International Journal of Innovative Pharmaceutical Sciences and Research

Transcription

1 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 International Journal of Innovative Pharmaceutical Sciences and Research FORMULATION AND VALUATION OF ORAL THIN FILMS CONTATING SAXAGLIPTIN D.Archana Jyothi *, Ch.S.Vijaya Vani, 3 Dr.V.Uma Maheshwar Rao Department of Pharmaceutics, CMR College of Pharmacy, Kandlakoya, Medchal Road, Hyderabad-5INDIA Abstract The purpose of the present investigation was to formulate and develop RDF of Saxagliptin for oral use and deliver maximum amount of the drug in shortest duration of time with most comfort to the patient. Saxagliptin is an oral antidiabetic drug belongs to the class of gliptins and is a dipeptidyl peptidase enzyme inhibitor. Various grades of HPMC(3 LV,5 LV,5 LV) as film forming polymers, PG as plasticer, different flavours (lemon flavor,passion fruit flavour) Aspartame as sweetening agent, Citric acid as saliva stimulating agent were used in the formulation of rapidly dissolving films. FTIR Studies show no incompatability among drug and excipients.5 different formulations were prepared by using solvent casting method. The prepared formulations were evaluated for taste, in-vitro disintergration and dissolution. Other parameters measured for evaluation of RDF include mechanical properites % elongation and elastic modulus study. The optimized batch 9 contanting HPMC (3 LV), PG, Aspartame had acceptable characteristics in-vitro disintergration time is 5 sec and in-vitro dissolution drug realese in min is 98% and taste masking properties. SM study was also carried out to study the surface morphology. Keywords: Saxagliptin, HPMC, Flavours, PG. Corresponding Author D.Archana Jyothi Department of Pharmaceutics CMR College of Pharmacy, Kandlakoya, Medchal Road, Hyderabad-5, INDIA mail: archanaatv@gmail.com Mobile: Available online: November Issue 669

2 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 INTRODUCTION Rapidly dissolving dosage forms (RDDF) have recently acquired great importance due to their properties such as quick disintegration and dissolution, obviating need of water for disintegration and especially suitable for pediatric and geriatric patients. Orally disintegrating tablets (also called quick disintegrating tablets, mouth dissolve tablets) are the most common and widely used rapidly dissolving dosage form []. Fast-dissolving drug delivery was pioneered by scientists at Wyeth Laboratories in the UK during the late 97s, which resulted in patenting of the Zydis drug delivery system. Fast-dissolving drug delivery systems can be manufactured by a variety of technologies, including direct compression, wet granulation, freeze drying, spray drying, vacuum drying and use of super disintegrants [] Rapidly dissolving films (RDF) Oral film strips have hit the mainstream in the last few years as a new way of freshening the breath. The wafers are slipped into the mouth and dissolve quickly to release the mint flavour (Pfister W,Ghosh T 5).[,3]. The product attributes that a patient today seeks in a dosage form are- Better portability ase and accuracy of dosing Overall convenience These films generally dissolve within seconds to release the active agents but can be modified to release the drug more slowly depending upon film thickness and selection of the polymer matrix. A film or strip can be defined as a dosage form that employs a water dissolving polymer which allows the dosage form to quickly hydrate, adhere and dissolve when placed on the tongue or in the oral cavity to provide rapid local or systemic drug delivery. Drug release may be either quick or slow by varying the rate of dissolution of the films. The breath freshening strip was created by Pfizer s Warner-Lambert s consumer healthcare division, which launched Listerine PocketPaks in. Chloraseptic relief strips were the first oral thin film product to incorporate a drug and were introduced in the United States in September, 3 by Prestige Brands international for relief of sore throat. Zengen Inc developed this new delivery technology, which is a medicated oral strip structured as a proprietary bilayer system. These films typically contain water soluble hydrocolloids such as HPMC, pullulan, pectin, carboxymethylcellulose, an effective dose of active agent, other additives such as flavoring agents, plasticizers and preservatives. The Available online: November Issue 67

3 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 disintegration and dissolution characteristic of thin film is dependent on thickness and combination of hydrocolloids. RDF are already being used in breath freshening product introductions from Warner Lambert and Wrigley's in the USA and urope, and Boots in the UK, as well as vitamin products. Consumers have now been exposed to this concept through the introduction of multiple breath-freshening products introduced over the past years, and the trend is now towards developing over the counter (OTC) and prescription products in this delivery form. The delivery system is simply placed on a 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 oramucosal absorption or, with formula modifications, will maintain the quick-dissolving aspect but allow for gastrointestinal absorption to be achieved when swallowed (Vollmer U,6, Corniello CM,6). [-] The benefits of film over conventional delivery systems are numerous: Faster absorption into the bloodstream; More portable than syrups and tablets; asy to administer; More cost-effective than conventional tablet solutions. The key advantage for rapidly dissolving film is patient compliance and convenience. The main drawback is with drug loading. Drug loading is generally limited to roughly mg. This problem can be addressed by increasing the thickness of the strip, but that in turn may change the dosage form to slowly dissolving film. But drug companies have been interested in this technology as it provides fast, accurate dosing that is expected to increase compliance, particularly among children. There is no need for water or measuring, and upon melting, the dose of medicine is swallowed. The likely candidates for rapidly dissolving films or oral thin films are nicotine replacing its transdermal delivery, antiulcer drug and antihistamine products. Prescription products, antipsychotic and sleeping disorder drugs are the potential candidates [-]. The Aim of the Present study was to formulate and develop RDF of Saxagliptin for oral use and deliver maximum amount of the drug in shortest duration of time with most comfort to the patient. Saxagliptin is an oral antidiabetic drug belongs to the class of gliptins and is a dipeptidyl peptidase enzyme inhibitor. The RDF of Saxagliptin using various grades of HPMC LV were prepared by solvent casting method Available online: November Issue 67

4 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 MATRIALS AND MTHOD Materials used Saxagliptin, HPMC 3 LV,HPMC 5 LV, HPMC 5 LV, Sucralose, Citric acid anhydrous, Menthol, Polyethylene glycol, Aspartame, Passion fruit and lemon flavours Methodology Analytical Methods Standard Graph of Saxagliptin Preparation of calibration curve of Saxagliptin Standard plot of Saxagliptin was prepared using ph phosphate buffer. mg of Saxagliptin was weighed and transferred into volumetric flask. To this add small quantity of p H 6.8 phosphate buffer to dissolve the drug and then the solution was made up to ml using p H phosphate buffer. This is stock solution (A). From stock solution (A), ml was transferred into ml volumetric flask and made up to the mark. This is stock solution (B). From stock solution (B), appropriate dilutions,, 6, 8, were made and absorbance was measured by using UV- Spectrophotometer at 8 nm. Preformulation studies: Preformulation testing is the first step in the rational development of dosage forms of a drug substance. It can be defined as investigation of physical and chemical properties of the drug substance alone and when combined with excipients. These studies should focus on those physicochemical properties of the new compound that could affect drug performance and development of an efficacious dosage form.(solubility Analysis and Melting Point) Drug-xcipient Compatibility Studies FTIR interaction studies Drug-excipient compatibility study was performed by Fourier transform infrared (FTIR) Spectroscopy. In the preparation of formulation, the drug and polymers were in close contact with each other, which could leads to instability of drug. Thus preformulation studies regarding drug-polymer interaction is very important in selecting appropriate polymers. Method of preparation of rapidly dissolving films and its evaluation Preparation of rapidly dissolving films (RDF) The RDF of Saxagliptin using various grades of HPMC LV were prepared by solvent casting method. An aqueous solution of the polymer HPMC LV was prepared in distilled water. Available online: November Issue 67

5 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 Available online: November Issue 673 Saxagliptin was added to the aqueous polymeric solution. This was followed by addition of menthol which was previously dissolved in ethyl alcohol (95%) and plasticizers like PG or glycerol. Sweeteners like aspartame and sucralose were also added to the above solution. Citric acid and flavour were also mixed with it. The solution was casted on a glass petridish (diameter 9 cm) and dried at room temperature for hr. The film was carefully removed from the petridish, checked for any imperfections and cut into the required size to deliver the equivalent dose ( x cm) per strip. The samples were stored in a desiccator at relative humidity 3-35 % until further analysis. Film samples with air bubbles, cuts or imperfections were excluded from the study. The calculation for the strips of RDF to be prepared is shown below- Diameter of petridish = 8.97 cm, Surface area of petridish = 63.3 cm, Number of strips obtained =6 Table : Composition of Oral Thin Films Contating Saxagliptin Ingredi ents/ba tch F F F 3 F G G G 3 G Saxagli ptin HPMC 5 LV HPMC 5 LV HPMC 3 LV Menthol Glycero l PG Asparta me (%) Distilled Water (ml)

6 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 valuation of RDF The RDF were evaluated for the following parameters-. Measurement of mechanical properties of the RDF. In-vitro disintegration studies 3. In-vitro dissolution studies. nvironment Scanning electron microscopy (SM) 5. Taste evaluation Measurement of mechanical properties of the film Mechanical properties of the RDF were evaluated using Lloyd universal testing machine, UK with load cell range - N. Films of dimension x.5 cm and free from physical imperfections were used for the study. The films were held between two clamps at distance of 5 cm. The RDF were pulled by the clamp at the rate 5 mm/min. Measurements were done in triplicate for each batch. The mechanical properties tensile strength, elastic modulus and % elongation were calculated for the RDF from the above measurements. Tensile strength is the ratio of maximum stress applied to a point at which the film specimen breaks and can be computed from the applied force at rupture to the cross sectional area of the fractured film as a mean of three measurements and described in the equation- Tensile strength = Force at break (N) Initial cross sectional area of the film (mm) lastic modulus is the ratio of applied stress and corresponding strain in the region of approximately linear proportion of elastic deformation on the load displacement profile and calculated using the following equation- lastic modulus = Force at corresponding strain (N) x Cross-sectional area of the film corresponding strain Percentage elongation was calculated by the following equation- Study of Physical properties: Weight variation: = Increase in length x Original length Three films each of cmwas cut at three different places from the casted film were taken and Available online: November Issue 67

7 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 weighed individually on analytical electronic balance and weight of each film was noted and weight variation was calculated. It was found to be in a range of 53.5±.3 to 5.68 ±.33. The weight of all the films was found to be uniform. From all the formulations it has been observed that increase in concentration of polymer increases weight of the film. Weight variation is an important parameter to consider as any variation in the weight of film leads to under medication or over medication. Thickness: Thickness of films was measured by screw gauge at different locations. It is essential to determine uniformity in the thickness of the thickness of the film as this is directly related to accuracy of dose in films. The average thickness and standard deviation were reported. Moisture Uptake: The film sample was weighed and placed on a preweighed stainless steel wire mesh. The wire mesh was then submerged in a Petri dish containing ml distilled water. Increase in weight of the film was determined at regular time intervals until a constant weight was obtained. The hydration ratio of the film was calculated using following formula: Where, W t = Weight of film at time t W = Weight of film at zero time. Moisture Loss: The percent moisture loss was determined by placing prepared film in desiccators containing anhydrous calcium chloride. After three days, the film was taken and reweighed. The percent moisture loss was calculated using following formula: Where, W = Initial weight W t = Final weight. In-vitro disintegration studies Disintegration time study was slightly modified to mimic the in-vitro and in-vivo conditions. For the study, film as per the dimensions ( x cm) required for dose delivery were placed on a Available online: November Issue 675

8 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 stainless steel wire mesh containing ml distilled water. Time required for the film to break and disintegrate was noted as in- vitro disintegration time. Since, the film is expected to disintegrate in the mouth in presence of saliva, only ml of medium was used. In-vitro dissolution studies The in-vitro dissolution studies were conducted using three media namely distilled water(5 ml), simulated gastric fluid (9 ml) and simulated saliva (5 ml). The dissolution studies were carried out using USP dissolution apparatus XXIV (lectrolab, Mumbai, India) at C and at 5 rpm using specified dissolution media. ach film with dimension ( x cm) was placed on a stainless steel wire mesh with sieve opening 7μm. The film sample placed on the sieve was submerged into dissolution media. Samples were withdrawn at, 5,, 5, 3, 6, min time intervals and filtered through.5μmwhatman filter paper and were analyzed spectrophotometrically at 8 nm (UV 5Shimadzu, Japan). To maintain the volume, an equal volume of fresh dissolution medium maintained at same temperature was added after withdrawing samples. The absorbance values were converted to concentration using standard calibration curve previously obtained by experiment. The dissolution testing studies were performed in triplicate for all the batches. nvironment scanning electron microscopy (SM) The surface morphology of the film forming excipient, drug and the film was observed using nvironment scanning electron microscope (Philips, XL 3, The Netherlands). The film sample was placed in the sample holder and the photomicrographs were taken using tungsten filament as electron source and GS detector at 65x and 35x magnification. Taste evaluation Taste acceptability was measured by a taste panel (n=6) with mg drug and subsequently film sample containing mg drug held in mouth until disintegration, then spat out and the bitterness level was then recorded. The volunteers were asked to gargle with distilled water between the drug and film sample administration. The scale for the bitterness study was as follows: + = very bitter, ++ = moderate to bitter, +++ = slightly bitter, ++++ = tasteless/taste masked = excellent taste masking Available online: November Issue 676

9 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 RSULTS AND DISCUSSIONS Analytical Methods Determination of Saxagliptin: It was performed in ph 6.8 phosphate buffer. Fig. : λ max of Saxagliptin The drug solution was subjected to scanning between to nm and absorption maximum was determined. The λ max of saxagliptin was found as 8nm and that was selected for analysis. Standard graph for Saxagliptin in 6.8 ph phosphate buffer at 8nm. The standard graph of Saxagliptin in ph 6.8 phosphate buffer showed a good linearity with r of.9997 in the concentration range of - µg/ml. Table : Standard graph of Saxagliptin Concentration (µg/m) Absorbance (nm) Preformulation studies Fig.: Standard graph of Saxagliptin Preformulation studies for the selected drug Saxagliptin include test for identification (examination of physical appearance, melting point determination, and IR spectroscopy) and solubility studies. Tests for Identifications: Available online: November Issue 677

10 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 Physical appearance: Saxagliptin was found to be a white to off white crystalline powder, nonhygroscopic in nature. Melting point: Saxagliptin was found to be melting at 8 C Solubility Analysis: A definite quantity (5 mg) of drug was dissolved in 5 ml of each solvent at room temperature. The solubility was observed only by the visual inspection. Table 3 S.No Solvents Solubility Distilled water Sparingly soluble thyl acetate Slightly soluble 3 Methanol, ethanol, IPA, Acetonitrile; PG Soluble Drug Compatibility Studies FT-IR-spectra: The characteristic peaks were determined by FT-IR spectra, which identified the purity of drug. Compatibility Studies: FTIR interaction studies. As described in the methodology section, drug- polymer compatibility studies were carried out using Fourier Transform Infrared Spectroscopy to establish any possible interaction of Saxagliptin with the polymers used in the formulation. It was expected that the intermolecular hydrogen bonding between hydroxyl groups of HPMC and amino (-NH) groups of Saxagliptin might be involved. In order to have better understanding of type of interaction between the blended polymers, FTIR spectra of all different combinations of polymers with the drug were studied. The results indicated that the characteristic absorption peaks due to pure Saxagliptin have appeared in the formulated FDF s, without any significant change in their position after successful formulation, indicating no chemical interaction between Saxagliptin and polymers. Fig. 3: FTIR Spectra Saxagliptin Available online: November Issue 678

11 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 Preliminary trials Fig. : FTIR Spectra of optimized formulation The preliminary trials were undertaken for designing the RDF wherein the effects of various grades of HPMC namely 3, 5 and 5 LV on the characteristics of the films were assessed. All the three grades were varied in a concentration range of to % w/v. Initial trials were taken to check the suitability of various grades of HPMC LV for the formation of RDF without addition of the drug. In-vitro disintegration time studies as shown in Table 7.3 suggested that films prepared using all 3 grades of HPMC LV had in-vitro disintegration time below 3 sec and was thus, acceptable for further formulation. Table : In-vitro disintegration time of blank preliminary batches In-Vitro Disintegration Time (Sec) Grade/Concentration % % 3% % HPMC 3 LV 7.5 () Very Thin, Brittle.5 ().5 (3).5() HPMC 5 LV 7.5 (F) Very Thin, Brittle.5 (F) 5 (3F) 5(F) HPMC 5 LV.5 (G) Very Thin, Brittle 7.5 (G) 5 (3G) 3(G) Figures in bracket indicates batch number; n=3. Films prepared at % w/v concentration using all the three grades were very thin, brittle and were easily broken. Films with % to % w/v concentration for all three grades were clear, transparent and easily separated. Therefore, further batches containing the drug were formulated using % to % w/v of HPMC LV grades. Table 5: Preliminary trials using HPMC 5 LV as a polymer Ingredients*/Batch F F F3 F Saxagliptin HPMC 5 LV Menthol Distilled Water (ml) In-Vitro Disintegration Time (Sec) Film Property Brittle, Very Thin Brittle, Very Thin Good Good Available online: November Issue 679

12 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 *All quantities are in mg, Batch size 6 strips The RDF containing mg HPMC 5 LV formulated with Saxagliptin resulted in highly brittle films compared to films containing mg HPMC 5 LV which were separated easily. Thus, films containing mg HPMC 5 LV were further evaluated for various parameters. The reason for the brittle film formation in the presence of the drug using mg HPMC 5 LV might be insufficient amount of sample required for film formation. The in-vitro disintegration time of batches containing mg HPMC 5 LV was acceptable i.e. 5 sec. Trials were also taken with the same formulation in presence (containing.7 mg menthol per strip) and absence of menthol as a cooling agent. Table 6: In-vitro dissolution profile of batch F3 and F in distilled water Time (min) Cumulative % Drug release F3 F In-vitro dissolution study of batch F3 and F was carried out in distilled water. It was observed that complete drug released in min and 3 min respectively for batch F3 and F. Table 7: Formulation trials containing HPMC 5 LV as a polymer Ingredients*/Batch G G G3 G Saxagliptin HPMC 5 LV Menthol (%) Distilled Water (ml) In-Vitro Disintegration Time (Sec) Film seperation Good Good Good Good *All quantities are in mg, Batch size 6 strips G to G containing HPMC 5 LV as a film forming polymer. The RDF containing mg HPMC 5 LV formulated with Saxagliptin resulted in films with good quality and acceptable invitro disintegration time (5 sec). Films with mg HPMC 5 LV resulted in higher in-vitro Available online: November Issue 68

13 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 disintegration time (95 sec). This might be due to delayed disintegration time with higher viscosity grade of HPMC LV at higher concentrations. Table 8: In-vitro dissolution profile of batch G, G, G3 and G Time (min) Cumulative % drug release G G G3 G Table shows in-vitro dissolution profile of batches G to G. Batches G and G showed 67-69% drug release in min and 96% and 9% drug release in 5 min but as the amount of HPMC 5 LV was increased, drug release was retarded and complete drug release was observed in hr. Thus, HPMC 5 LV retarded the dissolution behaviour of rapidly dissolving films. Table 9: Formulation trials containing HPMC 3 LV as a polymer Ingredients*/Batch 3 Saxagliptin HPMC 3 LV Menthol Distilled Water (ml) Total weight/strip Film separation No No No Partial *All quantities are in mg, Batch size 6 strips Saxagliptin when incorporated in mg of HPMC 3 LV films resulted in formation of very brittle and thin films. When Saxagliptin was incorporated in mg of HPMC 3 LV, it resulted in slightly brittle films. Thus, to improve the characteristics of the film addition of plasticizer was found to be necessary. Various preliminary formulations 5 to using mg HPMC 3 LV were prepared to check film separation property using glycerol and menthol as plasticizer. Table : Formulation batches with HPMC 3 LV using glycerol Ingredients*/Batch Saxagliptin HPMC 3 LV Menthol (%) Glycerol (.:) (.:) Available online: November Issue 68

14 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 PG Distilled Water (ml) Total weight/strip.7.7 Film seperation No No No Yes *All quantities are in mg, Batch size 6 strips None of the above batches resulted in good film separation property. So, further trials were carried out using PG as plasticizer. Table : Formulation batches with HPMC 3 LV using PG Ingredients*/Batch 9 Saxagliptin HPMC 3 LV Menthol (%) Glycerol PG (.:) (.:) Distilled Water (ml) Film seperation Yes Yes Yes, soft Partial Invitro disintegration time (Sec) *All quantities are in mg, Batch size 6 strips PG at (plasticizer: polymer) ratio of.: resulted in better elasticity than glycerol. Thus, it could be concluded that film separation could be improved in the presence of plasticizer PG. In-vitro dissolution study of batch 9 was carried out in 3 different dissolution media as shown in Table 7.. Table : In-vitro dissolution study of batch 9 Cumulative % Drug Release Time (Min) Batch 9 PH 6.8 Phosphate Buffer.N HCl Simulated Saliva The in-vitro disintegration time of batch 9 containing mg HPMC 3 LV, Saxagliptin and PG was 5 sec. The comparative drug release of batch 9 in different dissolution medium Available online: November Issue 68

15 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 indicated 85% drug release in min in ph 6.8 Phosphate Buffer, 8% drug release in min in.n HCl and 78% drug release in minutes in simulated saliva. Fig. 5: Comparative in-vitro dissolution profile of batch 9 Thus, it can be concluded that the viscosity grades of HPMC LV affected the mechanical properties, disintegration and dissolution characteristics of the RDF. The higher the viscosity of HPMC LV grades, there was an increase in the in-vitro disintegration and dissolution time. Although batches containing mg HPMC 5 LV and mg HPMC 5 LV in presence of drug had an in-vitro disintegration time of 5 sec, the in-vitro dissolution time was 3 min and 5 min in distilled water respectively. Batch 9 had 98% drug release in min in distilled water. Therefore, further studies were carried out using HPMC 3 LV as a polymer for the RDF formulation trials. RDF containing Saxagliptin prepared using HPMC 3 LV also possessed satisfactory mechanical property, in-vitro disintegration and in-vitro dissolution time and were used for further optimization. Taste masking of Saxagliptin films Saxagliptin being bitter in taste, the taste masking of the films was found to be essential to improve the patient acceptability. To improve the taste of the films, flavours and sweeteners were incorporated in the formulation. Various amount of menthol (5% w/w of drug and polymer amount) and sucralose (%w/w of drug and polymer amount) at various plasticizer ratios were added to Saxagliptin containing films. Table 3: Formulation batches with HPMC 3 LV Ingredients/Batch Saxagliptin HPMC 3 LV Menthol (5%) Aspatame (%) Flavour - - Yes Yes Available online: November Issue 683

16 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 Glycerol PG Distilled Water (ml) Total Weight/Strip Film Separation No, Film Too soft No, Film Too soft None of the above batches resulted in taste masking of the film. Thus, further trial batches S to S were taken with another sweetener sucralose. This too did not result in taste masking of Saxagliptin. As none of the above excipients resulted in complete taste masking of the film further trials were taken using combination of sweeteners i.e. aspartame and sucralose. Table : Selection of sweetener for the taste masked films Ingredients/Batch S S S3 S Aspartame Sucralose PG - Film Separation No yes Partial Yes Invitro disintegration time(sec) Taste Masking *All quantities are in mg, Batch size 6 strips All batches contained mg HPMC 3 LV and 5 mg Saxagliptin. All batches were formulated in ml distilled water. Table shows that batch S exhibited an in-vitro disintegration time of 5 sec. The batch S possessed good taste masking property but was followed by bitter aftertaste. Table 5: In-vitro dissolution of batch S in ph6.8 phosphate buffer,.n HCl and simulated saliva Batch S Time (Min) Cumulative % release in different medium ph 6.8 Phosphate buffer.n HCl Simulated Saliva In-vitro disintegration time of batch S was found to be sec. In-vitro dissolution study of batch S in 3 different dissolution media distilled water,.n HCl and simulated saliva is shown in Table. In-vitro dissolution study of batch S in 3 different dissolution media ph 6.8 phosphate buffer,.n HCl and simulated saliva is shown. Available online: November Issue 68

17 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 Fig. 6: In-vitro dissolution study of batch S in 3 different dissolution media ph 6.8 Phosphate Buffer,.N HCl and simulated saliva Thus, formulation trials were carried out by using flavouring agents such as lemon and passion fruit flavour and sour ingredients like citric acid. Table 6: Selection of flavour for the taste masked films Ingredients/Batch T T T3 T Flavour Passion fruit Lemon Passion fruit Lemon PG Citric acid Film Separation Partial Yes Yes Yes In-vitro disintegration time(sec) lasticity Good Good Very good Very good Taste masking *All quantities are in mg, Batch size 6 strips All batches were formulated contained mg HPMC 3 LV, 5 mg Saxagliptin, mg aspartame and 8 mg sucralose in ml distilled water. Table indicates that further addition of flavouring agents like citric acid and passion fruit flavour (T to T) resulted in completely taste masked film of batch T3. The in-vitro disintegration time was 5 sec. In-vivo disintegration time of batch T3 was sec. Addition of lemon flavour (T and T) resulted in highly acidic taste of the film which was unacceptable. Batch T3 showed good elasticity and taste masking properties. In-vitro dissolution profile of batch T3 in different dissolution media i.e. Phosphate buffer 6.8pH,.N HCl and simulated saliva is shown Table 7.5. Table 7: In-vitro dissolution profile of batch T3 in ph6.8 Phosphate buffer,. N HCl and simulated saliva Batch T3 Time (min) Cumulative % release in different medium Phosphate buffer 6.8pH.N HCl Simulated saliva Available online: November Issue 685

18 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 Fig.7: Comparative in-vitro dissolution study profiles of batch T3 Figure indicates the comparative in-vitro dissolution profile of batch T3 in different dissolution medium. It can be concluded from the Figure that in min batch T3 showed % drug release in ph 6.8 Phosphate Buffer, 98% in.n HCl and 8% in simulated saliva. nvironment scanning electron microscopy (SM) The SM of HPMC 3 LV shown in Figure7.8 indicated irregular cylindrical to spherical shaped particles at 5x magnification. Saxagliptin particles could not be seen distinct as such. On dispersing it in acetone as shown in Figure7.9 cylindrical distinct particles could be observed at 35x magnification. Figure 7. indicates optimized film at 35x magnification which was uniform with few pores and solid particles without any striations. Fig. 8: SM of HPMC 3 LV powder Fig.9: SM of Saxagliptin powder at 5x magnification at 35x magnification Fig. : SM of T3 film at 35x magnification Available online: November Issue 686

19 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 Study of mechanical properties A suitable RDF requires moderate tensile strength, good percentage elongation and low elastic modulus. Table 8: Comparative mechanical properties of various batches Batch Tensile Strength (N/mm) % longation lastic Modulus (N/mm) S T Table shows the comparative mechanical properties of various formulations prepared during the study. It can be observed that RDF containing % and % HPMC 3 LV alone i.e. batches and showed extremely high tensile strength, poor % elongation values and very high elastic modulus. The same formulation in the presence of drug and plasticizer (9) demonstrated lower tensile strength compared to batch and. The % elongation values increased and elastic modulus values decreased. The taste masked batches S and T3 were found to possess acceptable mechanical properties. The tensile strength values were in moderate range (-9 N/m). The % elongation (-8) and elastic modulus (35-65) were also satisfactory. These changes in the mechanical properties can be attributed to the presence of plasticizer in the batches 9, S and T3. Compared to films containing pullulan, HPMC 3 LV films possessed higher % elongation and lower elastic modulus. The low % elongation value indicates brittle nature of the pullulan film. Higher elastic modulus values indicate more toughness of pullulan containing films compared to HPMC 3 LV films. Batch T3 showed most acceptable mechanical properties along with complete taste masking which might be due to presence of suitable plasticizers and flavours. Batch T3 showed most acceptable mechanical properties along with complete taste masking which might be due to presence of suitable plasticizers and flavours. Study of Physical properties: Weight variation: Three films each of cmwas cut at three different places from the casted film were taken and weighed individually on analytical electronic balance and weight of each film was noted and weight variation was calculated. It was found to be in a range of 53.5±.3 to 5.68 ±.33. The weight of all the films was found to be uniform. From all the formulations it has been observed that increase in concentration of polymer increases weight of the film. Weight variation is an Available online: November Issue 687

20 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 important parameter to consider as any variation in the weight of film leads to under medication or over medication. Batch Table 9: Comparative Physical properties of various batches Thickness (µm)* Mean Weight (* Film) (mg)* % Moisture Uptake % Moisture Loss.3± ± ±..89 ± ±..5 ± S.± ± T3.3±. 36.± * Mean ± SD; n = 3 Moisture absorption: Moisture absorption study was performed to check the physical integrity of films. The films were weighed accurately and placed on a preweighed stainless steel wire mesh. The wire mesh was then submerged in a Petri dish containing ml distilled water. Increase in weight of the film was determined at regular time intervals until a constant weight was obtained. Moisture absorption study is an important parameter to be performed, as the presence of moisture possesses a critical challenge on drug stability. Moisture accelerates the hydrolysis of drug as well as facilitates reaction with other excipients, thereby affecting stability and shelf life of the final dosage form. All the reported values were shown. And it has been observed that all the film forming polymers HPMC 3LV, 5LVand 5LV were of hydrophilic in nature and the obtained values were in a range of.87 to 5.7%. Moisture loss: Moisture loss study was performed to check physical stability of films at dry environment. Film was weighed accurately and kept in desiccator containing anhydrous calcium chloride for 3 days and films were removed and reweighed and moisture loss was calculated. The moisture loss study gives an idea about films stability nature and ability of films to withstand its physicochemical properties under normal conditions. It also gives an idea about hydrophilicity of film formulations. All the obtained values were reported. The obtained values were in a range of.8to.9. Stability studies The stability studies of the optimized batch T3 was carried out at C/75%RH, 5 C/6%RH and 5 C/%RH. These films were found to be unacceptable. Films stored at C/75%RH were Available online: November Issue 688

21 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 highly unstable within month storage. Films stored at 5 C/6%RH were unstable after months period by developing colour change (yellow) and becoming sticky in appearance. Films stored at 5 C/%RH were found to be stable for one year period. The batch was found be acceptable visually, mechanically, with slight change in in-vitro and in-vivo disintegration time 55 sec, sec respectively. The above observations indicate that temperature and humidity plays a critical role in the stability of the rapidly dissolving films containing HPMC 3 LV as the film forming polymer. Therefore, precautions would be required during packaging and selection of packaging container would play a crucial role for stability of the RDF. Time % of drug dissolved in min (Distilled water) Table : Stability studies of optimized batch In vitro disintegration time (sec) In vivo disintegration time (sec) Initial 5 Month 5 Months Months 99 9 Appearance Transparent, white, Acceptable Transparent, white, Acceptable Transparent, white, Acceptable Transparent, white, Acceptable CONCLUSION Rapidly dissolving films using different grades of HPMC LV were formulated using Saxagliptin. It was formulated especially suitable for pediatric and geriatric patients. An ideal rapidly dissolving drug delivery system should have following properties Transportability, ase of handling and administration, No special packaging material and/or processing requirements, No water necessary for application and pleasant taste. It was prepared by solvent casting method.it was observed that type of grade of HPMC 3 LV significantly contributed to in-vitro disintegration and in-vivo dissolution. Higher viscosity grade of HPMC increased in-vitro disintegration and in-vitro dissolution. HPMC 3 LV was found to be suitable polymer for the formation of rapidly dissolving films. As Saxagliptin is being bitter in taste, taste masking using combination of sweeteners, flavours and citric acid was used. The optimized batch had acceptable characteristics which include mechanical properties, in-vitro disintegration time is 5 sec, in-vitro dissolution drug release % in min and taste masking properties. SM study was also carried out to study the surface morphology. These present findings suggest that the formulation contaning Saxagliptin developed disintegrate within a minute hence is potentially useful for Available online: November Issue 689

22 RSARCH ARTICL Jyothi et.al / IJIPSR / (),, Department of Pharmaceutics ISSN (online) 37-5 pediatric and geriatric patients who show unwillingness to take tablets. It can be concluded that the RDF of Saxagliptin which can be a promising drug delivery system. RFRNCS. Arnum PV, Outsourcing solid dosage manufacturing, Pharm Tech, 3(6), -5, June 6.. Pfister W, Ghosh T, Intraoral delivery systems: An overview, current status and future trends. In Tapash Ghosh, William Pfister (d.), Drug Delivery to the Oral eavity: Molecules to Market (pp. -3). Florida: ere Press, Taylor & Francis gp, Pfister W, Ghosh, T, ehatterjee D, Jarugula V, Fadiran, Hunt J, Lesko L, Tammara V, Hare D, Quick dissolving oral dosage forms: Scientific and regulatory considerations from a clinical pharmacology and biopharmaceutics perspective. In Tapash Gh osh, William Pfister (d.), Drug Delivery to the Oral eavity: Molecules to Market (pp ). Florida: ere Press, Taylor & Francis gp, 5.. Liang AC, Chen LH, "Fast Dissolving Intraoral Drug Delivery Systems", xp. Opin. Ther. Patents, (6), ,. 5. Mishra R, Amin A, "Quick API Delivery," Pharm Tech (urope), 9(), 35-39, Mishra R, Amin A, "Formulation development of taste masked rapidly dissolving films of cetirizine hydrochloride", Pharm Tech (USA), 33(), 8-56, Vondrak B, Barnhart S, "Dissolvable films for flexible product format in drug delivery". Pharma Technol., Suppl, S -8, Barnnart S, Sloboda M, "Dissolvable films-the future of dissolvable films", Drug Del Tech, 7(8), 3-37, Sept Novartis launches first systemic OTe in film strip format. Pharmacist counseling can prevent unintentional errors with thin strip dosage forms. Arnum PV, "Outsourcing solid dosage manufacturing", Pharm Tech, 3(6), -5, June 6.. Corniello CM, "Quick dissolve films Quick -Dissolve strips: From concept to commercialization", Drug Delivery Technology, 6(), Feb 6. Available online: November Issue 69