoadhesive interactions with mucosal glycoproteins and are an established component in mucoadhesive drug delivery systems [11,12].

 

2.6 Formulation of Glipizide Mucoadhesive Microspheres

Glipizide mucoadhesive microspheres were prepared by the ionotropic gelation technique. Accurately weighed quantities of Gum Karaya and HPMC K15M (as per Table 6) were dispersed sequentially in 20 mL of distilled water under continuous magnetic stirring at 600 rpm for 2 hours to obtain a homogeneous, lump-free polymer solution. GK was added first and allowed to hydrate for 1 hour, followed by addition of HPMC K15M and further stirring for 1 hour. Glipizide (10 mg per batch) was then dispersed into the polymer solution and the mixture stirred for an additional 1 hour to ensure uniform drug distribution. The pH of the polymer–drug dispersion was adjusted to 5.5–6.0 using 0.1 N NaOH prior to extrusion.

 

The resultant dispersion was extruded dropwise through a 23-gauge hypodermic needle (tip-to-bath distance: 5 cm) into a gently stirred crosslinking bath containing 50 mL of 2% w/v calcium chloride solution at room temperature (25 ± 2°C), maintained at 100 rpm. Microspheres formed instantaneously upon contact with the divalent cation crosslinker. After 30 minutes of curing, microspheres were recovered by vacuum filtration through Whatman No. 1 filter paper, washed three times with 10 mL of distilled water to remove residual CaCl₂, and spread in a single layer on wax-coated weighing paper. Microspheres were dried in a hot air oven at 40 ± 2°C for 6 hours and stored in a glass desiccator containing silica gel at room temperature until further use. The rationale for the one-factor-at-a-time (OFAT) design was to isolate the effect of GK concentration on microsphere properties, with HPMC K15M maintained constant (300 mg) as the baseline hydrophilic matrix-forming polymer, consistent with established OFAT optimization approaches in mucoadhesive microsphere literature [6,13].

 

Table 6: Formulation design of Glipizide mucoadhesive microspheres F1–F8 (*Optimized formulation)

2.7 Evaluation of Microspheres

2.7.1 Optical Microscopy and Surface Morphology

The shape and surface morphology of dried microspheres were examined under a calibrated optical microscope (Magnus MLX-B) equipped with a digital camera at 40× magnification. Representative photomicrographs were captured for each formulation. Surface morphology was also qualitatively assessed for sphericity, smoothness, and absence of aggregation.

 

2.7.2 Particle Size Analysis

Mean particle diameter was determined by optical micrometry. A small quantity of microspheres was uniformly dispersed in liquid paraffin on a clean glass slide and examined under the calibrated optical microscope. The stage micrometer calibration factor was 1.52 µm per ocular division. A minimum of 100 microspheres per formulation batch were individually measured along the longest (a) and shortest (b) axes; the mean diameter was calculated as (a + b)/2. Results are expressed as mean ± standard deviation (SD). The experiment was performed in triplicate (n=3).

 

2.7.3 Zeta Potential

Zeta potential of the microsphere dispersions was measured using a Malvern Zetasizer Nano ZS at 25°C. Microspheres (approximately 2 mg) were dispersed in 10 mL of distilled water and sonicated for 30 seconds prior to measurement. Results are expressed as mean ± SD (n=3). Zeta potential values more negative than −20 mV indicate adequate electrostatic repulsion for physical colloidal stability; values more negative than −30 mV indicate excellent stability [14].

 

2.7.4 Percentage Yield

The percentage production yield of each formulation batch was calculated gravimetrically as the ratio of the practical weight of dried microspheres (W_practical) to the theoretical total weight of all components used — drug plus polymers (W_theoretical) — expressed as a percentage: % Yield = (W_practical / W_theoretical) × 100.

 

2.7.5 Drug Entrapment Efficiency (%EE)

An accurately weighed quantity of crushed microspheres equivalent to 10 mg of Glipizide was transferred to a 100 mL volumetric flask, dissolved in HPLC-grade methanol, and the volume made up to 100 mL. The solution was filtered through a 0.45 µm membrane filter and suitably diluted with PBS pH 6.8 prior to spectrophotometric analysis at λmax = 272 nm. %EE = (actual drug content / theoretical drug content) × 100. All measurements were performed in triplicate.

2.7.6 Swelling Index

The swelling behaviour of microspheres was assessed gravimetrically. Pre-weighed microspheres (W_dry, approximately 50 mg) were placed in the basket of a USP dissolution apparatus (rotating basket, Type I, 100 rpm) containing 900 mL of 0.1 N HCl (pH 1.2) at 37 ± 0.5°C. At predetermined time intervals (0.5, 1, 2, 3, 4, 5, and 6 hours), microspheres were carefully removed from the basket, blotted gently with Whatman No. 1 filter paper to remove superficial moisture, and immediately weighed (W_wet). Swelling index (SI) = [(W_wet − W_dry) / W_dry] × 100. All experiments were performed in triplicate.

 

2.7.7 Mucoadhesion Study (In Vitro Wash-Off Method)

In vitro mucoadhesion was evaluated by the modified wash-off method. Fresh goat small intestinal mucosa was obtained from a local abattoir within 1 hour of slaughter and used immediately. A 3 × 3 cm segment of intestinal mucosa was carefully mounted, mucosal side outward, on a glass slide using cyanoacrylate adhesive and equilibrated in simulated intestinal fluid (SIF, pH 6.8 without enzymes) at 37°C for 15 minutes. Approximately 50 dried microspheres were spread uniformly on the moistened mucosal surface and allowed to adhere for 30 minutes at 37°C. The slide was then attached to the basket holder of a USP disintegration apparatus and subjected to an up-and-down dipping motion in 200 mL of PBS pH 6.8 at 37 ± 1°C. The number of microspheres remaining adherent on the mucosa was counted under a low-power magnifying lens at 1, 2, 4, 6, 8, and 12 hours. % Mucoadhesion = (number adhered / total applied) × 100. Animal tissue use was in accordance with institutional ethical guidelines (JNTUA-OTPRI-IAEC-2024-12). Experiments were performed in triplicate (n=3).

 

2.7.8 Powder Flow Properties

Bulk density (ρ_bulk), tapped density (ρ_tapped), Carr's compressibility index (CI), Hausner's ratio (HR), and angle of repose (θ) were determined for all formulations using established pharmacopoeial methods (USP ⟨1174⟩). Carr's index = [(ρ_tapped − ρ_bulk) / ρ_tapped] × 100; HR = ρ_tapped / ρ_bulk; tan θ = height/radius of powder cone. These parameters collectively assess the flowability and compressibility of the microsphere powder, which are critical for uniform dosage unit filling during large-scale manufacturing.

 

2.7.9 In Vitro Drug Release Study

In vitro dissolution studies were carried out using a USP Type II (paddle) dissolution apparatus (Lab India DS 8000) at 37 ± 0.5°C and 100 rpm. Microspheres equivalent to 10 mg of Glipizide were filled in hard gelatin capsules (size 0) to simulate a unit dose. A biorelevant biphasic dissolution medium was employed: 900 mL of 0.1 N HCl (pH 1.2) containing 0.02% w/v Tween 80 for the first 2 hours (simulating gastric transit), followed by medium replacement with 900 mL of PBS pH 6.8 for the remaining 10 hours (simulating intestinal transit). Aliquots of 10 mL were withdrawn at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours, immediately replaced with equal volumes of fresh pre-warmed dissolution medium to maintain sink conditions, filtered through 0.45 µm membrane filters, and analysed spectrophotometrically at λmax = 272 nm. The cumulative percentage drug release (%CDR) was calculated and plotted as a function of time. All experiments were performed in triplicate (n=3).

 

2.8 Release Kinetics Modelling

In vitro drug release data were subjected to curve fitting with four mathematical models: Zero-order (Qt = Q₀ + K₀t), First-order [log(Qr) = log Q₀ − K₁t/2.303], Higuchi diffusion (Qt = K_H · t½), and Korsmeyer–Peppas (F = K · tⁿ), where Qt = amount of drug released at time t, Q₀ = initial amount of drug, Qr = drug remaining, K₀, K₁, K_H, and K are the respective rate constants, and n is the diffusion exponent. The best-fit model was identified by the highest coefficient of determination (R²). The transport mechanism was classified using the n value from the Korsmeyer–Peppas model: n ≤ 0.45 (Fickian diffusion), 0.45 < n < 0.89 (Non-Fickian anomalous transport), n = 0.89 (Case-II transport / zero-order) [15,16].

 

2.9 Accelerated Stability Studies

The optimized formulation (F5) was subjected to accelerated stability testing as per ICH Q1A(R2) guidelines [17]. Microspheres were filled into amber glass vials, sealed, and stored at 40 ± 2°C / 75 ± 5% RH in a calibrated stability chamber (Thermo Fisher Scientific). Samples were withdrawn at 0, 1, 2, and 3 months and evaluated for physical appearance, drug content, particle size, and in vitro drug release profile. Statistical analysis was performed using one-way ANOVA with post-hoc Tukey's test (GraphPad Prism 9.0); p < 0.05 was considered statistically significant.

 

 

 

 

Table 10: Accelerated stability data for optimized formulation F5 (n=3, mean ± SD; NS = not significant, one-way ANOVA with Tukey's post-hoc test)

The optimized formulation F5 demonstrated excellent physicochemical stability throughout 3 months of accelerated testing (Table 10, Figure 12). No statistically significant changes were observed in physical appearance, drug content, particle size, FTIR spectral pattern, or in vitro drug release profile (p > 0.05 for all parameters). The integrity of the GK–HPMC K15M
crosslinked matrix under conditions of elevated temperature and humidity confirms the stability of ionotropic crosslinks formed with Ca²⁺ ions and the absence of moisture-induced degradation under stressed conditions. Long-term real-time stability studies at 25 ± 2°C / 60 ± 5% RH are currently ongoing and will be used to formally calculate shelf-life per ICH Q1E guidance.

The present study successfully demonstrates, to the best of the authors' knowledge, the first formulation and comprehensive evaluation of Glipizide-loaded mucoadhesive microspheres using a novel binary blend of Gum Karaya and HPMC K15M via ionotropic gelation. Systematic optimization of the GK:HPMC K15M ratio identified F5 (1:1 w/w, 2% w/v CaCl₂) as the optimal formulation, demonstrating particle size of 254.82 ± 0.64 µm, spherical morphology, zeta potential of −28.7 ± 1.6 mV, EE of 94.76 ± 1.23%, swelling index of 96.84 ± 1.54%, mucoadhesion of 94.2 ± 1.8% at 12 hours, and 12-hour CDR of 96.42 ± 2.11%. Preformulation FTIR and DSC studies confirmed physicochemical drug–excipient compatibility. Drug release followed the Higuchi diffusion model with Non-Fickian anomalous transport (n = 0.589), reflecting a combined diffusion–erosion mechanism through the interpenetrating GK–HPMC K15M polymer network. Accelerated ICH stability studies confirmed physicochemical robustness for at least 3 months under stressed conditions.

 

The synergistic mucoadhesive performance of the GK–HPMC K15M binary system — superior to either polymer alone — constitutes the central scientific novelty of this work. This sustained-release mucoadhesive platform offers a clinically promising strategy to reduce Glipizide administration from three times daily to once daily, potentially improving patient compliance and glycaemic management in Type 2 Diabetes Mellitus. Future studies will include in vivo pharmacokinetic and pharmacodynamic evaluation in streptozotocin-induced diabetic rat models, XRPD characterization to confirm amorphization within the microsphere matrix, and formal ICH Q1E shelf-life estimation from ongoing long-term stability studies.

 

5. ETHICAL STATEMENT

The use of goat intestinal mucosa for in vitro mucoadhesion studies was approved by the Institutional Animal Ethics Committee (IAEC) of JNTUA-Oil Technological and Pharmaceutical Research Institute, Ananthapurumu, Andhra Pradesh, India (Approval No. JNTUA-OTPRI-IAEC-2024-12). No live animals were used in this study; all tissue was obtained as abattoir by-product in accordance with applicable regulations.

 

6. CONFLICT OF INTEREST

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

 

7. ACKNOWLEDGEMENTS

The authors are sincerely grateful to Sun Pharmaceutical Industries Ltd., Mumbai, India for providing Glipizide as a gift sample, and to Colorcon Asia Pvt. Ltd., Goa, India for supplying HPMC K15M (Methocel K15M Premium). The authors also acknowledge the Management, Principal, and Head of Department of Pharmaceutics and Pharmacology, JNTUA-Oil Technological and Pharmaceutical Research Institute, Jawaharlal Nehru Technological University Anantapur (JNTUA), Ananthapurumu, Andhra Pradesh, for providing the laboratory facilities, instrumentation, and the enabling research environment to carry out this work.

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