Development, In-Vitro and Ex-Vivo Evaluation of Muco-adhesive Buccal patches of Candesartan cilexetil
Kumara Swamy Samanthula1, Shobha Rani Satla2, Agaiah Goud Bairi3
1Vaagdevi Pharmacy College, Bollikunta, Warangal.
2Centre for Pharmaceutical Sciences, IST, JNTU, Kukatpally, Hyderabad.
3SRR College of Pharmaceutical Sciences, Valbhapur, Warangal.
*Corresponding Author E-mail: kumar4koty@gmail.com
ABSTRACT:
Candesartan cilexetil (CC), is an anti-hypertensive drug belongs to angiotensin-II receptor antagonist. CC possesses poor oral bioavailability due to first-pass metabolism and poor aqueous solubility. Various approaches are known to reduce the problems of first-pass metabolism. Hence, buccal drug delivery was an approach to improve bioavailability. The present study, buccal muco-adhesive patches were prepared by using hydroxyl propyl methyl cellulose (HPMC E15) and eudragit RLPO and evaluate for physicochemical properties, such as thickness, weight uniformity, folding endurance, drug content, surface pH, swelling index, moisture absorption and ex vivo permeation studies. Among all the formulations, F7 was selected as an optimized formulation and was found to be 100.55% of drug in 6 hrs, and exhibited controlled drug release, follows zero-order kinetics with diffusion as a release mechanism. The ex-vivo permeation studies revealed that 100% of drug permeated in 6 hrs. Therefore, the buccal patches of CC were successfully developed and enhancement in oral bioavailability is further confirmed by conducting in-vivo studies.
KEYWORDS: Candesartan cilexetil, first-pass metabolism, Buccal muco-adhesive patches, In-vitro, ex-vivo.
INTRODUCTION:
The oral route is the most preferred and widely applicable route for the delivery of the majority of the drugs. But the problems such as poor aqueous solubility, less residence time, chemical instability in the gastrointestinal tract minimizes the bioavailability (BA) of orally administered drugs1. Further, metabolism through various barriers or enzymes also degrades the drug before reaching a site of action. Hence, various alternative drug delivery systems are developed to enhance the oral BA of these drugs. The delivery systems include; enhancement of solubility through solid dispersions2, complexation with cyclodextrins3, liquisolid compacts4, increase the stability and prolonged residence time through floating systems5,6, increase the mucoadhesive property7, lipid-based delivery systems for bypassing metabolism with solid lipid nanaoparticles8, transfersomes9, nanostructured lipid carriers10 and micronization for reducing particle size using nanosuspensions11.
The oral cavity is easily accessible for self-medication and is well accepted by patients. The oral cavity is the most attractive route for drug delivery due to its ease of administration. Both locally acting and systemic acting drugs can be administered by this route. The site-specific release of drug at mucosa is achieved when used for local activity and systemic action requires drug absorption through the mucosal barrier to reach systemic circulation12.
In the last three decades, there is a great interest in the research of buccal drug delivery system. Buccal delivery of drugs provides an attractive alternative to the oral route of drug administration, particularly in overcoming deficiencies associated with the oral route13. Drug delivery via the buccal route using bioadhesive dosage forms offers a novel route of drug administration.14,15.
The main attractive route for drug delivery of new and existing drugs is transmucosal drug delivery and also the only choice of route for delivery of some drugs available today through parenteral route16,17. The buccal mucosa and sublingual area are the most suitable sites for local and systemic drug delivery than the various sites available for drug delivery18,19.
Candesartan cilexetil (CC) is used widely for treating hypertension. Candesartan cilexetil has high first-pass metabolism and poor oral bioavailability, hence it is a suitable drug candidate for buccal drug delivery. Candesartan cilexetil was selected as a model drug for investigation because of its suitable properties like high first-pass metabolism and poor oral bioavailability. The aim of the present research was to develop and evaluate the mucoadhesive buccal patches of Candesartan cilexetil to improve the oral bioavailability.
MATERIALS AND METHODS:
Candesartan cilexetil was obtained as a gift sample from Dr. Reddys labs, Hyderabad India. Hydroxy propyl methyl cellulose (HPMC E15), Eudragit RLPO and ethyl cellulose were obtained from Chemi-nnova Remedies, Hyderabad. PVP K 30, Polyethylene oxide and PEG 6000 obtained from Laksmi chemicals, Hyderabad, India. All other ingredients used in formulations were of analytical grade.
Preparation of Buccal Adhesive Patches:
Solvent casting technique was used to prepare buccal adhesive patches. Weighed quantity of HPMC E15 or Eudragit RLPO was taken in a boiling tube and added 20 ml of dichloromethane: methanol (1:1) and magnetically stirred.
The boiling tube was set-aside for 5 hours to allow the polymer to swell. Then 5 ml propylene glycol was mixed and magnetically stirred. Finally weighed quantity of Candesartan cilexetil was dissolved in 5 ml of solvent mixture, added to the polymer solution and mixed well. It was set-aside for some time to exclude any entrapped air and was then transferred into a previously cleaned anumbra plate and allowed to form uniform patches on the smooth and uniform level platform which were dried in an oven for 8 hours
The secondary polymeric solution was prepared by dissolving ethyl cellulose, polyethylene oxide and 1.5 ml of propylene glycol in 15 ml of solvent mixture and poured on the primary layer and allowed for drying at room temperature. The developed patches were removed carefully, cut to size and stored in desiccators.
Table 1: Formulation of muco-adhesive buccal patches of Candesartan cilexetil
|
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
|
Primary layer |
|
|||||||
|
Candesartan cilexetil (mg) |
400 |
400 |
400 |
400 |
400 |
400 |
400 |
400 |
|
HPMC E15 (mg) |
1500 |
2000 |
2750 |
3000 |
-- |
-- |
-- |
-- |
|
Eudragit RLPO |
-- |
-- |
-- |
-- |
1500 |
2000 |
2750 |
3000 |
|
PVP K 30 (mg) |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
|
Propylene glycol (ml) |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
|
Secondary layer |
|
|||||||
|
Ethyl Cellulose (mg) |
350 |
350 |
350 |
350 |
350 |
350 |
350 |
350 |
|
Polyethylene oxide(mg) |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
|
Propylene glycol (ml) |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
The patches so formed were removed carefully, placed in a vacuum oven and vacuum was applied to remove traces of solvent if any. They were stored in a desiccator till the evaluation tests were performed. Two different polymers were used to prepare buccal patches with different concentrations. The compositions of the patches were shown in table 1.
Evaluation of muco-adhesive buccal Patches:
Weight variation test:
Three randomly selected different patches of each formulation was cut into an equivalent size (2Χ2 cm2), their weight was measured individually using Shimadzu digital balance and the mean weights of the patch were calculated for all the formulations20.
Thickness test:
From each formulation, three randomly selected patches were used. The thickness of the patches were measured at six different points by digital caliper. The average values were taken21.
Surface pH of patch:
For the compatibility of the buccal patch was determined by measuring surface pH. The patches were allowed to swell by keeping it in contact with 25 mL of phosphate buffer (pH 6.8) at 37°C±0.5°C for 2 hrs at room temperature. The pH was measured by bringing the pH-meter electrode, in contact with the surface of the swollen patch and allowing it to equilibrate for 1 min22, 23.
Content Uniformity:
To determine the drug content uniformity, three patches from each formulation were separately dissolved in 100 mL of pH 6.8 phosphate buffer for 12 hrs under occasional shaking. The solutions were filtered, diluted suitably and estimated spectrophotometrically at 256 nm. Each formulation was casted in triplicate and the average of drug contents of three patches was taken as final reading24.
Moisture Absorption Studies:
The study of moisture absorption shows the water retaining power of polymers and gives an indication whether or not the integrity of the film is maintained throughout its shelf life. The updated procedure was employed for the conduct of the above experiment25.
Two percentage agar is prepared in hot distilled water and was transferred into Petri plates, allowed to solidify. Three patches of each formulation were cut into 2Χ2 cm2 and weighed26.
They were placed in desiccators overnight prior to the study to remove moisture if any. They were placed on the surface of the agar and incubated at 370C for one hour in incubator27,28. The patches were removed and weighed again. The percentage of moisture absorbed can be calculated using the following formula:
Final weight Initial weight
% Moisture absorption = ------------------------------------- Χ100
Initial weight
Folding endurance:
Folding endurance of the buccal patch was determined by repeatedly a small strip of size (2Χ2 cm2) of film at the same place till it broke, which is considered satisfactory to reveal good film properties. The value of the folding endurance was calculated by counting the number of folds made at the same place without the film breaking. The mean value of folding endurance was taken29.
Mechanical Properties of the buccal patch:
The mechanical properties of the patches were evaluated by using a advanced equipment with a motorized test stand with a 5 kg load cell (Ultra Test, Mecmesin, UK). The patch was cut into the dimensions 60 x 10 mm and was held between two clamps positioned at a distance of 3 cm. A cardboard was attached on the surface of the clamp to prevent the patch from being cut by the grooves of the clamp30. During measurement, the patch strips were pulled by the top clamp at a rate of 2.0 mm/s to a distance till the patch break down31. The Tensile strength and percentage elongation were determined by measuring the distance obtained by the maximum length just before the breaking point of the patch on the scale. Measurements were run in three replicates for each formulation and the average readings were taken32. The following equations were used to calculate the mechanical properties of the patch 33.
Force at break (kg)
Tensile strength (N/mm-2) = ------------------------------------------------
Cross sectional area of the patch (mm2)
Increase in length (mm) 100
Elongation at = ----------------------------- Χ ------------------------------
break (%) Original length Cross sectional area (mm2)
In vitro release of CC:
Release of CC from the buccal patch was studied using Franz diffusion cells, the receptor chamber of which was filled with 20 ml of pH 6.8 isotonic phosphate buffer. The prepared buccal patches were placed in a donor compartment with 50 μl of water which was then mounted in the diffusion cells, with the patch facing the receptor buffer. Uniform mixing of the receptor was provided by magnetic stirring. Samples of 1 ml were periodically taken from the receptor medium at certain time intervals and replaced with the same volume of buffer. Samples were assayed for CC at 256 nm using a UVVis spectrophotometer34.
Tissue Isolation:
In the present study, pig mucosa was used as the mucosal membrane because their buccal membrane closely resembles the human buccal membrane in terms of structure and permeability. The porcine buccal mucosa was obtained from local slaughter-house. It was immediately kept in the buffer solution at 40C. The mucosal tissue was transported to the laboratory; tissue was rinsed thoroughly using buffer solution, removed carefully any adherent fat and muscle and was used within 2 hours of isolated buccal tissue. It was equilibrated at 37±0.10C for few minutes in phosphate buffer pH 6.8. During the isolation process, sufficient care was taken to prevent any damage to the buccal epithelial tissue35.
Ex-vivo Permeation of CC through Porcine Buccal Membrane:
The buccal epithelium was carefully mounted in between the two donor and receptor compartments of a Franz diffusion cell and clamped together. The patch was placed on the mucosa in the donor compartment and slightly wetted with one mL of phosphate buffer pH (6.8).
The receptor compartment volume of 20 ml and was filled with phosphate buffer (pH 6.8). The diffusion cell was the rmostated at 37 ± 0.5 °C and the entire setup was placed over magnetic stirrer. The receptor compartment was stirred at a rate of 100 rpm. The sample of one mL was withdrawn at pre determined time intervals (0.5, 1.0, 2.0, 3.0, 4.0, 0.5 and 0.6 hrs) using a butterfly cannula and syringe. The buffer was immediately replaced using blank prewarmed buffer. After appropriate dilution the samples were analyzed for the drug permeation by using UV-Visible spectrophotometer at 256 nm. All the experiments were performed in triplicate36.
Differential Scanning Calorimetry (DSC):
For DSC study, Universal V4 TA instrument was used, samples 24 mg was weighed accurately, placed in aluminum pans and heated at 10°C per min rate in the range of 30-300°C in a nitrogen purging gas environment.
RESULTS AND DISCUSSION:
Weight uniformity test
Drug loaded patches (2 x 2.5 cm2) were tested for weight uniformity. Results of weight variation test indicated uniformity in weight of the patches, as evidenced by standard deviation values (table 2) and the weight of patches increased with increase in polymer concentration and their weight having ranged from 103.4±1.65 to 145.6±2.33 mg.
Table 2: Physicochemical parameters of bilayered buccal patches of CC
|
Formulation Code |
Weight variation (mg) |
Thickness (mm) |
Surface pH |
Drug content |
%Moisture Absorbed |
|
F1 |
106.5±2.16 |
0.44±1.63 |
6.7 |
98.45±1.36 |
57.25±2.69 |
|
F2 |
117.3±2.64 |
0.45±1.55 |
6.8 |
99.39±1.80 |
61.55±1.55 |
|
F3 |
128.6±2.63 |
0.49±2.33 |
6.7 |
99.19±2.23 |
65.68±2.73 |
|
F4 |
145.6±2.33 |
0.54±1.63 |
6.6 |
98.25±1.88 |
72.33±1.91 |
|
F5 |
103.4±1.65 |
0.41±2.45 |
6.6 |
98.26±1.25 |
58.46±2.66 |
|
F6 |
105.3±2.62 |
0.43±1.33 |
6.7 |
99.55±1.65 |
61.79±2.70 |
|
F7 |
117.5±2.55 |
0.45±2.13 |
6.9 |
99.59±1.36 |
66.25±2.65 |
|
F8 |
135.4±1.31 |
0.58±1.19 |
6.8 |
99.33±1.33 |
69.66±1.63 |
Thickness uniformity test:
In thickness variation test, the thickness was found to be uniform. The thickness increased with increase in polymer concentration and a direct relation existed between the thickness and weight of the patches. Results of thickness variation test indicated uniformity in thickness of the patches, as evidenced the ranges from 0.41±2.45 to 0.58±1.19 mm with SD values (table 2).
Surface pH of Films:
The prepared buccal patches surface pH of all formulations was within±0.5 units of the neutral pH. Hence no mucosal irritation symptoms were expected and finally it achieves patient compliance and all the results were shown in table 2.
Content Uniformity test:
The drug content in all formulations indicated that the drug was uniformly dispersed and varies between 98.25±1.88 and 99.59±1.36. The drug was uniformly dispersed in the polymer matrix; a significantly good amount of drug was dispersed in all the formulations. The assay values were within the limits and all the results were shown in Table 2.
Moisture Absorption Studies:
Results of moisture absorption studies presented in the table 2. The percentage moisture absorbed ranged from about 57.25±2.69 % to 72.33±1.91 % w/w for various formulations with HPMC E15 and eudragit RLPO. The formulations F1 and F4 more absorbed during the test. Hence, may be suitable for formulation of buccal patches as the structure of the patch might get deformed easily with the drug being released into the saliva, which is desirable. This indicates the moisture absorption capacities of these formulations are increased with increase in polymer concentration.
In eudragit patches, a different pattern was observed in moisture absorption capacities. With the increase in the polymer content, % moisture uptake also increased and none of the polymer got deformed. This may be attributed to low solubility of eudragit when compared to HPMC E and all the results were shown in table 2.
Folding endurance:
The folding endurance was found to be in the range of 282 ± 0.33 to 315 ± 0.65 and did not show any cracks even after folding are more than 300 times. The values were found to be within the limits and good film properties.
Mechanical Properties:
The tensile testing provides an indication of the strength and elasticity of the film, which can be reflected by the parameters Tensile strength (N/mm-2) and Elongation at break. The tensile strengths of eudragit patches were higher than HPMC patches. This is justified because dissolved CC strengthened the bonding of polymer chains. This indicates Hydroxy propyl methyl cellulose and eudragit produce effective cross-linking. The cross linking is also more with eudragit RSPO when compared to Hydroxy propyl methyl cellulose. Among all the patches studied patch F8 showed highest tensile strength and patch F1 showed lowest tensile strength. This must be due to the hydrogen bonding between drug and polymer. The tensile strengths of patches were increased with increased concentration of polymers.
In-Vitro Release Studies:
Phosphate buffer pH 6.8 containing was used as medium for the release studies. Figure 1 shows the drug release profile of CC patches containing different ratios of polymers (HPMC E15 & eudragit RLPO) to drug. It is apparent from the plots that the drug release was governed by polymer content. An increase in the polymer concentration was associated with decrease in drug release rates.
Figure 1: In vitro drug release profile of formulations with HPMC E15
The release profiles of formulations with HPMC E 15, patch F1 to F3 released 100 % at less than six hours whereas F4 showed slower release of 99.19% at 6 hrs, among the series. In case of eudragit RL 100, patch F7 showed maximum released (100.55 %) at 6 hrs whereas F8 showed lowest released of 96.33 % 6 hrs, among the series. The release slowed down as the concentration of gelling polymer increased, thus it was confirming the dominant role of the swellable hydrophilic polymer in the release of CC from buccal patches.
Figure 2: In vitro drug release profile of formulations with Eudragit RLPO
The in-vitro dissolution studies clearly reveals that there is rapid drug release from buccal patches. The drug was completely released in the 4-6 hrs in all the formulations. This clearly indicates formulations in F1 to F3 and F5 to F6 are insufficient to retard the drug for controlled manner for a period of 6 hours. The results of UV analysis showed formulations F4 and F7 showed 99.59% and 100.55% drug release occurs respectively in 6 hrs. This clearly indicates an increase in polymer concentration the rate of drug release was decreased.
F4 and F7 formulations followed zero order and higuchi model release kinetics, as evidenced from the correlation coefficients of the formulations. These formulations showed a non-fickian release pattern as it was evidenced from the release exponent. As the polymer concentration increasing in the patches produced a water-swollen gel like state that could substantially reduce the penetration of the dissolution medium into the patches, and so drug release was delayed.
Table 3: Release kinetics and mechanism of optimized formulation
|
Formulation |
zero-order |
First-order |
Higuchi |
Korsmeyer |
|
F1 |
0.839 |
0.596 |
0.984 |
0.638 |
|
F2 |
0.946 |
0.481 |
0.983 |
0.621 |
|
F3 |
0.954 |
0.304 |
0.968 |
0.585 |
|
F4 |
0.971 |
0.559 |
0.972 |
0.487 |
|
F5 |
0.843 |
0.486 |
0.983 |
0.637 |
|
F6 |
0.926 |
0.521 |
0.998 |
0.604 |
|
F7 |
0.954 |
0.536 |
0.986 |
0.555 |
|
F8 |
0.983 |
0.599 |
0.965 |
0.492 |
The Eudragit layer minimizes the diffusion of the drug molecules from the patches. The formulation that showed controlled and complete release within 6 hrs was selected as the optimized formulation. Observation of all the R2 values indicated that the F7 optimized formulation showed higher R2 (0.996) value was found for higuchi model release. According to n value it was <0.5, so it follows non-fickian diffusion with zero order release mechanism (table 3).
Ex-vivo permeation studies:
Based on the drug release profile ex-vivo study was conducted using F7 formulation with PEG 6000 as permeation enhancer and control (without enhancer). The test drug release has shown 90.33±2.63 as against 75.96±2.55.
Figure 3: Ex-vivo drug release profile of formulations F7 and with Enhancer
Differential Scanning Calorimetry (DSC):
DSC analysis of CC and polymers of physical mixtures (PM in 1:1 ratio) and optimized formulations were performed using Universal V4 TA instruments, USA (Fig.4) and indicated that there was no interaction between the drug and the polymers used.
Figure 4: DSC thermograms of a) pure drug, b) HPMC E15, c) Eudragit RLPO d) optimized formulation
CONCLUSION:
This study was aimed to develop the buccal drug delivery system for CC with controlled effect and to avoid first pass metabolism. From the study, it is observed that formulation F7 was best in terms of drug release and mucoadhesive permeation performance across the mucosal membrane of the patch could be described using diffusion controlled mechanism. Hence, it can be concluded that the formulations of CC mucoadhesive buccal patches are promising one as the controlled drug delivery, improve bioavailability and may be a good candidate for buccal delivery. Further work is recommended to support its efficacy claims by pharmacokinetic and pharmacodynamic studies in animal models.
ACKNOWLEDGEMENTS:
The authors are thankful to Vaagdevi Pharmacy College management for providing necessary facilities in carrying out the present research work. The authors are also thankful to Dr. G. Kamal Yadav principal and Dr. M. Radha Kishan HOD, Vaagdevi Pharmacy College, Bollikunta, Warangal for their technical support.
REFERENCES:
1. Narendar D and Kishan V. Candesartan cilexetil nanoparticles for improved oral bioavailability. Ther deli, 2017; 8(2):79-88.
2. Ettireddy S, Reddy ND. Influence of β-Cyclodextrin and Hydroxypropyl-β-Cyclodextrinon Enhancement of Solubility and Dissolution of Isradipine. Int J Pharm Sci Nanotech 2017; 10(3):3752-3757.
3. Palem CR, Reddy ND, Satyanarayana G, Varsha BP. Development and optimization of Atorvastatin calcium-cyclodextrin inclusion complexed oral disintegrating tablets for enhancement of solubility, dissolution, pharmacokinetic and pharmacodynamic activity by central composite design. Int J Pharm Sci Nanotech 2016; 9(2): 1-11.
4. Arun B, Narendar D. Enhancement of solubility and dissolution rate of trandolapril sustained release matrix tablets by liquisolid compact approach. Asian J Pharm 2015; 9 (4); 290-297.
5. Narendar D and Kishan Veerabrahma. Candesartan cilexetil loaded solid lipid nanoparticles for oral delivery: characterization, pharmacokinetic and pharmacodynamic evaluation. Drug Delivery, 2016, 23 (2); 395-404.
6. Bomma R, Arjun N, Karthik Yadav J. Amoxycillin trihydrate floating-bioadhesive drug delivery system for eradication of helicobacter pylori: preparation, in vitro and ex vivo evaluation. J bioequ avail 2016; 8(3): 118-124.
7. Pitta S, Dudhipala N, Narala A and Veerabrahma K. Development and evaluation of zolmitriptan transfersomes by Box-Behnken design for improved bioavailability by nasal delivery. Drug Dev Ind Pharm2018;44(3):484-492.
8. Nagaraj K, Narendar D, Kishan V. Development of olmesartan medoxomil optimized nanosuspension using Box-Behnken design to improve oral bioavailability. Drug Dev Ind Pharm 2017; 43(7):1186-1196.
9. Senel S and Hincal AA. Drug penetration enhancement via buccal route; possibilities and limitations. J Control Release.2001, 72:133-144.
10. Vishnu M. Patel, Bhupendra G. Prajapati, and Madhabhai M. Patel, Effect of Hydrophilic Polymers on Buccoadhesive Eudragit Patches of Propranolol Hydrochloride Using Factorial Design, AAPS Pharm Sci Tech 2007; 8 (2) Article 45.
11. S. Sarojini1, P. Ravikumar, S. Saranya, A. Dhivya, K. Manimaran, B. Jayanthi, M. Komala, Formulation Development of Olmesartan Medoxomil Mucoadhesive Buccal Film, Asian Journal of Pharmaceutics, Oct-Dec 2016 (Suppl), 10 (4), S510.
12. Choy Fun Wong, Kah Hay Yuen, Kok Khiang Peh, Formulation and evaluation of controlled release Eudragit buccal patches, International Journal of Pharmaceutics, 178 (1999) 1122.
13. Anders, R, Merkle, H.P, Evaluation of laminated mucoadhesive patches for buccal drug delivery. Int. J. Pharm. 1989, 49, 231240.
14. Noha A N, Nabila A B, Fatma A I, Lobna M M, Design and characterization of mucoadhesive buccal patches containing cetylpyridinium chloride, Acta Pharm. 53 (2003) 199212.
15. Siriporn Okonogi1, Sakornrat Khongkhunthian, Sanchai Jaturasitha, Development of mucoadhesive buccal films from rice for pharmaceutical delivery systems, Drug Discoveries & Therapeutics. 2014; 8(6):262-267.
16. Munish Kumar Dhiman, Anupama Dhiman, and Krutika K. Sawant, Transbuccal Delivery of 5-Fluorouracil: Permeation Enhancement and Pharmacokinetic Study, AAPS PharmSciTech, Vol. 10, No. 1, March 2009.
17. Surya N. Ratha Adhikari, Bhabani S. Nayak, Amit K. Nayak, and Biswaranjan Mohanty, Formulation and Evaluation of Buccal Patches for Delivery of Atenolol, AAPS Pharm Sci Tech, Vol. 11, No. 3, September 2010.
18. Parthasarathy Govindasamy, Bhaskar Reddy Kesavan, Jayaveera Korlakunta Narasimha, Formulation of unidirectional release buccal patches of carbamazepine and study of permeation through porcine buccal mucosa, Asian Pac J Trop Biomed 2013; 3(12): 995-1002.
19. Chinna Reddy Palem, Ramesh Gannu, Narender Doodipala, Vamshi Vishnu Yamsani, and Madhusudan Rao Yamsani, Transmucosal Delivery of Domperidone from Bilayered Buccal Patches: In Vitro, Ex Vivo and In Vivo Characterization, Arch Pharm Res Vol 34, No 10, 1701-1710, 2011.
20. Himabindu P, Narendar D, Krishna Mohan C, Nagaraju B. Transmucosal delivery of duloxetine hydrochloride for prolonged release: preparation, in vitro, ex vivo Characterization and in vitro-ex vivo CorrelationInt J Pharm Sci Nanotech 2018, 11(5), 4249-4258.
21. Shaikh Ershadul Haque, Angappan Sheela, Development of polymer-bound fast-dissolving metformin buccal film with disintegrants, International Journal of Nanomedicine, 2015:10 (Suppl 1), 199205.
22. Verma N, Wahi AK, Verma A, Chattopadhayay P. Evaluation of a mucoadhesive buccal patch for delivery of atenolol: in vitro screening of bioadhesion. J Pure Appl Microbiol. 2007;1:1158.
23. Bottenberg P, Cleymaet R, Muynek CD, Remon JP, Coomans D, Slop D. Development and testing of bioadhesive, fluoride-containing slow-release tablets for oral use. J Pharm Pharmacol. 1991; 43: 457-464.
24. Semalty A, Semalty M, and Nautiyal U, Formulation and Evaluation of Mucoadhesive Buccal Films of Enalapril Maleate, Indian J Pharm Sci. 2010; 72(5): 571575.
25. Parthasarathy Govindasamy, Bhaskar Reddy Kesavan, Jayaveera Korlakunta Narasimha, Formulation of unidirectional release buccal patches of carbamazepine and study of permeation through porcine buccal mucosa, Asian Pac J Trop Biomed 2013; 3(12): 995-1002.
26. Varsha Agarwal, B.Mishra. Design and development and biopharmaceutical properties of buccoadhesive compacts of pentazocaine. Drug. Dev. Ind. Pharm, 1999, 25(6): 701-9.
27. Surya N. Ratha Adhikari,1 Bhabani S. Nayak,1 Amit K. Nayak,2 and Biswaranjan Mohanty2,3, Formulation and Evaluation of Buccal Patches for Delivery of Atenolol, AAPS Pharm Sci Tech, Vol. 11, No. 3, September 2011.
28. Attama A, Akpa PA, Onugwu LE, Igwilo G. Novel buccoadhesive delivery system of hydrochlorothiazide formulated with ethyl cellulose hydroxypropyl methylcellulose interpolymer complex. Scientific Res Essay. 2008;3(6):2633.
29. Shaikh Ershadul Haque, Angappan Sheela, Development of polymer-bound fast-dissolving metformin buccal film with disintegrants, International Journal of Nanomedicine 2015:10 (Suppl 1: Challenges in biomaterials research) 199205.
30. Amal Hassan El-Kamel,1 Lubna Y. Ashri,1 And Ibrahim A. Alsarra1 Micromatricial Metronidazole Benzoate Film As A Local Mucoadhesive Delivery System For Treatment of Periodontal Diseases AAPS Pharmscitech 2007; 8 (3) Article 75.
31. J Thimmasetty*,GS Pandey and PR Sathesh Babu Design and In-vivo Evaluation of Carvedilol Buccal Mucoadhesive Patches Pak. J. Pharm. Sci., Vol.21, No.3, July 2008, Pp.241-248.
32. Padula CP, Colombo G, Nicoli S, Catellani PL, Massimo G, Santi P. Bioadhesive Film for the Transdermal Delivery of Lidocaine: In Vitro nd In Vivo Behavior. J Control Release. 2003;88:277Y285.
33. Peh KK, Wong CF. Polymeric Films as Vehicle for Buccal Delivery: Swelling, Mechanical, and Bioadhesive Properties. J Pharm Pharm Sci. 1999;2:53Y61.
34. Puratchikody A, Prasanth VV, Sam TM, Ashok BK. Mucoadhesive patches of salbutamol sulphate for unidirectional buccal drug delivery: Development and evaluation. Curr Drug Deliv. 2011;8:416425.
35. V.V. Prasanth, A. Puratchikody, S.T. Mathew, and K.B. Ashok, Effect of permeation enhancers in the mucoadhesive buccal patches of salbutamol sulphate for unidirectional buccal drug delivery, Res Pharm Sci. 2014 Jul- Aug; 9(4): 259268.
36. Nakamura F, Ohta R, Machida Y, Nagai T. In vitro and in vivo nasal mucoadhesion of water soluble polymers. Int. J. Pharm. 1996; 134:173-81.
Received on 19.02.2019 Modified on 16.03.2019
Accepted on 06.04.2019 © RJPT All right reserved
Research J. Pharm. and Tech. 2019; 12(6): 3038-3044.
DOI: 10.5958/0974-360X.2019.00514.6