Novel Mucoadhesive Gastro Retentive Drug Delivery System of Ranitidine Hydrochloride

P. K. Wagh*, S. P. Ahirrao, S. J. Kshirsagar

Department of Pharmaceutics, MET’s Institute of Pharmacy, Bhujbal Knowledge City, Adgoan, 

Nashik 422 003 (M.S.) India, Affiliated by Savitribai Phule Pune University (SPPU), Pune

 

ABSTRACT:

Novel gastro retentive drug delivery system (GRDDS) of Ranitidine hydrochloride prepared in the present study based on unfolding mechanism. Ranitidine Hydrochloride, a H2 antagonist with a narrow absorption window was selected for this novel GRDDS due to its low bioavailability (50%) which might be due to colonic degradation by colonic bacteria and also low biological half-life of 2.5-3 hours necessitates the development of effective GRDDS of ranitidine. Hence in the present study Ranitidine hydrochloride films were prepared by solvent-casting method and by using polymers like HPMC K4M, Carbopol 934, Eudragit L100 and RLPO and plasticizer; polyethylene glycol 400.The film with zigzag folding in the capsule was shown to unfold in the stomach and provide drug release up to 8hours in the acidic medium. Films were evaluated by various parameters like film thickness, weight variation, Uniformity of drug content, swelling index, folding endurance, unfolding time, elongation at break, tensile strength, mucoadhesion study, in vitro drug release, in vivo gastric residence time, DSC, SEM, and IR. Formulation batch F5 was considered as optimized batch due to its good mucoadhesive time(487min)  and drug release was found in controlled manner; almost98.12% drug release up to 8 hours. Also in vivo study (Gastric residence Time in Rabbit)of optimized batch and mucoadhesion study (using Goat stomach mucosa) indicates that this Novel patch of Ranitidine hydrochloride was found to be mucoadhesive and profound basis for effective GRDDSas compared to other gastro retentive techniques due to its unfolding mechanism.

 

 

 

INTRODUCTION:

Ranitidine is a competitive inhibitor of histamine H₂ receptors, drug of choice in the treatment of ulcer and readily absorbed from gastro intestinal tract.^[15] The bioavailability of ranitidine following oral administration is about 50% which might be due to colonic degradation by colonic bacteria.^[9]

 

 

The bioavailability of ranitidine is markedly lower from the human colon that the upper part of gastro intestinal tract. Various attempts have been made to develop the formulation of mucoadhesive film of ranitidine for improving and enhancing bioavailability in a controlled release manner. It may also be possible to avoid the first pass effect and presystemic elimination in the gastro intestinal tract and liver.^[10] The recommended oral adult oral dose of ranitidine is 150 mg twice daily or 300 mg once daily. The effective treatment of erosive esophagitis requires administration of 150 mg of ranitidine 4 times a day. A conventional dose of 150 mg can inhibit gastric acid secretion up to 5 hrs. but not up to 10 hrs. an alternative dose of 300 mg leads to plasma fluctuations; thus, a sustained release dosage form of Ranitidine HCL is desirable.^[11] the biological half-life of drug (2.5-3 hours) also favors development of a controlled release formulation.^[12]

 

This system helps in continuously releasing the drug before it reaches at the absorption window. It is also reported that oral treatment of gastric disorders with an h₂ receptor antagonists like ranitidine or famotidine used in combination promotes local delivery of these drugs to the receptor of the cell wall. This principle applied for improving systemic as well as local delivery of Ranitidine hydrochloride, which reduce gastric acid secretion. Several approaches are currently used to prolong the gastric residence time. From above principle a strong need was the development of dosage form to deliver Ranitidine hydrochloride in the stomach and to increase the bioavailability of the drug providing controlled action. The present work done for applying a systemic approach to the development of gastroretentive ranitidine hydrochloride dosage form.^[17]

 

The development of controlled release formulations had a more impact on the drug delivery field particularly for drugs with a narrow absorption window. However, typical controlled release formulations are limited by insufficient retention in the stomach. To extend the residence time of dosage form in the stomach, a number of strategies have been developed, including reducing the density to promote floating in the gastric contents, increasing the density to promote  retention in the lower part of the stomach, introducing mucoadhesive properties and producing a formulation that swells or unfolds in the stomach to hinder its escape through the pyloric sphincter.^[1,2] The several approaches are currently used to retain the dosage form in the stomach.  These include bio adhesive systems, swelling and expandable systems, floating systems and other delayed gastric emptying devices.^[3,4]A gastroretentive dosage form can overcome this problem and is particularly useful for drugs that are primarily absorbed in the stomach, duodenum and upper part of small intestine. ^[9,5]The technique use in this article involves the formation of mucoadhesive film for sustained release of the drug.^[6,7] An alternative strategy is to combine bioadhesion with the ability to expand by unfolding and swelling. This paper describes the design of a formulation incorporating drug loaded polymeric film folded into the hard gelatin capsule. After ingestion the capsule dissolves and releases the film which then unfolds in the stomach and swells to a larger dimension resulting in its retention. The concept of a gastro retentive drug loaded polymeric films has been previously reported and the effects of shape, folding pattern and polymer characteristics on performance of gastroretention has been studied.^[8]

 

MATERIALS AND METHODS:

Ranitidine Hydrochloride was obtained as a gift sample from Perrigo Pharma Pvt Ltd. India, HPMC K4M and Carbopol 934 was obtained from coloron Pvt Ltd, Goa, India, Eudragit RLPO/L100 was obtained from Evonik Pvt. Ltd, Mumbai, Hydrochloric acid, polyethylene glycol used as a plasticizer, Dichloromethane and methanol was obtained from Thomas baker. For the in vivo study Application to be submitted to the CPCSEA, New Delhi after approval of Institutional Animal Ethics Committee (IAEC).

 

Preparation of gastroretentive mucoadhesive film:

Mucoadhesive film, was prepared by solvent casting method.

Polymer dissolve in mix of solvent

 

Drug dissolved in polymer dispersion

 

Add drug solution and polymer solution with constant stirring to obtain clear solution

 

Add plasticizer with constant stirring, sonicate to remove air bubbles

 

Allow to drying and use for evaluation^[21]

 

 

Fig 1: Film folded into hard gelatin capsule

 

Table 1: Different concentration of polymers used in formulation of gastroretentive mucoadhesive films of Ranitidine Hydrochloride

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
Drug (mg)	75	75	75	75	75	75	75	75	75
HPMC K4M (mg)	1000	1500	1500	1000	1500	1000	500	500	500
Eudragit RLPO (mg)	2000	1000	2000	1000	3000	3000	1000	3000	2000
Eudragit L100 (mg)	500	500	500	500	500	500	500	500	500
Carbopol 971 P NF (mg)	150	150	150	150	150	150	150	150	150
PEG 400 (ml)	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
Dichloromethane: Methanol (1:1)	100	100	100	100	100	100	100	100	100

 

Characterization of Gastroretentive Mucoadhesive Films:

1.    Preformulation study:

Obtained drug sample was examined by Fourier Transform Infrared Spectroscopy.

The drug was scanned in UV Spectrophotometer to detect the λ max of the drug and to draw the concentration curve of the drug. The drug was used in the concentration range of 0- 25 ppm.^[13] The molecular state of the drug was evaluated by performing DSC of the drug and optimized formulation.

 

2.     Unfolding time:

The film was folded in a zigzag manner and both films were inserted into individual capsule.  In each case six capsules were taken for in vitro dissolution study in 900 ml aqueous hydrochloric acid PH 1.2 at 37± 0.5°c using the USPXXIII Apparatus 1 (Basket) at 100 rpm.  Basket  were  removed  after  5,  10,  15,  20,  30,  60,  120,  240,  480  and  720  min  and  the  films  were  examined  for  their  unfolding  behavior.^[14]

 

3.    Weight variation:

Each formulation was prepared in triplicate and ten patches each equivalent to 4cm x 2cm was cut from each plate.  Their weight was measured using Shimadzu digital balance.  The mean  ±  SD  values  were calculated  for  all  the  formulations.^[13]

 

4.    Thickness:

The thickness of the patches was measured by digital screw gauge.  The mean SD values.  Were  calculated for  all  the  formulations.^[10]

 

5.    Folding endurance:

The  number  of  times  the  patch  could  be  folded  at  the  same  place  till  it  broke  gave  the  value  of  folding endurance.^[10]

 

6.    Uniformity of drug content:

Film taken dissolved in 100 ml 0.1 N HCL solution in 100 ml volumetric flask and kept for 24 hrs.  with occasional shaking.  The filtrate make dilution with 0.1 N Hcl. Then take UV.^[6]

 

7.     Swelling index:

Swelling of films was examined in the triplicate in simulated gastric fluid (P^H 1.2).  After recording the initial weight of a film (W1), it was immersed in medium maintained at 37 ± 1°c for 360 min and then weight again (W2).  Theswelling  ratio  was  determined  as (W2-W1)/W1.^[6]

 

8.    In vitro mucoadhesive time:

The time taken for detachment of film from goat stomach mucosa was measured in 0.1N hydrochloric acid (pH 1.2).  This  was  evaluated  by  an  in  vitro  adhesion  testing  method,  by  using  in  vitro  dissolution  apparatus.^[15]

A piece of goat stomach mucosa, (3cm diameter) was attached inside, 0.1 N HCL buffer containing beaker of dissolution apparatus assembly with cyanoacrylate glue and film was attached by applying pressure for 5m.Suitable rotation speed  of  dissolution  apparatus  assembly  was  maintained  at  37 ±  0.5°c and  observes  the  time  of  detachment  of  mucoadhesive  film  from  mucous  membrane.^[1]

 

9.    Tensile strength:

To determine tensile strength, polymeric film was sandwiched separately by corked linear iron plates.  One end of the film was sandwiched separately by corked linear plates.  One end of the film kept fixed with the help of an iron screen and other end was connected to a freely movable thread over a pully.  The weights were added gradually to the pan attached with the hanging end of the tread.  A pointer on the tread was used to measure the elongation of the film. The weight just sufficient to break the film was noted.  The tensile strength was calculated by using the following equation-

Tensile  strength  (Kg /  mm2) = Force  at  break  (Kg)/  Initial  cross  sectional  area  of  the  sample  (mm2).^[10]

 

10. Elongation at break:

The force and elongation were measured when the films were broken. Results from film samples, which were broken at end and not between the clamps were not included in observations. Measurements were run in six replicates for each formulation. The following  equations were  used to calculate the  mechanical properties of the  films.^[1]

 

                                                  Increase in length (mm) 100

Elongation at = ------------------------------------------------------------------

break (%mm-2)             (Original length) (Cross sectional area mm²)

 

11.   In vitro dissolution study:

In vitro dissolution studies were carried out employing USP dissolution apparatus (Basket apparatus). 2 cm x 4 cm size films containing 75 mg of equivalent weight of ranitidine was filled into hard gelatin capsule in zigzag manner.  Basket was rotated at 100 rpm. 900 ml of 0.1 N HCL pH 1.2 was taken the dissolution medium.10 ml aliquot were withdrawn at regular timeinterval until complete drug release and the sample was periodically withdrawn at suitable time interval and the volumes were replaced with fresh dissolution medium to maintain the sink condition.  The  aliquots  were  analyzed  using  UV-  Spectrophotometer  at  313 nm.^[3]

 

12.   Scanning Electron Microscopy:

The morphology of the GRDFs was studied by SEM. The patch was examined in a Scanning Electron Microscope equipped with a scanning image observation device using secondary electro imaging.^[14]

 

13.   In-Vivo Study:

In vivo gastric retention time is determined by X-ray technique in rabbits. For in vivo study, barium sulphate containing mucoadhesive films were prepared solvent casting method. In this case drug was replaced by barium sulphate. For in vivo retention study, the rabbit was overnight fasted and on the next day morning the film in capsule was administered orally followed by giving 25ml water.X- Ray photographs were taken at different time intervals like 0hrs, 6hrs and 12hrs. The Animal study Protocol was passed by the College animal ethical committee. The registration number and date of registration is 1344/PO/Re/S/10/CPCSEA;29^th April 2010. X-ray photos revealed the nature and position of film upto 12hrs.^[16]

 

 

Fig 2: FTIR of the drug, Excipients and formulation

 

RESULT AND DISCUSSION:

1)   Preformulation study:

The compatibility of drug and polymers were tested using FTIR and DSC techniques. FTIR study shows that drug and polymer does not show interaction shown in figure 2.DSC study shows that ranitidine shows peak at 149.4°c corresponding to its melting point it is shown in figure 3. calibration curve was constructed using a concentration range of 1-25 ppm at λmax of 313nm. The equation was found to be y = 0.0512x + 0.1128 and the Regression Coefficient R² = 0.9948 so it was concluded that the graph is linear. shown in figure 4.

 

 

Fig 3: DSC of Drug and Formulation

 

 

Fig 4: Concentration Curve

 

2)     Unfolding time

The unfolding time of the film show in figure 5. The unfolding time of the film was ranging from 11-19 min and the results were tabulated in table 2.

 

 

Fig5: Unfolding Behavior Study

Table 2: Evaluation parameters of prepared gastroretentive mucoadhesive film

Parameters	F1	F2	F3	F4	F5	F6	F7	F8	F9
Unfolding time	19±1	16.33±1.5	18.33±1.5	11±1	15.33±0.5	15.66±1.52	12±1	12.33±0.57	11.66±2.08
Uniformity of weight (mg)	491.7 ± 14.6	496.6±15.0	566.5 ± 5.2	332.6±101	332.6. ±10.1	550.3 ± 30.6	372.9± 21.0	432±12.6	380.6±10
Thickness (mm)	0.43± 0.010	0.45± 0.008	0.535± 0.005	0.323±0.0	0.548±0.012	0.465±0.005	0.31± 0.017	0.348±0.01	0.295±0.05
Folding Endurance	≥300	≥300	≥300	≥300	≥300	≥300	≥300	≥300	≥300
Drug Content (%)	83.97 ± 0.46	81.43 ± 0.51	87.48 ± 1.33	90.51±1.1	88.80 ± 1.02	84.90 ± 0.80	86.68 ± 0.88	82.52 ± 0.37	78.52 ± 0.36
Swelling Index (%)	86.60 ±0.62	93.30 ±1.6	121.60 ±4.6	73.1±1.0	150.85± 3.25	94.48 ± 4.26	52.52 ± 3.01	55.07 ± 3.27	54.64 ± 2.44
Tensile Strength (Kg/mm2± SD)	12.56 ± 0.02	13.87 ± 0.01	15.05 ±0.05	10.10±0.1	16.66 ±0.01	11.70± 0.05	7.84 ± 0.02	8.54 ± 0.03	8.06 ± 0.02
Elongation at Break (%)	35.2.5 ± 2.5	33.33 ± 1.44	30 ± 2.5	46.66±3.8	28.33 ± 1.44	42.5 ± 2.5	54.16 ± 3.81	50 ± 2.5	52.5 ± 2.5
In Vitro mucoadhesive time (hr.)	464.3 ± 4.0	487 ± 4.3	592.3 ± 2.5	465.6 ±3.0	601.6 ± 3.5	535.6 ± 4.0	425.3 ± 3.7	450.3 ± 4.1	435.3 ± 3.5

 

3)   Folding endurance:

The results of the folding endurance shown in table 2. The film did not show any visible cracks even after folding for more than 300 times for all the batches. It indicates that the good integrity and flexibility.

 

4)   Swelling index:

Swelling index of film was shown in table 2. The swelling index was directly proportional to the amount of hydrophilic polymer and hydrophobic polymer. The % swelling of various formulations was in the order of F5≥ F3≥ F6≥ F2≥ F1≥ F4≥ F8≥ F9≥ F7. Batch F5 shows high swelling index due to concentration of hydrophilic polymer and hydrophobic polymer is more. Batch F7 shows low swelling index due to low concentration of hydrophilic polymer and hydrophobic polymer.

 

5)   In vitro mucoadhesion time:

The mucoadhesive time for the patch ranging from 5-8hours. It is shown in table 2. The content of the HPMC K4M increased, the residence time of film increased. Batch F5 (8h)shows highest residence time this may be due to high content of hydrophilic polymer which leads to increase swelling of formulation thus, mucoadhesive bond formation for longer time. Batch F7 shows low residence time this may be due to low content of hydrophilic polymer.

 

 

Fig 6: In Vitro Mucoadhesive time

6)   Tensile strength:

Tensile strength of the film is shown in table 2. Tensile strength increased as increasing the concentration of polymer. Tensile strength of the optimized formulation was found to be 16.66 Kg/mm^2.

 

7)   Elongation at break:

Elongation at break of the film are show in table 2. Elongation at break decreases with increase the concentration of polymer. Elongation at break of the optimized formulation(F5) was found to be 28.33g.

 

8)   In vitro dissolution study:

In vitro dissolution studies were carried out employing USP dissolution apparatus (Basket apparatus). The results are shown in table 2. In vitro drug release was obtained in the range of 93.92-98.1%. from the results it is concluded that as the polymer concentration increases, the viscosity of the gel layer increases as well as the diffusion path length of the drug increases this cause the less drug release at the higher level of the HPMC and vice versa. Batch F9 shows less drug release compare to other batches because of the concentration polymer is less, while F5shows good drug release because of the concentration of the polymer is optimum. Korsmeyerpeppas model fits best for the dissolution data of F5 batch it shows highest value for R² and least slope value which indicate that the drug release from a system in which there was a change in the surface area and the diameter of the formulation.

 

 

 

 

 

 

 

 

 

Table 3: % Drug release of prepared gastroretentive mucoadhesive film

Time(hr.)	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0
1	51.59	50.98	42.8	57.31	32.31	52.23	59.4	57.47	58.1
2	68.18	64.16	55.38	72.08	45.59	63.88	77.9	73.37	77.85
3	75.7	74.39	68.33	79.39	57.1	74.2	82.4	80.9	83.7
4	81.88	81.15	77.91	86.13	67.83	83.0	87.8	87.8	89.94
5	89.50	87.67	84.85	92.3	75.0	86.02	90.9	89.6	91.01
6	92.4	91.27	88.27	93.49	85.80	88.1	92.6	91.8	92.68
7	94.17	93.00	92.1	94.6	93.6	92.1	93.90	93.7	93.67
8	96.54	94.88	96.2	95.78	98.1	96.85	94.39	94.90	93.92

 

 

Fig 7: Dissolution profile of the F1-F9 batches

 

9)     Scanning electron microscopy:

Scanning electron microscopy images shown in figure 7. It does not show any crystal of the drug on the surface of film. It indicates that drug is dispersed homogeneously in the polymeric matrices.

 

 

Fig 8: Scanning Electron Microscopy

 

10)  In vivo study:

The radio graphic images shown in figure 8. The gastric residence time of optimized formulation were evaluated by conducting in vivo x-ray study in rabbit. The x ray was taken in 1hr, 4hr, and 8hrintervals. formulation shows the gastric residence time upto 8 hours.

 

1hr                                 4hr                                                     8hr

 

 

8hr

Fig 9: In Vivo-X ray study

CONCLUSION:

Gastroretentive mucoadhesive film of Ranitidine Hydrochloride were prepared by solvent casting method by using different polymers like Carbopol, HPMC, Eudragit and Polyethylene glycol 400 used as plasticizer. The initial part of the work was started from the identification of drug. FT-IR study shows that there is no significant interaction between polymers and drug in the preliminary trials, the various polymers are used i.e. HPMC K4M, Ethyl cellulose and Eudragit. HPMC K4M and Eudragit RLPO were found to be suitable for Gastroretentive mucoadhesive film. The formulated films were evaluated for physical characterization like thickness, uniformity of weight, folding endurance, swelling index, mucoadhesive strength, tensile strength, Elongation at break, DSC, SEM and in vivo gastric residence time. All the physical parameters of the films were complying the specifications. % drug release of the formulations (F1-F9) was studied up to 8 hours and it was found that 94.88 to 98.12%, Unfolding time of the formulation(F1-F9) was found to be11-19, in vitro mucoadhesive time of the formulation (F1-F9) was found to be 285-487 min. in vivo study shows that dosage form is gastroretentive up to 8 hrs. by taking x-ray photograph using rabbit.

 

The cumulative percentage drug release was decreased by increase in polymer concentration of HPMC K4M and Eudragit RLPO.

 

ACKNOWLEDGEMENT:

The authors are thankful to Trustee, Bhujbal Knowledge City, METs Institute Pharmacy, Adgoan, Nashik for providing the necessary facilities for research work.

 

REFERANCES:

1.     Sathish, D., et al., Preparation and Evaluation of novel expandable drug delivery system with Captopril. Current Drug Therapy, 2013. 8 (3): p. 206-214.

2.     Srikanth, M.V., et al., Statistical design and evaluation of a propranolol HCl gastric floating tablet. Acta Pharmaceutica Sinica B, 2012. 2(1): p. 60-69.

3.     Sivaneswari, S., E. Karthikeyan, and P. Chandana, Novel expandable gastro retentive system by unfolding mechanism of levetiracetam using simple lattice design–Formulation optimization and in vitro evaluation. Bulletin of Faculty of Pharmacy, Cairo University, 2017. 55 (1): p. 63-72.

4.     Deshpande, A.A., et al., Development of a novel controlled-release system for gastric retention. Pharmaceutical research, 1997. 14 (6): p. 815-819.

5.     Streubel, A., J. Siepmann, and R. Bodmeier, Gastroretentive drug delivery systems. Expert opinion on drug delivery, 2006. 3(2): p. 217-233.

6.     Banerjee, N. and S. Singh. Design and evaluation of bilayered mucoadhesive film of cefpodoxime proxetil. International Journal of Pharmaceutical Sciences and Research, 2014. 5(4): p. 1295.

7.     Mohrle, R., Effervescent tablets‖ in Liberman, Lachman L. Schwartz. Pharmaceutical dosage form,―Tablets, 2005. 1.

8.     Klausner, E.A., et al., Expandable gastroretentive dosage forms. Journal of controlled release, 2003. 90 (2): p. 143-162.

9.     Basit, A.W. and L.F. Lacey, Colonic metabolism of ranitidine: implications for its delivery and absorption. International journal of pharmaceutics, 2001. 227 (1-2): p. 157-165.

10.  Alagusundaram, M., et al., Formulation and evaluation of mucoadhesive buccal films of ranitidine. International journal of pharmtech research, 2009. 1(3): p. 557-563.

11.  Somade, S. and K. Singh, Comparative evaluation of wet granulation and direct compression methods for preparation of controlled release ranitidine HCL tablets. Indian J Pharm Sci, 2002. 64 (285): p. 17.

12.  Dave, B.S., A.F. Amin, and M.M. Patel, Gastroretentive drug delivery system of ranitidine hydrochloride: formulation and in vitro evaluation. Aaps PharmSciTech, 2004. 5 (2): p. 77-82.

13.  Singh, B.N. and K.H. Kim, Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. Journal of Controlled release, 2000. 63 (3): p. 235-259.

14.  Darandale, S.S. and P.R. Vavia, Design of a gastroretentive mucoadhesive dosage form of furosemide for controlled release. Acta Pharmaceutica Sinica B, 2012. 2 (5): p. 509-517.

15.  Moës, A.J., Gastroretentive dosage forms. Critical reviews in therapeutic drug carrier systems, 1993. 10 (2): p. 143-195.

16.  Gudas, G.K., Development and in vivo evaluation of mucoadhesive tablets of Rebapimide.

17.  Dumpeti, J., Mekha L., Chinnala K, M., Vabalaboina V., Formulation and in vitro evaluation of Gastroretentive Drug Delivery System for Ranitidine Hydrochloride. International Journal of Pharmaceutical sciences and technology 2008. 1 (3): p 228-232.

Received on 27.09.2018       Accepted on 28.10.2018

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Asian J. Pharm. Res. 2019; 9(2): 80-86.