Development and Evaluation of Floating in-Situ Gel Solution of Lansoprazole

 

P.N. Remya^*, H. Gayathri, T.S. Saraswathi, R. Kavitha, S. Sangeetha, N. Damodharan

Department of Pharmaceutics, SRM College of Pharmacy, Kattankulathur-603 203

 

ABSTRACT:

An in situ gel drug delivery is a novel idea of delivering drugs as a liquid dosage. The advantages shown by in situ forming polymeric delivery systems are ease of administration, improved patient compliance, deliverance of acute dose as well as to prolong residence time of drug in gastric mucosa. Lansoprazole is a proton pump inhibitor belonging to a class of anti-secretory compounds that suppress gastric acid secretion by specific inhibition of the (H+-K+) ATPase enzyme system at the secretory surface of the gastric parietal cell. The drug has shorter half-life and requires multiple administrations. The present study deals with the development and evaluation of the oral sustained release of Lansoprazole from in situ gelling sodium alginate, Carbopol-936 and HPMC E5NV formulations. In situ gelling solutions were prepared by varying the concentrations of sodium alginate (1% and 2%), Carbopol (1% and 2%) and HPMC/sodium alginate with distilled water and stirred continuously with mechanical stirrer. Then sodium citrate (0.23%w/v) and Lansoprazole (150mg) were added and stirred. Lansoprazole In situ gelling solutions were characterized by physiochemical properties, viscosity, drug content, gelling capacity, In-vitro release studies, floating capacity and stability studies. The drug release of Lansoprazole from gel solutions was found to be around 96.4%. Based on these results, it is concluded that a sustained release of Lansoprazole is achievable using In situ gelling floating system.

 

 

INTRODUCTION:

The development of in-situ gel systems has received considerable attention over the past few years. This interest has been generated by the advantages shown by in situ forming polymeric delivery systems such as ease of administration and reduced frequency of administration, improved patient compliance and comfort. They undergo gelation in the stomach after administration and help to increase bioavailability of the drug as compared to conventional oral dosage form. In-situ gel formation occurs due to one or combination of different stimuli like pH change, temperature modulation and solvent exchange.^[1,5,7]

 

Lansoprazole is a proton pump inhibitor belonging to a class of anti-secretory compounds, the substituted benzimidazoles, that do not exhibit any anticholinergic or histamine H2-receptor antagonist properties, but rather suppress gastric acid secretion by specific inhibition of the (H+-K+) ATPase enzyme system.^[2] It is also used in the treatment of Gastro esophageal reflux disease (GERD), Helicobacter Pylori infections and stomach ulcers. This drug has a daily dose of 15-30 mg and because of its shorter half-life; it needs multiple administrations, which often results in dose related side-effects and poor patient compliance. In the commercial preparations, 10ml of the formulation should be taken 3 or 4 times daily in order to overcome a sustained drug delivery. Significant inhibition of gastric acid secretion is observed at 2 hours following single dose, and becomes better with consecutive dosing. The peak response occurs between 1-8 weeks depending on the condition to be treated. Tablet form of drug is difficult to administer to geriatric and pediatric patients.^[3,4]

In this study we assess the potential of sodium alginate, HPMC, and carbopol mixture as vehicle for sustained delivery of Lanzoprazole which are to be administered in liquid form and get converted into gels in the acidic environment of the stomach.

 

MATERIALS AND METHODS:

MATERIALS:

Lanzoprazole was received as a gift sample from Orchid Pharmaceuticals, Chennai. Sodium Citrate was obtained from Rainbow-2000B, PURA Laboratories, and Chennai. Calcium chloride, hydrochloric acid, potassium di-hydrogen phosphate, sodium alginate and potassium chloride were purchased from Rankem, Ranbaxy fine chemicals, New Delhi. Hydroxy Propyl Methylcellulose-E5NV (HPMC) was procured from Lobachemie, Mumbai. Carbopol was received from Himedia laboratories, Mumbai. All ingredients, reagents and solvents were of analytical grade.

 

METHODS:

PREPARATION OF INSITU GELS:

Six different batches of in situ gelling solutions were prepared by varying the concentration of Sodium alginate (1% and 2%), Carbopol (1% and 2%) and HPMC/Sodium alginate mixture (Table no.1) with distilled water and stirred continuously using mechanical stirrer. Then Sodium citrate (0.25%w/v), Calcium chloride (0.75%w/v) and Lansoprazole (150mg) were added and stirred with mechanical stirrer. These prepared solutions were stored in room temperature for further use.^[6,8]

 

TABLE 1 Formulation table

 

Evaluation of sols:

The prepared in situ gel solutions were evaluated for following parameters.^[9,10]

 

1. Physiochemical Properties:

The formulated sols were visually observed. It was found the sols were clear without any dispersed particles.^[5]

 

2. Rheological Behavior of Sols:

The rheological behaviors of the prepared solutions were determined by Brookfield viscometer. The spindle S34 was selected for the study. The samples containing Sodium alginate (1% and 2%) Carbopol (1% and 2%) and Sodium alginate-HMPC mixture sols were filled in the sample holder and the spindle was immersed in the samples. The study was carried out at 25°C with 150rpm. Measurement on each sample was performed in triplicate to analyze the result.^[11,12]

 

3. Determination of Drug Content:

A known quantity (150 mg) of the prepared sols was stirred in 100ml of buffer solution (pH 6.8) for 6 hours. Then the sample was filtered and the filtrate was measured spectrophotometric method at 306.1 nm.^[13,14]

 

4. In vitro Drug Release Studies:

For the determination of in-vitro drug release, USP Dissolution Apparatus-11 was used. Dilution methods were employed to maintain different pH conditions in the dissolution studies. 10ml of the solution was added to 100 ml of the solution flask and the temperature was maintained at 37°C with 50rpm. Aliquots of 5ml were withdrawn at frequent intervals and equal amount of fresh medium was replaced after each sampling up to 7 hours. The controlled samples were analyzed for the drug content using UV spectrophotometer at 360nm.^[15,16]

 

5. Stability Studies:

Stability studies were carried out at room temperature (32-37°C). The sols prepared were stored at room temperature for about four weeks. The sols were observed for their physical appearance and drug content at two different intervals.^[17,18]

 

6. In vitro Gelation Study:

The gelation study was carried out in stimulated gastric fluid (pH 1.2). The formulations showed immediate gelation when contacted with stimulated gastric fluid. Gelation was observed by visual examination and gelation time was noted down for each formulations.

 

7. In vitro Floating Study:

The floating stability of the prepared formulations was evaluated in stimulated gastric fluid. The floating time, the formulations took to emerge on the medium surface is known as floating lag time and the time the formulation constantly floats on the dissolution medium surface is known as ‘duration of floating’. Floating lag time and duration of floating was determined.^[19]

 

RESULTS AND DISCUSSIONS:

1. Physiochemical Properties:

The sols formed were clear and viscous with a pleasant appearance. Cross linking agents like calcium carbonate, calcium chloride and sodium citrate were added to determine floating properties. With sodium alginate and calcium carbonate soft gels were formed with less floating tendency. With carbopol and calcium carbonate poor gelation occurred. Calcium chloride as a cross linking agent along with carbopol were chosen to give excellent gels with excellent floating capacity. Good gels with minimum floating capacity were formed using HPMC as gelling agent and calcium chloride as cross linking agent. Addition of sodium citrate to the solutions helps to form a complex with the calcium ions present in the formulation maintaining the fluidity of gel.

 

Table 2 Viscosities of Different Formulations.

 

2. Rheological Behavior of Sols:

The viscosities of the samples were studied using Brookfield viscometer and was found that the viscosity increases on increase in polymer concentration. Table no.2 Thus, F6 showed maximum viscosity and F1 showed minimum viscosity.

 

3. Determination of Drug Content:

The drug content of the samples were found to be increasing with F6 showing the highest concentration and F1 showing the least concentration as shown in table no.3. Significant decrease in the rate and extent of release was observed with increase in polymer matrix and also an increase in the diffusional path length which the drug molecules have to traverse.

 

Table 3 Determination of drug content of different formulations

 

Table no.4 Drug release

TIME (MINUTES)	F1	F2	F3	F4	F5	F6
15	24.75	22.5	54	47.5	36	22.5
30	29.38	29.37	58.8	49.76	40.7	27.12
60	31.8	36.28	65.87	56.78	47.67	45.27
120	42.78	41.28	70.73	63.85	52.43	56.77
180	49.68	46.71	82.73	68.85	57.22	63.83
300	55.68	49.23	91.82	75.82	62.03	66.43
420	61.23	51.72	96.82	80.48	67.89	73.5

 

 

Table 5 Stability studies for different formulations:

 

 

Figure 1 Comparison of invitro dissolution profiles of F1 to F6

 

4. In Vitro Drug Release Studies:

When a solution is administered orally, it first reaches the stomach and it passes into small intestine. Hence in-vitro drug release under gastric pH1.2 conditions was studied.(Figure1,Table no.4)F4 showed maximum release of 96.4%. Rate and extent of drug release decreased with increase in the polymer concentration. The release of drug from these gels were characterized by an initial phase of high release (burst effect). However as gelation proceeds, the remaining drug was released at a slower rate followed by a second phase of moderate release. This bi-phasic pattern of releases characteristic feature of matrix diffusion kinetics.

 

5. Stability Studies:

The stabilities were determined for a period of 4 weeks and the results reported in the table no.5. All the batches showed a slight reduction in drug content and found to be mostly stable.

 

6. In Vitro Gelation Study:

The gelation study was carried out in stimulated gastric fluid (pH1.2). Formulations containing Calcium Carbonate showed less gelation when compared to other batches i.e. F4(220 sec) as shown in table no6. Formulations containing less content of Calcium Carbonate are preferred in liquid orals because they will be moved earlier from the stomach by the peristaltic movements.

 

Table 6 Gelling Time of Different Formulations

 

7. In Vitro Floating Study:

The floating ability of the prepared formulations were evaluated in stimulated gastric fluid. Formulations containing calcium carbonate demonstrated excellent floating ability and increase in polymer concentration resulted in increase in floating duration.

 

The floating time of the prepared formulations took to emerge on the medium surface (floating lag time) and the time the formulation constantly floated on the dissolution medium surface (duration of floating) are shown in table no. 7

 

Table 7 Floating lag time and floating duration

FORMULATION	FLOATING LAG TIME (SECONDS)	FLOATING DURATION
F1	380	40 MINS
F2	270	1.2 HRS
F3	190	2 HRS
F4	110	3.3 HRS
F5	95	4.5 HRS
F6	75	5.7 HRS

 

CONCLUSION:

This study has demonstrated the feasibility of forming gels in stomach by the oral administration of aqueous solution of sodium alginate, HPMC, and Carbopol containing calcium ions in a complex form. Furthermore, a sustained release of Lansoprazole is achievable from gel vehicles over a period of at least 7 hours. So we may conclude that the sodium alginate and Carbopol/sodium alginate may be useful oral sustained vehicles to improve patient compliance and bioavailability.

 

The developed formulations met all the prerequisites to become an in-situ gel floating system, gelled and floated instantaneously at pH conditions of the stomach.

 

The present study has demonstrated that alginate gels sustained the release of Lansoprazole and the formulation F3 was found to be the best formulation with in-vitro release of 96.82%.

 

REFERENCES:

1.       Aman Kant et al, An overview of in situ gelling systems .Pharmacology online. 2011 2:28-44.

2.       Drug Bank-Open data drug and drug database: Lansoprazole (DB00448).

3.       Essentials of Medical Pharmacology, 3^rd edition by Tripathi-628,633,637.

4.       Leon Lachmann, Herbert A.L, Joseph L.K; Sustained release of dosage forms. The theory and practice of Industrial Pharmacy 3^rd edition-1986-430.

5.       Remya P.N et al; Development and Evaluation of Floating insitu gelling sodium alginate formulation. Journal of Chemical and Pharmaceutical Research.2011; 3(3):814-821.

6.       Shozo Miyazaki, Hirotatsu Aoyama, Naoko Kawasaki, Wataru Kubo, David Attwood-Journal of Controlled release.1999; (30):287-295.

7.       Harish N.M et al Formulation and Evaluation of in situ Gels Containing Clotrimazole for Oral Candidiasis. Indian Journal of Pharmaceutical sciences.2009; 71(4):421-427.

8.       Doshi Nidhi et al., In situ gel: a novel approach of gastro retentive drug delivery. Asian Journal of Pharmaceutical Sciences and Research. 2013; 3(3).

9.       Dipen Bhimani R et al., Development and evaluation of floating in situ gelling system of clarithromycin. International Journal of Pharmaceutical Research.2011; 5(5).

10.     MoinModasiya K et al, Sodium alginate based insitu gelling system of famotidine: preparation and in-vivo characterizations-Journal of science and technology.2009; (1):27-42.

11.     Rishad R Javani el al., Development of Novel floating gels of narrow absorption drug Baclofen; Iranian Journal of Pharmaceutical Research. 2010; 9(4):359-368.

12.     Hala S Yousuf el al, Development of Novel drug delivery of Naproxen. Iraqi Journal of Pharmaceutical Science.

13.     P.S Rajnikanth et al, Development of novel drug delivery of Amoxicillin for H. Pylori. Indian Journal of Pharmaceutical science.2007; 335(2).

14.     Hetangi Rathod et al, Pectin based insitu gelling of Salbutamol. International Journal of Political Science and Development.2007; 3(1).

15.     Tommasina Coviello, Franco Alhaique. Journal of controlled release.2007; 119:5-24.

16.     Kawasaki and Ohkori R, Miyazaki S, Uno Y. Thermally reversible xyloglucan gels as vehicle for oral drug delivery. Int. J. Pharm 1999; 181; 227-34.

17.     Katayama H, Nishimura, Ochi S, Tsuruta Y. Sustained release of liquid preparations using sodium alginate for eradication of H. Pylori; Bio Pharm Bull; 1999;20(1);55-60.

18.     Liang Dong, AliciaYum, Joe and Patwong. Enhanced ideal absorption of a hydrophilic macromolecule, J. Biomed. Sci; 200415(5); 671-678.

19.      D.R. Mundhada et al. Evaluation Study of in-situ Gel Using Catanionic Surfactant Mixtures. Research J. Science and Tech. 2016; 8(4):165-178.

 

 

 

Accepted on 09.09.2017        © RJPT All right reserved

Research J. Pharm. and Tech 2017; 10(12): 4323-4327.