Exploration of Cassia fistula L. seed mucilage into floating drug delivery system

Abstract The aim of the present study was to explore Cassia fistula L. seed mucilage as a natural polymer in controlled release floating drug delivery system. First, seed mucilage was extracted and evaluated for phytochemical screening, solubility studies, swelling index, viscosity and surface tension. Then, Atenolol floating systems were prepared with and without the C. fistula L. seed mucilage by direct compression method. Phytochemical screening resulted from the presence of secondary metabolite carbohydrates, glycosides, flavonoids and phenolic compounds in good amounts. Results of hardness, friability, drug content and swelling index were satisfactory. The floating behaviour can increase the gastric residence time and eventually improve the bioavailability of the drug as evidence from in vitro buoyancy and dissolution studies. Interestingly, developed floating system showed remarkable increase in dissolution. Conclusively, the results suggest that developed Atenolol floating system with C. fistula L. seed mucilage demonstrate interesting attributes to be explored for potential pharmaceutical application. Graphical Abstract

novel drug delivery. Natural polymers are extracted from plants or animals such as cellulose, rubber, silk, and so on. which offer unique biological features in terms of biocompatibility and bioactivity (Tong et al. 2020).
Cassia fistula L. is popular with name Golden shower or Indian laburnum has medicinal importance since ancient times. C. fistula L. belongs to family Caesalpiniaceae has been widely used in different types of traditional medicinal systems as well as a folk medicine. Anthraquinone derivatives, carbohydrates, proteins, amino acids, resinous, waxy derivatives and different type of sugar moieties have been reported from the seeds of C. fistula L. (Mwangi et al. 2021). Two new bioactive compounds benzyl 2hydroxy-3,6-dimethoxybenzoate and its dimer have reported from C. fistula L. seeds extract (Sartorelli et al. 2012). It has been reported that phytoconstituents of C. fistula L. shown various pharmacological activities like antioxidant activity, aldose reductase inhibition and anti-cataract activity (Choudhary and Swarnkar 2011;Gacche and Dhole 2011). Moreover, many tribes of south Asia use C. fistula L. as a source of human food and nutrition (Barthakur et al. 1995).
Recently, a floating drug delivery system has gained more interest in the researchers because it was able to release the drug into the gastrointestinal tract and maintain an effective drug concentration for long period (Ma et al. 2008;Viveksarathi et al. 2011). Floating systems can be retained in the stomach and can improve the controlled delivery of drugs that have a narrow absorption window by continuously releasing the drug for a prolonged period of time thus ensuring its optimal bioavailability (Celli et al. 2017, Dave et al. 2004). The non-effervescent is based on mechanism of swelling of polymer or bioadhesion to mucosal layer (Nur and Zhang 2000).
Atenolol is a cardio selective b-1 adrenergic receptor blocking agent and it has been used for the treatment of hypertension. It is poorly absorbed from the lower gastrointestinal tract. Atenolol is insoluble in water and has half-life of about 6-8 h and possesses only 50% oral bioavailability (Havaldar et al. 2009).
Nowadays, interest in the use of natural polymers for pharmaceutical application has been progressively increased due to wide range of biocompatibility with drug and other materials. However, synthetic polymers from the biological standpoint often lack desired bioactivity and biocompatibility, which may translate into adverse side effects (Tong et al. 2020). It has been reported that C. fistula L. especially seed part contains rich source of carbohydrate which may utilize for the pharmaceutical application such as floating system (Deshpande and Bhalsing 2013). This natural material is easily available, and its economic reliability make the choice for usage in floating system.
To the best of our knowledge, no report is available in the literature on the use of C. fistula L. seed mucilage as a natural polymer in floating system for controlled release and evidence from in vitro buoyancy and in vitro dissolution studies to fill the gap of industrial applications of natural-based medicinal application, which is a current need of modern therapeutics. In view of these facts, the present study was designed to explore the floating potential of C. fistula L. seed mucilage with Atenolol as model drug.

Collection and extraction of C. fistula L. seed mucilage
The C. fistula L. plant was collected from Sahyadri valley, Western Maharashtra region, Kolhapur Dist. (Maharashtra, India) in the month of September and identification was made by Dr. M. M. Lekhak, Department of Botany, Shivaji University, Kolhapur. A voucher specimen of the plant was deposited in the herbarium, Department of Botany with an accession number SPJ-01. Extraction efficiency of ethanol solvent resulted more yields 13.52% in comparison to petroleum ether. Due to mid polar nature of ethanol, yield can be achieved more hence ethanol solvent was used as an extraction solvent.

Percentage yield
Ethanol solvent resulted in 13.52% yields while petroleum ether yields 5.12%.

Organoleptic evaluation
The extracted mucilage studied for organoleptic properties, which resulted brown colour, odourless, mild sweet taste and rough texture.

Phytochemical screening of extracted mucilage
Phytochemical screening study resulted the presence of various metabolite phytoconstituents in seed mucilage extract like alkaloids, fats, saponins, tannins, anthraquinones and amino acids while strong presence of carbohydrates, glycosides, flavonoids and phenolic compounds. C. fistula L. has medicinally important due to the presence of secondary metabolites which has shown various potent pharmacological activities. The result of phytochemical investigation of C. fistula L. seed mucilage has been depicted in supplementary material Table S1.

Determination of mucilage pH
1% solution of mucilage was prepared in water. Before the addition of mucilage, the initial pH of water was observed to be 6.5. The pH of 1% solution of mucilage in water was found to be 6.2. This pH is near to neutral hence it may not cause significant irritation.
2.2.5. Solubility study of extracted mucilage C. fistula L. seed mucilage was sparingly soluble in water (1 part of mucilage require 100 parts of water to dissolve) and insoluble in the ethanol, acetone, benzene and petroleum ether.
2.2.6. Swelling index of extracted seed mucilage The swelling index of C. fistula L. seed mucilage was found to be 24%. The swelling index of the polymer is very important because the swelling systems have been used to increase gastric retention times and consequently enhance the drug absorption within the stomach (Chen et al. 1999).

Viscosity and surface tension
The viscosity of C. fistula L. seed mucilage was found to be 2.0521 centipoise. The surface tension of C. fistula L. seed mucilage was found to be 47.878 dyne/cm. Viscosity and surface tension of the polymer provides a favourable film form between the liquid and polymer.

Fourier transform infrared spectrophotometer study (FTIR)
FTIR spectrum of C. fistula L. seed mucilage showed the peaks at wave numbers 1008.45 cm À1 for C-O deformation, 1438.41 cm À1 for C ¼ O stretching, 1535.51 cm À1 for N-O deformation, 1737.39 cm À1 for C ¼ O deformation. FTIR spectrum of C. fistula L. seed mucilage has been provided in supplementary material Figure S1.

Powder X-ray diffraction study (PXRD)
PXRD spectrum of C. fistula L. seed mucilage showed 2h peaks at 20 , 28 and 41 . The intensity of these peaks indicates the amorphous nature of seed polymer. PXRD spectrum of C. fistula L. seed mucilage has been depicted in supplementary material Figure S2.

Preparation of floating tablet
Total six F1-F6 batches were prepared. F1-F3 batches comprise floating system with the seed mucilage and F4-F6 batches were of plain Atenolol floating system without seed mucilage. Composition of F1-F6 batches was given in supplementary material Table S2.

Evaluation of floating tablet
The values of hardness, weight variation, friability, drug content and swelling index were found in the prescribed limits (Table S3). Statistically, insignificant difference was observed between the hardness, weight variation, % drug content and swelling index which may indicate similar behaviour between C. fistula L. seed mucilage and standard HPMC K15M floating polymer (student t' test, p > 0.05), while statistically significant difference was observed in friability (student t' test, p < 0.05).

In vitro buoyancy studies
The floating lag time of F1-F6 batches were found to be satisfactory, buoyancy duration for about 8 h was an evident showing a floating mechanism. Statistically insignificant difference was observed between the buoyancy lag time and total floating time which may indicates identical behaviour of both polymers (student t' test, p > 0.05). The result of buoyancy of F1-F6 batches shown in supplementary material Table S4. The result of buoyancy study demonstrates the adequate floating potential of prepared Atenolol floating system.

In vitro dissolution study
The in vitro drug release of tablets has shown a profound effect on the selection of the type of polymers and their concentrations. Release pattern of C. fistula L. seed mucilage and HPMC K15M was compared. Interestingly, Atenolol floating system with C. fistula L. seed mucilage showed remarkable increase up to 94% dissolution behaviour as compared to 55% of plain Atenolol floating system. The result of in vitro dissolution study was depicted in supplementary material Table S5. Statistically significant difference was observed in cumulative % drug release which may indicate that C. fistula L. seed mucilage would be a prominent alternative to the standard HPMC K15M for floating delivery (student t' test, p < 0.05).
Dissolution behaviour of Atenolol floating system with C. fistula L. seed mucilage and plain Atenolol floating system have been shown in Figure S3 and S4 respectively. Result suggests that C. fistula L. seed mucilage can be used as dissolution enhancer in pharmaceuticals.

Stability studies
All prepared floating tablet formulations were found to be stable for a period of 3 months. No physical or visual change in their organoleptic properties was observed. Viscosity, pH and drug content were unchanged.

Conclusion
Natural polymers play a key role in the nutraceutical domain due to wide range of biocompatibility with drug and other materials, which represents a new challenge to improve sustainability and medicinal value of natural ingredients into a pharmaceutical application. In this context, C. fistula L. seed mucilage floating formulations were prepared, which found to have adequate controlled release floating mechanism and can be used to control the fluctuations in the plasma drug concentration, increase the gastric residence time and eventually improve the bioavailability of the drug as evidenced from hardness, friability, drug content, swelling index, in vitro buoyancy and in vitro dissolution studies. Conclusively, Atenolol floating system with C. fistula L. seed mucilage was successfully prepared which has the adequate floating potential and showed remarkable increase in dissolution behaviour. Also, C. fistula L. seed mucilage can be used as dissolution enhancer in many pharmaceuticals. Furthermore, continuous research progress on C. fistula L. seed mucilage will promote the use of polymers from natural origin in modern therapeutics which is a global need. thankful to Dr. D. P. Mali, Assistant Professor, Bharati Vidyapeeth College of Pharmacy, Kolhapur, Maharashtra for strengthening the overall write-up of the manuscript.

Disclosure statement
No potential conflict of interest was reported by the authors.

Funding
The author(s) reported there is no funding associated with the work featured in this article.