Design And Optimization Of Compression-Coated Nateglinide Tablets: Modulation Of Drug Release And Release-Kinetic Mechanism

Vast amounts of literature have been written about the current and growing epidemic of diabetes mellitus (DM) and its associated complications. Diabetes mellitus, or simply diabetes, is a chronic disease that occurs when the pancreas is no longer able to make insulin, or when the body cannot make good use of the insulin it produces.^[1] Type 2 diabetes accounts for approximately 85 to 90 percent of all the diabetics in the country.^[2] Nateglinide is a novel D-phenylalanine derivative that inhibits ATP-sensitive K+ channels in pancreatic β-cells in the presence of glucose and there by stimulates the prandial release of insulin. ^[3,4] During past few decades, significant advance have been made in the area of controlled release as evidenced by an increasing number of patents, publication, as well as commercial controlled release products for the delivery of variety of pharmaceutical compounds. With a controlled release formulation a predictable and reproducible release rate can be achieved, at the target site for desired duration.^[5] New Enteric coated chemical entity often is first formulated as a wet coating for encapsulation of tablet. During the course of clinical development, the drug containing granulation usually is modified for compaction into a tablet product. The tablet product subsequently may be film coated for taste masking, identification, or other purposes. ^[6,7] The purpose of the study is to formulate and evaluate the controlled release tablet of Nateglinide. In this regard, we considered an erosion matrix tablet as the controlled release portion, and a dry coating of tablet as entric coating and outer prosion for immediate release of the nateglinide.

MATERIALS AND METHODS:

Materials

Nateglinide was obtained as gift sample (Cadila Chemical SBU, Ankleshwar, Gujarat.) HPMC K4M were obtained as gift samples (Crystal chemicals, Himmatnagar, Gujarat.), Eudragit L 100 was obtained as gift sample (Vikram Thermo Pvt. Ltd., Ahemdabad, Gujarat.). Distilled water was prepared in laboratory using all steel distillation apparatus. Other materials used in the study were of analytical grade.

Development of UV spectroscopy method in 0.1 N HCl: ^[8]

From the stock solution, appropriate aliquots were taken into different volumetric flasks and volume was made up to 10 ml with 0.1 N HCl so as to get drug concentrations of 5, 10, 15, 20, 25 and 30 ìg/ml. The absorbencies of these drug solutions were estimated at λmax 210 nm. This procedure was performed in triplicate to validate the calibration curve.

Development UV spectroscopy method in Phosphate Buffer (pH 6.8) solution: ^[8]

From the stock solution, appropriate aliquots were taken into different volumetric flasks and volume was made up to 10 ml with phosphate buffer (pH 6.8) solution so as to get drug concentrations of 5, 10, 15, 20, 25 and 30 ìg/ml. The absorbencies of these drug solutions were estimated at λmax 210 nm. This procedure was performed in triplicate to validate the calibration curve.

Drug–Excipient Compatibility Studies: ^[9]

Preformulation studies regarding the drug-polymer interaction for selecting appropriate polymers by FT-IR spectroscopy. The pure drug and drug with excipient were scanned separately. Potassium bromide was mixed with drug and/or polymer in 9:1 ratio and the spectra were taken.  FT-IR spectrum of nateglinide was compared with FT-IR spectra of nateglinide with polymer. The peaks were observed for any kind of interaction between the drug and excipient.

Formulation Development:

Dose Calculation ^[10-12]

Dose calculation for controlled release tablet was carried out and theoretical drug release profile was developed. So, in the present study attempts were made to design controlled release tablets of nateglinide using 60 mg in immediate release portion and 90 mg as Controlled release portion according to the developed theoritcal drug release profile.

Figure 01: Nateglinide controlled release dry coated tablet containing erosion matrix tablet

Procedure for Inner Core (Erosion matrix tablet): Wet Granulation Method

Nateglinide, HPMC K 4, MCC were mixed, make it granules with HPMC in Water (5%) granulating medium. The blend was passed through 10# sieve and after dry at 70° C. Passed these granules through 22# and 44# sieve. Take granules obtained from 44 # sieve and added 5% fine, magnesium stearate in granules. Then mixed it and punched the tablets. The granules was then compressed on 8-station rotary punching machine using concave faced punches 8 mm.

Procedure for Enteric coating: Direct Compression Method

Eudragit L 100, HPMC K 4, MCC was mixed and passed through 22# and 44# sieve. Then blend it properly. Fill half die cavity of 10 mm die with the blend and put inner core tablet and fill remaining half cavity with blend then compressed.

Procedure for Outer coat (immediate release portion): Direct Compression Method

Nateglinide, MCC, Lactose mixed and was passed through 22# and 44# sieve. Then blend it properly. Fill half die cavity of 12 mm die with the blend and put enteric coated tablet and fill remaining half cavity with blend then compressed.

Evaluation of granules and tablets ^[10-17]

The prepared granules were evaluated for angle of repose, bulk density, tapped density, compressibility index, and Hausner ratio. The prepared tablets were evaluated for weight variation, friability, hardness, thickness, and disintegration time.

The in vitro drug release study was carried out in a United States Pharmacopoeia (USP) dissolution apparatus I (Electrolab, Mumbai, India) using a rotating Basket at 50 rpm in 900 mL of 0.1 N HCl±0.5% sodium lauryl sulphate as dissolution medium and Phosphate Buffer (pH 6.8) solution while maintaining the temperature at 37 ± 0.5°C (12).  An aliquot of 10 mL was withdrawn at different time intervals and an equal volume of fresh dissolution medium was added to maintain the sink condition. Samples were suitably diluted and analysed in a UV-visible spectrophotometer at 210 nm to determine the amount of drug released (13). The fresh dissolution medium replacement was considered in the calculation of the amount of drug released.

Table 01: Preliminary Batches of Inner Core (Erosion matrix tablet)

*All values are in milligram

Table 02: Formulation Batches of inner Core using Different concentration of HPMC K4

*All values are in milligram

Table 03:  Preliminary Batches of enteric Coating

Table 04: Preliminary Batches of outer Coat

Full factorial design ^[18-20]

In preliminary studies Eudragit L 100, HPMC K 4 and MCC were selected as Coating agent for the preparation of tablets. In order to investigate the effect of formulation variables on the response that predict an optimized formulation, a 3² factorial design was adopted using software Design Expert. Nine batches were prepared as per the design layout. In the present work, a 3² full factorial design was adopted to find out the optimum combination of independent variables that give the desired values of dependent variables.

Table 05: Selection of Independent variables and Dependent variables

Table 06: Selection of levels for independent variables

Table 07: 3² Factorial design

RESULT AND DISCUSSION:

Calibration curve of nateglinide in 0.1 N HCl solution was prepared which has linearity equation y = 0.0278x + 0.016 and regression coefficient value is 0.998. Calibration curve of nateglinide in phosphate buffer solution (pH 6.8) was prepared which has linearity equation y = 0.0287x + 0.0128 and regression coefficient value is 0.9946. A drug-excipient interaction study at an early stage of product development is an important exercise in the development of a stable dosage form. The peaks of NTG and excipient were not affected and prominently same as observed in FT-IR spectrum of NTG alone.

Batches for selection of Inner core (Erosion matrix tablet) :

Preliminary batches P1-P4 were made to prepare the tablets using 6 mm punch on ‘B’ tooling punching machine using ingredients shown in the Table 01. Maximum weight of the inner core tablet is 100 mg whereas of dose of nateglinide in the inner core is 90 mg. Hence for controlling 90 mg of nateglinide we have add more polymer so have to move on the 8 mm Punch. Batches P-5 to P-7 were prepared using 8 mm punch on ‘B’ tooling punching machine by increasing the total weight of tablet 200-250 mg. From the results of the above batches it was found that Bach P7 shows the good Hardness (4.7 ± 0.6 kg/cm2)  and also pass the fraibility test so Batch P7 was selected for further optimization of polymer concentration.

Batches for selection of concentration of Polymer:

Batches F1-F5 were made to prepare the tablets using 8 mm punch on ‘B’ tooling punching machine using different concentration of HPMC K4. Drug release profile of F-1 to F-3 of the formulations mentioned above did not appear to be closer to the theoretical drug release profile as it not release up to 24 hrs. As F-4 showed 102.76 % of drug release in 24 hours.

Table 08: Evaluation of granules and tablets of preliminary batches of inner core

Table 09: Evaluation of granules and tablets of formulation batches of inner core

Table 10: Dissolution data of F1-F5

Figure 02: Comparison of in vitro release of nateglinide from the tablets of the batches F-1 to F-5 with theoretical drug release profile for 2 to 24 hr.

Batches for selection of Enteric coating :

Batches C-1 to C5 were prepared by using different concentration of Eudragit L100 , and HPMC K4. Batch C1 fails the disintegration test of enteric coated tablets. In 0.1 N HCl it disintegrates completely within 15 min.

Table 11: Evaluation of granules and Enteric tablets

Baches C2, C3 and C4 shows lamination during the compression coating (Figure no a). This might be because of lake binding proprieties of Eudragit L 100. In Batch C5 addition of HPMC MCC solved the problem of lamination (Figure no a) and also passes the disintegration test for enteric coating. it can with stand in 0.1 N HCl for 2 hr as it is (Figure no b). Though there is a scope for further improvement, amongst the batches tested the formulation C-5 is considered as the best batch, which needs to be finally optimized. Further optimization of coating was carried out by using experimental design.

Figure 03: a) Tablet laminate. b) It can withstand for 2 hr in 0.1 N HCl

Batches for outer coat (immediate release portion):

 The outer coat containing immediate release portion of drug (60 mg) was added by coating the enteric coated tablets using 12 mm punch as per methodology described earlier. Batch O2 show good coating and showing good constancy. So final outer coat was done using 12 mm punch keeping final weight 630 mg. This formula was also used in for coating of enteric coated tablet in factorial design.

Table 12: Evaluation of granules and Outer coated tablets

Formulation of batches as per factorial design:

The controlled release tablets were manufactured for the batches E1 to E9 using the ingredients shown. The properties of the manufactured tablets are shown in the below table.

Table 13: Evaluation Factorial design batches

Figure 04: Comparison of in vitro release of nateglinide from the tablets of the batches E-1 to   E-5 with theoretical drug release profile

The amount of Eudragit L 100 (X1) and HPMC K4 (X2) were chosen as independent variables in a 3² full factorial design using Design Expert Software. A statistical model incorporating interactive and polynomial terms was used to evaluate the responses.

Y = b₀ + b₁X₁ + b₂X₂ + b₁₂X₁X₂ + b₁₁X₁² + b₂₂X₂²………………………………………… Eq. 1

where, Y is the dependent variable, b₀ is the arithmetic mean response of the 9 runs, and b₁ is the estimated coefficient for the factor X₁. The main effects (X1 and X2) represent the average result of changing one factor at a time from its low to high value. The interaction terms (X1X2) showed how the response changes when two factors are simultaneously changed. The polynomial terms (X1² and X2²) are included to investigate nonlinearity. As shown in Table 13, % drug release for 2 hr, 12 hr, and 24 hr for the 9 batches (E1 to E9) showed a wide variation. The data indicates that the dependent variables such as % drug release for 2 hr, 12 hr, and 24 hr are dependent on the selected independent variables such as concentration of Eudragit L 100 and HPMC K4.

Table 14: Anova value for X1 and X2

Table 14 shows the results of the analysis of variance (ANOVA), which was performed to identify significant factors. In Design Expert software it suggests to choose model so for Y1 Two Factor Interaction model and for Y2 and Y3 Response Surface Linear model was selected. So it will give reduce equation only as per below,

Y1 = 41.86-1.69X2, In this case X2 is a significant model term.

Y2 = 63.68-2.65X1-8.82X2, In this case X1, X2 are significant model terms. 

Y3 = 96.13-1.63X1-6.08X2,  In this case X1, X2 are significant model terms.

Figure 05: Contour plot of X1 and X2 on Y1

Figure 06: Three-dimensional surface plot showing for X1 and X2 on Y1

Figure 07: Contour plot of X1 and X2 on Y2

Figure 08: Three-dimensional surface plot showing for X1 and X2 on Y2

Figure 09: Contour plot of X1 and X2 on Y3

Figure 10: Three-dimensional surface plot showing for X1 and X2 on Y3

The response surface plot and three-dimensional plot of X1 and X2 versus reponse are shown in Figures 04 to 09, respectively. The response plot showed that there is a significant effect of both factors on selected response.

Check point :

Table 15: Check point value

Table 16: Evaluation of check point batches

From the check point two batches were prepared and evaluated. Thus, from the results of statistical optimization techniques it can be concluded that all of the models are mathematically significant.

The model predicts the required drug release for Y1(T2%), Y2(T12%) and Y3(T24%) from point prediction, at X1 is 1 level and X2 is -0.791 level i.e. X1 (%) is 60 % X2(%) is 23.73% (E-3). The response T2% was predicted at 40.925% and T12% at 68.000% and T24% at 99.313.

Figure 11:  overlay plot for optimized batch