DESIGN AND FORMULATING GLICLAZIDE SOLID DISPERSION IMMEDIATE RELEASE LAYER AND METFORMIN SUSTAINED RELEASE LAYER IN BILAYER TABLET FOR THE EFFECTIVE POSTPRANDIAL MANAGEMENT OF DIABETES MELLITUS

DESIGN AND FORMULATING GLICLAZIDE SOLID DISPERSION IMMEDIATE RELEASE LAYER AND METFORMIN SUSTAINED RELEASE LAYER IN BILAYER TABLET FOR THE EFFECTIVE POSTPRANDIAL MANAGEMENT OF DIABETES MELLITUS

Purushottam S. Gangane ^{* 1}, Manish M. Kadam ², Debarshi Kar Mahapatra ¹, Nilesh M. Mahajan ¹ and Ujwala N. Mahajan ¹

Department of Pharmaceutics ¹, Dadasaheb Balpande College of Pharmacy, Nagpur - 440037, Maharashtra, India.

Department of Industrial Pharmacy ², IBBS College of Pharmacy, Malkapur - 443101, Buldhana, Maharashtra, India.

ABSTRACT: In order to effectively manage the diabetic mellitus type-II hyperglycemic surge, bilayered tablets comprising of gliclazide in immediate release layer (IRL) and metformin in sustained release layer (SRL) have been designed and fabricated for years. Gliclazide suffers from reduced aqueous solubility of 0.19 mg/mL which remained a crucial problem for the biological effect as a result of reduced dissolution and bioavailability. Therefore, in this research an effort was done to improve the aqueous solubility of gliclazide in a bilayer tablet by forming solid dispersions which will provide prompt release to completely manage the postprandial effectually. In this study, a bilayer tablet of gliclazide solid dispersion in IRL and metformin in SRL were fabricated by direct compression method, with an intention that the IRL of the formulation will release the gliclazide at its earliest to combat the postprandial hyperglycemic level followed by a control of steady state plasma glucose by sustained release metformin. The compatibility studies, pre-compression studies, post-compression studies, disintegration studies, dissolution studies, and kinetic release studies were performed. The formulation B3 was found to be highly optimized and demonstrated the highest cumulative drug release where the metformin followed the either zero-order or first-order and the gliclazide followed anomalous diffusion. Therefore, the designed formulation will offer a better therapeutic regimen and provide patient friendly postprandial hypoglycemic management, where an immediate control and maintenance dose are required.

Gliclazide, Metformin, Bilayer, Solid dispersion, Diabetes mellitus, Postprandial

INTRODUCTION: Insulin is the chief hormone responsible for the maintenance of glucose homeostasis in the human body. It performs by hastening the uptake of glucose molecules into the tissues and concurrently suppresses the glucose production ¹.

However, a lack of insulin level leads to several severe chronic metabolic disturbances of carbohydrate, fat and protein, that is often characterized termed as diabetes mellitus (DM) ². DM is a classified into two types; Type-I and Type-II, where the former is characterized by high blood sugar as the body does not generate enough insulin that is necessary to convert sugar into energy. In the later phase, cells do not properly use the produced insulin by the body ³.

DM Type-II is the fastest progressing metabolic disorder of this 21^st century where 400 million individuals are currently affected ⁴. In the due course of time, several anti-diabetic drugs were developed which inhibit diverse enzymatic targets like protein tyrosine phosphatase-1B, dipeptidyl peptidase-4, α-glucosidase, aldose reductase, etc. However, the majority of the drugs on their individual use for the long term management of hyperglycemia seemed inactive ⁵.

Due to the chronic disease and long term treatment; they usually suffer from low duration of activity, compromised pharmacokinetic profile, and often reduce the quality of life on long usage ⁶.

The effectiveness of the pharmacotherapy depends on designing drug formulations which provide better postprandial hyperglycemic control as well as day-long duration. The in-vivo secretion of insulin gets stimulated by the glucose, which classically follows a biphasic pattern in the time course ⁷. In the first phase secretion, with the increase in the glucose concentration, a brief stimulation occurred which promote insulin secretion. While in the second phase secretion, a steadily rising secondary stimulation is observed ⁸. In the case of DM type-II, a disturbance or loss of secretion in the insulin release pattern of the first phase is evidenced. In the second phase secretion, due to the inherent resistance in the cellular level and because of energy-dependent process, a hyperglycemic phase is habitually observed which results in elevated plasma glucose level ⁹. In both the cases seen cumulatively, after a heavy meal, hyperglycemia conditions are detected.

To combat such situation, a decade back, sustained release formulations were developed which had attributes in exhibiting activity for round the clock ¹⁰. The postprandial elevation of sugar level, which earlier remained a major challenge, was well managed by the arrival of bilayer dual formulation tablets ¹¹. Recently, based on the physiological feature several bilayer formulations comprising of an immediate release layer (IRL) having gliclazide and a sustained release layer (SRL) containing metformin were designed ¹². The two well-known hypoglycemic exhibit better therapeutic regimens and control the plasma sugar level effectually. Gliclazide, the second generation sulphonylurea offers good hypoglycemic excellence by increasing both basal and meal-stimulated insulin secretion along with enhancement of peripheral insulin sensitivity, ultimately leading to decline in fasting, postprandial glucose and glycosolated hemoglobin (HbA1c) levels ¹³. The drug is having a half-life of 10.4 h and is primarily metabolized extensively by liver to form oxidized and hydroxylated derivates, as well as glucuronic acid conjugates ¹⁴. The drug suffers from reduced aqueous solubility of 0.19 mg/mL which remained a crucial problem for the biological effect as a result of reduced dissolution and bioavailability.

Therefore, in this research an effort was made to improve the aqueous solubility of gliclazide in a bilayer tablet where solid dispersion (SD) of gliclazide was skillfully prepared in PEG 6000 containing three different weight ratios; 1:1, 1:2, and 1:5 and suitably fabricated in IRL. The solid dispersion was preferred as the smartest strategy for improving the dissolution properties and subsequently the bioavailability of gliclazide by dispersing in PEG 6000 carrier where reduced particle size, surface area enhancement, and transformation in amorphous form improves the solubility ¹⁵.

In this study, a bilayer tablet of gliclazide solid dispersion in IRL and metformin in SRL were fabricated by direct compression method, with an intention that the IRL of the formulation will release the gliclazide at its earliest to combat the postprandial hyperglycemic surge followed by a steady state plasma glucose level controlled by sustained release metformin. The compatibility studies, pre-compression studies, post-compression studies, disintegration studies, dissolution studies, and kinetic release profile were performed.

MATERIALS AND METHODS:

Chemicals: Metformin HCl was obtained as a generous gift from Cipla Pharmaceuticals Ltd., Mumbai. Gliclazide was provided to us as gift sample from Wockhard Pharmaceuticals Ltd., Aurangabad. Leben Laboratories Pvt. Ltd., remained the main supplier for the HPMC polymers of grade K4M, K15M, and K100M. Microcrystalline cellulose, polyethylene glycol 6000, and starch were purchased from Molychem Pharmaceuticals Ltd., Mumbai. Miscellaneous analytical grade chemicals were procured from Qualigens Fine Chemicals Ltd., Mumbai.

Instruments: The UV spectroscopic analyses were performed with double - beam Shimadzu® Ultraviolet-Visible Spectrophotometer of Model UV-1800, connected to a desktop, having the spectral bandwidth of 1 nm and wavelength accuracy of ±0.3 nm with a couple of 1 cm path length similar quartz cells. The FT-IR spectra were measured using IR Affinity-1 instrument employing the KBr discs. Shimadzu® electronic balance of Model AUW220D was used for weighing the chemicals. Transonic Digital S Sonicator was employed for sonication process. Dissolution studies were performed using USP Type-II dissolution test apparatus (Electrolab, Mumbai, India). The disintegration test of the tablets was performed using IP disintegration apparatus (Electrolab, TDT 08L, Mumbai, India). Additionally, vernier caliper (Indian caliper, Ambala, India), Pfizer hardness tester (Pfizer, Spacelabs, India), and Roche friabilator (Electrolab, India) were employed for the evaluation of prepared tablets.

Preparation of Gliclazide Solid Dispersions (SDs): The SD of gliclazide in PEG 6000 (gliclazide/PEG 6000) containing three different weight ratios; 1:1, 1:2, and 1:5 and here denoted as SD1/1, SD1/2 and SD 1/5, respectively, were prepared by the solvent evaporation method. In this method, to a solution of gliclazide in chloroform, an appropriate amount of PEG 6000 was added. The solvent was evaporated under reduced at room temperature by using petridish and the resulting residue dried under vacuum for 3 h. The mixture was stored overnight in a desiccator. The hardened mixture was powdered in a mortar, sieved through a 100-mesh screen, and stored in a screw-cap vial at room temperature until further use ¹⁶.

Characterization of Gliclazide Solid Dispersions:

Infrared Spectral Analysis: IR absorption spectrum of pure drug, PEG 6000, physical mixture, and SD formulations were recorded by potassium bromide dispersion technique in the range of 4000 - 400 cm⁻¹. The compounds were scanned at a resolution of 0.15 cm⁻¹ and scan speed was 20 scan/s ¹⁷.

Differential Scanning Calorimetric Analysis: The physical state of pure drug, PEG 6000, physical mixture, and SD formulations was characterized by differential scanning calorimeter (DSC) thermogram analysis. The DSC patterns were recorded on a Pyris Diamond TG/DTA Perkin Elmer. Each sample was heated in a platinum crucible along with alpha alumina powder as a reference at a scanning rate of 10 °C/min in an atmosphere of nitrogen (150 mL/min) using the range of 30 - 300 °C. The temperature calibrations were performed periodically using indium as a standard ¹⁸.

Formulation of Bilayer Tablet:

Formulation of Gliclazide Solid Dispersion Immediate Release Layer (Layer - 1): The immediate release layer was fabricated by direct compression method. Gliclazide, MCC, croscarmellose sodium, and magnesium stearate were weighed and sifted through a mesh sieve #44. The above weighed ingredients were mixed thoroughly in a mortar except magnesium stearate for 10 min. The magnesium stearate was properly added as a lubricant. The content was compressed by Chamunda^® minipress rotary tablet machine using 17 mm concave faced punches. The composition of the immediate release layer is described in Table 1.

TABLE 1: COMPOSITION OF IMMEDIATE RELEASE LAYER

Formulation of Metformin Hydrochloride Sustained Release Layer (Layer - 2): Metformin hydrochloride is a very moisture sensitive drug and hence it does not have good flow properties on exposure. To improve the flow properties, the granules were prepared by the wet granulation method. Simultaneously, various batches were prepared in duplicate using the same wet granulation technique. The formulation involved weighing metformin HCl, HPMC of grades K4M, K15M, and K100M, MCC, and magnesium stearate and sifted through mesh sieve #44. The components were mixed thoroughly in a mortar for 10 min except magnesium stearate. The binder solution was prepared by dissolving starch in purified water (10% starch solution) by gentle warming.

The binder solution was added slowly in the mixture and wetted. Subsequently, the wetted mass was forced through mesh sieve #22 to obtain granules. The wet granules were dried in hot air oven for 30 min and sifted through mesh sieve #22 to obtain proper granule size. The magnesium stearate was properly added as a lubricant.

The prepared granules were evaluated for various pharmacopeia parameters. Later, the granules were compressed using Chamunda^® minipress machine of 17 mm size punch to fabricate the tablet layer. The composition of the sustained release layer is mentioned in Table 2.

TABLE 2: COMPOSITION OF SUSTAINED RELEASE LAYER

Final Compression: Firstly, metformin HCl granules were added to die and gently compressed followed by pouring of gliclazide blend. The batches were prepared by following: M7 + G3 = B1; M8 + G3 = B2; and M9 + G3 = B3. Lastly, the final compression was applied to prepare the bilayered tablet using Chamunda^® mini press 17 mm concave faced punches.

Evaluation of Prepared Bilayer Tablets:

Compatibility Studies: The polymers which are to be incorporated into formulation should be compatible with the drug. The compatibility study or interaction study was done using Fourier transformed infrared spectroscopy. In an effort to determine any kind of interaction between drug candidate and the polymer, IR spectra were taken for pure metformin and in the combination with polymer. Furthermore, DSC was performed to determine whether any degradation or any incompatibility is identified.

Pre-compression Studies: The granules were evaluated suitably for their characteristic parameters such as angle of repose, Hausner’s ratio, bulk density, tapped density and Carr’s index. The angle of repose was determined by funnel method. Bulk density and tapped density were determined by cylinder method. Carr’s index (CI) and Hausner’s ratio (HR) was calculated.

Post-compression Studies: Based on reported standards/procedures, the compressed matrix tablets were characterized for their properties such as hardness, friability, thickness, content uniformity and weight variation. The hardness of tablet formulations was determined by using a Monsanto hardness tester. The friability was determined using Roche friability testing apparatus. Likewise, the thickness was determined using Vernier Calipers. The weight variation testing was carried out according to the guidelines mentioned in USP Pharmacopoeia.

Uniformity of Content: Five tablets metformin HCl and gliclazide was powdered in a mortar separately and a quantity equivalent to 500 mg of metformin hydrochloride and 80 mg of gliclazide was accurately weighed and dissolved in a suitable volume of distilled water / 7.4 pH phosphate buffer and 0.1 N HCl (pH 1.2) respectively. After making suitable dilutions the final solution was analyzed spectrophotometrically at 233 nm and 230 nm, respectively.

Disintegration Test of Immediate Release Layer: Tablet disintegration was carried by placing one tablet in each tube of the basket and top portion of the each tube was closed with disc and run the apparatus containing (pH 1.2) 0.1 N HCl (gastric fluid) maintained at 37 ± 0.1 °C as the immersion liquid. The assembly was raised and lowered between 30 cycles per minute ¹⁹. The time taken for the complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured and recorded. The experiment was carried out in triplicate.

Dissolution Studies: The two intact tablets from each batch were taken for dissolution study. The dissolution study was performed on IP-II (Basket) / USP Type-II dissolution test apparatus (Electrolab, TDT 08L, Mumbai, India). The dissolution medium used was 900 mL of 0.1 N HCl for first 2 hr and phosphate buffer (pH 7.4) for the next 10 h at 37 ± 0.1 °C. The paddle speed was kept constant at 50 rpm. Each time, 5 mL of sample was withdrawn at the interval of 5 min for gliclazide and 2 mL sample were withdrawn for metformin hydrochloride, for first 1 h and thereafter at intervals of 1 h. The withdrawn samples were analyzed spectrophotometrically at 230 nm for gliclazide and 233 nm for metformin hydrochloride. The same amount of fresh 0.1 N HCl and phosphate buffer pH 7.4 was used to replace the amount withdrawn for respective dissolution media. Percent cumulative release of both drugs from the tablet was calculated ²⁰.

Kinetic Analysis of Dissolution Data: In order to determine the mechanism of drug release from the bilayer tablet batches, data obtained from in vitro drug release studies were plotted in various kinetic models like zero-order, first order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas models. The criterion for selecting the most appropriate model was chosen on the basis of the goodness-or fit test. The zero-order kinetic describes the systems in which the drug release rate is independent of its concentration. The first order kinetic describes the systems in which the drug release rate is concentration dependent. Higuchi described the release of drug from an insoluble matrix as the square root of time dependent process. The Hixson-Crowell cube root law describes the drug release from systems in which there is a change in the surface area and the diameter of particles present in the tablet. In case of Korsmeyer-Peppas model the drug release from such devices having a constant geometry will be observed till the polymer chains rearrange to an equilibrium state ²¹.

RESULTS AND DISCUSSION:

Characterization of Gliclazide Solid Dispersions (SDs):

Infrared Spectral Analysis: The FTIR spectrum of gliclazide, PEG 6000, physical mixture, and SDs are shown in Fig. 1. The spectrum of gliclazide Fig. 1a showed char­acteristic peaks at 3502, 3274, 3112, 2942, 1708, 1430, 1160 cm^-1, respectively. The spectra of PEG 6000 Fig. 1b displayed no such prominent peaks, however few prominent peaks at 3350, 2773, 1403 cm^-1, etc. were seen. The peaks of the physical mixture Fig. 1c were predominantly seen at 3502, 3278, 3189, and 2942 cm^-1 which confirms the presence of drug in unchanged form. The spectrum of SD of gliclazide Fig. 1d exhibited analogous results. The observed prominent peaks are 3278, 3112, 1708, 1430, 1160 cm^-1, respectively, which are quite similar to the spectrum of gliclazide. This concluded that there were no such drug-polymer inter­actions in the SDs.

FIG. 1: FT-IR SPECTRA: (A) GLICLAZIDE; (B) PEG 6000; (C) PHYSICAL MIXTURE; AND (D) SOLID DISPERSION OF GLICLAZIDE

Differential Scanning Calorimeter Analysis: The DSC thermograms of gliclazide, PEG 6000, physical mixture, and SD are shown in Fig. 2. The pure drug showed a very pointed endothermic peak at 174.17 °C with peak onset at 169.26 °C, which corresponds to its melting point Fig. 2a. The sharp endothermic peak of gliclazide confirms crystallinity in the structure. In contrast, PEG 6000 exhibits no such endothermic peak over the entire scanning range of 30 - 300 °C, suggesting its polymeric nature Fig. 2b. The physical mixture highlighted the appearance of same drug peak with no difference, suggesting that there is no cross-reactivity between the drug and the polymer Fig. 2c. However, no characteristic peak of gliclazide was found in SDs over the tested temperature Fig. 2d, which clearly indicated that the drug is in amorphous state or high-energy state after the fabrication. Since amorphous state is considered as a state of high disorder, the solid particles present remain in highly dissolved state in SDs, which further confirms the ability of SDs in maintaining the drug in the dissolved state and thus improves the solubility of the drug.

FIG. 2: DSC THERMOGRAM: (A) GLICLAZIDE; (B) PEG 6000; (C) PHYSICAL MIXTURE; AND (D) SOLID DISPERSION OF GLICLAZIDE

Evaluation of Pre-compression and Post-Compression Factors: Compatibility studies: Interpretation of drug-polymer interaction was done by viewing the FTIR peaks in the metformin, polymer and metformin-polymer blend.

FIG. 3: COMPATIBILITY STUDY: (A) FT-IR SPECTRA OF METFORMIN; (B) FT-IR SPECTRA OF DRUG-POLYMER BLEND; (C) DSC THERMOGRAM OF METFORMIN; AND (D) DSC THERMOGRAM OF POLYMER BLEND

Principal peaks of the drug, due to the amines, amide, and aliphatic C-N were observed in wave numbers 3583, 3502, 3332, 2803, 1855, 1392, 1211 cm^-1 Fig. 3a. In the drug-polymer blend, prominent peaks were seen in wave numbers 3502, 3332, 2803, 1851, 1392, 1207 cm^-1 Fig. 3b. Due to similar observations of the peaks and closeness of peaks in the physical mixture, it may be concluded that no significant drug-polymer interaction occurred.

Besides that, the DSC thermograms in heat flow method depicted that the pure drug showed a very pointed endothermic peak at 232.52 °C with an energy of -2.80 w/g Fig. 3c, whereas the polymer-drug blend exhibited a nearly-broad endothermic peak at 211.24 °C with energy of -0.012 w/g Fig. 3d, representing no such interaction of polymer with the drug. It may be believed that a homogenous physical mixture is formed and may be assumed that no such interaction occurred.

Pre-compression Studies: The pre-compression parameters performed for the immediate release layer of bilayer tablet by direct compression technique are mentioned. For the evaluation of immediate release layer, the bulk and tapped density values of all the three formulations laid between 0.414 - 0.421 g/cm³ and 0.454 - 0.488 g/cm³. As per pharmacopoeial limit, the bulk and tapped density must be less than 1.2 g/cm³ which indicates a good packing. Therefore, the prepared batches passed the limit prescribed by pharmacopoeia and have the good packing ability. The value of the angle of repose was found to be 25°-21’-28°-45’, which indicated satisfactorily acceptable flow property. Hausner’s ratio and Carr’s index were found to be in range, 1.08 - 1.16 and 8.33 - 13.55%, respectively, which describes acceptable flow property as well as good packing ability. The results for granule characteristics are represented in Table 3.

TABLE 3: PRE-COMPRESSION STUDIES OF POWDER BLEND OF IMMEDIATE RELEASE LAYER

The powder blend used for manufacturing sustained release layer of the bilayer tablet by wet granulation according to the procedure is highlighted. For the evaluation of sustained release layer. The evaluated granules were observed to be acceptable as per the limits. The densities (both bulk and tapped) lie in the range of 0.457 - 0.513 g/cm³ and 0.467 - 0.521 g/cm³, respectively, which represented an excellent packing of the granules. The angle of repose was observed to be in range of 20°-90’-28°-33’ for the batches which indicated reasonably satisfactory flow property. The calculated Hausner’s ratio and Carr’s index were in the order of 0.96 - 1.04 and 2.4 - 3.7%, respectively which may be interpreted as relatively good packing ability. In short, the tablet blend demonstrated fairly good micromeritic attributes essential for exhibiting sustained release characteristics. The results for physical properties of granules are portrayed in Table 4.

TABLE 4: PRE-COMPRESSION STUDIES OF POWDER BLEND OF SUSTAINED RELEASE LAYER

Post-compression Studies: The tablets were subjected to evaluation tests according to IP standards. The hardness of tablets from each batch of formulation were found to be in the range 3.96 - 4.26 kg/cm². The friability was less than 1% for all the batches of tablets. The above parameters stated that the formulations are having required strength and resistibility. The weight variation was less than 4% and all tablets fall under the pharmacopoeial range of 304.1 - 305.8 mg. Practically, uniform drug content in the range 95.19 - 97.16% were detected among all the batches of the gliclazide immediate release layer of tablet. The evaluation values are depicted in Table 5.

TABLE 5: POST-COMPRESSION STUDIES OF IMMEDIATE RELEASE LAYER OF TABLET

 The evaluation parameters revealed that the prepared sustained tablet batches presented the essential attributes. All the fabricated batches displayed the necessary hardness of more than 5.63 - 6.98 kg/cm² along with friability value of less than 1%, ultimately representing the required strength and resistibility of the sustained layer. The starch, microcrystalline cellulose, and polymeric combination were found to exhibit a profound role in imparting hardness to the layer. The drug content was identified to be in the range of 94.01 - 97.19%. A weight variation of < 4% was observed for the prepared batches, indicating almost uniform drug content in all the fabricated batches. The post-compression parameters are described in Table 6.

TABLE 6: POST-COMPRESSION STUDIES OF POWDER BLEND OF SUSTAINED RELEASE LAYER

Disintegration Test of Immediate Release Layer: The disintegration time of batches G1 - G3 was found to be in the range of 1 - 3 min for gliclazide tablet. The disintegration time for gliclazide was found to be maximum for batch G1 and minimum for batch G3 containing the maximum amount of croscarmellose sodium. Table 7 highlighted the disintegration time of the immediate release layer batches.

TABLE 7: DISINTEGRATION DATA OF THE IMMEDIATE RELEASE LAYER

Dissolution Studies:

Sustained Release Layer Containing Metformin: All the formulations subjected to in-vitro dissolution studies, revealed that tablets containing release modifiers exhibited controlled release of metformin as compared with conventional tablets, which release the whole drug content in 4 - 5 h. Generally, fast dissolution takes place in case of highly water-soluble molecules, where drugs diffuse out of the matrix forming pores for entrance to solvent molecules. Formulation M1 and M2 displayed a cumulative release of nearly 91.8% in 8 h where 110 mg concentrations of polymers HPMC K4M and K15M were employed. In contrast, the formulation M3 exhibited better controlled release profile of 90.6% at 10 h Fig. 4a.

Here, the polymer HPMC K100M showed a better rate retardant ability than the above two variants at the same concentration. The hydration rate of HPMC increases with an increase in the hydroxyl-propyl content and the solubility of HPMC is pH independent ²². The water-repelling property of higher variants of HPMC retarded the drug release from the matrix by preventing penetration of solvent molecules.

The high level of microcrystalline cellulose, the binder cum disintegrant in the formulations also played imperative role in the drug release. In the development of successive batches M4 - M6, the polymer concentration was elevated to 130 mg.

The results revealed a diminutive retarded release of drug in the media owing to the concentration of release modifiers in the formulations. Batch M4 and M5 presented the cumulative drug release of 92.53% and 91.21% in 9 h Fig. 4b, respectively.

FIG. 4: IN-VITRO DRUG RELEASE: (A) SUSTAINED RELEASE LAYERS OF M1-M3 BATCH; (B) SUSTAINED RELEASE LAYERS OF M4-M6 BATCH; (C) SUSTAINED RELEASE LAYERS OF M7-M9 BATCH; AND (D) IMMEDIATE RELEASE LAYERS OF G1-G3 BATCH

This indicates that as the polymer concentration increased, the drug release rate was found to be retarded ²³. The batch M6 offered a better sustained release profile with 130 mg HPMC K100M polymer mix, leading to release of 90.1% in 10 h Table 8. HPMC K100M was judiciously selected in preparation due to its profound ability to form a strong viscous gel on contact with aqueous media, which helps in controlling the delivery of highly water-soluble drugs ²⁴. The formulation batches M7-M9 having a polymer concentration of 150 mg represented 95.28%, 96.19%, and 99.04% at 11 h Fig. 4c, respectively. The reason of the release profile is due to the optimization of release modifier concentration along with the amount of microcrystalline cellulose.

TABLE 8: IN VITRO RELEASE OF METFORMIN FROM THE SUSTAINED RELEASE LAYER

Immediate Release Layer Containing Gliclazide: The in-vitro drug release profile of SDs were studied and compared with the pure drug of gliclazide. In all the SDs prepared by PEG 6000 (gliclazide/PEG 6000) containing three different weight ratios; 1:1, 1:2, and 1:5, the last batch (G3) having 1:5 drug: polymer ratio demonstrated highest drug release of 95.59% as compared to the 93.13% drug release from batch G1 Fig. 4d. The fact is due to that the SDs prepared with higher ratios of polymer could offer more available space for surrounding of hydrophobic drug particle resulted in rapid hydration of drug molecules and consequently better wettability and enhancement in the dissolution ²⁵. Moreover, the transformation of the crystalline nature of pure gliclazide into the amorphous form as affirmed by the DSC and FT-IR results facilitates higher drug release rate over the pure drug. In addition to the fact that SD promoted significant improvement in dissolution, the formulations contained superdisintegrant croscar-mallose sodium, which provided a burst release leading to exposed surface area endorsing further release of drug in the media ²⁶. From above comparative in vitro drug release, it is concluded that from the above mentioned formulations G1-G3, the last batch, G3 formulation performed the best release of gliclazide Table 9.

TABLE 9: IN-VITRO RELEASE OF GLICLAZIDE FROM THE IMMEDIATE RELEASE LAYER

Evaluation of Prepared Bilayer Tablets:

Appearance: The dimension of the tablets fabricated was 17 × 7.5 mm. The physical characteristics of the tablet were found to be acceptable. The tablets were free from any defects like capping, picking and chipping.

Physical Characteristics: All the formulations were assessed for their desired characteristic attributes as per standard procedures for evaluation. The average weight of tablets from all the formulation were found to be in the range of 1050.84 - 1055.15 mg, which indicates that the all batches have the average standard weight as per the official standards. The drug content in all the batches of the formulation was in the range of 96.35 - 98.21% of metformin and 95.69 - 96.57% of gliclazide, respectively, reflecting uniform drug content practically. The thickness of the tablet was in the range of 7.37 - 7.63 mm. All the batches have good hardness and friability resistance as per standards. The hardness of the fabricated tablets was found to be in the range 5.84 - 6.3 kg/cm² and the friability of the batches was less than 1%. The parameters have stated that the prepared batches had the required strength to withstand wear and tear. The evaluation parameters of the prepared batches are illustrated in Table 10.

TABLE 10: EVALUATION PARAMETER OF BILAYER FORMULATIONS

Bilayered Tablet Containing Gliclazide and Metformin: The bilayered tablet comprising of gliclazide (in the immediate release layer) and metformin (in the sustained release layer) was evaluated for the drug release characteristics. The majority of the release controlling agent containing formulations displayed a steadily sustained release attribute as compared to conventional dosage forms. The release of drug from the matrix involves a complex interaction between drug dissolution, solubilization, diffusion, and erosion mechanism(s). The examined formulation B3 represented a sustain release pattern of drug release up to 12 h, in contrast to other two formulations; B1 and B2. Both the formulations (B1 and B2) demonstrated cumulative drug release of 92% Fig. 5a.

TABLE 11: IN-VITRO RELEASE OF METFORMIN FROM THE BILAYERED TABLET

The reason may be due to large concentrations of binder as compared to batch B3. The formulation B3 consisting of highest concentration of the polymer effectively retarded the release of drug (98.1%) up to 12 h Table 11.

The immediate release layer of B2 released the highest amount of gliclazide (94.58%) in the dissolution media after 40 minutes Table 12. The formulations B1 exhibited 93.89% release and B3 expressed 93.59% of drug release after 40 min Fig. 5b. Due to the presence of the highest amount of super-disintegrant, a burst release was observed in all the cases and the observations were so much closer in precision that all the tablet batches have equal attribute in the uniform release of the drug ²⁷.

When we compared the release of drug from bilayered tablet and release of drug from individual layers, we observed that the cumulative drug release of metformin was retarded from 99.04% to 98.09%. Quite similarly, the release of gliclazide from individual layer was 95.59%, while from bilayered tablet it was < 94.5% of all the cases. Therefore, it may be concluded that the punching and manufacturing processes might have a crucial role in the modification of drug release.

TABLE 12: IN-VITRO RELEASE OF GLICLAZIDE FROM THE BILAYERED TABLET

FIG. 5: IN-VITRO DRUG RELEASE FROM BILAYERED TABLET BATCHES (B1-B3): (A) METFORMIN AND (B) GLICLAZIDE

Kinetics Release Profile: The release mechanism of metformin and gliclazide from bilayered optimized formulation B3 was studied by fitting the data obtained from in-vitro release studies into zero-order, first order, Higuchi, Korsmeyer-Peppas and Hixson-Crowell models.

FIG. 6: KINETICS RELEASE PROFILE: (A) RELEASE OF DRUG FROM OPTIMIZED FORMULATION B3 BY ZERO-ORDER; (B) RELEASE OF DRUG FROM OPTIMIZED FORMULATION B3 FROM FIRST-ORDER; (C) GLICLAZIDE FROM IMMEDIATE RELEASE LAYER BY FIRST-ORDER; AND (D) GLICLAZIDE FROM IMMEDIATE RELEASE LAYER BY KORSMEYER-PEPPAS

On the application, it was found that the optimized formulation B3 followed the either zero-order Fig. 6a or first-order Fig. 6b based sustained drug release as indicated by the similar regression coefficient (r²) values of 0.978 in the case of metformin. The pharmacokinetic data for metformin was established according to the Acceptance Table of Test 4 given in USP-33 for the 12 h with dosing correlation coefficient (r²) value 0.998, this batch was selected for the further studies. Thus, the sustained - release tablet formulation displayed release of required quantity of drug with predetermined kinetics in order to maintain an effective drug plasma concentration. The pharmacokinetic data of the metformin release from the bilayer tablet are described in Table 13.

TABLE 13: PHARMACOKINETIC PARAMETERS FOR METFORMIN RELEASE

Sq. rt., square root; Conc., concentration; C. C., cumulative concentration

In the case of gliclazide from immediate release layer, there were two probabilities of drug release based on the regression coefficient; either first-order Fig. 6c or Korsmeyer-Peppas Fig. 6d order release which show constant drug release rate with time. The former expressed r² value of 0.979 and the latter exhibited 0.9659. In more detail, it may be believed that drug release was controlled by more than one process; somewhat an intermediate of both diffusion and erosion mechanism (called anomalous diffusion) after the burst due to the presence of super disintegrants ²⁸. The pharmacokinetic drug release data of gliclazide from the tablet are elaborated in Table 14.

TABLE 14: PHARMACOKINETIC PARAMETERS FOR GLICLAZIDE RELEASE

Sq. rt., square root; Conc., concentration; C. C., cumulative concentration

CONCLUSION: The present study involved in designing and fabricating an oral bilayer hypoglycemic tablet formulation which has attributed to deliver a first impulse of the dose in the shortest time possible (a few min) and a second fraction of the dose in a prolonged time at a constant rate for the duration of more than 10 h. The bilayer tablet comprised of the first layer formulated with gliclazide solid dispersion to obtain a prompt release of the drug, often regarded as the loading dose) whereas the second layer was a prolonged released hydrophilic matrix which designed to maintain an effective plasma level for a prolonged period of time, regularly called as maintenance dose. The formulation B3 was found to be highly optimized and demonstrated the highest cumulative drug release where the metformin followed the either zero-order or first-order and the gliclazide followed anomalous diffusion. Therefore, the designed formulation will offer a better therapeutic regimen and provide patient friendly postprandial hypoglycemic management, where an immediate control and a maintenance dose is required.

ACKNOWLEDGEMENT: The authors would like to thank Principal, IBBS College of Pharmacy, Malkapur; Principal, Dadasaheb Balpande College of Pharmacy, Nagpur; and President, Ambe Durga Educational Society, Nagpur for providing their support, facilities, and guidance in this research work.

CONFLICT OF INTEREST: The authors declare no conflict of interests.

REFERENCES:

1. Kuhite NG, Padole CD, Amdare MD, Jogdand KR, Kathane LL, Mahapatra DK. Hippuric acid as the template material for the synthesis of a novel anti-diabetic 1,3,4-thiadiazole derivative. Indian Journal of Pharmaceutical and Biological Research 2017; 5(3): 42-45.
2. Godbole MD, Mahapatra DK, Khode PD. Fabrication and Characterization of Edible Jelly Formulation of Stevioside: A Nutraceutical or OTC Aid for the Diabetic Patients. Inventi Rapid: Nutraceuticals 2017; 2017(2): 1-9.
3. Mahapatra DK, Bharti SK: Handbook of Research on Medicinal Chemistry. Apple Academic Press, First Edition 2017.
4. Mahapatra DK, Asati V and Bharti SK: Chalcones and their therapeutic targets for the management of diabetes: structural and pharmacological perspectives. European Journal of Medicinal Chemistry 2015; 92: 839-865.
5. Chhajed SS, Chaskar S, Kshirsagar SK, Haldar GA and Mahapatra DK: Rational design and synthesis of some PPAR-γ agonists: Substituted benzylideneamino-benzylidene-thiazolidine-2, 4-diones. Computational Biology and Chemistry 2017; 67: 260-265.
6. Mahapatra DK, Chhajed SS and Shivhare RS: Development of Murrayanine-Chalcone hybrids: An effort to combine two privilege scaffolds for enhancing hypoglycemic activity. International Journal of Pharmaceutical Chemistry and Analysis 2017; 4(2): 30-34.
7. Bansal P and Wang Q: Insulin as a physiological modulator of glucagon secretion. American Journal of Physiology Endocrinology Metabolism 2008; 295(4): E751-E761.
8. Rorsman P, Eliasson L, Renström E, Gromada J, Barg S and Göpel S: The cell physiology of biphasic insulin secretion. Physiology 2000; 15(2): 72-77.
9. Dickens F, Whelan WJ and Randle PJ: Carbohydrate Metabolism: and its Disorders. Elsevier Science, First Edition 2014.
10. Park K: Controlled drug delivery systems: past forward and future back. Jou of Control Release 2014; 190: 3-8.
11. He W, Huang S, Zhou C, Cao L, Yao J, Zhou J, Wang G and Yin L: Bilayer matrix tablets for prolonged actions of metformin hydrochloride and repaglinide. AAPS Pharm Sci Tech 2015; 16(2): 344-53.
12. Pavan Kumar K and Chandan M: Formulation and Characterization of Metformin Hydrochloride and Gliclazide Bilayer Tablets. International Journal of Pharma Research and Health Sciences 2015; 3(3): 794-802.
13. Al-Omary FA: Gliclazide. Profiles of Drug Substances Excipients and Related Methodology 2017; 42: 125-192.
14. Palmer KJ and Brogden RN: Gliclazide. Drugs 1993; 46(1): 92-125.
15. Shah N, Iyer RM, Mair HJ, Choi DS, Tian H, Diodone R, Tang K, Grippo J, Moreira SA, Go Z, Louie T, Ibrahim PN, Sandhu H, Rubia L, Chokshi H, Singhal D and Malick W: Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer stabilized solid dispersion prepared by a solventcontrolled coprecipitation process. Journal of Pharmaceutical Sciences 2013; 102(3): 967-981.
16. Dengale SJ, Ranjan OP, Hussen SS, Krishna BS, Musmade PB, Shenoy GG and Bhat K: Preparation and characterization of co-amorphous Ritonavir - Indomethacin systems by solvent evaporation technique: Improved dissolution behavior and physical stability without evidence of intermolecular interactions. European Journal of Pharmaceutical Sciences 2014; 62: 57-64.
17. Tajiri T, Morita S, Sakamoto R, Mimura H, Ozaki Y, Reppas C and Kitamura S: Developing dissolution testing methodologies for extended-release oral dosage forms with supersaturating properties. Case example: solid dispersion matrix of indomethacin. International Journal of Pharmaceutics 2015; 490(1): 368-374.
18. Umaredkar A, Dangre PV, Mahapatra DK, Dhabarde DM. Fabrication of chitosan-alginate polyelectrolyte complexed hydrogel for controlled release of cilnidipine: A statistical design approach. Materials Technology 2018; DOI: 10.1080/10667857.2018.1456617.
19. Desai D, Wong B, Huang Y, Tang D, Hemenway J, Paruchuri S, Guo H, Hsieh D and Timmins P: Influence of dissolution media pH and USP1 basket speed on erosion and disintegration characteristics of immediate release metformin hydrochloride tablets. Pharmaceutical Development and Technology 2015; 20(5): 540-545.
20. Frizon F, de Oliveira Eloy J, Donaduzzi CM, Mitsui ML and Marchetti JM: Dissolution rate enhancement of loratadine in polyvinylpyrrolidone K-30 solid dispersions by solvent methods. Powder Technology 2013; 235: 532-539.
21. Newton AM, Indana VL and Kumar J: Chronotherapeutic drug delivery of Tamarind gum, Chitosan and Okra gum controlled release colon targeted directly compressed Propranolol HCl matrix tablets and in-vitro evaluation. International Journal of Biological Macromolecules 2015; 79: 290-299.
22. Mujtaba A, Ali M and Kohli K: Statistical optimization and characterization of pH-independent extended-release drug delivery of cefpodoxime proxetil using Box–Behnken design. Chemical Engineering Research and Design 2014; 92(1): 156-165.
23. Franek F, Holm P, Larsen F and Steffansen B: Interaction between fed gastric media (Ensure Plus®) and different hypromellose based caffeine controlled release tablets: Comparison and mechanistic study of caffeine release in fed and fasted media versus water using the USP dissolution apparatus 3. International Journal of Pharmaceutics 2014; 461(1): 419-426.
24. Patil MD, Mahapatra DK and Dangre PV: Formulation and in-vitro evaluation of once-daily sustained release matrix tablet of nifedipine using rate retardant polymers. Inventi Rapid PharmTech 2016; 4: 1-7.
25. Dangre PV, Godbole MD, Ingale PV and Mahapatra DK: Improved dissolution and bioavailability of eprosartan mesylate formulated as solid dispersions using conventional methods. Indian Journal of Pharmaceutical Education and Research 2016; 50(3): S209-S217.
26. Sharma R, Mittal S, Kumar D, Singla P, Garg V and Arora A: Formulation and evaluation of bi-layer tablet of Aceclofenac sodium and Tramadol hydrochloride. Journal of Fundamental Pharmaceutical Research 2014; 2: 22-34.
27. Gorantla N, Ahad HA and Mishra SK: Fabrication and Characterization of Bilayer Sustained Release Tablets Using Ibuprofen and Methocarbamol as Model Drugs. International Journal of Chemical and Life Sciences 2017; 2(3): 1132-1135.
28. Abbasi S, Yousefi G, Ansari AA and Mohammadi-Samani S: Formulation and in vitro evaluation of a fast-disintegrating/sustained dual release bucoadhesive bilayer tablet of captopril for treatment of hypertension crises. Research in Pharmaceutical Sciences 2016; 11(4): 274.
    

    ---

    How to cite this article:

    Gangane PS, Kadam MM, Mahapatra DK, Mahajan NM and Mahajan UN: Design and formulating gliclazide solid dispersion immediate release layer and metformin sustained release layer in bilayer tablet for the effective postprandial management of diabetes mellitus. Int J Pharm Sci & Res 2018; 9(9): 3743-56. doi: 10.13040/IJPSR.0975-8232.9(9).3743-56.

    ---

    All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---