V S Rama Krishna Ganduri et al. / Journal of Pharmacy Research 2016,10(5),

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1 Research Article ISSN: V S Rama Krishna Ganduri et al. / Journal of Pharmacy Research 216,1(5), Available online through Effect of Pullulan concentration in fast dissolving films formulation and exploration of film properties V S Rama Krishna Ganduri 1,2,*, N Meher Reethika 1, M Jayasai 1, V Sirisha 1, S Vasudha 1, Sudhakar Poda 2 1 Department of Biotechnology, K. L. University, Green Fields, Vaddeswaram , Guntur (Dist), A.P., India. 2 Department of Biotechnology, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur , A.P., India. *Corresponding author. G. V. S. Rama Krishna, Assistant Professor, Department of Biotechnology, K. L. University, Green Fields, Vaddeswaram, Guntur , A.P., India. Received on: ; Revised on: ; Accepted on: ABSTRACT Background: Dissolvable oral thin films made from biopolymers gain much attention by Pharmaceutical industries due to their fast dissolution capabilities. Objective: To cast the pullulan based film with plasticizer and silver nitrate and to explore the film properties for appearance, thickness, and disintegration and dissolution times for various films. Materials and methods: Aqueous solutions of pullulan (1-5%), 1-5 % of poly ethylene glycol (4, 6 varieties) and 1-1 mm silver nitrate were formulated into films by solvent casting method. Thickness was measured by screw gauge and disintegration and dissolution times were physically observed and reported. Results: Formulated films were clear transparent, translucent and opaque in color. Least values of disintegration (15 sec) and dissolution (37 sec) times were observed and increase in the concentration of polymer and plasticizers increased the disintegration and dissolution times. Conclusion: The prepared pullulan based films can be used as fast dissolving films for systemic delivery of active pharmaceutical ingredients (APIs). KEYWORDS: Fast dissolving films, pullulan, plasticizers, dissolution, disintegration. INTRODUCTION New trends in new drug delivery systems demand efficacy, safety and patient acceptability of dosage forms. For pediatric and geriatric people, dysphasic and schizophrenic patients the modern oral drug dosage form is by orally fast disintegrating and dissolving films. These films get hydrates by soaking saliva, when placed on tongue, very fast. Generally, hydrophilic polymers with plasticizers used for preparing films that allow them to quickly release incorporated Active Pharmaceutical Ingredient (API), just in seconds. Scientific literature reports that these fast dissolving films were generally made from film formers, plasticizers, saliva stimulating and sweetening agents, and APIs. Most of these, fast dissolving oral films formulations were prepared using incorporated drugs for diseases like cough, cold remedies, and sore throat, allergy, nausea, pain and nervous system disorders. Water soluble, fast disintegrating and good film forming polymers like hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyethylene oxide (PEO), polyvinyl pyrolidine (PVP), pullulan, etc are used make these films 1,2. Of all these, owing to excellent film formation, mouth feel, edible, water soluble and better mechanical properties, pullulan is being extensively used in rapid films making. Pullulan, an exo-, homo-, neutral polysaccharide produced using black, yeast-like fungus called Aureobasidium pullulans from sucrose, and starch as carbon substrates. It is a colorless, odorless, tasteless, white powder that has increased solubility, flexibility, strength, stability over a wide range of temperature. The recent developments show pullulan based rapid films incorporated with wide range of drugs, granisetron-, Tramadol-, Ropinirole-, cetirizine-, Ondansetron- hydrochlorides for their formulation and evaluation 3. These oral films are most acceptable and accurate dosage form that could bypass the hepatic system and show more therapeutic response 4. The type of plasticizer and its concentration plays a major role in the total dry weight of film and that would help the flexibility and reduces the brittleness of formed film strip. In the present study, Pullulan polymer is mixed with different plasticizers such as poly ethylene glycol (PEG) - 4, -6 and silver nitrate in various concentrations to study the film properties like dissolution and disintegration time. MATERIALS AND METHODS Materials Biopolymer, Pullulan (Kopulan) was purchased from M/s. Kumar

2 V S Rama Krishna Ganduri et al. / Journal of Pharmacy Research 216,1(5), Organic Products Ltd., Bengaluru, India. Plasticizers used in this study, Poly Ethylene Glycol (PEG) 4, 6 were obtained from SD Fine Chem. Ltd., Mumbai, India. Silver Nitrate (MW: g/mol) was procured from M/s. Merck Specialties Pvt. Ltd., Mumbai, India. All ingredients used were of analytical grade. Aqueous solutions of pullulan formulations were prepared using ultra-filtered high pure deionized water. METHODS Film formation Placebo films were made using 1 to 5 % of aqueous pullulan, 5% (fixed) concentration of pullulan with 1.5%, 2%, 2.5%, 3%, 3.5% and 4% (varying) concentrations of PEG-4, PEG-6 solutions, and 1 to 1 mm silver nitrate solutions. Increasing concentrations of pullulan polymer solutions with various plasticizers were prepared using solvent-casting method on magnetic stirrer with hot plate at a temperature of 6 C and 1 rpm, to make the films. All the preparations were prepared in beakers and stirred continuously for 15 minutes. These solutions were casted on glass petri dishes in duplicate in equal amounts (1 ml). Petri dishes were kept in hot air oven at 8 C to completely dry the films. After drying, rectangular sizes (2 X 3 cm) of strips were cut. Film properties estimation Freshly cut film strips were measured for their thickness using micrometer screw gauge at 3 different strategic locations. In-vitro disintegration time and In-vitro dissolution time were visually observed and noted the time taken. Each strip was placed in a glass dish containing 25 ml of distilled water to determine its disintegration and dissolution times. Time take by the film strip to start break or disintegrate is called as disintegration time, whereas time taken by the strip to completely get dissolved is called dissolution time. Pictures of film strip during disintegration and dissolution time were also captured. Appearances of films were also evaluated by visual observation such as transparent or translucent or opaque. All the studies were done in triplicate for each batch and average values were reported. RESULTS AND DISCUSSION Figures 1 (a), (b) and (c) shows the appearance of films (dried) made from pullulan, pullulan + PEG and pullulan + silver nitrate solutions. Very clear, shiny and transparent films were resulted from pullulan solutions. Films prepared with PEG-4 or -6 appeared in translucent i.e. white in color, manner and this was due to reacting nature of PEG with pullulan that formed white precipitate. Silver nitrate mixed pullulan solutions yielded opaque films and are light brown in color. Figure 1. Photographs of fast dissolving films made from (a) pullulan polymer (b) pullulan + PEG solution (c) pullulan + silver nitrate solution Evaluation parameters of formulated films were shown in Tables 1, 2, 3 and 4. Disintegration and dissolution times (in bar diagrams) of all

3 V S Rama Krishna Ganduri et al. / Journal of Pharmacy Research 216,1(5), the formulated films were shown in figures 2, 3, 4, and 5. The pullulan based film formulations has shown excellent film formation capacity, lowest disintegration time (15 sec) and dissolution time (37 sec) and these were quite comparable of results obtained in another studies The films prepared using pullulan in combination with plasticizers (PEG-4, -6) have taken disintegration and dissolution times in the orders of 1-3 minutes. Disintegration times of film formulated using silver nitrate are comparatively less than poly ethylene glycol made films. Figure 6 compares the process of disintegration and dissolution of regular film size (2 cm X 3 cm) placed in petri plate containing double distilled water. Table 1. Properties of films made using pullulan solutions Pullulan Thickness In-vitro In-vitro concentration 2cm x 3 cm Disintegration Dissolution size, mm time, sec time, sec 1% % % % % Table 2. Properties of films made using pullulan + PEG-4 solutions Pullulan +PEG-4 Thickness In-vitro In-vitro (Plasticizer) 2cm X3 cm Disintegration Dissolution concentration, w/v size, mm time, sec time, sec 5% + 1.5% % + 2% % + 2.5% % + 3% % + 3.5% % + 4% % + 4.5% % + 5% Table 3. Properties of films made using pullulan + PEG-6 solutions Pullulan +PEG-6 Thickness In-vitro In-vitro (Plasticizer) 2cm X3 cm Disintegration Dissolution concentration, w/v size, mm time, sec time, sec 5% + 1.5% % + 2% % + 2.5% % + 3% % + 3.5% % + 4% Table 4. Properties of films made using pullulan + silver nitrate solutions Pullulan + Thickness In-vitro In-vitro silver nitrate 2cm X3 cm Disintegration Dissolution concentration, size, mm time, sec time, sec w/v + mm 5% % % % % % % % % % Time (sec) Figure 2. Graphical representation (in bars) of in-vitro disintegration and dissolution for pullulan films % 2% 3% 4% 5% Pullulan concentration (% w/v) 5% + 1.5% 5% + 2% 5% + 2.5% 5% + 3% 5% + 3.5% 5% + 4% 5% + 4.5% 5% + 5% Pullulan + PEG 4 concentration, % w/v Figure 3. Graphical representation (in bars) of in-vitro disintegration and dissolution for pullulan + PEG-4 films.

4 V S Rama Krishna Ganduri et al. / Journal of Pharmacy Research 216,1(5), % + 1.5% 5% + 2% 5% + 2.5% 5% + 3% 5% + 3.5% 5% + 4% 5% + 1 5% + 2 5% + 3 5% + 4 5% + 5 5% + 6 5% + 7 5% + 8 5% + 9 5% + 1 Pullulan + PEG 6 concentration, % w/v Pullulan + Silver Nitrate concentration, % w/v + mm Figure 4. Graphical representation (in bars) of in-vitro disintegration and dissolution for pullulan + PEG- 6 films. Figure 5. Graphical representation (in bars) of in-vitro disintegration and dissolution for pullulan + silver nitrate films. Figure 6. Photographs showing disintegration and dissolution (in distilled water) of films made from (a) pullulan polymer (b) pullulan + PEG (c) pullulan + silver nitrate.

5 V S Rama Krishna Ganduri et al. / Journal of Pharmacy Research 216,1(5), CONCLUSION The results obtained in the present study shows that the pullulan could be used as fast dissolving film forming polymer. Pullulan in combination with plasticizers (PEG- 4, -6) and silver nitrate were formulated and concentrations of PEG and silver nitrate were critical for film casting. The film properties like appearance, thickness, dissolution and disintegration times, pattern of disintegration and dissolution were shown. Increasing pullulan concentrations resulted in formation of thick films. Less concentration of polymer with plasticizer/ silver nitrate had taken least disintegration and dissolution time and hence these films may be used as fast dissolving oral films as novel drug delivery methods. ACKNOWLEDGEMENTS All the authors express their deep thanks to the management of K L University, Green Fields, Vaddeswaram, Guntur-District, Andhra Pradesh, India, for their kind support and encouragement. CONFLICT OF INTEREST All the authors declare no conflict of interests. REFERENCES 1. Vondrak B, Barnhart S, Dissolvable films for flexible product format in drug delivery, Pharma Technol., Suppl, 28, S Corniello C M, Quick-Dissolving Strips: From Concept to Commercialization, Drug Delivery Technology, 26, 6(2), Preis M, Pein M, Breitkreutz J, Development of a tastemasked orodispersible film containing dimenhydrinate, Pharmaceutics, 212, 4, Balaji A, Kranthi Kumar P, Achuth Reddy V, Fast dissolving oral films for immediate drug release: a review, World journal of Pharmaceutical research, 214, 3(2), Dhagla R C, Vishnu A P, Usmangani K C, Harsha V P, Alisgar J K, Exploration of film forming properties of film formers used in the formulation of rapid dissolving films, Intl. J. of chem. Tech., 211, 3(2), Dhagla R C, Vishnu A P, Usmangani K C, Harsha V P, Alisgar J K, Natural polysaccharides as film former: A feasibility study for development of rapid dissolving films of Ondansetron hydrochloride, Intl. J. of Pharm. Pharmaceutical Sci., 212, 4(3), Seema S, Samta, Rana A C, Sumit G, Optimization of formulation of fast dissolving films made of pullulan polymer, Intl. J. of Pharm. Sci. Rev. Research, 211, 9(1), Mital S P, Hiren P, Aarti B, Vadalia K R, Formulation and evaluation of mouth dissolving film of Ropinirol Hydrochloride by using pullulan polymers, Intl. J. of Pharm. Res.& Allied Sci., 212, 1(3), Frey, Film Strips and Pharmaceuticals, Pharma Mfg & Packag Sourcer, 26, Leduy A., Zajic J.E., Luong J.H.T., Pullulan In: Encyclopedia of Polymer Science and Engineering, 2nd Edition, Edited by H.F. Mark et al., Wiley & Sons, NewYork, 1988, Arya Arun, Chandra Amrish, Sharma Vijay, Pathak Kamla, Fast Dissolving Oral Films: An Innovative Drug Delivery System and Dosage Form, Int. J. Chem. Tech Res., 2(1), 21, Source of support: Nil, Conflict of interest: None