Formulation and evaluation of bilayer tablet by using melt granulation technique for treatment of diabetes mellitus.

The objective of present study was to prepare and characterize Bilayer tablet formulation containing Metformin HCl in extended release matrix form and Pioglitazone HCl in immediate release form for the treatment of diabetes mellitus. Different formulations containing Metformin HCl were manufactured using 3(2) factorial designs. Influence of hydrophilic carrier, hydrophobic polymer on drug release was studied. Immediate release layer of Pioglitazone was optimized using different super disintegrants. All formulations were evaluated for percentage drug release. Optimization results indicated that release rate of Metformin is directly proportional to the levels of Eudragit S 100 and PEG 6000. Results confirmed that Bilayer tablet formulation containing extended release of Metformin HCl and immediate release of Pioglitazone HCl could be developed by using melt granulation technique.

Type 2 diabetes mellitus is a heterogeneous disorder characterized by multiple defects in the pancreatic β-cell, liver, and peripheral tissues such as skeletal muscle and adipose tissue.[1] Combination therapy has various advantages over monotherapy such as problem of dose-dependent side effects is minimized. a low dose combination of two different agent reduces the dose related risk, the addition of agent may counteract some deleterious effects of the other, using low dosage of two different agents minimize the clinical and metabolic effects that occur with maximal dose of individual component of the combined tablet.[2] The major therapeutic goals in subjects with type 2 diabetes are to optimize blood glucose control. Multiple dosing regimens together, along with large doses, dose dependent absorption, and poor bioavailability of Metformin HCI are not preferred since it leads to patient noncompliance, potential side effects and danger of overdosing. It is therefore imperative to shift from multiple dosing to once-a-day or twice-a-day dosing regimens.

Metformin is an oral anti-hyperglycemic agent, shows incomplete absorption from the gastrointestinal tract and the absolute bioavailability is 50 – 60% with relatively short plasma half-life of 1.5-4.5 h.

The pioglitazone, act by binding and activating the peroxisome proliferation-activated receptor-γ (PPAR-γ) and, do not stimulate insulin release or because hypoglycaemia. These agents can reduce, mean HbA1c both as monotherapy and in combination. In combination with metformin, it improved glycemic control, insulin sensitivity and beta-cell function. Pioglitazone has an oral bioavailability of 83% and peak plasma concentrations of pioglitazone are achieved in 2–2.5 hours. Elimination half of Pioglitazone is 3 to 7 hrs.[3]

Melt granulation method can be used for granulating water sensitive material and producing SR granulation. This technique fulfills today's pharmaceutical industry need because of its simplicity, continuous and efficient process and due to many advantages over conventional methods of granulations such as wet and dry granulation.[45]

The objective of present study was to formulate and evaluation of Bilayer tablet containing Metformin HCl in extended release matrix form by using hydrophobic polymer Eudragit and hydrophilic melting polymer PEG 6000 by melt granulation technique and Pioglitazone HCl in immediate release form By using super disintegrants for the treatment of diabetes mellitus.

Materials and Methods

Metformin Hcl and Pioglitazone Hcl obtained as gift sample from Tristar Formulation Pvt Ltd, Eudragit S100, PEG 6000, and Kyron T-314, crosscarmelose sodium, other excipients and solvent use were of analytical grade.

Method for preparation of formulation

Preparation of Extended release layer of metformin hcl was optimized by using 32 factorial designs outlined in [Table 1]. In the present study content of Eudragit S100 (8-12%) and content of PEG 6000 (10-14%) were selected as independent variables. Percentage of drug release in 1 hr (rel1 hr) (Y1), percentage of drug release in 8 hr (rel8hr) (Y2) were selected as dependent variables. All batches were prepared by using hot melt granulation technique. Metformin HCl, Eudragit S100 and Dibasic calcium phosphate was sifted through 20 mesh and heated at 75°C by spreading on metal tray. PEG 6000 was melted at 75°C. The melt granulation was carried out by slowly adding melted PEG 6000 in hot Metformin HCl by high shear mixing for 5 minute. For Immediate layer batches were prepared by dry blending of ingredients followed by direct compression using composition outlined in [Table 2]. First extended release blend of Metformin HCl was introduced into the die cavity and immediate release tablet of Pioglitazone HCl was placed over it and final compression was made using 18×8mm oblong shaped punches of 8 station compression machine.

Table 1

Formulation of metformin HCl matrix tablet as per 32 factorial design

Table 2

Formulation of immediate release tablet of pioglitazone HCl

Results and Discussion

Extended release layer blends of metformin hcl were preperd by melt granulation method and evaluated various physicochemical parameter. Melt granules was found excellent flow properties. Hardness range was 6-7 kg/cm2. friability of all batch were in range of 0.16 to 0.30%.and assay values in range of 98.23-99.49%. The in-vitro drug release was performed using USP type II apparatus using 900 ml of 0.1N HCl for first two hour and then with phosphate buffer pH 6.8 for further Ten hours at the rotations of 50 rpm at 37± 5°C. The samples were withdrawn at predetermined time intervals and replaced with fresh medium. The samples were filtered through 0.45 μm membrane filter, suitably diluted and analyzed at 233 nm for metformin HCl and 269 nm for Pioglitazone HCl by UVspectrophotometer. The content of drug and cumulative percentage drug release was calculated using calibration curve. The Cumulative % released of the immediate release layer of Pioglitazone hcl is achieve 90% drug is release in withine 15 min by using Kyron T-314 in 2% [Figure 1]. The metformin Hcl layer containing Eudragit S100 12%, PEG 6000 12% give the 90% drug Release after 10 hr [Figure 2].

Figure 1

Comparative release profile of pioglitazone HCl

Figure 2

Comparative release profile of metformin HCl

Conclusion

Bilayer tablet of metformin Hcl extended release layer and pioglitazone Hcl was succesfuly developed by using melt granulation technique and in combination of the hydrophilic and hydrophobic combination.