Formulation and Evaluation of Pantoprazole Delayed Release Tablets using Eudragit L30D55

 

Divakar Kanakagiri1*, Hari Omprakash1, Kishore Kumar M1, Vishwanadham Y2

1PNR College of Pharmacy, Pedda Shapoor, Shamshabad, R. R. District, Telangana-509325.

2Vishnu Institute of Pharmaceutical Education and Research, Narsapur, Medak, Telangana-502313.

*Corresponding Author E-mail: divakar.kanakagiri@yahoo.com

 

ABSTRACT:

Pantoprazole sodium is a proton pump-inhibitor which is used in the treatment of peptic ulcer. In this study Pantoprazole enteric coated tablets were prepared by using Methacrylate co-polymers (Eudragit L30D55).Eight formulations of enteric coated tablets of Pantoprazole were developed by preparing core tablets using Mannitol as diluent and Crospovidone as super disintegrant and Povidone (PVP K-30) as binder in different proportions and varying the compositions of sub coating and enteric coating using Sicovit yellow ,titanium dioxide and Eudragit (L30D55) .The core tablets were prepared by dry granulation method.F7 was found to be best of all the trials showing drug release matching the innovator product. The best formulation F7 was repeated again for reproducibility, and all the quality control tests were done for conformation. Stability study is carried out for 2 months at 25°C; 60% RH: and 40°C; 75%RH, according to ICH guidelines. The tablets were tested for acid release during the stability period and confirmed that results were found within the limits. The identified formula shall be utilized for the formulation development and other studies for successful launching of the product.

 

KEYWORDS: Delayed Release Tablets, Enteric Release, Peptic Ulcers, Proton Pump Inhibitor.

 


INTRODUCTION:

Controlled1 drug delivery is delivery of drug at a rate or at a location determined by needs of body or disease state over a specified period of time. The oral controlled release systems are classified as follows:

a)       Continuous release systems

b)       Delayed transit and continuous release systems

c)       Delayed release systems

 

DELAYED RELEASE SYSTEMS:

The Active Pharmaceutical Ingredient irritates gastric mucosa, for example aspirin or strong electrolytes Drugs that produce nausea and vomiting. Active Pharmaceutical Ingredient is sensitive to low pH, for example erythromycin. Release the drug undiluted, for example intestinal antibacterial, antiseptic agents, intestinal vermifuge, etc.

 

This dosage form is intended to hydrate and begin to dissolve in duodenum (pH 4 to 6) or in small intestine where pH increases to 7 to 8. The presence of esterase’s or bile salts like surface active agents plays a role in drug release. The design of such system involves release of drugs only at a specific site in the gastrointestinal tract. The drugs contained in such a system are those that are:

1.        Destroyed in the stomach or by intestinal enzymes

2.        Known to cause gastric distress

3.        Absorbed from a specific intestinal site or

4.        Meant to exert a local effect at a specific gastrointestinal site.

 

Pantoprazole Sodium:

Pantoprazole sodium is a proton pump inhibitor used to treat peptic ulcer, duodenal ulcer, gastro oesophageal reflux disease by inhibiting the enzyme H+ /K+ATPase , the acidic pump. It is also used to treat Zollinger-Ellison syndrome, erosive esophagitis.

 

Fig.1. Structure of Pantoprazole

 

Site and Mode of Action:

Pantoprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H+ /K+ ATPase, the acidic pump2. This effect on the final step of the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of the stimulus.

 

MATERIALS AND METHODS:

Pantoprazole sodium was received as a gift sample from Natco Pharmaceuticals ltd, Hyderabad and all other ingredients are obtained from Vijaya Enterprises, Saidabad, and Hyderabad through invoice. EUDRAGIT L 30 D-55(POLYMER) is a Polymethacrylate which is cationic and anionic polymers of the meth acrylic acids. It is used as enteric coating film former resistant to gastric juice and dissolves readily above pH 5.5.

 

Mannitol:

Mannitol occurs as white, odorless, crystalline powder or free flowing granules, sweet in taste and used as a Diluent.

 

Polysorbate:

Polysorbate 80 has a characteristic odor and warm, somewhat bitter taste. It is yellow oily liquid at 25°C used in sub coating as nonionic surfactant.

 

Sodium Lauryl Sulphate:

Sodium Lauryl Sulphate is White or cream to pale yellow colored crystals, flakes, bitter taste and a faint odor of  fatty substances and used as Anionic surfactant.

 

Cross Povidone:

Cross Povidone is White to creamy-white, finely divided; free flowing, practically tasteless, odorless or nearly odorless, hygroscopic powder used as a Disintegrant.

 

Hypromellose:

Hypromellose is white or creamy white fibrous or granular, odorless, tasteless powder used as a coating agent.

 

Propylene Glycol:

Propylene Glycol is a Liquid occurs as clear, colorless or slightly colored, viscous liquid, has a slight but characteristic odor and a bitter, slightly burning taste. Used as a plasticizer.

 

Sodium Carbonate:

Sodium Carbonate is White Solid Hygroscopic Material used as an acid regulator.

 

Formulation of Pantoprazole Sodium Delayed Release Tablets:

Pantoprazole sodium3 delayed release tablets were prepared by Dry granulation4 technique using different excipients as well as with varying concentrations of polymer proportions using Methacrylate5 copolymer (EudragitL30D55) as enteric coating material.

 

Formulation Development of Pantoprazole Enteric Coated Tablets:

Based on Preformulation data various excipients6 were selected and their compilation was shown in table no. 1.


Table: 1 Compilation of Pantoprazole Enteric Coated7 Tablets

S. No.

Ingredients

F 1

F 2

F 3

F 4

F 5

F 6

F 7

F 8

 

Drug loading stage

Q/mg

Q/mg

Q/mg

Q/mg

Q/mg

Q/mg

Q/mg

Q/mg

1

Pantoprazole sodium11

45.11

45.11

45.11

45.11

45.11

45.11

45.11

45.11

2

Mannitol

90

45.11

45.11

45.11

45.11

45.11

45.11

45.11

3

Kollidon CL

1.5

1.5

1.5

3.0

3.0

3.0

3.0

3.0

4

Sodium Lauryl Sulphate

1.55

1.55

1.55

1.55

1.55

1.55

1.55

1.55

5

Povidone (PVPK-30)

15.4

15.4

15.4

15.4

15.4

10

8

8

6

Sodiumcarbonate

10.30

10.30

10.30

10.30

10.30

10.30

10.30

10.30

7

Calcium stearate

1

1.5

1.5

1.5

1.5

1.5

1.5

1.5

8

Sub coating Stage

 

 

 

 

 

 

 

 

9

HPMC (5CPs)

-

17.48

17.48

17.48

12.87

12.87

12.27

12.27

10

Sicovit yellow

-

0.77

0.77

0.77

0.57

0.57

0.57

0.57

11

Propylene glycol

-

1.50

1.50

1.50

1.0

1.0

1.0

1.0

12

Titanium dioxide

-

0.40

0.40

0.40

0.283

0.283

0.283

0.283

13.

Purified water

-

175.6

175.6

175.6

129.3

129.3

129.3

129.3

14

Enteric coating stage

 

 

 

 

 

 

 

 

15

Eudragit L30D5512

-

27.0

33.12

33.12

33.12

33.12

33.12

33.12

16

Triethyl citrate

-

1.0

1.73

1.73

1.73

1.73

1.73

1.73

17

Polysorbate 80

-

0.3

0.48

0.48

0.48

0.48

0.48

0.48

18

 Purified water

-

59.67

59.67

59.67

59.67

59.67

59.67

59.67

 


 

 

In F1:

Here the blend showed very poor flow due to the fine grade of Active pharmaceutical ingredient. Physical feasibility was not good and found sticking problem also.

 

In F2:

To reduce the sticking problem Calcium Strearate concentration was increased. Mannital was added in intra and extra granular phase. To improve flow equal quantities of API and Mannital were taken and subjected to compaction. But in this trial Acid resistance was found to be failed.

 

In F3:

To improve the acid resistance in acid medium concentration of enteric coating material was increased in this trial. And acid resistance was improved. But here drug release was less in PH 6.8 Phosphate Buffer.

 

In F4:

To improve the drug release disintegrant concentration was increased in this trial. Drug release was found to be failed.

 

In F5:

To improve the drug release sub coating concentration was decreased. But release rate was quite less.

 

In F6:

In this trial disintegrant, subcoating concentration kept as such and binder concentration was decreased. Here drug release was more but less when compared to that of innovator.

 

In F7:

To improve the drug release concentration of binder was decreased in this trial. Finally drug release was improved and found equivalent to that of innovator.

 

In F8:

The trial 7 was repeated once again for reproducibility.

 

Manufacturing of Pantoprazole delayed release tablets:

Pantoprazole Delayed Release Tablets were prepared by Dry granulation method.

The process was displayed in the flow chart.

 

Step 1: Compaction:

Using single pan electronic balance, equal quantities of Pantoprazole and mannitol were weighed, mixed and subjected to compaction in roller compactor.

 

Step 2: Milling:

Compacts obtained in the step 1 were collected and milled in the multi mill.

Step 3: Sifting:

These granules were sifted through #30 mesh and #60; retained particles were collected and took for further process.

 

Step 4: Mixing of all ingredients:

All the excipients were sieved through #40 meshes and mixed with #60 retained particles.

 

Step 5: Compression:

The above blend was compressed by the use of compression machine.

 

Step 6: Preparation of sub coating solution:

1.     Titanium dioxide and Propylene glycol were mixed and this was added to purified water and mixed by using mechanical stirrer.

2.     Hypromellose was added to the above mixture. Finally sicovit yellow8 is mixed with small quantity of water and added to the above mixture.

 

Step 7: Sub coating:

Core tablets were weighed and loaded in the coating pan. Coating was continued till the desired build up (8.5%) was obtained.

 

Step 8: Preparation of enteric coating solution:

1.        Polysorbate 80 was mixed in purified water.

2.        Triethyl citrate and polysorbate 80 were individually added to eudragit with the help of Mechanical stirrer.

 

Step 9: Enteric coating:

1.        Sub coated tablets were weighed and loaded in the coating pan.

2.        Enteric coating9 was continued till the desired build up (16%) obtained.

 

Totally 8 Formulation trials were done using the same procedure. During all the stages of the manufacturing process, temperature and humidity was maintained at 25 ± 50C and 50 ± 10 % RH. To optimize the formulation, the tablets were characterized by physical and chemical parameters like weight variation, hardness, thickness, friability, disintegration, acid resistance analysis, and assay and drug release study.

 

RESULTS AND DISCUSSION:

The present study was undertaken to formulate Pantoprazole enteric coated tablets. The study involves pre-formulation studies of drug and excipients, formulation and processing development along with evaluation of tablets made with the optimized formulation. Finally delayed release10 tablets were evaluated by in-vitro methods. Results and discussion of the above studies are presented in table 2.


Table – 2 (Pre-formulation studies) 11

S. No.

Characteristics

Results

1.

Physical appearance

A white powder

2.

Solubility

Drug was freely soluble in water and in anhydrous ethanol, practically insoluble in n-hexane

3.

Bulk density

0.55gm/ml

4.

Tap density

0.69gm/ml

5.

Compressibility index

20.0%

6.

Hausner’s ratio

1.25

7.

Melting point

Because of gradual degradation of Pantoprazole during heating, the melting point cannot be determined.

8.

Molecular weight

432.4

 

Table – 3 (Physical Evaluation (Core tablet)) 12

S. No

Physical  parameter

F 1

F 2

F 3

F  4

F 5

F 6

F 7

F 8

1

Weight variation

-

1.62

1.65

1.63

1.61

1.62

1.64

1.63

2

Hardness (Kg/Square inch)

-

6.5

7.2

6.8

7.1

6.8

5.8

5.5

3

Thickness (mm)

-

2.34

2.32

2.31

2.33

2.32

2.35

2.30

4

Friability

-

0.49

0.51

0.56

0.58

0.57

0.66

0.68

5

Disintegration time

-

6min 31sec

6min 9sec

5min 45sec

5min 30sec

5min 56sec

6min 03sec

6min 11sec

 

Table – 4 (Physical Evaluation after Sub Coating and Enteric Coating)

AFTER  SUBCOATING

F1

F 2

F 3

F 4

F 5

F 6

F 7

F 8

Hardness

8.0

8.1

8.4

8.2

8.6

8.1

6.5

6.1

Thickness

2.41

2.41

2.44

2.43

2.46

2.48

2.44

2.39

ENTERIC COATING

F1

F 2

F 3

F 4

F 5

F 6

F 7

F 8

Hardness

10.1

10.3

10.6

10.9

11.1

10.5

7.9

7.9

Thickness

2.51

2.54

2.58

2.55

2.56

2.55

2.51

2.53

                 

Fig. 2: acid release,test for F7 Formulation at different temperature.

                   

Fig. 3: acid release, test for F8 Formulation at different temperature.

 


 

Acid Release:

This indicates that the dosage form is resistance to acid media after 2 hours. In 7 trail the acid release of the drug from tablets was found to be 1.93% initially, after 1 month it raises to 2.04% and 2.01%, later it was found to be 2.17and 2.13% after 2months at 400C/75%RH and 250C/75%RH  respectively. This indicates that there is no change in the acid resistance of Pantoprazole delayed release tablets for batch 7. In 8 trail the acid release of the drug from tablets was found to be 1.88 % initially, after 1 month it raises to 1.95% and 1.92%, later it was found to be 2.06% and 2.00% after 2months at 400C/75%RH and 250C/75%RH respectively. This indicates that there is no change in the acid resistance of Pantoprazole delayed release tablets for batch 8.

 

DISSOLUTION STUDIES:

Table – 5: Standard graphs for Pantoprazole Sodium.

S. no

Conc. (µg/ml)

Absorbance (λ-max at 289 nm)

1.

2.

3.

4.

5.

6.

2

4

6

8

10

12

0.081

0.173

0.260

0.352

0.442

0.534

 

 

Fig. 4: Calibration Curve of Pantopraole

 

Fig. 5: comparative dissolution profile for Pantoprazole Sodium

 

SUMMARY AND CONCLUSION:

The pantoprazole sodium is a proton pump-inhibitor which is used in the treatment of peptic ulcer. In this study pantoprazole enteric coated tablets were prepared by using methacrylate co-polymers (Eudragit L30D55). Eight formulations of enteric coated tablets of pantoprazole were developed by preparing core tablets using mannitol as diluent and Crospovidone as super disintegrant and povidone (PVP K-30) as binder in different proportions and varying the compositions of sub coating and enteric coating using sicovit yellow ,titanium dioxide and Eudragit (L30D55) .The core tablets were prepared by dry granulation method. F7 was found to be best of all the trials showing drug release matching the innovator product. The best formulation F7 was repeated again for reproducibility, and all the quality control tests were done for conformation.  Stability study is carried out for 2 months at 25°C; 60% RH: and 40°C; 75%RH, according to ICH guidelines. The tablets were tested for acid release during the stability period and confirmed that results were found within the limits. The identified formula shall be utilized for the formulation development and other studies for successful launching of the product.

 

REFERENCES:

1.        Agis Kydonieus “Treatise on controlled drug delivery” page no.302-303, arcel Dekker, New York

2.        H.P. Rang, M.M. Dale “Pharmacology” 5th edition, Page 248-9, 369,370.

3.        Mary Anne Koda-Kimble, Lloyd Yee Young, Wayne A. Kradjan, B. Joseph Gueglielmo.  APLLIED THERAPEUTICS. “The clinical use of drugs.” Eight Editions. Page no: 27(11)-27(14), Lippincott Williams, New York.

4.        Leon Lachman, Herbert A. Lieberman and Joseph L. Kanig. “The theory and practice of industrial pharmacy” 3rd edition. Page no: 331-332 and 364-368, Varghese - Bombay.

5.        Susan Budavari, Maaryadale J. O Neil, Ann Smith, Patricia E. Heckelman, Joanne F. Kinneary. THE MERCK INDEX. “An Encyclopedia of Chemicals, Drugs, and Biologicals”. Twelth Edition, 1996. Page no: 1392 (8272), Merck Research Laboratories (USA).

6.        Raymond C. Rowe, Paul J Sheskey, and Paul J Weller. “Hand book of pharmaceutical excipients. Fourth edition 2003 page no: 373.568.297.454.641.566. and AAPS Pharmscitech 2007, Royal Pharmaceutical society of Great Britain (London).

7.        Walter G. Chambliss Diana A. Chambliss “Development and evaluation of enteric-coated penicillaine tablets” Research article. Sep 1983

8.        Sicovit yellow coloring used in enteric coating “modified release system” colorcon page no. 87-89

9.        .J.G. Hardy, S.W. Lee and J.R. Reynolds “ Gastrointestinal transit of an enteric-coated delayed-release 5-aminosalicylic acid tablet” Alimen .Pharmacol .Therapy.(1987)

10.     Lars Borgstrom, Boekman. “In-vitro and In-vivo evaluation of controlled release and enteric coated formulations of sodium salicylate”, 1983

11.     J.G. Hardy, J.N.C. Healey ”evaluation of an enteric-coated delayed-release 5-aminosalicylic acid tablet in patients with inflammatory bowel disease” Aliment .pharmacol .therpy.(1987)

12.     Walter G. Chambliss Diana A. Chambliss “Development and evaluation of enteric-coated penicillin tablets” Research article. Sep 1983

 

 

 

Received on 22.11.2016             Modified on 14.12.2016

Accepted on 26.12.2016           © RJPT All right reserved

Research J. Pharm. and Tech. 2017; 10(2): 421-425.

DOI: 10.5958/0974-360X.2017.00084.1