In vitro Evaluation of Gastro Retentive Drug Delivery System of Lansoprazole

 

Veeranagoud Biradar1, Jeevan Matada Basavarajaiah2*,

Myat Thu Thu Win3, Leneena Gudugunta4, Suresh  KV5 , Sathiyavathi Mahendra Kumar 6, Neeraja Turagam7,

Lavanya Priya8

1SM Pharmaceuticals SDN. BHD, Sungai Petani, Malaysia.

2Department of Oral Pathology, AIMST University, Malaysia.

3Department of Pharmacology, Faculty of Medicine AIMST University, Malaysia

4Department of Conservative and Endodontic, AIMST University, Malaysia.

5Department of Oral Medicine and Radiology, Faculty of Dentistry, SEGI University, Malaysia

6Department of Pedodontics, AIMST University, Malaysia.

7Department of Prosthodontics, AIMST University, Malaysia.

*Corresponding Author E-mail: mbjeevan@gmail.com

 

ABSTRACT:

Objective: Drug given by orally is the simplest and easiest way in compared to other routes. But, the oral bioavailability of drugs is lower than other routes because it is influenced by first pass hepatic effect and absorption factors.To overcome therestrictions of conventional dosage forms like poor compliance, variability of drug leveland increase the bioavailability of the drugs for avoiding frequent dosing and subsequent degradation of drug in intestine, floating drug delivery system of lansoprazolewas explored in this study. Materials and Methods: By using floating tablets formulation, HPMC K4M and HPMC K15M were used as matrix forming agent. Microcrystalline cellulose, talc, sodium bicarbonate, citric acid and magnesium stearate (lubricating agent) are included in this formulations. The lack of any drug, polymers and excipients interactions were confirmedby Fourier transform infrared spectroscopy. Results: The results showed that F4 of HPMC K4M and F6 of HPMC K15M gave maximum release of drug upto 100% within 24hrs. All formulations were examined for five different models viz. zero and first order, Higuchi matrix, Peppas model and Hixson-Crowell equations and all the formulations according toPeppas model. Conclusion: This study showed that F4 of HPMC K4M series and F6 of HPMC K15M canbe stable for 30 days at 40ºC and 75%relative humidity (RH) stability. It is suggested that a controlled release lansoprazole floating tablets may be developed from our study which will be beneficial in clinical practice.

 

KEYWORDS: Lansoprazole, Floating drug, Bioavailability.

 

 

INTRODUCTION:

Lansoprazole is timoprazole derivative, a 2, 2, 2- trifluoroethoxypyridylthat inhibits proton pumpsimilar to omeprazole and use in diseases like duodenal ulcer, acid-related dyspepsia, benign gastric ulcer, Zollinger-Ellison syndrome, Barrett's  esophagus  and prevention of nonsteroidal anti-inflammatory drug (NSAID) associated benign gastric ulcers.1 It is also effective against Helicobacter pylori. Although elimination half-life is less than 2 hours, it inhibits acid more than 24 hours.2 80% of gastric acid secretion is inhibited by single dose of lansoprazole 30mg orally. 90% of gastric acid secretion can be reducedd after seven days administration daily.

 

Basal secretion of gastric acid is also effected by lansoprazole. 70% of basal acid secretion is reduced by first single dose of 30 mg lansoprazole and the patients' symptoms are consequently relieved.3

 

Among route of drug administration, oral route is the most convenient and effective route. Oral drug administration can produce systemic effects by 90% of all drugs. Self-administration is impossible by parenteral route so not useful for routine. Topical route is one of the routes of drug administration to produce systemic effects. It is important to know the drug can produce desired effect by orally or not for new drug discovered. If not, the drug can be given at hospital or physician's office. That’s why drug given by oral route is the most preferred class of product out of all administrations. The reasons for these preferences of oral route are well known.4

 

 

Half-life and its therapeutic index determine the frequency or dosage interval of any drugs. Mostly, limitations related with conventional dosage forms to achieve ideal dosage regimen occurs because of shorter dosage interval than drug half-life.5

 

The fluctuation in drug concentrations and frequent dosing intervals can overcome by using sustained or controlled drug delivery systems. The basic principle forsustained or controlled drug delivery systems is that changes the pharmacokinetics and pharmacodynamics of pharmacologically active substances by molecular structure modification, novel drug delivery system usage or by physiological parameter as well as combinations of these.6 Formulations of controlled drug delivery system includes approach based on drug modification, drug complex, drug absorbate, prodrug, approach based on modification of dosage form, matrix formation and barrier mediated model development.7

 

Gastro retentive drug delivery systems improve the sustained delivery of drug in specific region of the gastrointestinal tract.8 By prolonged gastric retention, drug solubility (drug less soluble in a high pH), bioavailability can be improved and reduction of drug waste.9 Drug can be given to stomach and small intestines by local drug delivery methods.10 To provide better availability of new products with new therapeutic effects, gastric retention is helpful and substantial benefits for patients.8,11 Major types of gastro retentive delivery systems (GRDS) are floating drug delivery systems, bioadhesivesystems, high-density systems, hydrogels and superporous hydrogel,expansive gastro retentive dosage forms as in Figure 1.12

 

Floating Drug Delivery Systems (FDDS) includes two types; effervescent system and non- effervescent system.13 It is effective for the treatment of Helicobacter pylori(H. pylori), causative organism for chronic gastritis and peptic ulcers.14 The H. pylori eradication requires high concentrations of antibioticswithin the gastric mucosa for long duration. FDDS application can retain dosage form at absorption sitethat results in improve the bioavailability, minimizeplasma drug concentration due to variable gastric emptying15

 

MATERIALS AND METHODS:

The materials used in this research were either analytical research grade (AR) and lab research (LR) grade. lansoprazole (Cipla pharmaceutical, Mumbai), HPMC K4M (Colorcon Asia Ltd, Goa), HPMC K15M (Colorcon Asia Ltd, Goa), microcrystalline cellulose (Ozone international, Mumbai), sodium bicarbonate (Qualigens fine chemicals, Mumbai), citric acid (Qualigens fine chemicals, Mumbai), magnesium stearate (Qualigens fine chemicals, Mumbai), hydrochloric acid (Loba Chemie Pvt Ltd, India) and sodium hydroxide (Loba Chemie Pvt Ltd, India) were used in this study. Other materials used were electronic balance (Sartorious, Germany), tablet compression machine (Rimek minis press I), Monsanto hardness tester (Secor, India), programmable friability test apparatus (Roche friabilator, Electro Lab), vernier caliber, tablet dissolution tester (Electro Lab), UV spectrometer (Shimadzu-1700) and stability chamber (Osworld model JRIC-11). Preliminary studies were done for suitable polymer and excipients selectionfor the proposed formulations.

 

Drug excipients compatibility studies:

Physical changes like discoloration and odor of the samples were checked and no changes were observed during compatibility study. Drug and polymer chemical interaction was not observed by infrared spectra.

 

Selection of suitable Experiment design:

According to the results of preliminary study, experimental factorial design was developed by using matrix forming polymers HPMC K4M and HPMC K15M. For a full factorial deign,

 

possible combinations are chosen after studying all the factors. The influence of individual variables and their interactions were estimated most efficiently using minimum experimentations.

 

During this study, polymer concentration and gas generating agent mixture were chosen as two factors to consider for fitting a 32 factorial design (FD) by three concentration levels. Lansoprazole polymer, microcrystalline cellulose, sodium bicarbonate andcitric acids were passed through sieve No.40 separately. It was mixed with polymers, other ingredients and then

 

lubricated by magnesium stearate (presifted through 40#), talc (2%w/w). After that tablet compression by using 10.0mm flat-face tooling on a tablet compression machine (Rimek minis press).

 

The stability was examined up to 45 days for selected formulations at 40ºC and 75% relative humidity (RH). For stability study, the tablets were sealed inside with polyethylene coated aluminium packaging. Then, dosage form release mechanism and kinetics of dose release rate were analyzed by zero order, first order, Higuchi matrix, Pappas and Hixson Crowell model using PSP-DISSO – V2 software. The best-fit model was selected according to the R-value. State plus 2008 and table curve 3.0 CD were used in this study.

 

RESULTS:

Characterization of lansoprazole:

Physical appearance of the drug was white to yellowish powder. The melting point was in the range of 120ºC to 122ºC. Drug was sparingly soluble inwater, soluble in alcohol.

 

Spectroscopical analysis:

The max was 276 nm in 0.1 N hydrochloric acid solutions. The lansoprazole calibration curve of was obtained in 0.1 N HCL at 276 nm. Beer-Lambert’s law was obeyed between 5-25μg/ml concentration range. The data obtained was statically evaluated for calculation standard deviation of the said values and correlation coefficient (R2), it was 0.999 as in Figure 2.

 

Infrared spectrum (IR) interpretation:

The infrared spectrum of pure lansoprazole was recorded and given in figure 3.

 

Evaluation of tablets:

Preliminary study was carried out for suitable polymer and excipients selection of the proposed formulations. The tablet evaluation data was recorded as in tableI.

 

All the floating tablet formulations prepared as per factorial design were evaluated and the results were seen in the following tables II and III. The thickness of tablets prepared with HPMC K4M and HPMC K15M were in the range of 2.51 to 3.13mm. The weight variations and friability for all formulas were within the specified limit. The hardness values of tablets for HPMC K4M and HPMC K15M was between 4.23±0.8 kg/cm2 to 5.73± 0.2 kg/cm2 and 4.5±0.5 kg/cm2 to 5.63±0.5 kg/cm2 respectively. The friability values were also within the prescribed limit. Floating behavior of drug containing matrix tablet was studied and the results of HPMC K 4M and HPMC K 15M were 5 to 23 h and 5 to 22 h respectively.

 

In vitro dissolution studyfactorial design formulations:

For all the factorial design formulations, In vitro drug release was studied for 24 hours in 0.1 N HCl. The formulation F1, F2, F3 prepared with HPMC K4M and HPMC K15M showed tablet floating timeswere 12 to15 hours and 12 to 22 hours respectively, the percentage of drug release were observed between 93.23% to 95.13% and 92.45 to 95.25% respectively. Thus, floating principle for the desire period of time was not followed by these formulations.

 

The floatation times were between 22 to 24h and percent drug release was observed between 89.54 to 96.21% and 93.46 to 95.45% respectively for F4, F5, F6 formulations prepared with HPMC K4M and HPMC K15M. The formulations F7, F8, F9 prepared with HPMC K4M and HPMC K15M floated for more than 24 hours and percentage of drug release were observed between 86.65 to 88.88%, and 85.27 to 91.95 respectively upto 24 hours. The tablets prepared here revealed that’s lower release form which is due to the polymer coats on drug particles. It is expected that the penetration of dissolution medium in to the matrix may be low and thus the dissolution and release of the drug occurs at a slower rate.

 

Graphical presentation showed that polymer amount increasing lead to reduction in the drug release from the system. The same effect occurred with increasing gas generating agents mixture amount as in Figure (4).

 

Stability:

The tablet is stable even after 5 weeks of the stability tests. The similar stability was obtained with F4 for HPMCK4M and F6 for HPMCK15M as shown in table IV.

 

DISCUSSION:

The differences in gastric physiology like gastric pH and motility which might cause the intra- and inter-subject variability would lead to great impact on gastric retention time and drug delivery behavior significantly.16 So, it is interesting to make new formulations for gastro retentive dosage forms. Many approaches for prolongation of the gastric residence times (GRT) are currently used. Among them, the most common used was floating dosage forms.17 Technological attempts were done for the development of rate controlled oral drug delivery systems to overcome physiological adversities like GRT and unpredictable gastric emptying times (GET).18

 

The hypothesis of our study was that to prolong the flotation in the stomach for a long period of time to increase the oral bioavailability of lansoprazole gastric residence time. So, we determined systematically effect of formulation variables effect on the release and floating properties of lansoprazole.19 Polymers such as HPMC K4M and HPMC K15M for preparation of the gastro retentive floating tablets of lansoprazole in this research. The preliminary results of the drug were satisfactory and met all the requirements. The standard graph showed that the drug obeyed beer’s law between 5– 25 μg/ml concentration range in 0.1N HCl at 276 nm. The results of IR spectra of drug revealed that it was intact with the various polymers. According to the preliminary evaluation of granules and floating tablets prepared by various retardant materials such as HPMC K4M, HPMC K15M, and mixture of gas generating agent like citric acid and sodium bicarbonate, HPMC K4M and HPMC K15M were selected and successfully formulated.20 Among all formulations of HPMC K4M and HPMC K15Mwere chosen for nine preparations respectively, each formulationwereoptimized based on floating time and drug release profile.19,21 Formulation F4 containing HPMC K4M and formulation F6 containing HPMC K15M found to be the best not only in floating behavior but also in the best drug release profile. Formulation F4 showed almost similar floating time and drug release profile as that of F6 but the proportion of HPMC K4M was little more when compared to formulation F6 containing HPMC K15M. Hence HPMC K15M found to be the best retardant material.22

 

The polymers used were low density, highly soluble in shortest time andthese upon contact with water then a hydrogel layer was formed as a gel boundary for the release of drug.23 Use of Microcrystalline Cellulose (MCC) gave good gastro retentive property and avoids the matrix from erosion in the dissolution medium.24 Formulation by incorporation of citric acid and sodium bicarbonate mixture would liberate carbon dioxide (CO2) when tablets contact with gastric acid.

 

The liberated CO2 entrapped in swollen hydrocolloids and caused buoyancy to the dosage form.25Thus, the amount of the gas generating agent in formulation plays a very important role for drug release. Besides its buoyancy effect due to the liberation of CO2 after interacting with simulated gastric fluid, the formation of pores by CO2 also increased drug release. So, the polymers’ wetting rate increased by water entry through pores subsequently and alkalinizing effect by sodium bicarbonate contributed the solubility of drug better in all the formulations.17,26

 

Stability studies were done for each formulation from HPMC K4M and HPMC K15M (F4& F6) which showed good stability within permissible limits .The optimum concentration of HPMC K4M required was 110mg/tablet.22,27 Concentrations ranging from 50mg/tablet to 170mg/tablet were investigated.28 Similarly the optimum concentration of HPMC K 15M required was found to be 70mg/tablet. Concentrations ranging from 30mg/tablet to 110mg/tablet were investigated.,29 Formulation F4 from HPMC K4M series and F6 from HPMC K15M series gave maximum cumulative drug release at 24 hours i.e. 97.78 & 96.99% respectively.30Therefore, these formulations were selected for further stability studies.

 

CONCLUSION:

In this study, F4 of HPMC K4M and F6 of HPMC K15M gave maximum drug releaseupto 100% within 24hours. It revealed that concentration polymers and mixture of gas generating agent had significant influence on floating ability and drug release. Formulations F4 of HPMC K4M series and F6 of HPMC K15M were found to be stable for 30 days at 40ºC, 75%RH stability study. From this study, it was suggested that a promising controlled release lansoprazolefloating tablets mightbe developed. But, further researchesare required to establish efficacy of these formulations.

 

REFERENCE:

1.             National Center for Biotechnology Information. PubChem Compound Database; CID=3883, https://pubchem.ncbi.nlm.nih.gov/compound/3883 (accessed July 6, 2018).

2.             Takeda Pharmaceuticals America. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/050757s021lbl.pdf (accessed July 6, 2018).

3.             Electronic Medicines Compendium (EMC).Generics UK. Available from: https://www.medicines.org.uk/emc/product/4394/smpc#companyDetails(accessed 04 Jan 2018)

4.             Lachman, L, Lieberman HA, Kanig JL, The theory and practice of industrial pharmacy; Eds.; 3rd; Varghese Pub. House: Bombay, 2003, p 293 –294.

5.             Brahamanker DM., Jaiswal SB. Biopharmaceutics and Pharmacokinetics; Vallabh Prakashan: Delhi, 2004, Delhi. pp 335.

6.             Robinson JR., Lee VH. Controlled Drug Delivery, Marcel Dekker, Inc:New York, 2005, 29, pp 4, 5, 296.

7.             Lordi NG, Kanig J. Sustained release dosage form. Eds.; 3rd; Varghese Pub.House: Bombay, 2003, 440-443.

8.             Dave BS, Amin AF, Patel MM. Gastroretentive drug delivery system of ranitidine hydrochloride: formulation and In vitro evaluation. AAPS PharmSciTech. 2004 1, 5 (2):77-82.

9.             Vyas SP, and Khar RK. Controlled Drug Delivery Concept And Advances.1stedition New Delhi: Vallabh Prakashan. 2000.

10.          Jain NK. Progress In Controlled And Novel Drug Delivery System. 1stedition New Delhi: CBS Publisher and Distributor. 2004:76-97.

11.          Deshpande AA, Shah NH, Rhodes CT, Malick W. Development of a novel controlled-release system for gastric retention. Pharm Res. 1997, :815-819

12.          Wise DL. Handbook Of Pharmaceutical Controlled Release Technology. 1st Indian reprint New York: Marcel Dekker, Inc.. 2005:211.

13.          Asmussen B, Cremer K, Hoffmann HR, Ludwig K, Roreger M. Expandable Gastroretentive Therapeutic System With Controlled Active Substance Release In Gastrointestinal Tract. US patent 6 290 989. September 18, 2001.

14.          Arora S, Ali J, Ahuja A, Khar RK, Baboota S. Floating drug delivery systems: a review. AAPS PharmSciTech. 2005 1, 6(3):E372-90.

15.          Singh BN, Kim KH. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. Journal of Controlled release. 2000 3, 63(3):235-59.

16.          Talukder R, Fassihi R. Gastroretentive delivery systems: a mini review. Drug Dev Ind Pharm. 2004, 30(10):1019-28.

17.          Avinash Y Kaushik, Ajay K Tiwari, and Ajay Gaur. Role of excipients and polymeric advancements in preparation of floating drug delivery systems. Int J Pharm Investig. 2015, 5(1): 1–12.

18.          Khan R. Gastroretentive drug delivery system-a review. Int J Pharm Bio Sci. 2013, 4(2):630-46.

19.          Muthusamy K, Govindarazan G, Ravi TK. Preparation and evaluation of lansoprazole floating micropellets. Indian journal of pharmaceutical sciences. 2005, 67(1):75.

20.          Singhal P, Kaushik RD, Kumar VJ, Verma A, Gupta P. Preparation and In vitro characterization of solid dispersion floating tablet by effervescent control release technique with improved floating capabilities. Pak J Pharm Sci. 2016 , 29(5):1661-1670.

21.          PK Lakshmi, M Sridhar, B Shruthi. Comparative evaluation of single and bilayered lamotrigine floating tablets. Int J Pharm Investig. 2013 Jul-Sep, 3(3): 157–162.

22.          Pawar HA, Gharat PR, Dhavale RV, Joshi PR, Rakshit PP. Development and Evaluation of Gastroretentive Floating Tablets of an Antihypertensive Drug Using Hydrogenated Cottonseed Oil. ISRN Pharm. 2013 Dec 18, 2013:137238.

23.          Fu Y, Kao WJ. Drug release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems. Expert opinion on drug delivery. 2010 1, 7(4):429-44.

24.          Zhao T, Chen Z, Lin X, Ren Z, Li B, Zhang Y. Preparation and characterization of microcrystalline cellulose (MCC) from tea waste. Carbohydr Polym. 2018 15, 184:164-170.

25.          Ram HN, Lachake P, Kaushik U, Shreedhara CS. Formulation and evaluation of floating tablets of liquorice extract. Pharmacognosy Res. 2010, 2(5):304-8.

26.          Chavanpatil MD, Khdair A, Patil Y, Handa H, Mao G, Panyam J. Polymer-surfactant nanoparticles for sustained release of water-soluble drugs. J Pharm Sci. 2007 Dec, 96(12):3379-89.

27.          Gharti K, Thapa P, Budhathoki U, Bhargava A. Formulation and In vitro evaluation of floating tablets of hydroxypropyl methylcellulose and polyethylene oxide using ranitidine hydrochloride as a model drug. J Young Pharm. 2012, 4(4):201-8.

28.          Mohamed FA, Roberts M, Seton L, Ford JL, Levina M, Rajabi-Siahboomi AR. The influence of HPMC concentration on release of theophylline or hydrocortisone from extended release mini-tablets. Drug Dev Ind Pharm. 2013, 39(8):1167-74.

29.          Elzoghby AO, Vranic BZ, Samy WM, Elgindy NA. Swellable floating tablet based on spray-dried casein nanoparticles: Near-infrared spectral characterization and floating matrix evaluation. International journal of pharmaceutics. 2015 1, 491(1-2):113-22.

30.          Hamed R, Al Baraghthi T, Sunoqrot S. Correlation between the viscoelastic properties of the gel layer of swollen HPMC matrix tablets and their In vitro drug release. Pharm Dev Technol. 2016 21:1-11.

 

 

 

 

Received on 08.02.2019            Modified on 13.03.2019

Accepted on 16.04.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2019; 12(8):3649-3653.

DOI: 10.5958/0974-360X.2019.00622.X