FLASH RELEASE ORAL FILM OF CANDESARTAN CILEXETIL FORMULATION AND IN-VITRO EVALUATION

FLASH RELEASE ORAL FILM OF CANDESARTAN CILEXETIL FORMULATION AND IN-VITRO EVALUATION

Chandrasekar G, Abdual Hasan Sathali A *, Umamaheswari D and Prabhu R

Department of Pharmaceutics, College of Pharmacy (COP), Madurai Medical College, Madurai, Tamil Nadu, India.

ABSTRACT: In the present study, to develop a novel flash release fast dissolving oral film of candesartan cilexetil to achieve rapid dissolution and further improve the bioavailability of the drug. Also, to resolve the swallowing problems in pediatrics, geriatric patients by rapid dissolution in saliva and improve the patient compliance. Fast dissolving flash release oral flim of candesartan cilexetil was formulated using HPMCE5, HPMCE15 and HPMCK15 as film-forming polymers. Glycerol, polyethylene glycol and propylene glycol were used as a plasticizer by solvent casting method and found to satisfy the mouth dissolving film and other film parameters. The formulated films of candesartan cilexetil were evaluated for parameters like thickness, weight variation, folding endurance, SEM, surface pH disintegration time, drug content, in-vitro dissolution studies and kinetics studies. The in-vitro disintegration time of the optimized batch F5 was found to be 56 ± 0.12 sec. The films exhibited satisfactory thickness and folding endurance. The optimized batch F5 (HPMCE15) showed a faster disintegrating time, showing 96.02 ± 0.49 drug release within 30 min. The in-vitro release profile of optimized formulation F5 followed a first-order kinetic model with non-fickian diffusion law.

Keywords: Candesartan Cilexetil, Flash release, Solvent casting method, oral film

INTRODUCTION: Oral delivery is the safest, most convenient and economical method of drug delivery. Mouth dissolving strips have attained great importance in the pharmaceutical industry due to their unique properties and advantages ¹. Fast dissolving drug delivery system gaining popularity and acceptance as new drug delivery.

A system because they are easy to administer and leading to better patient compliance. Oral fast-dissolving dosage form consists of mouth dissolving tablets & fast dissolving films. Mouth dissolving tablets are associated with many problems like leaving residues in the mouth, which causes feeling of grittiness in mouth; there is a fear of choking and difficulty in swallowing tablets.

To beat the issues of mouth dissolving tablets, a new drug delivery system for the oral delivery of the drugs was investigated, known as Fast dissolving films/oral dispersible film/ mouth dissolving films / oral disintegrating film/ oral dissolving film ^{2, 3}.

Fast dissolving flash release oral film was developed based on the technology of the transdermal patches for oral delivery of drugs. The delivery system consists of a thin film of the size of a postage stamp placed on the patient’s tongue or mucosal tissue, where it instantly hydrates by absorbing saliva; the film then rapidly disintegrates and dissolves to release the drug for oral mucosal absorption. The availability of a larger surface area of the film leads to rapid disintegration in the oral cavity. It is retained at the application site and rapidly releases the active agent for local and/systemic absorption. Patients suffering from dysphasia, repeated emesis, motion sickness, mental disorder, pediatric and geriatric patients prefer this dosage form as they cannot swallow large quantities of water ^{4, 5}. The oral or buccal mucosa being highly vascularized, drugs can be absorbed directly and can enter the systemic circulation without undergoing first-pass hepatic metabolism. This advantage can be exploited in preparing products with improved oral bioavailability of molecules that undergo first-pass effect ⁶. Candesartan cilexetil is an anti-hypertensive agent, angiotensin II receptor antagonist used to treat hypertension, congestive heart failure, and diabetic nephropathy. It has 15% oral bioavailability due to poor aqueous solubility that makes absorption and dissolution rate limited. This novel drug delivery system can also be beneficial for meeting the industry's current needs: improved solubility/stability, biological half-life, and bioavailability enhancement of drug ⁷.

MATERIAL AND METHOD: Candesartan cilexetil was obtained as a gift sample from Medopharm Pvt limited, Bangalore. HPMC E5, HPMC E15 and HPMC K15 were obtained from Swiss Garnier Genenexiaa Sciences, Sikkim. All other chemicals and ingredients were used for the study are of Analytical grade.

Drug Polymer Compatibility: Pure drug (Candesartan Cilexetil) and polymers were subjected to FTIR (Shimadzu, Japan) studies alone and in combinations. The pellets were placed in the sample holder for recording the IR spectra to study the interference of polymers with the drug ⁸. The scanning range was   400-4000 cm^-1, and the resolution was 4 cm^-1.

TABLE 1: COMPOSITION OF FLASH RELEASE ORAL FILM OF CANDESARTAN CILEXETIL (F1-F4)

 TABLE 2: COMPOSITION OF FLASH RELEASE ORAL FILM OF CANDESARTAN CILEXETIL (F4-F8)

 Formulation of Flash Release Oral Film: Candesartan Cilexetil flash release oral film was prepared by the Solvent casting method. The formulation composition of the different batches was Shown in Tables 1, 2, 3. First, the water-soluble polymers are dissolved in water at 100 rpm at a magnetic stirrer, and all other excipients are dissolved in a suitable solvent separately. Then both the solutions are mixed thoroughly and stirred at 1000 rpm. The obtained solution is incorporated with drug dissolved in a suitable solvent. The entrapped air is removed by vacuum and cast into Petri plate and dried. The film was carefully removed from the petriplate, checked for imperfections and cut to the required size to deliver the equivalent dose per strip (2 × 2 cm^-2 sizes). Film samples with imperfections were excluded from study ⁹.

TABLE 3: COMPOSITION OF FLASH RELEASE ORAL FILM OF CANDESARTAN CILEXETIL (F9-F12)

 TABLE 4: CALIBRATION OF CANDESARTAN CILEXETIL USING PHOSPHATE BUFFER PH 6.8

Evaluation of Flash Release Oral Film:

Surface Morphology: Properties such as homogeneity, transparency, and surface of the oral films were evaluated by scanning electron microscopy (SEM Tescan, Europe ¹⁰.

Film Thickness: The film thickness of the film was measured by vernier Caliper (Linker, Mumbai) at a different location (center and four corners) and meant ± S.D calculated. This is crucial to determine the film thickness uniformity as this is directly correlated to the dose accuracy in film ¹¹.

TABLE 5: FTIR SPECTRUM INTERPRETATION OF CANDESARTAN CIEXETIL AND POLYMER

Weigh Variation of Films: Average Weight is studied by individually weighing five randomly selected films and calculating the average weight. The average weight should not deviate significantly from the average weight ¹².

Average weight of films = weight of 5 films/5

Folding Endurance: The flexibility of the film is measured quantitatively in terms of what is known as folding endurance. The folding endurance of the film was determined by repeatedly folding a small strip of the film at the place till it broke.

The number of times the film can be folded without breaking gives The folding endurance value. This test was performed on five films of each formulation and mean ± S.D was calculated ¹³.

TABLE 6: FTIR SPECTRUM INTERPRETATION OF CANDESARTAN CIEXETIL AND POLYMER MIXTURE

 Drug Content Uniformity: The films were tested for drug content uniformity by UV - visible spectrophotometric method. Films of the required size (2 cm × 2 cm) were cut at three different places from the casted film. Each cut film was placed in 100 ml volumetric flask and was dissolved using methanol and set aside for 2 h. From this stock solution, 1 ml was pipette out and transferred into a 10 ml volumetric flask and the volume was made to the mark with methanol. The absorbance of the resulting solution was measured at 255 nm against blank using UV visible spectrophotometer. The percentage drug content was determined using the standard graph ¹⁴.

Surface pH Study: The fast-dissolving strip's surface pH was determined to investigate the possibility of any side effects in-vivo. As an acidic or alkaline pH may cause irritation to the oral mucosa, it was determined to keep the surface pH as close to neutral as possible.

A combined pH electrode was used for this purpose. Oral strip was slightly wet with the help of water and kept for 30 sec. The pH was measured by bringing the electrode in contact with the surface of the oral film and allowing equilibrating for 1 min. This study was performed on three films of each formulation, and mean ± S.D was calculated ¹⁵.

TABLE 7: FTIR SPECTRUM INTERPRETATION OF CANDESARTAN CIEXETIL ORAL FILM FINAL PRODUCT

 In-vitro Disintegration Studies: Disintegration time indicates the disintegration characteristics and dissolution characteristics of the film. As per the dimensions (3×2 cm) required for dose delivery, the film was placed on a stainless steel wire mesh placed in a petridish containing 10 ml phosphate buffer pH 6. The time required for the film to break was noted as in vitro disintegration time. This test was performed on six films of each formulation, and mean ± S.D calculated ¹⁶.

TABLE 8: CHARACTERISTICS OF CANDESARTAN CIEXETIL ORAL FILMS

 TABLE 9: CHARACTERISTICS OF CANDESARTAN CIEXETIL ORAL FILMS

 TABLE 10: IN-VITRO CUMULATIVE % DRUG RELEASE OF CANDESARTAN CILEXETIL ORAL FILMS

 TABLE 11: IN-VITRO CUMULATIVE % DRUG RELEASE OF CANDESARTAN CILEXETIL ORAL FILMS

 In-vitro Dissolution Test: A dissolution test of films was performed using (400 ml) phosphate buffer pH6.8 with USP dissolution apparatus I (Lab India, Mumbai).

The dissolution medium was kept at 37 ± 0.5 °C and stirred at 50 rpm for 30 min. The drug release was analyzed spectro-photometrically at λ_max 255 nm using an ultraviolet (UV) spectrophotometer (Shimadzu, Japan) by using a calibration. The film was placed into each vessel and the test (5ml) sample was withdrawn at a particular time interval (2, 5, 10, 15, 20 and 30 min) and replaced with fresh dissolution media.

This test was performed on six films of each formulation and mean ± S.D was calculated ^{17, 18}.

Kinetic Modeling of Drug Release: To analyze the mechanism for the release and release rate kinetics of Candesartan cilexetil, the data obtained were fitted to various kinetic equations such as zero-order, the first order, Higuchi matrix and Korsmeyer- Peppas equation.

The regression coefficient values were calculated. In this, by comparing the regression coefficient values obtained, the best fit model was selected ¹⁹.

RESULTS AND DISCUSSION:

Determination of λ_max: The absorption maximum (λ_max 255 nm) of Candesartan cilexetil was estimated by scanning the drug solution (50 µg/ml) between 400-200 nm regions on UV spectro-photometer. The obtained spectrum showed that the absorption maximum (λ_max) was 255 nm for the Cand. cilexetil. Also, absorption maximum showed that the drug sample was authenticated in Fig. 1.

TABLE 12: KINETIC ANALYSIS OF IN-VITRO DRUG RELEASE DATA OF CANDESARTAN CILEXETIL ORAL FILMS

FIG. 1:  ABSORPTION MAXIMUM (Λ_MAX) OF DRUG SAMPLE                               

FIG. 2:  STANDARD CURVE OF DRUG IN PHOSPHATE BUFFER PH 6.8

Calibration Curve of Candesartan Cilexetil: The Standard Calibration curves of Candesartan cilexetil was prepared using phosphate buffer pH 6.8. The absorbance was measured at λ_max of 255 nm. The correlation coefficient was found to be 0.9998. Candesartan cilexetil obeys the beer’s law within the concentration range of (10-50 µg/ml). The calibration plot of Candesartan cilexetil in phosphate buffer pH 6.8 was shown in Table 4 and Fig. 2.

Compatability Studies (Fourier Transform Infrared Spectroscopic (FT-IR): Drug polymer interaction was checked by comparing the IR spectra of pure drug Fig. 3. and the physical mixture of the drug with the excipients used Fig. 5, 10. and optimized/final formulation Fig. 4. The results found no possible interactions between drugs and polymers used in the study were shown in Table 5, 7.

FIG. 3: FTIR SPECTRUM OF CANDESARTAN CILEXETIL                         

 FIG. 4: FTIR SPECTRUM OF ORAL FILM OF FINAL PRODUCT

FIG. 5: FTIR SPECTRUM OF HPMCE5                            

FIG. 6: FTIR SPECTRUM OF HPMCE15

FIG.7: FTIR SPECTRUM OF HPMCK15                                 

FIG. 8: FTIR SPECTRUM OF CANDESAR AN DRUG + HPMCE5

FIG. 9: FTIR SPECTRUM OF CANDESARTAN DRUG + HPMCE15                                           

FIG. 10: FTIR SPECTRUM OF CANDESARTAN DRUG + HPMCK15     

 A 2 KK    B 250 KK   C 500 KK  D 1000 KK

FIG. 11: SEM IMAGES OF FLASH RELEASE ORAL FILM OF OPTIMIZED FORMULATION F5

FIG. 12: IN-VITRO CUMULATIVE % OF CANDESARTAN CILEXETIL ORAL FILMS                           

FIG. 13: IN-VITRO CUMULATIVE % OF CANDESARTAN CILEXETIL ORAL FILMS

Surface Morphology: Properties such as homogeneity, transparency, and surface of the oral films were evaluated by scanning electron microscopy with a magnification of 1K × to 1000K × was shown in Fig. 11.

Film Thickness: The film thickness of the film was measured by vernier calliper with and the average thickness of the film was given in Table 8. Hence the thickness was varied in the range of 51-110 µm.

Weight Variation of Films: The weight variations for the different formulation was calculated and the results were shown in Table 8.

Folding Endurance: Folding endurance of the film was determined by repeatedly folding a small strip of the film at the place till it broke. Folding endurance was found to be highest for F6 films (124 ± 1.9) and lowest for F9 films (53 ± 1.7). The optimum film exhibited good physical and mechanical properties are shown in Table 8.

Drug Content Uniformity: All the films were found to contain an almost uniform quantity of the drug, as per content uniformity studies indicating reproducibility of the technique. In case three, 2 × 2 films were cut an average drug content was calculated. The drug dispersed in the range of 87.00 ± 1.76 to 105.25 ± 1.20 was shown in Table 9. Thus, the preparation met the criteria of IP content uniformity (85-110%).

Surface pH Study: The pH of the film was measured and found to be between 6.14-6.98 for all the formulations. The results were presented in Table 9.

FIG. 14: IN-VITRO CUMULATIVE % DRUG RELEASE OF CANDESARTAN CILEXETIL ORAL FILMS

In-vitro Disintegration Studies: The disintegration time of all the formulation were noted and shown in Table 9. Formulation F5 was found to give minimum disintegration time (56 ± 0.12) sec compared to other formulations.

FIG. 15: RELEASE ORDER KINETICS OF OPTIMIZED FORMULATION F5

In-vitro Dissolution Test: In-vitro dissolution and release studies of various formulations were performed using pH 6.8 phosphate buffer as dissolution medium and measuring drug concentration spectrophotometrically at 255 nm by using a calibration. The in vitro drug release profiles of formulations were given in Table 10, 11, and Fig. 12, 14. The drug release rate was very good with formulation (F5) containing HPMCE15 as a polymer.

Kinetic Modeling of Drug Release: In this study, the in-vitro drug release data were fitted to commonly employed release kinetic models, namely zero-order, first-order, Higuchi and Peppas models and Hixon-Crowell model to analyze drug release mechanism from the polymeric system as shown in Table 12. The highest regression coefficient (r²) value of optimized formulation F5 was obtained 0.9832 (First order). The value of release exponent (n) was found to be greater than 0.5 that indicates non- Fickian diffusion (anomalous) based mechanism of drug release. Kinetics of drug release were shown in Fig. 15.

CONCLUSION: In the present investigation, an attempt was made to develop a flash release oral film of Candesartan cilexetil to achieve fast dissolution characteristics with improved bioavailability by the oral route.

Candesartan cilexetil flash release oral films were prepared by solvent casting method using HPMC E5, HPMC E15, HPMC K15 as a film-forming agent. Based on this physiochemical characterization, in-vitro drug release and drug release kinetics of candesartan cilexetil showed F5 formulation 96.02% at 30 min and followed the non-Fickian release mechanism.

From the results, it can be concluded that the fast dissolving oral film of candesartan cilexetil showed fast disintegration dissolution of drugs in salivary pH. Thus the prepared fast dissolving films of candesartan cilexetil could be a better alternative for achieving rapid oral bioavailability.

ACKNOWLEDGMENT: The authors would like to acknowledge the Dean gratefully. Dr. J. sangumani, M. D. Madurai Medical College, Madurai, for providing these necessary facilities for this research work.

CONFLICTS OF INTEREST: The authors declare no conflict of interest

REFERENCES:

1. Quazi Bilal, Shirkrushna Unhale, Snehal Shelke Purvakale Prof Sarode and Dr. KR Biyani: A a review on mouth dissolving films. European Journal of Pharmaceutical and Medical Research 2020; 7(3): 232-38.
2. Satbir Singh, Tarun Virmani, Roshnu Viramani, Pankaj kumar and Geeta Mahlawat: Fast dissolving drug delivery systems: Formulation, preparation techniques and evaluation. UniJournal of Pharma Res 2018; 3(4): 60-69.
3. Priyanka Gupta, Amrita Bisht and Dr. NG Raghavendra Rao: Fast dissolving oral films: Comprehensive Review. World Journal of Pharmaceutical and Medical Research 2019; 5(7): 116-27.
4. Rada Santosh kumar, Nagasatya T and Yagnesh: Oral dissolving films: an effective tool for fast therapeutic action. Journal of Drug Delivery and Therapeutics 2019; 9(1): 492-99.
5. Usha kiran Reddy T, Sunil kumar Reddy K, Katta Manogna and Prof K: Thyagarajum a detailed review on fast dissolving oral films. Indo American Journal of Pharmaceutical Research 2018; 8(06): 1315-25.
6. Tuhina Banerjee, Vaseem A, Ansari, Satyaprakash singh, Tarigue Mahmood and Juber Akhtar: A review on fast dissolving films for buccal delivery of low dose drugs. International Journal of Life Sciences and Review 20151; (4): 117-23.
7. Shruti S. Sarwade, Jadhav WN, Khade BC and Bhusare SR: Synthesis and characterization of Ag(I) complex with Candesartan. Der Chemia Sinica 2015; 6(4): 18-22.
8. Verena Ingeborg Garsuch: [Dissertation]. Heinrich Heine University 2009; 90-92.
9. Raghavendra HL and Prem Kumar G: Development and evaluation of polymer-bound glibenclamide oral thin film. Journal of Bioequivalence & Bioavailability 2017; 9(1): 324-30.
10. Somesh Bawane, Roshan Teirandhe and Pande SD: Formulation and evaluation of oral fast dissolving film of bisoprolol fumarate, International journal of Pharmaceutics & Drug Analysis 2018; 6(2): 105-15.
11. Jeganath S and Senthilkumaran K: Design, preparation and characterization of oral disintegrating films of candesartan cilexetil. International Journal of Research in Pharmaceutical and Nano Sciences 2012; 1(2): 269-73.
12. Jameel Ahmed Mulla, Utkarsh A Chopade, Suraj B kumbhar and Pallavis Marathe: Formulation and evaluation of fast dissolving oral films of domperidone. Indian Journal of Novel Drug Delivery 2018; 10(2): 68-75.
13. Nisha kumari: Formulation, fabrication and in-vitro evaluation of fast dissolving oral film of cilnidipine. World Journal of Pharmaceutical Research 2017; 6(8): 1460-67.
14. Sanjay P, Vishal Gupta N, Goeda DV and Praveen Sivadasu: Formulation and evaluation of oral disintegrating film of atenolol. Asian Journal of Pharmaceutical and Clinical Research 2018; 11(8): 312-5.
15. Renuka Mishra and Avani Amin: Formulation and characterization of rapidly dissolving films of cetirizine hydrochloride using pulllan as a film forming agent. Ind J Pharm Edu Res 2011; 45 (1): 71-77.
16. Bhatt P and Patel M: Formulation and evaluation of fast dissolving film of rizatriptan benzoate. International Journal of Medical PharmaResearch 2015; 1(2): 58-77.
17. Raju S, Sandeep Reddy P, Anirudh Kumar V, Deepthi A, Sreeramulu Reddy K and Madhava Reddy PV: Flash release oral films of metoclopramide hydrochloride for pediatric use: Formulation and in-vitro J Chem. Pharm Res 2011; 3(4): 63646.
18. Tekade BW, Jadhao UT, Patil VR and Sumit D: Formulation and evaluation of chlorpheniramine maleate fast dissolving film as an anti-allergic medication. Eur J Pharm Med Res 2017; 4(5): 340-45.
    

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    How to cite this article:

    Chandrasekar G, Sathali AHA, Umamaheswari D and Prabhu R: F lash release oral film of candesartan cilexetil formulation and in-vitro evaluation. Int J Pharm Sci & Res 2021; 12(9): 4753-63. doi: 10.13040/IJPSR.0975-8232.12(9).4753-63.

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