Design, Development and Optimization of Pulsatile Drug ... · specific pulsatile drug delivery system of drug Irbesartan. Keywords: Pulsatile, Pulsincap, Irbesartan, Hypertension,

Vishal V. Bilaskar et al., , 2018/ Design, Development and Optimization of Pulsatile Drug

International Research Journal of Pharmaceutical and Biosciences (IRJPBS) 4 (6) 1

RESEARCH ARTICLE

International Research Journal of Pharmaceutical and Biosciences

Pri -ISSN: 2394 - 5826 http://www.irjpbs.com e-ISSN: 2394 - 5834

Design, Development and Optimization of Pulsatile Drug Delivery of Antihypertensive Drug

Vishal V. Bilaskar*, Indrajeet S. Patil, Omkar A. Patil, Girishchandra R. Mandke, Shrinivas K. Mohite

Department of Pharmaceutics, Rajarambapu College of Pharmacy, Kasegaon, Maharashtra India- 415404.

Article info Abstract

Article history: Received 03 APR 2018 Accepted 10 APR 2018

*Corresponding author: [email protected]

Copyright 2018 irjpbs

The aim of present study was to Design, develop and optimize the pulsincap formulation on the principle based on the pulsatile drug delivery system using Irbesartan drug. Irbesartan is mainly used for treatment of high blood pressure, diabetic nephropathy, and to increase the chances of living longer after a heart attack. It is an angiotensin II receptor antagonist that is selective for the type II angiotensin receptor. Formalin treatment has been employed to modify the solubility of gelatin capsules. Quantitative test for formaline residue was carried out. FTIR study shown drug and excipient are compatible with each other. Hydrogel plug of various components are prepared and used in pulsincap formulation. The drug content of the formulated pulsincap was found to be in the range 92.65 to 101%. In vitro drug release study in pH 1.2 buffers was zero percent and capsule was intact for first 2 hrs. F8 formulation batch was selected as best formulation as F8 batch released maximum drug in pH 7.4 phosphate buffer than other formulation batches. In the present work an attempt has been made to develop, evaluate and optimize a time or site specific pulsatile drug delivery system of drug Irbesartan.

Keywords: Pulsatile, Pulsincap, Irbesartan, Hypertension, Response surface methodology.

INTRODUCTION

Pulsed or pulsatile drug release is defined as the rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off-release period [1]. These delivery systems release the drug rapidly and completely after a lag time, thus provide spatial and temporal delivery and increasing patient compliance, have generated increasing interest during recent years for a number of diseases and therapies [2]. The system is designed according to Circadian rhythm or biological clock which delivers the



drug at the right time and at the right place and in the right amount thus, increasing patient compliance. In the pulsatile drug delivery system, initially there is no drug release after which there is an immediate or controlled release of the drug [3]. In recent years, there is a continuous interest in the development of controlled drug release systems to achieve the optimal therapeutic effect of drugs. This is based on the increasing awareness of the importance of circadian rhythms with respect to physiology, disease state and drug action which has given rise to the related fields of chronotherapeutics and chronopharmacology [4].

Pulsincap system comprises of a water insoluble capsule body, soluble cap and Hydrogel plug. When this capsule comes in contact with the dissolution fluid, it dissolves and after a lag time, the plug gets pushed itself outside the capsule and rapidly releases the drug. The length of the plug and its point of insertion into the capsule controls the lag time [5].

The capsule bodies of size 0 were treated with formaldehyde vapors to make capsule body water insoluble. The amino group in the gelatin molecular chain could react with an aldehyde group of formaldehyde by a Schiff’s base condensation reaction to produce a water insoluble body. Caps were left untreated. When the capsule comes in contact with dissolution media, the cap gets solubilized and the Hydrogel plug comes in contact with dissolution media and it gets hydrated and starts to swell and after ejection of the plug from the body, the drug release is facilitated [6].

Irbesartan is used to treat high blood pressure. It is well absorbed after oral administration and the bioavailability of about 70%and mean peak concentration of Irbesartan is reached in 0.5-1 hour after dosing. It minimizes the risk of heart attack and stroke. It works by blocking the action of certain natural substance that tighten the blood vessels allowing the blood to flow smoothly and heart to pump efficiently [7].

The main objective of this study was to design, formulate and optimize a pulsatile drug delivery system. For treatment of hypertension central composite design has been commonly used for designing and optimizing different pharmaceutical formulations and processes.

MATERIALS AND METHOD

Materials

Irbesartan was obtained as gift sample from Lupin Pharmaceuticals (Pune) and HPMC K4m, Ethyl Cellulose, Poly Vinyl Pyrolidone supplied by Research- Lab Fine Chem. Industries (Mumbai). All the ingredients used in research work are analytical grade.

Experimental Design A central composite design was employed containing two factors evaluated at three levels with α=1 was employed as per the standard protocol based on prefromulation and the experimental trials were performed at all 9 possible combinations. The studied factors (independent variables) were amount of polymer HPMC (X1), and Ethyl cellulose (X2). While drug release (DR) at 4 h (Y1), drug release (DR) at 8 h (Y2), drug release (DR) at 12 h (Y3) were



used as dependent (responses). Formulation table for pulsincap is given in (Table 1). The process variables (factors) and levels with experimental values are reported in (Table 2) Table 1: 32 Full Factorial Experimental Design Layout for Irbesartan Pulsincap

Factor 1 Factor 2 Run A:HPMC B:Ethyl

Cellulose mg mg

1 0 -1 2 - 0 3 0 1 4 1 1 5 1 0 6 -1 1 7 0 0 8 -1 -1 9 1 -1

Table 2: Variables levels with experimental values

Sr. No. Independent Variables Levels

-1 0 +1

1 HPMC amount(mg) X1 40 60 80

2 Ethyl Cellulose amount(mg) X2 30 45 60

Drug –Characterization

UV Spectroscopy

Calibration curve of Irbesartan was plotted in water, and buffer of pH 1.2, 7.4 and 6.8 with different concentration (1, 2, 3, 4, 5 μg/ml). The absorbance of the solution was taken at wavelength 244 nm against the blank solution using UV spectrophotometer. (Drug excipient interaction study) Fourier Transform Infrared (FT-IR) Spectroscopy Infrared spectroscopy was used to predict possible interaction between drug and excipients using a FTIR spectrometer (Jasco 4600) at 4000-650cm -1 [8].

Preparation of Cross-Linked Gelatin Capsules: Formalin treatment was employed to modify the solubility of gelatin capsules. Exposure to formalin vapours resulted in an unpredictable decrease in solubility of gelatin owing to the



cross-linkage of the amino group in the gelatin molecular chain aldehyde group of formaldehyde by Schiff’s base condensation [9,10].

Method Hard gelatin capsules of size 0 were taken. Bodies were separated from cap. 25 ml of 15% (v/v) formaldehyde was taken into desiccator and a pinch of potassium permanganate was added to it, to generate vapours of formalin. The wire mesh containing the empty bodies of capsule was then exposed to formaldehyde vapours. The desiccator was tightly closed. The caps were not exposed leaving them water-soluble. The reaction was carried out for 12 hrs after which the bodies were removed and dried at 500C for 30 min to ensure completion of reaction between gelatin and formaldehyde vapours. The bodies were then dried at room temperature to ensure removal of residual formaldehyde. These capsule bodies were capped with untreated caps and stored in a polythene bag [11].

Tests for Formaldehyde Treated Empty Capsules Various physical tests include visual defect, identification attributes namely dimensions, solubility studies of treated capsules, and chemical test were carried out simultaneously for formaldehyde treated and untreated capsules. The length and diameter of the capsules were measured before and after formaldehyde treatment, using digital Vernier calliper. Variations in dimensions between formaldehyde, treated and untreated capsules were studied.

Solubility study of treated capsules For the solubility study, the treated capsule bodies were exposed to 15% formaldehyde solution in varying time intervals. Then formaldehyde exposed capsule bodies were dried in hot air oven. The solubility of bodies was tested in 0.1N HCL. The time at which the capsule dissolves or forms a soft fluffy mass was noted [12].

Qualitative test for free formaldehyde: Formaldehyde treated bodies of about 25 capsules were cut into small pieces and taken into a beaker containing distilled water. It was stirred for 1 hrs with a magnetic stirrer, to solubilise the free formaldehyde. The solution was then filtered into a 50 ml volumetric flask, washed with distilled water and volume was made up to 50 ml with the washings. Method

To 1ml of sample solution, add 9 ml of water, 1mL of the resulting solution was taken into a test tube and mixed with 4ml of water and 5ml of acetone. The test tube was heated in a water bath at 40oC and allowed to stand for 40 min. The solution was less intensely colored than a reference solution prepared at the same time and in the same manner using 1ml of standard solution instead of the sample solution. The comparison was made by examining tubes down their vertical axis [13].

Preparation of hydrogel plug The Pulsincap hydrogel plug was prepared by compressing equal amount of HPMC K4M and lactose using 7mm punches and dies on a rotary tablet press, keeping variation in thickness and hardness values of tablet plug.



Characterization of prepared hydrogel plug

The prepared hydrogel plug evaluation was carried out for hardness, thickness and lag time test. Hydrogel plugs were plugged to capsule bodies containing formulated granules and the cap was closed. The lag time test was conducted in 7.4 pH phosphate buffer for 6 hrs using USP II dissolution testing apparatus and the drug release was observed [14].

Preparation of Irbesartan granules Irbesartan granules were prepared by wet granulation method. The composition of different formulations used in the study is represented in Table 3. HPMC K100 and ethyl cellulose were sieved (no.60) separately and mixed with Irbesartan. These powders were blended and granulated with PVP K30. Isopropyl alcohol was used as a granulating agent. The wet mass was passed through a mesh and granules were dried at 500C.

Table 3: Formulation Table of Irbesartan granules

Sr. no Run Factor 1 Factor 2 HPMC Ethyl Cellulose

mg mg 1. 1 60 30 2. 2 40 45 3. 3 60 60 4. 4 80 60 5. 5 80 45 6. 6 40 60 7. 7 60 45 8. 8 40 30 9. 9 80 30

Characterization of Irbesartan granules formulated with HPMC K4M The prepared granules were evaluated for different flow properties which comprised angle of repose, bulk density, tapped density, compressibility index, Hausner’s ratio and drug content. The drug content was evaluated by an UV spectrophotometric method based on the measurement of absorbance at 244 nm [15].

Formulation of Pulsatile (modified Pulsincap) drug delivery system

Preparation of modified pulsincap

Equivalent to 80 mg of drug, the prepared granules were filled in the capsule bodies and plugged with formulated hydrogel plug. The treated body and the cap of the capsules were sealed by using 5% ethyl cellulose ethanolic solution. The sealed capsules were coated with enteric coating (5% CAP) to reduce variability in gastric emptying time; coating was repeated until an expected weight gain of 8-12% was obtained [16].



Evaluation of modified pulsincap Weight variation 10 capsules were selected randomly from each batch and weighed individually for weight variation.

Thickness of cellulose acetate phthalate coating The thickness of coating cellulose acetate phthalate to capsule was measured with Vernier calliper and expressed in mm [17].

In-vitro release profile Dissolution studies of Irbesartan Pulsincap was carried out by using USP dissolution Type I apparatus (Basket). In order to simulate the pH changes along the GI tract, three dissolution media with phosphate buffer pH 1.2, 7.4, 6.8 were sequentially used. When performing experiments, the pH 1.2 medium was first used for 2h (since the average gastric emptying time is 2hour), then removed and the fresh pH 7.4 phosphate buffer was added. After 3 hours fresh pH6.8 dissolution medium was added for subsequent hrs. During the experiment 900 ml of the dissolution medium was used each time. Rotation speed was 50rpm and temperature was maintained at 37ºC. 5ml of dissolution media was withdrawn at predetermined time intervals and fresh dissolution media was replaced. The withdrawn samples were analyzed at 244 nm, UV visible spectrophotometer [18].

Statistical analysis of the data and optimization Various RSM computations for the current optimization study were performed employing Design Expert software (Design Expert trial version 7.0.3 State-Ease Inc, Minneapolis, MN). Polynomial models including interaction and quadratic terms were generated for all the response variables using multiple linear regression analysis (MLRA) approach. The general form of the MLRA model is represented as the following equation:

Y = β0+ β1 X1+β2 X2 +β3 X1X2+ β4 X12 + β5 X22 +β6 X1 X22+ β7 X2 X12 Here, b0 is the intercept representing the arithmetic average of all quantitative outcomes of 13 runs; b1 to b7 are the coefficients computed from the observed experimental response values of Y; and X1 and X2 are the coded levels of the independent variable(s). The terms X1X2 and X2 i(i= 1–2) represent the interaction and quadratic terms, respectively. Statistical validity of the polynomials was established on the basis of ANOVA provision in the Design expert Software. Subsequently, the feasibility and grid searches were performed to locate the composition of optimum formulations Three-dimensional (3D) response surface plots and two dimensional (2-D) contour plots were constructed based on the model polynomial functions using Design Expert software. These plots are useful to study the effects of various factors on the response at one time and predict the responses of dependent variables at the intermediate levels of independent variables.



RESULTS AND DISCUSSION Drug Characterization UV Spectroscopy From calibration curve of Irbesartan, UV absorption maximum of drug was found at 244 nm. As per calibration curve, the correlation coefficient was found to be 0.999 (pH 1.2), 0.999 (pH 7.4) and 0.997 (pH 6.8). Calibration curve obeyed Beer's law in the range of 1-5 μg/ml. FT-IR spectroscopy The drug-excipients compatibility was assessed by comparing IR spectra of the drug, and drug-excipient mixture. From the interpretation of spectra it was found that there was no worth change in the wave numbers of the drug and drug-excipients combination. Hence, the drug and excipients were found to be compatible with each other. (Figure 1 and 2)

Fig.1: FTIR for pure Irbesartan

Fig. 2: FTIR for drug-excipient mixture



Evaluation of Irbesartan granules The results of evaluation of the prepared granules are highlighted in (Table 4). All the formulation showed good angle of repose, flow property, Hausner’s ratio and Cars index.

Table 4: Evaluation of Irbesartan granules

All values are expressed as mean ±SD (n=3).

Evaluation of hydrogel plug The formulated hydrogel plugs were evaluated for thickness, hardness and lag time. It was found that 90 mg plug showed 2 hrs lag time and 100 mg plug exhibited 3 hrs lag time. Thus, 100 mg plug was optimized. Evaluation of formulation treated empty capsules The evaluation of treated empty capsule (cap and body) was carried out by length and diameter of capsules. The observations are recorded in Table 5.

Table 5: Evaluation of treated capsule

Solubility study for the treated capsules When solubility studies were carried for capsule in 0.1 N HCl for 24 hrs, it was observed that for normal capsules, both cap and body dissolved within 15 minutes, whereas for formaldehyde treated capsules, only the cap got dissolved within 15minutes and the remaining body of capsule remained intact for about 24 hours. Thus, the present work

Batch No.

Bulk density (g/cm3)

Tapped density (g/cm3)

Hausner’s ratio

Carr’s index (%)

Angle of repose

%Drug content

F1 0.403±0.002 0.468±0.005 1.16±0.004 14.31±0.003 250.18±0.04 96±0.002 F2 0.343±0.001 0.402±0.005 1.17±0.005 15.17±0.002 210.23±0.03 95±0.0036 F3 0.434±0.005 0.519±0.001 1.18±0.003 15.60±0.005 270.81±0.003 94±0.0013 F4 0.392±0.001 0.465±0.001 1.16±0.005 14.40±0.005 260.95±0.01 95±0.0018 F5 0.314±0.003 0.363±0.005 1.13±0.005 12.12±0.005 260.21±0.01 94±0.0034 F6 0.328±0.001 0.463±0.002 1.14±0.002 15.13±0.002 250.35±0.02 96±0.004 F7 0.368±0.001 0.457±0.001 1.16±0.005 13.27±0.003 240.85±0.04 93±0.0057 F8 0.376±0.002 0.474±0.005 1.17±0.003 14.57±0.004 260.89±0.01 95±0.0065 F9 0.356±0.001 0.460±0.004 1.13±0.005 15.67±0.005 230.56±0.04 95±0.0028

Sr.no. Initial Length of Capsule (mm)

Average Length after formaldehyde

treatment (mm)

Initial Diameter of Capsule (mm)

Average Diameter after formaldehyde

treatment (mm) 1 19.70 19.70±0.02

6.81 6.82±0.009



concluded that 8 hr formaldehyde treatment is sufficient to sustain the release for 18hr and found that the capsule maintained the physical stability during the dissolution process.

Quantitative test for free formaldehyde

The formaldehyde treated capsules were tested for the presence of free formaldehyde. The sample solution was not more intensely colored than the standard solution inferring that less than 20μg free formaldehyde is present in 25 capsule.

Weight variation and thickness of coating

The capsules filled with granules pass the weight variation test as their weights were found within the specified limits and the thickness of the CAP coating was measured by Vernier calliper which ranged from 0.053-0.070 mm.

In-vitro release studies

In vitro dissolution test for capsules was performed in dissolution media of pH 1.2 and 6.8. The formulations F1 to F9 showed more than 70% drug release (Table 6). Batch F8 exhibited more than 90% drug release. During the dissolution studies, it was observed that, the enteric coat of the cellulose acetate phthalate was intact in pH 1.2, but dissolved in intestinal pH, leaving the soluble cap of capsule, which also got dissolved in pH 7.4 phosphate buffer. Thus, from % drug release studies of various formulation batches, F8 batch was selected as best formulation as it achieved maximum drug release in pH 7.4 phosphate buffer as compared to other formulation batches. The drug release from the formulation was observed to be decreased with an increase in the amount of polymer added in each formulation. (Figure 3 and 4)

Table 6: In-vitro Dissolution studies

Sr.No. Hrs. Average % Drug release F1 F2 F3 F4 F5 F6 F7 F8 F9

1 1 0 0 0 0 0 0 0 0 0 2 2 0 0 0 0 0 0 0 0 0 3 3 9 9.08 9.22 8.50 9.31 9.02 9.27 9.90 9.30 4 4 15.78 16.2 13.35 13.22 12.23 15.6 15.56 18.24 16.96 5 5 22.70 23.67 22.89 24.2 25.16 23.84 24.63 25.30 26.22 6 6 31.6 32.45 32.78 34.26 33.18 40 35.68 37 36.25 7 7 41.58 40 45.26 47.54 45.48 52.85 46.32 52.41 47.28 8 8 62.46 60.62 63.65 60.14 59.31 63.69 62.6 63.12 61.14 9 9 71.25 67.5 70.6 67.25 65.1 70.87 70.54 70.47 72.20

10 10 79.9 74.58 78.45 73.87 71.64 75.8 74.7 76.22 80.52 11 11 85.33 82.27 81.26 82.25 80.33 81.98 82.7 85.2 86.3 12 12 91.56 90.61 87.34 90.42 85.56 90.54 90 92.65 91.54



Fig.3: In-vitro Dissolution studies F1to F5

Fig.4: In-vitro Dissolution studies F6 to F9

Effect of formulation variables on drug release at 4 h Drug release play important role in all formulation as we know the drug release of dosage form is depend up on amount of polymer used in formulation. Amount of polymer used in formulation having significant effect on drug release. In formulations, F1–F9 drug release was in the range of 15.78 to 16.96 at 4 h, maximum drug release 18.24 was shown by formulation F8, where as minimum drug release was shown by 13.22, was shown by formulation F4. The effect of the variables on the drug release in formulations F1–F9 are shown in below (Figure 5) and (Figure 6) respectively Y1 = 15 – 1.17x1 -1.22X2 (1) All the polynomial equations were found to be statistically significant (𝑃<0.0010), as determined using ANOVA, as per the provision of Design Expert software. The combined effect of concentration of HPMC and Ethyl cellulose on drug release at 4 h was shown in

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12

%Drug release

Time(Hrs.)

In vitro Dissolution Studies

F1

F2

F3

F4

F5

0 10 20 30 40 50 60 70 80 90

100

1 2 3 4 5 6 7 8 9 10 11 12

%Drugrelease Time(Hrs)

In vitro Dissolution Studies

F6

F7

F8

F9



counter plot and in 3D response surface plot. In above equation X1 Bears / having negative sign and X2 also Bears / having negative sign which shows that decreased / at lower concentration of HPMC and Ethyl cellulose is required for get optimum drug release at 4h. From the plots and polynomial equation it can concluded that both factor HPMC (X1) and Ethyl cellulose(X2) having significant effect on drug release at 4 h. Table 7: ANOVA for response surface quadratic model for drug release at 4 hrs Analysis of

variance table. Parameters Sum of

Squares df Mean

Square F

value p-value Prob

> F Remark

Drug release at 4 hrs(Quadratic model)

22.79 2 11.40 14.91 0.0010 significant

X1 10.87 1 10.87 14.22 0.0037 X2 11.92 1 11.92 15.60 0.0027 Residual 7.64 10 0.76 Lack of Fit 7.64 6 1.27 Pure Error 0.000 4 0.000 Cor Total 30.43 12

Fig. 5: Contour plot (A) showing the effect of the amount of polymer HPMC and Ethyl Cellulose on drug release at 4 h from Irbesartan Pulsincap

Design-Expert® SoftwareFactor Coding: ActualQ4 (%)

Design Points18.24

12.23

X1 = A: HPMCX2 = B: Ethyl Cell

40 50 60 70 80

30

36

42

48

54

60Q4 (%)

A: HPMC (mg)

B: Eth

yl Ce

ll (mg

)

14

15

16

17

5



Fig. 6: Response surface plot (A) showing the effect of the amount of polymer HPMC and Ethyl cellulose on drug release at 4 h from Irbesartan Pulsincap

Effect of formulation variables on drug release at 8 h

Drug release play important role in all formulation as we know the drug release of dosage form is depend up on amount of polymer used in formulation. Amount of polymer used in formulation having significant effect on drug release. In formulations, F1–F9 drug release was in the range of 59.31 to 63.69 at 8 h, maximum drug release 63.69 was shown by formulation F6, where as minimum drug release was shown by 59.31, was shown by formulation F5. The effect of the variables on the drug release in formulations F1–F9 are shown in below (Figure 7) and (Figure 8) respectively

Y2 = 62.60 – 0.87X1 + 0.11X2 – 0.49X1X2 - 1016 X1 + 0.38X2 (2) All the polynomial equations were found to be statistically significant (𝑃<0.0010), as determined using ANOVA, as per the provision of Design Expert software. The combined effect of concentration of HPMC and Ethyl cellulose on drug release at 8 h was shown in counter plot and in 3D response surface plot. In above equation X1 Bears / having negative sign and X2 also Bears / having negative sign which shows that decreased / at lower concentration of HPMC and Ethyl cellulose is required for get optimum drug release at 4h. From the plots and polynomial equation it can concluded that both factor HPMC (X1) and Ethyl cellulose(X2) having significant effect on drug release at 8 h.


Design points above predicted value18.24

12.23


30

36

42

48

54

6040

50

60

70

80

12

13

14

15

16

17

18

19

Q4

(%)

A: HPMC (mg) B: Ethyl Cell (mg)



Table 8: ANOVA for response surface quadratic model for Drug release at 8 hrs Analysis of

variance table [Partial sum of squares - Type III].

Parameters Sum of Squares

df Mean Square

F Value p-value Prob > F

Remark

Drug release at 8 hrs (Quadraticmodel)

18.59 5 3.72 9.03 0.0058 Significant

X1 6.09 1 6.09 14.80 0.0063

X2 0.091 1 0.091 0.22 0.6527

X1X2 0.97 1 0.97 2.36 0.1687

X12 9.43 1 9.43 22.91 0.0020

X22 1.01 1 1.01 2.45 0.1617

Residual 2.88 7 0.41

Lack of Fit 2.88 3 0.96

Pure Error 0.000 4 0.000

Cor Total 21.48 12

Fig. 7: Contour plot showing the effect of the amount of polymer HPMC and Ethyl Cellulose on drug release at 8 h from Irbesartan Pulsincap.


Design Points63.69

59.31


40 50 60 70 80

30

36

42

48

54

60Q8 (%)

A: HPMC (mg)

B: Eth

yl Ce

ll (mg

)

61

62

63

5



Fig. 8: Response surface plot (A) showing the effect of the amount of polymer HPMC and Ethyl cellulose on drug release at 8h from Irbesartan Pulsincap

Effect of formulation variables on drug release at 12 h

Drug release play important role in all formulation as we know the drug release of dosage form is depend up on amount of polymer used in formulation. Amount of polymer used in formulation having significant effect on drug release. In formulations, F1–F9 drug release was in the range of 85.56 to 92.65 at 12 h, maximum drug release 92.65 was shown by formulation F8, where as minimum drug release was shown by 85.65, was shown by formulation F5. The effect of the variables on the drug release in formulations F1–F9 are shown in below (Figure 9) and (Figure 10) respectively

Y3 = 90.02 – 1.05X1 – 1.15X2 (3)

All the polynomial equations were found to be statistically significant (𝑃<0.0010), as determined using ANOVA, as per the provision of Design Expert software. The combined effect of concentration of HPMC and Ethyl cellulose on drug release at 8 h was shown in counter plot and in 3D response surface plot. In above equation X1 Bears / having negative sign and X2 also Bears / having negative sign which shows that decreased / at lower concentration of HPMC and Ethyl cellulose is required for get optimum drug release at 4h. From the plots and polynomial equation.


Design points above predicted valueDesign points below predicted value63.69

59.31


30

36

42

48

54

60

40 50

60 70

80

59

60

61

62

63

64

Q8

(%)

A: HPMC (mg)

B: Ethyl Cell (mg)



Table 9: ANOVA for response surface quadratic model for drug release at12hrs Analysis of variance table [Partial sum of squares - Type III].

Parameters Sum of Squares

df Mean Square

F Value p-value Prob > F

Remark

Drug release at 12hrs

(Quadraticmodel)

19.34 2 9.67 4.81 0.0345 significant

X1 8.76 1 8.76 4.35 0.0635

X2 10.58 1 10.58 5.26 0.0448

Residual 20.12 10 2.01

Lack of Fit 20.12 6 3.35

Pure Error 0.000 4 0.000

Cor Total 39.45 12

Fig. 9: Contour plot showing the effect of the amount of polymer HPMC and Ethyl Cellulose on drug release at 12 h from Irbesartan Pulsincap.


Design Points92.65

85.56


40 50 60 70 80

30

36

42

48

54

60Q12 (%)

A: HPMC (mg)

B: E

thyl

Cell (

mg)

88

89

90

91

92

5



Fig.10: Response surface plot (A) showing the effect of the amount of polymer HPMC and Ethyl cellulose on drug release at 12h from Irbesartan Pulsincap.

Optimization criteria for Irbesartan Pulsincap This was the most important part of response surface methodology. The formulation of the drug which released the drug in controlled and complete manner was selected for optimum formulation. The criteria for optimum formulation of Irbesartan Pulsincap are given in (Table 10).

Table 10.Release kinetics of optimum formulation

Release property Range

Release at 4 h 15 – 18 %



Optimization of Irbesartan Pulsincap Formulation F8 was select as optimized formulation. This fit in given criteria for optimization of formulation. Formulation F8 releases the drug in controlled and complete manner.

CONCLUSION Novel pulsincap formulations were successfully developed by filling of granules in a capsule body. The capsule body containing granules after plugging with a polymer and sealed with a cap was completely enteric coated with 5% w/w cellulose acetate phthalate. Formulation F-8 was considered as the best formulations as they shown a complete lag time 24 of hours and


Design points above predicted valueDesign points below predicted value92.65

85.56


30

36

42

48

54

60

40

50

60

70

80

83.578

85.9351

88.2922

90.6493

93.0064

95.3635

Q12

(%)

A: HPMC (mg)

B: Ethyl Cell (mg)



released 92.65% at the end of 12 hours respectively. Thus, pulsincap formulations will prove to be suitable for optimum colonic delivery of Irbesartan in the treatment of hypertension as per chronotherapy.

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Design, Development and Optimization of Pulsatile Drug ... · specific pulsatile drug delivery system of drug Irbesartan. Keywords: Pulsatile, Pulsincap, Irbesartan, Hypertension,