Bioscience Biotechnology Research Communications Vol 14 No (4) Oct-Nov-Dec (2021)

Biotechnological Communication

Development and Optimization of Floating

Microspheres in Amethopterin

Raghav Mishra*
Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.

ABSTRACT
Due to the complexity of gastric emptying, as well as its considerable variability, the in vivo efficacy of drug delivery devices cannot
be predicted. When it pertains to drugs with an absorption window in the upper small intestine, a controlled drug delivery system
with a longer residence period in the stomach may be of considerable practical significance. Recent developments have shown that
floating microspheres are particularly well suited for mixing sustained and delayed releases to achieve a variety of release models
with a minimal risk of dumping. The aim of present investigation is to develop and analyze the floating microspheres of amethopterin,
which after oral administration could increase the gastric residence time and enhance the bioavailability of the drug by sustained
release and minimize the dose dependent side effects as well as improves patient compliance. Floating microspheres of ethyl
cellulose, Polyvinyl alcohol and polyvinyl pyrrolidone-K90 were formulated by emulsification solvent evaporation technique. The
various parameters of prepared microspheres were studied for SEM, flow properties, buoyancy, yield, percent drug loading, in vitro
dissolution studies, stability in different pH and FTIR studies. Microspheres prepared with different concentrations of polymers were
spherical in shape with smooth surface. The size of microspheres was in range of 256.02 µm and 362.84 µm. Good drug entrapment
and buoyancy were observed for formulation F2. The in vitro drug release after 6h was found to be in range from 58.15% to 96.28%.
It was established that the newly created floating microspheres of Amethopterin provide an appropriate and practical solution for
the sustained release of medication over a longer period of time, resulting in increased oral bioavailability, effectiveness, as well as
better patient compliance.

KEY WORDS: Amethopterin, Antineoplastic, Buoyancy, Floating microspheres.

INTRODUCTION of natural origin or synthetic origin and also semisynthetic

substances. Floating microspheres can be prepared by using
Oral route of administration is the most convenient and both hydrophilic and hydrophobic polymers. The concept
widely used method of drug administration, and the of floating or porous microspheres can also be utilized
development of stomach specific oral controlled- release to minimize the irritant effect of weakly acidic drugs on
delivery systems is a challenging job due to the variation stomach by avoiding direct contact with the mucosa and
of pH in different segments of gastrointestinal tract, the providing a mean of getting low dosage for prolonged
fluctuation in gastric residence time and the difficulty in periods (Bulgarelli et al. 2000; Davoudi et al. 2013; Prakash
localizing an oral delivery system in a selected region of et al. 2015; Srikar et al. 2018; Mishra et al. 2020; Birajdar
the gastrointestinal tract. Rapid gastrointestinal transit can et al. 2021; Kumar et al. 2021).
prevent the absorption of complete drug in the absorption
zone and reduce the efficacy of administered dose since the Amethopterin synonym Methotrexate (MTX) (Figure 1)
majority of drugs are absorbed in stomach or upper part of is an antineoplastic agent whose mechanism is similar
small intestine. Polymers are generally employed in the to alkylating agents. It is a highly toxic drug with a very
development of floating microspheres. A number of different low therapeutic index. It causes toxicities like stomatitis,
substances have been investigated for the preparation of gingivitis, glossitis, ulceration, and bleeding of the mucous
floating microspheres; these materials include polymers membrane when given orally and hematological effects like
leucopenia, thrombocytopenia, anemia, hemorrhage from
various sites in single-dose intravenous administrations,
Article Information:*Corresponding Author: raghav.mishra@gla.ac.in and also some hepatic toxicities by administering as
Received 25/09/2021 Accepted after revision 21/12/2021 conventional dosage forms. Sustained and targeted delivery
Published: 31st December 2021 Pp- 1538-1543 of amethopterin will reduce these toxicities considerably
This is an open access article under Creative Commons License,
Published by Society for Science & Nature, Bhopal India.
Available at: https://bbrc.in/ DOI: http://dx.doi.org/10.21786/bbrc/14.4.26 1538
Mishra
by maintaining a low and constant level of drug in the tan ϴ = h/r
blood. Therefore, floating microspheres have emerged as
an efficient means of prolonging gastric residence time, where,
targeting stomach mucosa, and enhancing the bioavailability.
Floating microspheres remain buoyant due to lower density h = height of the pile and r = radius of the cone formed after
than the gastric and intestinal fluids. They are not subjected making the microspheres flow through glass funnel from a
to ‘all or nothing’ gastric emptying nature of single unit fixed height (Kale et al. 2007).
system and releases the drug in a controlled fashion. In
the current research, emulsification solvent evaporation The particle size of floating microspheres was performed
including EC, PVP-K90, and PVA polymers were used to with the help of optical microscope for randomly selected
form hollow microspheres containing Amethopterin. (Chen sample for all formulations (Table 2).
et al. 2000; Singh et al. 2000; Shishu et al. 2007; Garg et
al. 2008; Brunton et al. 2011; Rathor et al. 2011; Abbas et • Buoyancy test for microspheres: In triplicates,
al. 2020; Kumal et al. 2020; Tomar et al. 2021; Thakur et microspheres (100mg) were dispersed in solution
al. 2021; Kharb et al. 2021). composed of HCl (300 mL, pH 1.2 at 37℃) containing
Tween 20 (0.02% w/v) to simulate gastric conditions
MATERIAL AND METHODS (Patel et al. 2011, Raveendra et al. 2012).

Amethopterin was obtained as a gift sample (Naprod Life The use of 0.02% Tween 20 was to account for the
Science Mumbai) whereas ethyl cellulose (EC), polyvinyl wetting effect of the natural surface-active agents, such
pyrrolidone K-90 (PVP K-90) and polyvinyl alcohol (PVA) as phospholipids in the gastrointestinal tract (GIT) (Jain
were obtained from Merck India, Mumbai. Other chemicals et al. 2009).
used were of analytical grade. Floating microspheres
containing amethopterin were-prepared by emulsification The mixture was stirred on magnetic stirrer at 100 rpm
solvent evaporation technique using EC, PVP-K90 and PVA and 37±0.5℃. After 12hours, the floating particles were
polymers for microspheres (Soppimath et al. 2001) (Table separated by filtration. The sinking particles were separated
1). Amethopterin (100 mg) was weighed accurately and by filtration. Both particle types were weighed after drying
dissolved in 8 mL ethyl alcohol, followed by the addition at 40℃ overnight. The buoyancy was determined by the
of 2 mL isopropyl alcohol and 5 mL methylene dichloride. weight ratio of the floating particles to the sum of floating
The polymer solution was slowly introduced into 100 mL and sinking particles. Percent buoyancy of formulations is
of 1% polyvinyl alcohol aqueous solution while stirring shown in Table 3.
at 250 rpm using a mechanical stirrer equipped with a
3-blade propeller. The solution was stirred for 10 minutes
and microspheres were collected by filtration. The floating
microspheres were collected by decantation, while the
non-floating microspheres were discarded along with any
polymer precipitates. The microspheres were dried in an where,
oven at 50℃ for 2hours, weighed and then stored in a Qf = Weight of floating microspheres and Qs = Weight of
desiccator at room temperature for further use. settled microspheres

The developed floating microspheres were evaluation • Yield of Microspheres: The prepared microspheres
considering following parameters: were collected and weighed. The actual weight of
• Surface Morphology: The prepared microspheres were obtained microspheres divided by the total amount
fixed on a brass stub using double sided adhesive tape of all drug and polymers solid material that was used
and then made electrically conductive by coating, for the preparation of all the microspheres (Patel et al.
in vacuum, with a thin layer of gold for 30 minutes 2006). Yield of microspheres is shown in Table 3.
and then examined by scanning electron microscope
(SEM) operated at 10kV (JOEL-JXA840A electron
probe micro-analyser, Japan) (Jain et al. 2005) (Figure
2(A) and 2(B))
• Flow Properties: Flow properties were determined • Percent Drug Loading: Amethopterin content in the
in terms of Carr’s index (CI) using the following floating microspheres was estimated by a UV-Visible
formulae: Spectrophotometer (Lambda 25, Perkin Elmer,US)
method based on the measurement of absorbance
at 303 nm in distilled water (Semalty et al. 2007).
where, Microspheres equivalent to 100 mg were weighed and
pt = Tapped density and pb = Bulk density added in 100 ml of distilled water. The volumetric flask
The angle of repose [ϴ] of the microsphere, which measures was stirred continuously for 24 hours on a magnetic
the resistance to flow, was determined by fixed funnel stirrer. At the end of 24 h sample was withdrawn,
method, using the following equation: diluted suitably and measured spectrophotometrically
at 303 nm for drug content. Quantitative estimation of

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 Mishra
amethopterin was calculated by using equation obtained formulation residence time in stomach. Particle size was
by Linear regression analysis of calibration curve in determined on the preset time periods (Kalaria et al. 2009).
distilled water. The drug loading in microspheres was The results are recorded in Table 4.
estimated using the formula:
• IR Spectroscopic Studies: Drug-Polymer interaction
Drug Loading (L) = (Qm / Wm) ×100 was studied by FT-IR spectroscopy (Shimadzu Affinity
I, FT-IR spectrophotometer). Samples were prepared by
where, triturating 10 % of the drug or microspheres with 95%
Wm is the weight of microspheres and Qm is the quantity of of KBr in glass pestle-mortar. The IR spectra of the
drug present in Wm of microspheres (Semalty et al. 2008). drug and the microspheres were recorded, the identical
Percent drug loading of various formulations is shown in peaks of the drug and drug with polymers concluded
the Table 3. that neither the polymer nor the method of preparation
has any significant effect on the drug stability (Jain et
• In vitro dissolution studies: In vitro dissolution studies al. 2006; Kaushik et al. 2010).
were performed using USP XXIII, Type-II (paddle)
dissolution apparatus. The accurately weighed sample RESULTS AND DISCUSSION
(50 mg) of formulations from F1 to F6 were dropped
individually into 500 mL of phosphate buffer (pH 7.2) The floating microspheres of amethopterin were prepared by
maintained at a temperature of 37±0.5℃ and stirred at emulsion solvent evaporation method using ethyl cellulose,
a speed of 50 rpm. At different time intervals, 1mL polyvinyl pyrrolidone and polyvinyl alcohol (Saravanan
aliquot of the sample was withdrawn and the volume et al. 2011; Ahmadi et al. 2020; Ramadan et al. 2020;
was replaced with an equivalent amount of buffered Maddibovina et al. 2020).
dissolution medium kept at 37℃. The collected samples
were filtered and diluted with 9mL of phosphate
buffer and analyzed at ƛmax 303nm using a UV- Visible Figure 1: Amethopterin
spectrophotometer (Lambda 25, Perkin Elmer,US)
against the buffer taken as blank. (Figure 3) Percent
cumulative drug release from floating microspheres
was calculated using Beer- Lambert’s Equation. The
drug release was calculated using various models and
shown in Table 3 (Patel et al. 2005).
• Stability of microsphere at different gastric pH:
Floating microspheres are low density systems that
have sufficient buoyancy to float over gastric contents
and remain in stomach for prolonged period where they
are exposed to different pH and different enzymatic Table 1. Composition of floating microspheres
conditions which can influence their physiochemical
properties and drug release behavior and can alter their Ingredient F1 F2 F3 F4 F5 F6
physiochemical properties and drug release behavior Drug 0.1 0.1 0.1 0.1 0.1 0.1
and can alter their stability characteristics. To test this EC 0.5 1.0 1.5 0.5 1.0 1.0
hypothesis, drug loaded microspheres were subjected PVP-K90 - - - 1.0 0.5 1.5
to different pH media where they encountered different PVA 1.0 1.0 1.0 1.0 1.0 1.0
ionic strengths and enzymatic conditions and the
change in their properties was elucidated by counter EC: Ethylcellulose; PVP K-90: Polyvinyl pyrrolidone K-90;
checking their particle size. The pH dependent stability PVA: Polyvinyl alcohol.
studies were carried out in following media:
The prepared floating microspheres were evaluated for
a) pH 1.1: 12 mL HCl (32%) with 1188 mL H2O. different physicochemical tests such as particle size, true
b) pH 3.5: 150 mL solution (10.5g citric acid + 100mL density, flow properties, drug content, in vitro float ability
NaOH of 1M + 395.5 mL H2O) with 100mL HCl. and in vitro drug release studies (Mahor et al. 2020).
c) Simulated Gastric Fluid (SGF): 0.2% NaCl, Pepsin 0.7% Scanning electron microscopy showed that F1, F2, F4, F5,
HCl with pH 1.2. F6 formulation produced spherical microspheres compared
to F3. The scanning electron microscopy confirmed the
10 mL of simulated fluid were added to 10mg of hollow nature of microspheres with pores on the surface of
microspheres. The samples were analyzed after a period floating microspheres, which imparted floating properties
of 12hours in each of the above media. The above time to the prepared floating microspheres.
intervals were selected for the study based on expected

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Table 2. Flow Properties of floating microspheres Figure 2(B): A single microsphere

Formulation Angle of Carr’s Average

code Repose Index Particle
[ϴ] [%] size [µm]

F1 28.35±0.670 18.32±0.364 342.32±3.240

F2 24.64±0.502 15.25±0.342 362.84±2.452
F3 23.54±0.341 12.54±0.322 356.42±0.2465
F4 21.65±0.422 17.53±0.232 260.56±1.8602
F5 24.52±0.438 13.66±0.522 256.02±2.5446
F6 22.61±0.246 12.42±0.426 276.24±2.6773

Results are shown as Mean ± Standard Deviation, (n=3)

To estimate flow properties of prepared floating

Figure 2(A): The cluster of microspheres microspheres, micromeritic properties like particle size
and true density were determined. The densities of floating
microspheres were found to be less then density of gastric
fluid, therefore tended to float over gastric fluid. So, the
prepared microspheres combine the advantages of multiple
unit systems and good floating properties. However, like all
floating systems their efficacy is dependent on the presence
of enough liquid in the stomach, requiring frequent drinking
of water. Particle size analysis of different formulation
was done by optical microscopy. The average particle size
for microspheres was in the range between 256.02µm and
362.84µm. The average particle size of microspheres was
found to be increasing with the increase in concentration
of polymer (Ramadan et al. 2020).

Table 3. Release parameters of floating microspheres

Formulation Drug release % Drug % Buoyancy %Yield

code after 6 h loading

F1 71.81% ±1.28 84.36±0.36 96.28±1.48 78.96±2.64

F2 92.71% ±2.36 58.84±0.82 94.36±1.86 95.38±0.38
F3 80.32% ±1.10 53.92±1.46 90.62±1.54 82.56±1.64
F4 68.22% ±1.46 95.36±2.36 60.26±2.62 70.48±1.74
F5 67.57% ±1.48 42.62±1.68 54.56±2.84 76.32±1.38
F6 58.15% ±1.02 76.38±1.72 68.38±1.36 82.93±1.76

Results are shown as Mean ± Standard Deviation, (n=3).

Drug content in F1, F2, F3, F4, F5 and F6 formulation Significant difference was observed in the release pattern
were estimated by UV spectrophotometric method. Percent of amethopterin floating microspheres EC, PVA and PVP.
loading efficiency were found in the range of 42.62% to It was found that the drug release from the formulations
95.36%. Formulation F4 containing ethyl cellulose (0.5%) were distinguishably different for the different polymers
and polyvinyl pyrrolidone (1%) showed maximum loading used in the formulations. The rank order of drug release
of drug up to 95.36%. The rank order of percent loading after 6 hours was found to be 92.71, 80.32, 71.81, 68.22,
was found to be as followed F4>F1>F6>F2>F3>F5. In vitro 67.57, 58.15 percent of formulation F2, F3, F1, F4, F5, F6
drug release studies of all the formulations were performed respectively. Formulation F2 containing ethyl cellulose
in phosphate buffer of pH 7.2 at 303 nm. (1%) showed the maximum release after 6 hours. Stability

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studies of microspheres at pH 1.1, 3.5 and SGF were The authors received no direct funding for this research.
conducted and found to be stable (Yang et al. 2021). FT-IR Moreover, authors acknowledge with gratitude the
studies showed that there was no interaction between the Department of Pharmacy, GLA University, Mathura, Uttar
drug and polymers. Pradesh for providing the necessary infrastructure and
facilities to conduct this research work.

Figure 3: The in vitro drug release profile Conflict of Interests: Authors declare no conflict of
interests to disclose.

REFERENCES
Abbas, A. K., and Alhamdany, A. T. (2020). Floating
Microspheres of Enalapril Maleate as a Developed
Controlled Release Dosage Form: Investigation of the
Effect of an Ionotropic Gelation Technique. Turkish
Journal of Pharmaceutical Sciences, 17(2), 159.
Ahmadi, P., Jahanban-Esfahlan, A. and Ahmadi, A. (2020).
Development of Ethyl Cellulose-based Formulations:
A Perspective on the Novel Technical Methods. Food
Reviews International, 1-48.
Table 4. Stability Studies of floating microspheres
Birajdar, A. A., Deshmukh, M. T. and Shete, R. V. (2021).
Medium Initial Size Final Size A Review on Gastro-Retentive Floating Microspheres.
Journal of Drug Delivery and Therapeutics, 11(1), 131-
pH1.1 256.02±2.5446 258.12±2.5446 138.
pH3.5 256.02±2.5446 260.42±2.5446 Brunton, L. L., Chabner, B. A. and Knollmann, B. C.
SGF 256.02±2.5446 258.68±2.5446 (2011) In Antineoplastic agents: Goodman and Gilman’s.
The pharmacological basis of therapeutics, Mc Graw Hill.
Results are shown as Mean±Standard Deviation, (n=3). New York Pages 1243-1247.
Bulgarelli, E., Forni, F. and Bernabei, M. T. (2000). Effect
CONCLUSION of Matrix Composition and Process Conditions on Casein-
Gelatin Beads Floating Properties. International Journal
The current Amethopterin formulation research was carried of Pharmaceutics, 198(2), 157-15.
out in an effort to develop a floating drug delivery system Chen, J. and Park, K. (2000). Synthesis of fast-swelling,
composed of a floating multiple-unit system. By emulsion
super porous sucrose hydrogels. Carbohydrate Polymers,
solvent evaporation, novel floating hollow microspheres
41(3), 259-268.
were effectively developed for the sustained and stomach-
specific action of Amethopterin. As a result of its low density, Davoudi, E. T., Noordin, M. I., Kadivar, A., et al. (2013).
this multiparticulate drug delivery method demonstrated Preparation and Characterization of a Gastric Floating
excellent flotation characteristics. From in vitro drug release Dosage Form of Capecitabine. BioMed Research
studies, it can be concluded that, by changing the ratio of International, 2013, 495319.
polymer and solvent, drug release can be controlled. The Garg, R. and Gupta, G. (2008). Progress in controlled gastro
results of all the physiochemical tests of all formulations retentive delivery systems. Journal of Pharmaceutical
were found to be satisfactory. In vitro float ability studies Research, 7(3), 1055-1066.
revealed that most of the microspheres (54.56 % to 96.28 Jain, S. K. and Gupta, A. (2009). Development of glucose
%) were floatable. The in vitro drug release was found to be 43/01 beads of metformin hydrochloride for floating
in range of 58.15 % to 92.71 % at the end of 6 hours. The delivery, AAPS Pharm Sci Tech, 10, 1128-1136.
proposed solution, which combines good buoyant ability
Jain, S. K., Agarwal G. P. and Jain N. K. (2006). Evaluation
with an appropriate drug release pattern, may be beneficial
of porous carries based floating orlistat microspheres for
in terms of improved Amethopterin bioavailability. The
findings of the present study presented that these floating gastric delivery. AAPS PharmSciTech, 7(4), 2006, E54-
microspheres can be selected for the development of gastro E62.
retentive drug delivery system of Amethopterin for potential Jain, S. K., Awasthi, A. M., Jain, N. K., et al. (2005).
therapeutic use. Calcium silicate-based microspheres of repaglinide for
gastro-retentive floating drug delivery: Preparation and
ACKNOWLEDGEMENTS in-vitro characterization. Journal of Controlled Release,
107(2), 300-309.

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS Clear Cell Odontogenic Carcinoma 1542

Mishra
Kalaria, D. R., Sharma, G., Beniwal, V. et al. (2009). and Research, 6(5), 807-817.
Design of biodegradable nanoparticles for oral delivery of Ramadan, A. A., Elbakry, A. M. and Sarhan, H.
doxorubicin: In vivo pharmacokinetics and toxicity studies A. (2020). Silymarin loaded floating polymer (s)
in rats. Pharmaceutical Research, 26(3), 492-501. microspheres: characterization, in-vitro/in-vivo evaluation.
Kale, R. D. and Tayade, P. T. (2007). A multiple unit Pharmaceutical Development and Technology, 25(9),
floating drug delivery system of piroxicam using eudragit 1081-1089.
polymer. International Journal of Pharmaceutical Science, Rathor, S. and Ram, A. (2011). Porous microsphere of
69(1), 120-123. 5-FU. A tool for site specific drug delivery in gastric cancer.
Kaushik, D., Sardana, S. and Mishra D. (2010). In International Journal of Current Pharmaceutical Research,
vitro characterization and cytotoxicity analysis of 5-FU 3(1), 38-42.
loaded chitosan microsphere for targeting colon cancer. Raveendra, M., Narayana, K. L., Reddy, C. S., et al. (2012).
International Journal of Pharmaceutical Education and Formulation and in vitro evaluation of floating microspheres
Research, 44(3), 267-273. of timolol maleate. Journal of Pharmaceutical, Chemical
Kharb, M., and Tanwar, Y. (2021). Development and and Biological Sciences, 3, 936-946.
statistical optimization of gastroretantive floating Saravanan, M., and Anupama, B. (2011). Development
microspheres of pregabalin prepared by W/O/O multiple and evaluation of ethylcellulose floating microspheres
emulsion method. International Journal of Applied loaded with ranitidine hydrochloride by novel solvent
Pharmaceutics, 4(8), 199-206. evaporation-matrix erosion method. Carbohydrate
Kumal, V. B., Thapa, C., Ghimire, P., et al. (2020). polymers, 85(3), 592-598.
Formulation and optimization of Enalapril Maleate-loaded Semalty, A. and Semalty, M. (2007). Preparation and
floating microsphere using Box–Behnken design: In vitro characterisation of mucoadhesive microspheres of
study. Journal of Applied Pharmaceutical Science, 10(08), ciprofloxacin hydrochloride. Indian Drugs, 44, 368-372.
095-104. Semalty, M. and Semalty, A. (2008). Gastro-retentive
Kumar, A., and Bharkatiya, M. (2021). A Recent Update on floating microspheres of diltiazem hydrochloride. Pharma
Formulation and Development of Gastro-Retentive Drug Buzz, 3(12), 24-28.
Delivery Systems. International Journal of Pharmaceutical Shishu, Gupta, N. and Agarwal, N. (2007). Stomach
Sciences and Nanotechnology, 14(1), 5257-5270. specific drug delivery of 5-FU using floating alginate
Maddiboyina, B., Hanumanaik, M. and Nakkala, R. K. beads. AAPS PharmSciTech, 8(2), E143-E149.
(2020). Formulation and evaluation of gastro-retentive Singh, B. N. and Kim, K. H. (2000). Floating drug delivery
floating bilayer tablet for the treatment of hypertension. systems: an approach to oral controlled drug delivery via
Heliyon, 6(11), e05459. gastric retention. Journal of Controlled Release, 63(3),
Mahor, S., Chandra, P., and Prasad, N. (2021). Design 235-259.
and in-vitro Evaluation of Float-adhesive Famotidine Soppimath, K. S., Kulkarni, A. R. and Aminabhavi, T. M.
Microspheres by using Natural Polymers for Gastroretentive (2001). Development of hollow microspheres as floating
Properties. Indian Journal of Pharmaceutical Education controlled-release systems for cardiovascular drugs:
and Research, 55(2), 407-417. Preparation and release characteristics. Drug Development
Mishra, R. and Mishra, A. (2020). An Overview on Floating and Industrial Pharmacy, 27(6), 507-515.
Microsphere. International Journal of Pharmaceutical Srikar, G. (2018). Floating microspheres: A prevailing
Research, 12(04), 377-386. trend in the development of gastroretentive drug delivery
Patel, A., Ray, S. and Thakur, R. S. (2006). In vitro system. Asian Journal of Pharmaceutics, 12(04), 235-
evaluation and optimization of controlled release floating 242.
drug delivery system of metformin hydrochloride. DARU, Thakur, S., Ramya, K., Shah, D. K., et al. (2021). Floating
14(2), 57-64. Drug Delivery System. Journal of Drug Delivery and
Patel, J. K., Patel, R. P. and Patel, M. P. (2005). Formulation Therapeutics, 11(3-S), 125-130.
and evaluation of mucoadhesive glipizide microspheres. Tomar, A., Singh, A., Gupta, A., et al. (2021). Floating
AAPS PharmSciTech, 6(1), EE49-EE55. drug delivery system: A review. International Journal of
Patel, K.., Jain, P. K., Baghel, R., et al. (2011). Preparation Indigenous Herbs and Drugs, 6(1), 33-39.
and in vitro evaluation of a micro balloon delivery system Yang, L., Wang, S., Wang, R., et al. (2021). Floating chitosan-
for domperidone. Pharma Letter. 3, 131-141. alginate microspheres loaded with chlorantraniliprole
Prakash, S., Bhandari, A., Mishra, R., et al. (2015). effectively control Chilo suppressalis (Walker) and
Development and optimization of floating microspheres of Sesamia inferens (Walker) in rice fields. Science of The
gliclazide. International Journal of Pharmaceutical Science Total Environment, 783, 147088.

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