Ramu Samineni1*, Shaik Firoz2, Nagaraju Bandaru1, Swagat Lenka3, P. Pravallika4,
S. Ooha4, Sampath A Gouru5, M. Sivakumar6
1Department of Pharmaceutics, School of Pharmaceutical Sciences,
Sandip University, Nashik, Maharashtra 422213.
2Department of Pharmaceutics, Sri Venkateswara College of Pharmacy,
Chittoor, Andhra Pradesh, India - 517127.
3Assistant Professor, Department of Pharmaceutics, Ranchi College of Pharmacy,
Chandaghashi, Kutetoli, Ranchi, Jharkhand - 834003.
4Assistant Professor, Sri Venkateswara College of Pharmacy, Chittoor, Andhra Pradesh, India - 517127.
5Senior QA Specialist, ND Global Consulting Services, Texas, USA – 75070.
6Professor and Head, Department of Pharmacognosy, Faculty of Pharmacy,
Sree Balaji Medical College and Hospital, BIHER (DU), Chromepet, Chennai - 600044.
*Corresponding Author E-mail: samineniramu123@gmail.com, firoz.kallur@gmail.com
ABSTRACT:
An anti-diabetic drug called Empagliflozin is used to control blood glucose levels in type 2 diabetics. Due to the high rate of hepatic first pass metabolism, it exhibits limited bioavailability. The current study was done to create Mucoadhesive buccal films of Empagliflozin with the aim of increasing bioavailability, patient compliance, and therapeutic efficacy. The solvent casting process used for the preparation of Empagliflozin Mucoadhesive buccal films by using the Mucoadhesive polymers like HPMC K100 and HEC. The prepared films' evaluated for weight variation, thickness, surface pH, uniformity of the drug content, in-vitro residence time, folding durability, in-vitro release, and permeation investigations were all assessed. Formulations (F1-F4) were created by altering the concentrations of various polymers, with F2 and F4 formulations having the highest polymer ratios and the longest-lasting drug release rates. According to characterization results such as in-vitro dissolution experiments, the sustained release formulation F2, F4 shows the best drug release rate, the order of drug release is F1>F3>F2>F4. It was determined that the films could be chosen for the development of buccal films for effective therapeutic applications because they exhibited effective enlargement, a practicable residence duration, and promising controlled drug release.
KEYWORDS: Buccal films, Empagliflozin, Ex-vivo studies, In-vitro studies, Mucoadhesion.
INTRODUCTION:
Administration via mouth is easiest, most convenient, and preferable. Hepatic first-pass metabolism, GI tract metabolism, or both may affect oral medicines.
Hepatic first-pass metabolism, GI tract metabolism, or both may occur in oral medications of peptides and proteins so this cannot be taken orally.
Distribution of such drugs via nasal, rectal, vaginal, ocular, and oral mucosa may be possible1.
These Mucoadhesive drug delivery devices increase drug bioavailability by preventing first-pass effects and presystemic clearance in the GI tract. Buccal mucosa is the best Mucoadhesive drug delivery site for local and systemic medications. This route is suitable for Mucoadhesive drug distribution owing to its unique anatomical and physiological features, such as smooth muscles with high arterial perfusion and no hepatic first pass metabolism. These dosage forms are inexpensive and patient-friendly2.
Mucosal microenvironment controls the disintegration and mucosal penetration of the drug. With the aid of Mucoadhesive drug delivery systems, the mucosal microenvironment can be altered or modified. These systems are devised and formulated utilizing Mucoadhesive polymers, which have a high molecular weight, high viscosity grades, increased flexibility, and optimal chain length. For buccal drug delivery, numerous Mucoadhesive polymers have also been studied3-5. When compared to other Mucoadhesive drug delivery methods, such as oral gels and buccal tablets, buccal films work more favorably because of their significantly extended residence time, increased comfort and flexibility in enveloping the buccal mucosa. When combined with diet and exercise, Empagliflozin may assist individuals with type 2 diabetes in better controlling their blood sugar levels. Its bioavailability is low because of rapid first-pass metabolism in the liver6.
Therefore, the medicine may be delivered via the buccal route through buccal films in order to increase its therapeutic efficacy and bioavailability7 Administration of Empagliflozin by buccal route may circumvent hepatic first-pass metabolism and increase bioavailability8. Because of this, the current study focuses on developing and characterizing a Mucoadhesive buccal film of the medication Empagliflozin utilizing HPMC K100, HEC, PEG, and glycerin.
MATERIALS AND METHODS:
HPMC K100, HEC, PEG, and glycerin were purchased from Bross Chemicals in Tirupati, and Empagliflozin was a gift sample from Aurabindo Pharmaceuticals in Hyderabad. There was also analytical-grade compounds used. Solvent casting was used to create the films.
Mucoadhesive buccal films preparation:
An Empagliflozin Mucoadhesive buccal film was made by solvent casting technique with a film-forming polymer9. In accordance with the formulation table, the required amount of polymers HPMC K100and HEC was accurately weighed and steeped for one hour to allow polymer swelling. Empagliflozin was precisely weighed and dissolve in 5ml of ethanol in a separate beaker. With the aid of a magnetic stirrer, the drug solution was added to the polymer solution, polyethylene glycol was added as a plasticizer, and glycerin was added as a sweetener. The aforementioned solution was sonicated for twenty minutes to remove air pockets. The glass mould (petridish) with a diameter of 8.6cm was placed on a flat surface, and the resulting 15ml solution was deposited into the petridish slowly, drop by drop, and evenly distributed. For uniform evaporation, the funnel was placed upside down over the petridish. The polymeric drug solution contained in the petridish was allowed to dry at ambient temperature for 24 hours. After removing the dried films from the molds, identical formulations F1, F2, F3, and F4 were prepared10. The purpose of analyzing these new films was to select the one with the finest qualities. The desiccated films were cut into 2-centimeter-diameter pieces, wrapped in aluminium foil, and preserved in a desiccator for future use. Table 1 depicts the formulation of Mucoadhesive buccal films.
Table 1: Formulation of Mucoadhesive Buccal Films
|
Content |
F1 |
F2 |
F3 |
F4 |
|
Empagliflozin (mg) |
100 |
100 |
100 |
100 |
|
HPMC K100 (mg) |
200 |
300 |
- |
- |
|
HEC(mg) |
- |
- |
200 |
300 |
|
PEG (ml) |
0.4 |
0.4 |
0.4 |
0.4 |
|
Glycerin (ml) |
0.2 |
0.2 |
0.2 |
0.2 |
|
Distilled water (ml) |
10 |
10 |
10 |
10 |
HPMC-Hydroxypropyl methyl cellulose, HEC- Hydroxyethyl cellulose, PEG- Polyethylene glycol.
Physical Evaluations:
Thickness: The mean weights were determined by weighing 3 films of each formulation on a digital scale. Three films were made from each recipe, and the thickness was measured at 3 different sites using a micrometer screw gauge to get an average film thickness11.
Folding endurance:
The folding endurance test consisted of repeatedly folding a 2-centimeter-wide film strip in the same location until it broke. The average folding endurance (based on three measurements and standard deviation, the number of pleats the film could withstand at the same location)12.
Drug content:
Separate 100ml volumetric containers were filled with three film units of each formulation. 100ml of phosphate buffer with a pH of 6.6 was then added, and the mixture was agitated continuously for 24hours to ascertain the homogeneity of the drug's composition. The solutions were filtered, appropriately diluted, and subjected to UV spectrophotometer analysis at 225nm. The final reading was determined by averaging the drug content of three movies13.
pH: Buccal films were deposited on agar plates and allowed to enlarge for one hour in order to determine their surface pH. The agar plate was created by dissolving 2% (w/v) agar in a tepid, isotonic phosphate buffer with a pH of 6.6 while agitating, and then emptying the solution into a Petri dish until it solidified at room temperature. A pH paper was placed on the surface of the expanded film to determine its pH.14.
Swelling index (%):
A 10X10 mm2 drug-loaded film was weighed on a pre-weighed cover slip to evaluate the swelling qualities. A 50 ml solution of pH 6.6 phosphate buffer was added, and it was stored in a Petri plate. The cover slip was taken off after every five minutes and weighed for up to 30 minutes. Due to water absorption and film swelling, the weight differential results in an increase in weight. The following calculation was used to compute the percent swelling15.Percent swelling (% S) is calculated
as (Xt-Xo/Xo) 100, Equation 1
Where Xt-the weight of the film before swelling and Xo-the weight of the film at the beginning of swelling.
In vitro residence time:
Phosphate buffer was used as the disintegration medium in an compendia disintegration equipment, and the in vitro residence time was calculated. (900ml maintained at 37±2°C). Vertically linked glass slabs were covered with rat intestinal mucosa segments about 3cm in length. Placed in contact the mucosal membrane with three films of each formulation after hydrating them with pH 6.6 Phosphate Buffer on one surface. The device enabled the vertically mounted glass slab to rise and fall. The film was completely immersed in the buffer solution at both its lowest and highest positions16. Table 2 displays the time required for the film to fully dissolve or detach from the mucosal surface (n=3).
In vitro release:
The USP six station dissolving apparatus type 1 (Veego Ltd., India) with 900ml pH 6.6 phosphate dissolution medium was used for the in vitro release investigation. With cyanoacrylate adhesive, one film from each formulation was adhered to the center shaft. Throughout the release investigation, the apparatus was kept at 37 °C±0.5°C and 50rpm, respectively. The release investigation lasted two hours. Once an hour, samples were collected from each station, filtered, diluted appropriately, and then analyzed spectrophotometrically at 225nm.
Ex-Vivo permeation:
A modified Franz diffusion cell was utilized for ex vivo permeation experiments of Mucoadhesive buccal films of Enalapril through an excised layer of porcine buccal mucosa (washed in isotonic phosphate buffer (pH 6.6) after excision and pruning of the sides)17-19. Each formulation was applied as a 2.0cm diameter film in close proximity to the excised porcine buccal mucosa, with an aluminum foil-wrapped underlying membrane. A magnetic stirrer was used to agitate the 100ml of pH 7.4 phosphate buffer that was added to the receptor compartment along with a Teflon bead, while maintaining a 37°C temperature throughout the experiment. Each hour, samples were withdrawn, filtered, and appropriately diluted prior to 225nm UV spectrophotometer analysis20-22.
RESULTS AND DISCUSSION:
Mucoadhesive buccal films Characterization:
Fourier Transforms Infra-Red spectroscopy
Compatibility studies were conducted to determine the potential interactions between the drug and formulation excipients. FTIR spectra of drug, polymers (HPMCK100 and HEC), and physical mixture represented in figure 1 and interpretation values are represented in table 2. From the interpretation data, it can be concluded that there was no interaction between drug and polymer.
Figure No.1: FTIR Spectra of a. Drug, b. HPMCK100, c. HEC, d. Physical mixture
Table 2: FT-IR Interpretation
|
S. No |
Sample |
Characteristics bands pure drug |
Physical mixture(1) |
Physical mixture(2) |
Possible functionalities |
|
1 |
Empagliflozin |
2940.66 |
2942.44 |
2937.42 |
C-H stretching |
|
1586.76 |
1585.84 |
1586.13 |
C-C stretching |
||
|
1452.98 |
1453.12 |
1453.09 |
C-H bending |
||
|
1113.41 |
1111.78 |
1111.87 |
C-O stretching |
||
|
1035.63 |
1034.07 |
1035.50 |
C-N stretching |
Physical evaluation:
Mucoadhesive polymers such as HPMC K100, HEC, PEG, and glycerin were used to create Empagliflozin buccal films using the solvent casting method. On the developed films, various physicochemical tests were conducted. And results represented in the Table 3. The thickness of each film was consistent throughout. The measured film thickness ranged from 0.693±0.002 to 0.716±0.016mm, with an average thickness of 0.612 mm. The weights of several formulations were determined to be between 58±1.93mg and 86±0.63mg. Both the degree of polymer hydration and drug release may be affected by the acidic or alkaline pH, which may also irritate the buccal mucosa. Therefore, it was decided what pH the buccal film's surface should be to maximize mucoadhesion and medication release.
Due to the fact that the surface pH of all formulations fell within the neutral pH range (7±0.5), no mucosal irritation was anticipated and patient compliance was achieved. To ascertain the folding endurance, the film was manually folded until it broke. Even after being folded over 222 times, the films exhibited no signs of cracking. Therefore, it was considered the conclusion. The folding endurance was discovered to fall between 293±5.0 and 171±.11.22. It was discovered that the values were ideal for revealing good film qualities. The medication was evenly disseminated, according to the content uniformity findings, which showed that its concentration ranged from 18.19 to 23.0mg/cm2.
Table 3: Physical evaluation of Empagliflozin Mucoadhesive buccal films
|
Formulations |
Swelling Index (SI)(%) |
Thickness (mm) |
Folding Endurance (FE) |
pH |
Drug content (%) |
|
F-1 |
109 |
0.693 |
222 |
7.48 |
96.34 |
|
F-2 |
112 |
0.827 |
226 |
7.14 |
94.07 |
|
F-3 |
98 |
0.420 |
207 |
7.24 |
95.04 |
|
F-4 |
105 |
0.760 |
225 |
7.32 |
93.13 |
In phosphate buffer solution with a pH of 6.6, the films' swelling was seen. The relative swelling of different formulations followed the following pattern: F2>F4>F1>F3 In films F2 containing HPMC k10 and PEG, swelling was more pronounced owing to the presence of more hydroxyl groups. The inclusion of HEC significantly diminished F3's edema percentage. The in-vitro residence times for different formulations were as follows: F1>F3>F4>F2 is illustrated in figure2. The proper in-vitro residence duration for the films was identified, and as a result, they exhibited advantageous swelling and drug release properties. Due to the uniform dispersion of the medication within the polymer matrix, each formulation contained a substantial quantity of substance. The drugs were found to be present in the following order: F1>F3>F4>F2. Using pH 6.8 phosphate buffer as the solubility medium, in vitro release tests of several formulations were carried out. At 225nm, the drug concentration was measured spectrophotometrically. Photographs of prepared Mucoadhesive buccal films (F1-F4) represented in figure 3.
Figure No. 2: In-vitro release profile of F1-F4
Figure No. 3: Photographs of Mucoadhesive Buccal Films (F1-F4)
Additionally, formulations F1 and F2 (which comprise HMPC and PEG) were found to exhibit positive swelling a practical residence time, and show a potential drug release by considering the release pattern, swelling, and duration of residence. The physical characterization of every formulation produced excellent results. The study's findings demonstrate that therapeutic doses of Empagliflozin can be administered orally. The results of this investigation suggest that these erodible Mucoadhesive buccal films containing Empagliflozin may hold great promise for providing systemic circulation with effective dosages. These might also have the extra benefit of avoiding the liver's first pass metabolism. Films displayed controlled release for longer than three hours.
CONCLUSION:
By using the solvent casting technique, Empagliflozin Mucoadhesive buccal films were created. This competitive sodium-glucose co-transporter 2 (SGLT2; SLC5A2) inhibitor is orally available and has hypoglycemic effects. PEG 600 functions as a plasticizer in addition to being a co-solvent for causing drug solubility. Drug releases from Mucoadhesive buccal films vary depending on the kind and composition of the polymer. As the concentration of more hydrophilic polymers in the Mucoadhesive buccal films increases, an increase in medication release has been seen. Formulations F1, F2, F3, and F4 were created by altering the concentrations of various polymers, with F2 and F4 formulations having the highest polymer ratios and the longest-lasting drug release rates. According to characterization studies such in-vitro dissolution experiments, the F2, F4 formulations shows a sustained release and exhibits the best drug release rate (the order of drug release is F1>F3>F2>F4). According to the results of the investigation, such Mucoadhesive buccal films of Empagliflozin were well tolerated and produced sustained glycemic effectiveness over a lengthy period of time in Type 2 diabetes mellitus patients
ACKNOWLEDGMENTS:
Authors thankfully acknowledge Bross Chemicals in Tirupati and Aurabindo Pharmaceuticals in Hyderabad for providing HPMC K100, HEC, PEG, and glycerin and Empagliflozin as gift samples. The authors are also thankful to School of Pharmaceutical Sciences, Sandip University, Nashik, and Management for providing the entire necessary facilities and infrastructure.
CONFLICT OF INTEREST:
Nil.
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19. Ramu Samineni, Sumalatha K, Dharani G, Rachana J, Anitha P, Manasa K. Formulation and Evaluation of Oral Disintegrating Tablets of Montelukast Sodium and Desloratidine. Research Journal of Pharmaceutical Dosage Forms and Technology. 2019; 11(3): 152-158. DOI: 10.5958/0975-4377.2019.00026.0
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21. Ramu Samineni, Jithendra Chimakurthy, Sathish Kumar Konidala, VenkateswaraoYamarthy. Development and Validation of Analytical Method for Estimation of Balofloxacin in Bulk and Pharmaceutical Dosage Form by RP-HPLC. Research J. Pharm. and Tech. 2022; 15(7): 2992-2996. DOI: https://doi.org/10.52711/0974-360X.2022.00499
22. Sathish Kumar Konidala, Ramu Samineni, Yamarthi Venkateswara Rao, Jithendra Chimakurthy, Chaitanya SucharithaKolakaluri, VishaliKorrapati. Novel RP-UPLC Method Development and Validation for Simultaneous Quantification of Emtricitabine, Tenofovir and Efavirenz in Bulk and Tablet Dosage Forms. Research J. Pharm. and Tech. 2022; 15(7): 3141-3146. DOI: https://doi.org/10.52711/0974-360X.2022.00525
Received on 15.02.2023 Modified on 27.06.2023
Accepted on 21.10.2023 © RJPT All right reserved
Research J. Pharm. and Tech 2023; 16(12):5576-5580.
DOI: 10.52711/0974-360X.2023.00901