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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 9  |  Issue : 3  |  Page : 315-321

Design, formulation, and evaluation of delayed release oral dosage form of proton pump inhibitor


1 Department of Pharmaceutics, KLE University's College of Pharmacy, Hubballi, Karnataka, India
2 VerGo Pharma Research Laboratories Pvt. Ltd., Verna Industrial Estate, Goa, India

Date of Web Publication21-Dec-2016

Correspondence Address:
Dr. V G Jamakandi
Department of Pharmaceutics, KLE University's College of Pharmacy, Vidyanagar, Hubballi - 580 031, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2349-5006.196331

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  Abstract 

Background: A proton pump inhibitor is an acid labile drug which degrades at stomach pH 1.2. Delayed release pellets were prepared to stabilize the formulation applying an enteric coat.
Objective: the objective of the study was to design, formulation and evaluation of delayed release oral dosage form of proton pump inhibitor.
Materials and Methods: Twelve different formulations of pellets were prepared by fluid bed technology (bottom spray technique) using different polymers for different coating processes namely seal coat (HPMC); drug coat (HPMC); barrier coat (Ethyl cellulose) and enteric coat (HPMC Phthalate). The formulated pellets were evaluated.
Results: FTIR studies revealed that there was no physic-chemical interaction between drug and excipients. Micromeritic property study for pellets revealed that the values were within the permissible limits. The pellets were filled into the capsules and evaluated for drug content, %loss on drying, weight variation and in vitro dissolution.
Conclusion: The filled weight of the capsule was in the pharmacopeail limits, the 5 drug content of all the formulation was fund to be in the range of 97-99 % and the % LOD was less that 35. F1-F12 formulations exhibited a release in a range of 60-90.37% in 45 min at PH 6.8.Optimized Formulation F10 Exhibited maximum release of 90.37% in 45 min . The barrier coat of the all the formulations effectively prevented the release of the drug in the stomach. The stability study revealed that the formulation F10 was stable when stored at 30°C±2°C/65±5% RH for one month.

Keywords: Bottom spray, film formation, fluid bed technology, proton pump inhibitor pellets


How to cite this article:
Jamakandi V G, Kubasad KA, Kundu S, Dasankoppa F S. Design, formulation, and evaluation of delayed release oral dosage form of proton pump inhibitor. Indian J Health Sci Biomed Res 2016;9:315-21

How to cite this URL:
Jamakandi V G, Kubasad KA, Kundu S, Dasankoppa F S. Design, formulation, and evaluation of delayed release oral dosage form of proton pump inhibitor. Indian J Health Sci Biomed Res [serial online] 2016 [cited 2020 Aug 5];9:315-21. Available from: http://www.ijournalhs.org/text.asp?2016/9/3/315/196331


  Introduction Top


Pellets for the pharmaceutical applications are defined as spherical/semi spherical, free flowing solid units with a narrow size distribution, typically varying in diameter between 500 and 1500 µm. These multi-particulates spread uniformly throughout the gastrointestinal tract, resulting in less variable bioavailability and a reduced risk of local irritation. Coated pellets are most frequently used for oral controlled drug delivery compared to coated tablets and capsules.[1],[2]

Proton pump inhibitors are anti secretory agents used in the treatment of gastric and duodenal ulcers, gastroesophageal reflux disease, and Zollinger–Ellinson syndrome. Rabeprazole sodium is acid-labile and require on enteric coating to protect them from degradation in the stomach when given orally. However, this leads to delayed absorption and onset of action. Rabeprazole sodium belongs to the class of benzimidazole having oral bioavailability of 52%. Hence, present study aims at formulating and evaluating delayed release pellets of rabeprazole sodium.[3]

Fluid bed processing helps to attain the granulation, coating, and drying of a product, so that uniform coating and drying takes place. The principle involved in such techniques may be either by bottom spray or top spray or tangential spray process. These principles depend on the positioning of the spray gun in the equipment. The top spray process helps in achieving the uniform palletization or granulation. The bottom spray process uses a Wurster coating unit for the spray.[4],[5]


  Materials and Methods Top


The materials used in this study were gifted by VerGo Pharma Research Laboratories Pvt. Ltd, Verna, Goa.

Drug, sugar spheres, hydroxy propyl methyl cellulose, mannitol, talc, ethyl cellulose, magnesium stearate, hydroxyl propyl methyl cellulose phthalate, diacetylated monoglycerate, isopropyl alcohol, dichloromethane, ethanol, acetone, water.

Analytical studies

Standard calibration curve

Standard calibration curve of drug was carried out in pH 8 0.06M tris buffer solution. One hundred milligrams of drug was weighed and dissolved in 100 ml of solution; further dilutions were made in order to achieve solutions within Beer's range of 2–18 μg/ml. The absorbance of each concentration was measured at 292 nm. This procedure was performed in triplicate to validate calibration curve.

Compatibility study

Prior to the development of dosage forms the preformulation study was carried out. The drug and the excipients must be compatible with one another to produce safe and stable formulation. The physical mixture of drug and excipients (1:1 ratio) was taken for compatibility studies using Fourier transform infrared spectroscopy (FTIR).[6]

Optimization of excipients by film formation study

Polymers were selected for the formulation based on the film formation study using different solvents. The film formation study was carried out in Petri plates for all four types of coating processes (seal coat, drug coat, barrier coat, and enteric coat). Solutions of different concentrations of excipients were prepared and solutions were kept overnight for drying. Films were evaluated for different parameters such as color, texture, appearance, and roughness.[7]

Formulation design

Twelve formulations were prepared in fluid bed processor using bottom spray technique.

Selection of core material

Core was selected based on the reference product as a reference. Nonperial seed or sugar spheres of size 500–600 µ were selected for the formulation.

Formulation method

The formulation includes different types of coating process on a core material namely seal coat, drug coat, barrier coat, and enteric coat.

Preparations of coating solutions

Seal coat

Hydroxypropyl methyl cellulose was dissolved in water. Pearlitol which acts as a pore forming agent was added to the above solution. An antisticking agent purified talc was added to the above mixture to form a homogenous dispersion of 10% w/v [Table 1].
Table 1: Composition of seal coating (F1-F12)

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Drug coat

Magnesium oxide was dissolved in isopropyl alcohol(IPA) in a homogenizer. Hydroxypropyl methyl cellulose (HPMC) was dissolved in dichloromethane (methylene chloride [MDC]). Both the solutions were mixed homogenously using conventional stirrer. Active pharmaceutical ingredient (API) was added to the mixture to form 10% w/v dispersion. IPA and MDC were used in the ratio of 50:50 [Table 2].
Table 2: Composition of drug coating (F1-F12)

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Barrier coat

Magnesium oxide was mixed in IPA using homogenizer. Ethyl cellulose mixed in MDC using a conventional stirrer. Both the above solutions were mixed homogenously using a conventional stirrer followed by the addition of magnesium stearate. IPA and MDC were used in a ratio 50:50 [Table 3].
Table 3: Composition of barrier coating

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Enteric coat

HPMC Phthalate was dissolved in MDC in a stainless steel container. Purified talc was dissolved in IPA. Both the solutions were mixed homogenously using conventional stirrer. To the mixture diacetylated monoglycerate which acts as a plasticizer was added and mixed thoroughly to get 8% w/v dispersion [Table 4].
Table 4: Composition of enteric coating

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Procedure

The prepared coating solutions were sprayed on sugar spheres in fluid bed processor. Bottom spray technique (Wurster spray) was used. % loss on drying (LOD) was measured after each coating process. % weight gain was checked to know the total percentage of coat.[8]

Evaluation parameters

Micromeritic properties

Bulk density

Bulk density is the weight of particles of material is divided by the volume occupied by the particles. Bulk density was calculated by the following formula.[9]



Tapped density

Tapped density is the weight of the powder to the tapped volume of the powder. Tapped density is calculated by following formula.[9]



Angle of repose

It was determined by funnel method. Accurately weighed powder was taken in the funnel. The blend was allowed to flow through the funnel freely on to the surface. The diameter of the powder was measured. Angle of repose was calculated by using the formula.[9]

Tan θ = h/r

Where, h is the height of the pile, r is the radius of the powder cone, θ is the angle of repose.

Compressibility index

Compressibility index of the powder blend was determined by Carr's compressibility index. It was calculated by the formula.[9]



Hausner's ratio

It is the ratio of tapped density to bulk density. It is calculated by using the formula.[9]



Postformulation studies

Weight variation

The weight variation test was determined by USP specifications. Twenty capsules were individually weighed and the average weight is determined. The test requirements are met if none of the individual weights are <90% or more than 110% of the average.[10]

Drug content

Content of API in pellets was determined by ultraviolet (UV) spectrophotometer. Crushed powder of pellets was taken equivalent to the 10 mg of the API and transferred into the 100 ml volumetric flask. About 0.6M Tris Buffer was added to the volumetric flask, and the volume was made up to 100 ml. Further dilution was carried out and the solution was measured spectrometrically at 292 nm.[9]

% Loss on drying

The moisture content of a product at each step was determined by LOD instrument. Two grams of sample was taken and kept it on an aluminium plate at 105°C for 10 min. % LOD was checked.[11]

In vitro dissolution

In vitro drug release was carried out as per the US Food and Drug Administration specification.In vitro dissolution study was carried out using USP apparatus type II (paddle). It was carried out in 0.1N HCl for 2 h at 75 RPM followed by pH 6.8 0.05M Phosphate buffer (after acid stage, add 250 ml of 0.2 mol/L trisodium phosphate solution) for 45 min at 60 RPM. Five milliliters sampling was done every 5 min for buffer stage. The concentration was measured using UV Spectrophotometer at 292 nm against blank.[12]

Stability studies

The optimized formulation was subjected for accelerated stability study as per the International Council on Harmonisation guidelines. The capsules were filled into 60CC HDPE container and sealed. It was carried out in a stability chamber at 40°C/75% RH for 30 days. The parameters such as drug content, weight variation, in vitro dissolution, and % LOD were evaluated for every 7 days.[13]


  Results Top


Micromeritic properties such as bulk density, tapped density, angle of repose, compressibility index, and Hausner's ratio for all the 12 formulations were within the range [Table 5] and postformulation parameters such as weight variation, drug content, and % LOD were carried out [Table 6].In vitro dissolution studies were carried out for all the formulations.
Table 5: Micromeritic properties: Angle of repose, bulk density, tapped density, Carr's index, Hausner's ratio

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Table 6: Postformulation: Weight variation, drug content, percentage loss on drying

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  Discussion Top


From the standard curve of API, it was observed that the drug obeys Beer's law in concentration range of 2–18 µg/ml in 0.6M Tris buffer [Figure 1]. From the results, it was evident that there was no major difference in the FTIR spetra of API and the physical mixture of the drug and excipients [Figure 2]. Film formation study was carried out for all types of coats seal coat, drug coat, barrier coat, and enteric coat. The physical parameters of the films were evaluated [Table 7],[Table 8],[Table 9],[Table 10],[Table 11],[Table 12]. The optimized coating formula was S2 for seal coat, D5 for the drug coat, B2 for the barrier coat and E5 for the enteric coat. Practical yield from each coating step was found to be in a range of 97–99%, the size fractions of pellets were found to be 30/35 mesh, only 3–9% of pellets retained on mesh no. 30, and over 91–97 of the pellets retained on mesh no. 35. All the formulations were within the pharmacopoeial limits when subjected to micrometric properties and postformulation studies [Table 5] and [Table 6].In vitro dissolution studies were carried out, 0% release was observed in pH 1.2 and maximum release was found to be 90.37% within 45 min in pH 6.8 0.05M phosphate buffer [Figure 3] and [Figure 4]. Hence, F10 formulation was optimized and further subjected for stability studies.
Table 7: Composition for film formation of seal coat 1 aqueous

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Table 8: Composition for film formation of seal coat 2 nonaqueous

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Table 9: Composition for film formation of drug coat aqueous and nonaqueous

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Table 10: Composition for film formation of barrier coat 1 nonaqueous

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Table 11: Composition for film formation of barrier coat 2 nonaqueous

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Table 12: Composition for film formation of enteric coat nonaqueous

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Figure 1: Standard calibration curve of active pharmaceutical ingredient

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Figure 2: Fourier transform infrared spectroscopy spectra of active pharmaceutical ingredient and excipients

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Figure 3: In vitro cumulative % drug released v/s time for formulation F1–F6

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Figure 4: In vitro cumulative % drug released v/s time for formulation F7–F12carried

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Stability study revealed that optimized formulation F10 was stable when stored at 30 ± 2°C/65 ± 5% RH for 1 month [Table 13].
Table 13: Results for stability study of F10 formulation expose to accelerated stability conditions of 30°C±2°C/65±5% RH

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Punia S, Bala R, Rana AC. Pelletization techniques: A literature review. Int Res J Pharm 2012;3:43-7.  Back to cited text no. 1
    
2.
Muschert S, Siepmann F, Leclercq B, Carlin B, Siepmann J. Prediction of drug release from ethylcellulose coated pellets. J Control Release 2009;135:71-9.  Back to cited text no. 2
    
3.
Laurence LB, Bruce AC, Bjorn CK. Goodman and Gilman's the Pharmaceutical Basis of Therapeutics. 12th ed. New Delhi: The McGrow-Hill-Companies; 2011. p. 1311.  Back to cited text no. 3
    
4.
Pasupathi RT, Rao VT. Fluidized bed processing: A Review. Indian J Res Pharm Biotechnol 2014;2:1360-5.  Back to cited text no. 4
    
5.
Leuenberger H, Lay B, Struder J. New development in the control of a moist agglomeration and pelletization process. STP Pharm Sci 1990;6:303-9.  Back to cited text no. 5
    
6.
Deepthipriya Y, Chowdary AY, Murthy TE, Seshagiri B. Design and evaluation of atomoxetine HCL pellets by MUPS technology. Int J Pharm Pharm Sci 2014;6:110-5.  Back to cited text no. 6
    
7.
Hirapara F, Debnath KS, Saisivam S. Optimization and screening of different film forming polymers and plasticizers in fast dissolving sublingual film. Int J Pharm Pharm Sci 2014;6:41-2.  Back to cited text no. 7
    
8.
Rakesh S, Vinodkumar G. Stabilized Pharmaceutical Composition Containing Rabeprazole Sodium with Improved Bioavailability. Torrent Pharmaceuticals Limited. European Patent, PCT/IN2005/000207; 17 June, 2005.  Back to cited text no. 8
    
9.
Senthilkumar KL, Muthukumaran M, Chenchuratnam B. Formulation and evaluation of rabeprazole sodium enteric coated pellets. Int J Adv Phar Biol Chem 2012;1:7-14.  Back to cited text no. 9
    
10.
Lachman L, Libermann HA, Kanig J. Theory and Practice of Industrial Pharmacy. 4th ed. New Delhi: CBS Publishers and Distributors; 2013.  Back to cited text no. 10
    
11.
Shanbhag PP, Bhalerao SS. Development and evaluation of reconstitutable systems of cephalexin. Int J PharmaTech Res 2010;2:502-6.  Back to cited text no. 11
    
12.
Available from: http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults.cfm. [Last accessed on 2016 Jan 21].  Back to cited text no. 12
    
13.
Petchimuthu S, Narayana N, Subashini U. Formulation and characterization of lansoprazole DR pellets by fluid bed coating technique. Int J Biol Pharm Res 2013;4:977-86.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13]


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