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1 Available online at Scholars Research Library Der Pharmacia Lettre, 2011, 3(1): ( ISSN USA CODEN: DPLEB4 Design and Development of Sublingual Fast Dissolving Films for an Antiasthmatic Drug N.L Prasanthi *, C. Sowmya Krishna, M. Eswar Gupta, S.S. Manikiran and N. Rama Rao Department of Pharmaceutics, Chalapathi Institute of Pharmaceutical Sciences, Lam, Guntur , Andhra Pradesh ABSTRACT The present study was aimed to develop a novel fast dissolving drug delivery system for an antiasthamtic drug such as Salbutamol suphate. The fast dissolving films were prepared by solvent evaporation technique using different water-soluble polymers (hydroxy propyl methylcellulose, hydroxy propyl cellulose and Sodium Alginate) taken through sublingual route. In this study Tween 80 is used as a solubilizing agent and Aspartame is used as a sweetener. Concentration of water soluble polymers, Tween 80 and Aspartame were optimized during preliminary studies. The prepared films were evaluated for thickness, uniformity in drug content, folding endurance, disintegration time, swelling index, moisture loss, in-vitro drug release studies and drug-polymer compatibility studies. The results obtained showed no physicalchemical incompatibility between the drug and the polymers. The prepared films were clear, transparent and smooth surface. Film containing hydroxy propyl methylcellulose (2%w/w), Tween 80 (0.5%w/w) and Aspartame (0.5% w/w) showed optimum performance against all other prepared formulations. Keywords: Fast dissolving films, sublingual route, water soluble polymers, aspartame. INTRODUCTION Many pharmaceutical dosages are administered in the form of pills, granules, powders, and liquids. The pills, which include tablets and capsules, are able to retain their shapes under moderate pressure. However, some patients, particularly pediatric and geriatric patients, have difficulty swallowing or chewing solid dosage forms due to fear of choking. Hence orally dissolving tablets have come into existence. Even with these differences, most of the existing 382

2 oral dissolving drug delivery systems are in the form of solid tablets and designed to dissolve/disintegrate in the patient's mouth without the need to drink or chew. However, the fear of taking solid tablets and the risk of choking for certain patient populations still exist despite their short disintegration/dissolution times. Hence oral film drug delivery is a better alternative in such cases [1, 2]. The delivery system consists of a very thin oral strip, which is simply placed on the patient s tongue or any oral mucosal tissue, instantly wet by saliva the film rapidly hydrates and adheres onto the site of application. It then rapidly disintegrates and dissolves to release the medication for oromucosal absorption or with formula modifications, will maintain the quick-dissolving aspects allow for gastrointestinal absorption to be achieved when swallowed [3, 4]. Salbutamol sulphate, (RS)-l-{4-hydroxy-3-hydroxymethyl phenyl)-2-(tert-butylamino) ethanol sulphate, a p-receptor agonist, is most widely used as a sympathomimetic for the treatment of acute as well as chronic asthma. Generally, it is given through the inhalation route but is also effective after oral administration [5]. But it undergoes first pass metabolism. Hence in the present study an attempt was made to prepare the sublingual fast-dissolving film of Salbutamol sulphate. The aim of the present investigation is to design and develop fast dissolving film of Salbutamol suphate by using different water soluble polymers, to evaluate the films and to study the various formulation variables that affect the drug release. MATERIALS AND METHODS Materials Salbutamol sulphate was obtained as gift sample from Microlabs, Bangalore, India. The HPC and HPMC K100 were purchased from S.D. Fine chemicals Ltd., Mumbai, India. Sodium Alginate was purchased from Loba Chemie, Pvt. Ltd., Mumbai, India. Tween 80 and Aspartame were received from Yarrow chemical products, Mumbai, India. All other materials used were of analytical grade. Methods Preparation of blank patches: Polymers were accurately weighed and dissolved in respective solvent and then casted in a plastic petridish. The films were allowed to dry in a hot air oven at controlled temperature at 50 o c for 24 hour. Formulation of salbutamol fast dissolving films [6, 7]: Salbutamol sulphate fast dissolving films were prepared by solvent-casting method as per the formula given in Table 1. The water soluble polymers were soaked in water for 4 h to obtain a uniform dispersion. Salbutamol sulphate, Tween 80 and aspartame were dissolved in the polymeric dispersion and stirred to get a homogenous dispersion. Then the Solution was poured on the plastic petridish having surface area of 56.71cm 2 and dried at 50 o C for 24 hours in hot air oven. The films were carefully removed from Petri plates and cut into strips of dimensions 1 1 cm 2, stored in an air tight glass bottle. Drug incorporated for each 1x1 cm 2 patch was 2.14 mg. 383

3 Table.1: Formula of salbutamol sulphate fast dissolving films Formula Ingredients (mg) code Salbutamol sulphate HPC HPMC K100 Sodium alginate Tween 80 Aspartame Water (ml) A A A A A A A A A A B B B B B B B B B B C C C C C C C C C C Evaluation of prepared films: Thickness: The thickness of the polymer films was measured by using screw gauge. The thickness of each strip at six different areas was determined and standard deviation was calculated. [8] Moisture loss studies [9]: The percent moisture loss studies were carried out to check the physical stability and integrity of the films. In the present study the moisture loss capacity of the films was determined by placing the known weight and predetermined size (1x1) of films in dessicator containing anhydrous calcium chloride (inside the dessicator) for three days. The films were removed and reweighed, and the percentage moisture loss of the films was measured by using the formula. 384

4 Initial weight Final weight Percent moisture loss = X 100 Initial weight Folding Endurance: The folding endurance was measured manually for the prepared films. A strip of film was repeatedly folded at the same place till it broke [10]. The number of times the film could be folded at the same place without breaking gave the value of folding endurance. The folding endurance of prepared films was measured in triplicate. In vitro disintegration time: In vitro disintegration time is determined visually in a glass dish of 25ml distilled water with swirling every 10 sec. The disintegration time is the time when the film starts to break or disintegrates. The disintegration time of prepared films was measured in triplicate [11]. Uniformity of drug content: The film of area 1x1 cm 2 was cut and dissolved in 6.8 phosphate buffer solution and made up to 100 ml in a volumetric flask. Then 1 ml was withdrawn from the solution and diluted to 10mL. The absorbance of the solution was taken at 276 nm and concentration was calculated. By correcting dilution factor, the drug content was calculated. The test was performed in triplicate [12]. In-vitro dissolution studies: Dissolution study was carried out in USP paddle type apparatus using 300 ml of stimulated salivary fluid (ph 6.8) as a dissolution medium at 50 rpm. Temperature of the dissolution medium was maintained at 37±0.5ºC. Samples of 5ml were withdrawn at every 4 minute interval, filtered (through 0.45µ) and replaced with 5ml of fresh dissolution medium. The samples were suitably diluted and estimated spectrophotometrically at 276 nm by using ELICO-164 double beam UV-Visible spectrophotometer. The dissolution experiments were conducted in triplicate. Dissolution rate was studied for all designed formulations and dissolution parameters were calculated. Drug release kinetics: To analyze the mechanism of drug release, the release data were fitted to the following kinetic models. Zero order kinetics: Q t = Q 0 + k 0 t Where Q 0 is the initial amount of drug in the pharmaceutical dosage form, Q t is the amount of drug in the pharmaceutical dosage form at time t and k 0 is a zero order rate constant. First order kinetics Q t = Q 0 e -k 1 t or lnq t = lnq 0 + k 1 t Where Q t is the amount of drug released in time t, Q 0 is the initial amount of drug in the solution and k 1 is the first order release constant. Khan suggested dissolution efficiency (DE) as a suitable parameter for the evaluation of in vitro dissolution data [13]. Dissolution efficiency is defined as the area under dissolution curve up to a certain time t expressed as percentage of the area of the rectangle described by 100% dissolution in the same time. 385

5 Drug-Excipients Interaction studies Interaction of Salbutamol sulphate with the respective polymers that is HPC, HPMC and Sodium Alginate; and individual excipients formulation was established by Infrared Absorption Spectral Analysis (FTIR). Any changes in the chemical composition after combining with the excipients were investigated with IR spectral analysis. Infra red spectra were obtained by using Shimadzu FTIR-281 spectrophotometer. RESULTS AND DISCUSSION Drug-excipients interaction studies were performed for salbutamol sulphate with polymers prior to the preparation of films. The characteristic peaks of Salbutamol sulphate were observed at cm -1 indicating the presence of C-O stretching vibrations of primary alcohol, C-O vibrations of phenol at cm -1, C-H stretching vibrations of tertiary carbon at cm -1 and C-H stretching vibrations at cm -1. In the FT-IR spectrum of sodium alginate powder various peaks of alginate are evident of hydroxyl group appeared at cm -1, carbonyl at cm -1 and carboxyl and carboxylate groups appeared between 1000 to 1400cm -1. The principle peaks of HPMC and HPC were observed to be at cm -1, cm -1 and cm -1 corresponds to Hydroxyl, C-H stretching and C-O stretching vibrations respectively. The physical mixtures of Salbutamol sulphate with polymers were analyzed and compared to that of individual spectra thus indicating compatibility between drug and excipients. The thickness of the films varied from 0.08 to 0.18 mm. The values indicating that as the concentration of polymer increases thickness was gradually increased. The moisture loss of all the prepared films was measured. Out of all the films, the formulation B7 of HPMC films showed lowest percent moisture loss. This might be because of the high water permeability of HPMC polymer. The film having more amount of sodium alginate scored lower folding endurance than the higher ones. Formulation A3 containing 2% HPC had scored highest folding endurance. The values indicating that as the concentration of polymer increases the folding endurance capacity increases. Disintegration test was performed for all the batches and all the batches found to disintegrating within 25 seconds. Films prepared with HPMC had shown fast disintegration compared to other polymers because it is having high solubility in ph 6.8 than HPC and sodium alginate. Formulation containing high concentration of polymers had comparatively high disintegration time. The drug content was in the range of to 99.8%. All the batches were found satisfactory. The parameters for physical evaluation data of the prepared films was given in the Table

6 Table 2: Physical characteristics of salbutamol sulphate fast dissolving films Formulation Thickness ± S.D (mm) Folding endurance Disintegration time ± S.D (min) Moisture loss (%) ± S.D Drug Content (%) A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± B ± ± ± B ± ± ± B ± ± ± B ± ± ± B ± ± ± B ± ± ± B ± ± ± B ± ± ± B ± ± ± B ± ± ± C ± ± ± C ± ± ± C ± ± ± C ± ± ± C ± ± ± C ± ± ± C ± ± ± C ± ± ± C ± ± ± C ± ± ± In vitro dissolution study of all films was carried out in simulated saliva (ph 6.8) as a dissolution medium. The results obtained in the in vitro drug release study of salbutamol sulphate films containing HPC were tabulated in Table

7 Table 3: Drug release profile of salbutamol sulphate films containing HPC Time Percent of Salbutamol sulphate released (min) A1 A2 A3 A4 A5 A6 A7 A8 A9 A Fig. (1) depicts the effect of concentrations of HPC on the drug release of Salbutamol sulphate from the prepared films (A1-A3). As the HPC concentration increases the release of Salbutamol sulphate from the films is decreased. Fig. 1: Comparative release profile of salbutamol sulphate films containing HPC Fig. (2) depicts the effect of concentrations of Tween 80 on the drug release of Salbutamol sulphate from the prepared films (A4-A6). As the Tween 80 concentration increases the release of Salbutamol sulphate was also increased. Fig. (3) depicts the concentrations of aspartame on the drug release of salbutamol sulphate from the prepared films (A7-A9). 388

8 Fig. 2: Comparative release profile of salbutamol sulphate from HPC films containing Tween 80 Fig. 3: Comparative release profile of salbutamol sulphate from HPC films containing aspartame The results obtained in the in vitro drug release study of Salbutamol sulphate films containing HPMC were tabulated in Table 4. Fig. (4) depicts the effect of HPMC concentrations on the drug release of Salbutamol sulphate from the prepared films (B1-B3). Table 4: Drug release profile of salbutamol sulphate films containing HPMC Time Percent Salbutamol sulphate released (min) B1 B2 B3 B4 B5 B6 B7 B8 B9 B

9 Fig. 4: Comparative release profile of salbutamol sulphate films containing HPMC Fig. (5) depicts the effect of Tween 80 concentrations on the drug release of Salbutamol sulphate from the prepared films (B4-B6). Fig. 5: Comparative release profile of salbutamol sulphate from HPMC films containing Tween 80 Fig. (6) depicts the concentrations of aspartame on the drug release of Salbutamol sulphate from the prepared films (B7-B9). The films prepared with HPMC had shown fast release of Salbutamol sulphate i.e. 92.4% in 4 minutes when compared to films formulated by using HPC and Sodium alginate. 390

10 Fig. 6: Comparative release profile of salbutamol sulphate from HPMC films containing aspartame The results obtained in the in vitro drug release study of Salbutamol sulphate films containing Sodium Alginate were tabulated in Table 5. Fig. (7) depicts the effect of Sodium Alginate concentrations on drug release of Salbutamol sulphate from the prepared films (C1-C3). Table 5: Drug release profile of salbutamol sulphate films containing Sodium Alginate Time Percent Salbutamol sulphate released (min) C1 C2 C3 C4 C5 C6 C7 C8 C9 C Fig. 7: Comparative release profile of salbutamol sulphate films containing Sodium Alginate 391

11 Fig. (8) depicts the effect of Tween 80 concentrations on the drug release of Salbutamol sulphate from the prepared films (C4-C6). Fig. 8: Comparative release profile of salbutamol sulphate from Sodium Alginate films containing Tween 80 Fig. (9) depicts the aspartame concentrations on the drug release of Salbutamol sulphate from the prepared film (C7-C9). Fig. 9: Comparative release profile of salbutamol sulphate from Sodium Alginate films containing aspartame The dissolution parameters of the prepared films were given in Table 6. The data indicating that the release of Salbutamol sulphate from the films following first order release kinetics. The time required to release 50% of Salbutamol sulphate from the films was found to be less in case of B10. Based on results of physical evaluation data, disintegration time and drug release data B10 is considered as a best formulation. The optimized formulations of A10, B10 and C10 was compared with marketed tablet (Asthalin- SA, Cipla) and the dissolution profiles of all formulations are shown in Table 7 and Fig. (10).The drug release property of A10, B10, C10 and Asthalin-2 at 4 minutes was 87.5%, 92.8%,81.4% and 34.4%, respectively, indicating good fast releasing property of the optimized formulations. 392

12 Table 6: Dissolution parameters of salbutamol sulphate Fast Dissolving Films T 50 Zero order First order K 1 DE 10 Formulation (min) r r (min -1 ) (%) A A A A A A A A A A B B B B B B B B B B C C C C C C C C C C Table 7: Comparative dissolution profiles of optimized films of Salbutamol sulphate with marketed conventional tablet Time Percent of Salbutamol sulphate released (min) A10 B10 C10 Asthalin-SA

13 Fig. 10: Comparative dissolution profiles of salbutamol sulphate from the optimized films and marketed formulation CONCLUSION The fast dissolving films could be formulated with the easily available components such as HPMC, HPC and Sodium Alginate. Salbutamol sulphate, a highly water soluble and bitter drug could be successfully incorporated in the fast dissolving films with the help of solubilizers such as Tween 80 and the bitter taste of the drug could successfully be masked by the use of Aspartame in the films. Optimized formulation passed all evaluation tests and scores better convenience than the marketed tablets of salbutamol sulphate. In vitro evaluation of the films confirmed their potential as an innovative dosage form to improve delivery of Salbutamol sulphate. Acknowledgements The authors are thankful to Chalapathi Educational Society, Guntur for providing the necessary facilities. REFERENCES [1] Subash Vijaya Kumar, Basani Gavaskar, Guru Sharani, Y.Madhusudan Rao. International Journal of Pharmacy and Pharmaceutical Sciences. May 2010;3(2): [2] Crama A, Breitkreutzb J, Desset Brèthesc S, Nunnd T and Tuleuf C, Int J Pharm. 2009; 365: 1 3. [3] S.Malke, S.Shidhaye, J.Desai & V.Kadam. The Internet Journal of Pediatrics and Neonatology. 2010; 11 (2). [4] Arun Arya, Amrish Chandra, Vijay Sharma, Kamla Pathak. International Journal of ChemTech Research. Jan-Mar 2010; 2 (1):

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