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Abstract Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs via various pharmaceutical products of different dosage forms. Gastro retentive drug delivery systems are the systems which are retained in the stomach for a longer period of time and thereby, improve the bioavailability of drugs. GRDDS can improve the controlled delivery of drugs that have an absorption window by continuously releasing the drug for a prolonged period of time before it reaches its absorption site, thus ensuring its optimal bioavailability. Floating matrix tablet of Ramipril was prepared using HPMC K4M & Carbopol 934NF. The NaHCO3 & Citric acid was used in combination as gas generating agent. Sodium CMC was used as gelling agent. A 32 factorial design was applied for preparing Formulation and evaluation of floating matrix tablet of Ramipril and to study the effect of independent variables i.e. concentration of HPMC K4M [X1 (%w/w)] and concentration of carbopol934NF [X2 (%w/w)] on various responses i.e. hardness, friability, swelling and In-vitro drug release at Q8hr through matrix tablet. A constant complex weight of 250 mg was incorporated in all the formulation batches. The In-vitro drug release of all the formulation batches was determined by measuring the absorbance. The results indicated that F9 showed least In-vitro drug release whereas F7 showed the highest release of 98.6%. Infect higher amount of HPMC K4M in the complexes provided the formation of a three dimensional hydrogel structure which was responsible for higher drug release. Key words: GRDDS, Ramipril, HPMC K4M, Carbopol934NF, Sodium carboxymethylcellulose (Na CMC), NaHCO3 *Corresponding Author: Syed Iftequar, Dr. Rafiq Zakaria Campus, Maulana Azad Educational Trust`s, Y. B. Chavan College of Pharmacy, Post Bo.No. 33, Rauza Bagh, Aurangabad (Maharashtra) India.

1. Introduction

Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systemic

delivery of drugs via various pharmaceutical products of different dosage forms. The reasons that the oral route achieved such popularity are its ease

JIPBS

Research article

Formulation and evaluation of floating drug delivery system of ramipril Syed Iftequar*, Maria Saifee, Lahoti Swaroop, Zahid Zaheer, Sabina Meraj, Furqan khan, Sarfraz Khan, Qazi Yasar, Shaikh Abdulla

Dr. Rafiq Zakaria Campus, Maulana Azad Educational Trust`s, Y. B. Chavan College of Pharmacy, Post Bo.No. 33, Rauza Bagh, Aurangabad (Maharashtra) India.

http://www.jipbs.com/

Syed Iftequar et al., JIPBS, Vol 3 (1), 85-95, 2016

86

of administration. In fact, the development of a pharmaceutical product for oral delivery, irrespective of its physical form (solid, semi-solid or liquid dosage forms) involves varying extents of optimization of dosage forms characteristics within the inherent constraints of GI physiology. [1] Conventional oral dosage forms provide a specific drug concentration in systemic circulation without offering any control over drug delivery. Controlled-release drug delivery systems (CRDDS) provide drug release at a predetermined, predictable, and controlled rate. An important requisite for the successful performance of oral CRDDS is that the drug should have good absorption throughout the gastrointestinal tract, preferably by passive diffusion, to ensure continuous absorption of the released drug. The average time required for a dosage unit to traverse the GIT is 3 - 4 h, although slight variations exist among various dosage forms. The concept of sustained or prolonged release of biologically active agents has been well appreciated and rationalized for decades. In the exploration of oral controlled release drug administration, one encounters three areas of potential challenge. [2]

1. Development of a drug delivery system: To develop a viable oral controlled release drug delivery system capable of delivering a drug at a therapeutically effective rate to a desirable site for duration required for optimal treatment. [4]

2. Modulation of gastro intestinal transit time: To modulate the GI transit time so that the drug delivery system developed can be transported to a target site or to the vicinity of an absorption site and reside there for

prolonged period of time to maximize the delivery of a drug dose. [8]

3. Minimization of hepatic first pass elimination: If the drug to be delivered is subjected to extensive hepatic first pass elimination, preventive measures should be devised to either bypass or minimize the extent of hepatic metabolic effect. [3]

2. Materials and Methods Materials: Ramipril hydrochloride was obtained as a gift sample (Shriya life sciences Aurangabad. It is official in most of the pharmacopoeia’s i.e. USP and BP. It was standardized as per official compendia and also characterized as per Analytical profile of drug substance provided by Florey.). Hydroxypropyl methylcellulose K4M (HPMC K4M) and Carbopol934NF were received as gift samples from the Lobachemie, Mumbai. All other ingredients used were of analytical grade and were used as received. [29] Methods: Formulation Design: For Simplex Centroid Design formulation design expert 7.1.6 software (stat-ease) demo version was used. In formulation amounts of HPMC K4M (X1), Carbopol 934NF (X2) were selected as independent variables. The floating lag time (FLT), and times required for 50% of drug release (t50) and 90% of drug release (t90) were selected as dependent variables. In this optimization study Quadratic mix order and Scheffe design model were used. The targeted response parameters were statistically analyzed by applying one-way analysis of variance (ANOVA) at 0.05 levels in Design-Expert 7.1.6 version soft ware (Stat-Ease Inc., Minneapolis, MN).


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Stability studies The best formulation was kept for stability studies in a stability chamber (Thermo lab) for a period of three months at temperature 400C ± 20C and RH 75 ± 5%. The changes in physical appearance, weight, drug content, in-vitro drug release was observed after intervals of one month. Fabrication of Ramipril Hydrochloride floating tablets: Ramipril Floating tablets were formulated as per the formulations given in Table 1. All the ingredients were weighed accurately. Drug was mixed with required quantity of all ingredients by geometric mixing. This blend was directly compressed into tablets using 8.5-mm flat-face round tooling on Karnavati, 8 station RINEK rotary tablet press. Compression force was adjusted to obtain

tablets with hardness in range of 5 to 6 kg/cm2. Tablets weighed 250 mg, and were round flat-face with an average diameter of 10 ± 0.1 mm and thickness of 3.4 ± 0.2 mm. 9 Formulations of the factorial batches (F1 to F9) are shown in Table 3.

Table 1: Ramipril tablet formulation Ingredients Qty./tablet

(mg) Qty./20

tablet(mg) Ramipril 2.5 50

HPMC K4M 83.33 1666.6 Carbopol934NF 12.5 250

NaHCO3 25 500 Citric acid 12.5 250

Na CMC 8.3 166.66 Lactose 108.35 2117

Talc 4.16 83.2 Mg-stearate 4.16 83.2

Table 2: Pre-compressional parameters for Ramipril gastro retentive tablets

FC Bulk Density Tapped Density Carr’s Index Angle of Repose F1 0.750±0.04 0.865±0.02 13.29±0.04 29.05±0.14 F2 0.624±0.02 0.786±0.03 20.60±0.03 29.24±0.13 F3 0.636±0.03 0.769±0.02 17.29±0.02 26.84±0.14 F4 0.646±0.05 0.876±0.05 26.25±0.06 28.24±0.16 F5 0.634±0.03 0.824±0.05 23.05±0.07 28.36±0.16 F6 0.664±0.05 0.745±0.03 10.87±0.03 27.22±0.14 F7 0.630±0.03 0.789±0.02 17.49±0.02 26.15±0.14 F8 0.71±0.04 0.825±0.02 13.49±0.04 29.02±0.14 F9 0.614±0.02 0.786±0.03 21.60±0.03 27.24±0.13

Table 3: Composition of Ramipril gastro retentive factorial batches Batches/Ingredients F1 F8 F9 F2 F4 F5 F3 F6 F7

Ramipril 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

HPMC K4M 50 50 50 75 75 75 100 100 100

Carbopol 934NF 7.5 12.5 17.5 12.5 17.5 7.5 17.5 12.5 7.5

NaHCO3 25 25 25 25 25 25 25 25 25

Citric acid 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5

Na CMC 8.3 8.3 8.3 8.3 8.3 8.3 8.3 8.3 8.3

Lactose 126.6 121.6 116.6 96.68 91.68 101.6 66.6 71.6 76.68

Talc 4.16 4.16 4.16 4.16 4.16 4.16 4.16 4.16 4.16

Mg-stearate 4.16 4.16 4.16 4.16 4.16 4.16 4.16 4.16 4.16

Total(mg) 250 250 250 250 250 250 250 250 250


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Ramipril gastro retentive factorial batches were prepared by using two different variables i.e. HPMCK4M and Carbopol934NF their varying conc. are given in the tab. Batches F1, F8, and F9 shows X1=50 mg HPMC K4M i.e. X1= -1, similarly X1=0 in the Batches F2, F4 and F5. X1= +1 in the batches F3, F6 and F7. The X2 i.e. second variable is carbopol934NF X2= -1 in the batches F1, F5 and F7. X2=0 in the batches F2, F6 and

F8. similarly X2= +1 in the batches F3, F4 and F9. Post-compressional parameters The Post-compressional parameters like thickness, hardness, friability, drug Content and percent swelling are calculated after formulation of each factorial batch the values are given in the Table 4. All the parameters are within the prescribed limit.

Table 4 :Post -compressional parameters for Ramipril gastro retentive tablets

In Vitro Buoyancy Studies: The in vitro buoyancy was determined by floating lag time as per the method described by Rosa et al, 10. The tablets were placed in a 100-mL glass beaker containing simulated gastric fluid (SGF), pH 1.2, as per USP. The time required for the tablet to rise to the surface and float was determined as floating lag time. 3. Results In the present investigation, combinations of three polymers were studied using the Quadratic design model. The mathematical models developed for all the

dependent variables using statistical analysis software. In all Tablets batches (F1 to F9) floating lag time variation were observed. Floating lag time Polynomial equation magnitudes of coefficients and mathematical signs suggested significant effect on floating lag time and varying amount of HPMC K4M, Carbopol 934P, Sodium carboxy methyl cellulose. As the amount of HPMC K4M and sodium carboxy methylcellulose increased, TFT increased; this is because of increased gel strength of matrices due to hydrophilic nature of HPMC, which produces easy swelling of tablets, which

F Thickness Hardness Friability Average Drug Content Swelling (%)

F1 2.06± 0.04 4.0±0.02 0.28 248 97.46 89.2

F2 2.14± 0.08 4.0±0.04 0.36 251 98.42 86.44

F3 2.12±0.06 4.5±0.06 0.48 253 98.24 80.21

F4 2.08±0.02 4.2±0.02 0.56 248 99.58 88.66

F5 2.96± 0.04 4.3±0.04 0.34 247 99.84 84.01

F6 2.16± 0.06 4.0±0.04 0.64 252 97.56 86.42

F7 2.36± 0.06 4.3 ±0.02 0.61 247 97.8 98.69

F8 2.11± 0.07 4.5±0.07 0.52 248 98.9 87.25

F9 2.56± 0.09 4.4±0.06 0.32 255 92.4 81.44


89

prevents escape of evolved carbon dioxide from matrices, leading to decreased density. Also the amount of Carbopol 934NF increased, TFT increased this may be due to high affinity of carbopol towards water, which promotes water penetration into tablet matrices, leading to increased density. In Vitro Dissolution Studies: The in vitro dissolution study of Ramipril hydrochloride tablets was performed using USP apparatus fitted with paddles (100 rpm) at 370C ± 0.50C using SGF (pH 1.2; 900 ml) as a dissolution medium. At the predetermined time interval, 5-mL samples were withdrawn, filtered through a 0.45-μm membrane filter, diluted, and assayed at 207.5 nm using a Shimadzu UV/vis double-beam spectrophotometer. There is a clear pharmaceutical need for advanced delivery systems that continuously supply narrow absorption window drugs to their absorption site for an extended time period. Provide effective and sustained drug concentrations in the

blood for prolonged periods of time. It would also eliminate the need for frequent drug administration and the use of inconvenient modes of administration (e.g. parenteral infusion). Optimizing the CR-GRDFs performance in-vivo was based on in-vitro release properties of the drug This IVIVC was proven here as a practical tool to predict the in-vivo release and absorption pattern based on the GRDF design. Specifically, the dose finding-study together with the - in vitro release rate finding experiment was carried out as follows: after the first prototype (CR GRDF. Kinetics of Drug Release: To study the release kinetics from hydrogel based matrix tablets, the release data were fitted to the well-known exponential equation (Korsmeyer–Peppas equation) and which is often used to describe the drug release behavior from polymeric systems when the mechanism is not well known or when more than one type of release phenomenon is involved.

Table 5: In vitro drug release profile with minimum concentration of HPMC K4M

Time (hours) Percent drug release ± Std. Deviation (n=3)

F1 F8 F9

1. 37.019±7.28 34.549±2.32 32.256±1.96

2. 40.400±3.67 57.32±1.04 40.197±1.35

3. 63.202±1.99 70.339±1.96 58.236±1.99

4. 71.489±1.35 73.02±1.99 63.672±3.67

5. 78.409±2.32 77.301±1.35 69.667±7.28

6. 80.954±1.96 80.546±3.67 72.87±1.42

7. 86.511±1.04 82.924±7.28 76.619±1.04

8. 89.273±1.42 87.254±1.42 81.444±2.32


90

Graph 1: In vitro drug release profile graph (minimum HPMC K4M) Series 1= F1 Series 2=

F8 Series 3= F9

Table 6: In vitro drug release profile with optimum concentration of HPMC K4M


F2 F4 F5

1. 31.198±7.28 29.963±1.96 40.37±2.32

2. 48.305±1.42 35.421±1.35 52.413±1.04

3. 68.682±3.67 62.959±1.99 65.581±1.96

4. 83.35±1.04 68.952±3.67 70.176±1.99

5. 86.102±1.99 75.858±7.28 75.147±1.35

6. 89.748±1.96 82.976±1.42 78.733±3.67

7. 95.882±2.32 87.31±1.04 81.807±7.28

8. 97.46±1.35 88.666±2.32 84.014±1.42

Graph 2: In vitro drug release profile graph (optimum HPMC K4M) Series 1= F2 Series 2= F4

Series 3= F5


91

Table 7: In vitro drug release profile with High concentration of HPMC K4M


F3 F6 F7

1. 52.895±1.04 43.898±7.28 31.198±1.42

2. 58.304±1.42 59.136±1.42 48.305±7.28

3. 67.976±7.28 68.107±3.67 68.682±3.67

4. 73.113±2.32 73.245±1.04 83.35±1.35

5. 76.689±3.67 77.175±1.99 86.102±1.99

6. 78.871±1.99 81.124±1.96 90.101±1.96

7. 81.063±1.35 83.682±2.32 95.354±1.04

8. 86.44±1.96 86.427±1.35 98.694±2.32

Graph 3: In vitro drug release profile graph (high HPMC K4M) Series 1= F3 Series 2= F6

Series 3= F7

Figure 3 shows release profile of simplex centroid batches. Formulations F1, F2, F3, F4, F5, F6 exhibited anomalous (non Fickian transport) diffusion/polymer relaxation mechanism with a value ranging from 0.59 to 0.78. Whereas in case

of formulations F7 exhibited zero-order release profile as their ‘n’ values were very close to 0.5681. Surface response plot:

Figure 1: Response surface plot (3D) showing the effect of the amount of amount of HPMC

K4M, CARBOPOL 934P and sodium carboxy methylcellulose on floating lag time, T50% and T90% respectively

Design-Expert® SoftwareFactor Coding: Actual% drug release

Design points above predicted valueDesign points below predicted value98.69

80.21

X1 = A: hpmc k4mX2 = B: carbopol

-1.00

-0.50

0.00

0.50

1.00

-1.00

-0.50

0.00

0.50

1.00

80

85

90

95

100

%

dru

g r

ele

as

e

A: hpmc k4m

B: carbopol


92

Figure 1 shows the 3D surface plot of the amount of HPMC K4M (X1), of Carbopol 934P (X2) and amount of sodium carboxymethylcellulose (X3) versus % Drug Release It may also be concluded that the high level of X1 (amount of HPMC K4M) and the lower level of X2 (amount of carbopol 934P) and X3 (amount of sodium carboxymethylcellulose) favor low floating lag time. Time required release to 50% of drug (t50%) and time required release to 90% of drug (t90%) showed wide variation DCS study: DSC of Ramipril & Ramipril Tablet Mixture:

DSC thermogram of drug, and physical mixture were obtained. Ramipril shows a characteristic endothermic peak at 114.770C which corresponds to its decomposition melt (Figure 2). DSC thermogram of Ramipril and physical mixture (Figure 3) showed an endotherm at 154.040C corresponding to Ramipril hydrochloride. The difference in thermal peaks between the pure components and physical mixture blend may be attributed to sample geometry effects and to reduction of individual purity in the presence of other component). DSC thermogram of Ramipril was found to be similar to that given in Analytical profile of drug substances by Florey (Figure2 and Figure 3 respectively).

0.00 2.00 4.00 6.00 8.00 10.00

Time [min]

-10.00

-5.00

0.00

mW

DSC

100.00

150.00

200.00

250.00

C

Temp

110.74 x100COnset

120.45 x100CEndset

105.99 x100CStart

121.56 x100CEnd

114.77 x100CPeak

-224.58 x100mJ

-76.39 x100J/g

Heat

-11.05 x100mWHeight

File Name: Ramipril.tadDetector: DSC60Acquisition Date 12/04/30Acquisition Time 16:15:15Sample Name: RamiprilSample Weight: 2.940[mg]Annotation:

[Temp Program]Start Temp 100.0Temp Rate Hold Temp Hold Time[C/min ] [ C ] [ min ]20.00 250.0 0

Thermal Analysis Result

Ramipril.tadRamipril.tad

TempDSC

Figure 2: DSC of Ramipril

0.00 2.00 4.00 6.00 8.00 10.00

Time [min]

-4.00

-2.00

0.00

2.00

mW

DSC

100.00

150.00

200.00

250.00

C

Temp

146.59 x100COnset

160.78 x100CEndset

127.26 x100CStart

163.75 x100CEnd

154.04 x100CPeak

-139.59 x100mJ

-30.75 x100J/g

Heat

-2.76 x100mWHeight

181.51 x100COnset

213.03 x100CEndset

174.32 x100CStart

218.62 x100CEnd

196.72 x100CPeak

-311.84 x100mJ

-68.69 x100J/g

Heat

-3.80 x100mWHeight

File Name: Ramipril tablet mixture.tadDetector: DSC60Acquisition Date 12/04/30Acquisition Time 16:31:07Sample Name: Ramipril tablet mixtureSample Weight: 4.540[mg]Annotation:

[Temp Program]Start Temp 100.0Temp Rate Hold Temp Hold Time[C/min ] [ C ] [ min ]20.00 250.0 0

Thermal Analysis Result

Ramipril tablet mixture.tadRamipril tablet mixture.tad

TempDSC

Figure 3: DSC of Ramipril Tablet Mixture


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4. Discussion An attempt was made to develop a gastro retentive drug delivery system of Ramipril HCL using HPMC K4M, Carbopol 934P, and Sodium carboxy methyl cellulose as matrixing agent, viscosity increasing agent, and gelling agent, respectively. A simplex centroid design was applied to investigate the combined effect of 3 formulation variables (i.e. amount of HPMC (X1), Carbopol 934P (X2), and sodium carboxymethyl cellulose (X3). From the in vitro buoyancy studies, it was found that almost all the batches containing effervescent agent showed immediate floatation followed by floatation period of more than 18hr. The values of diffusion exponent ‘n = 0.5681 determined from the Korsmeyer-Peppas equations obtained from modeling of dissolution profiles showing percent drug release of a 90% indicates an anomalous transport mechanism and that the mass transfer follows a non Fickian model. Conclusion The effervescent based floating drug delivery was a promising approach to achieve in vitro buoyancy. The addition of gel forming polymer (HPMC K4M) and gas generating agent sodium bicarbonate and citric acid were essential to achieve the in-vitro buoyancy. The drug release form the tablets were sufficiently sustained due to the presence of polymers. Ramipril hydrochloride floating tablet drug delivery system showed improved in-vitro bioavailability and extended drug release which may favor the reduced dose frequency and patient compliance. From the results obtained, it was concluded that the formulation F7 is the best formulations as the extent of drug release was found to be around 90 %. This batch also showed immediate floatation and

floatation duration of more than 18hr. The drug release model of this formulation complies with zero order kinetics. Based on the results we can certainly say that floating type gastro retentive drug delivery system holds a lot of potential for drug having solubility as well as stability problem in alkaline pH or which mainly absorb in acidic pH. We can certainly explore this drug delivery which may lead to improved bioavailability and ensured therapy with many existing drugs. Acknowledgements The authors are grateful to Maulana Azad Education trust’s Y.B. Chavan College of Pharmacy, Aurangabad for providing essential laboratory conditions for present research work. Also an author acknowledges to Sherya labs Pvt. Ltd (Aurangabad India), for providing gift sample of Ramipril HCL. References 1. Alaa Eldeen B. Yassin, Ibrahim A.Chitosan

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