Design and evaluation of sublingual immediate release films for treatment of osteoporosis

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1 Research Article ISSN: Available online through Design and evaluation of sublingual immediate release films for treatment of osteoporosis Megha G. Kakde Pharmaceutics division, Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Mahatma Fuley Shaikshanik Parisar, Amravati Road, Nagpur (MS),India Received on: ; Accepted on: ABSTRACT Raloxifene hydrochloride is recommended for treatment of osteoporosis. However, its oral bioavailability is 2 % due to extensive hepatic first pass metabolism and half-life is 27.7 hours after. Also nil solubility of drug makes it difficult for bioavailability achievement. Hence, it was envisaged to solubilize drug and developed by sublingual drug delivery system. Drug and polymers were characterized by FT-IR spectroscopy which found no interaction. For solubilization of drug in water, inclusion complex of raloxifene hydrochloride and ß-cyclodextrin (1:2 and 1:4) were prepared and optimized by kneading method. Phase solubility studies revealed that, solubility of raloxifene hydrochloride was increased by complexation with ß-CD and by addition of co-solvent ethanol and increase in ph. Sublingual immediate release films were prepared by solvent casting method by using inclusion complex of raloxifene (1:4), HPMC K4M, PVP K3, mannitol and xylitol. All formulation batches were evaluated for physicochemical parameters, mechanical studies, ex vivo mucoadhesive strength, ex vivo diffusion and in vitro drug release. Studies revealed that, with increase in HPMC K 4M concentration, tensile strength was increased whereas percent elongation and folding endurance were decreased whereas mucoadhesion strength was increased. Desired release was obtained in batch F2 with ±.53 % in vitro release and ±.426 % ex vivo permeation in 1 hour. Batch F2 (HPMC K4M and PVP K 3 in 3.5:1.5) exhibit best formulation. Stability studies on batch F2 revealed no significant reduction in drug content, in vitro dispersion time, ex vivo mucoadhesive strength and in vitro drug release. Keywords: Osteoporosis, raloxifene hydrochloride, ß-cyclodextrin, inclusion complex. INTRODUCTION Osteoporosis exerts a significant burden on both individuals and community 1,2. It becomes a serious health threat for aging postmenopausal women by predisposing them to an increased risk of fracture 3. Raloxifene hydrochloride is very well recommended for treatment of osteoporosis. It is selective estrogen receptor modulator which exhibits estrogen agonist activity on bone and cardiovascular tissue. It decreases rate of bone reabsorption and preserves bone density 4. It has biological half life of 27.7 hrs. It belongs to BCS class II drug i.e. low solubility in water and undergoes extensive hepatic first pass metabolism. Its oral bioavailability is 2%. A severe hepatic first pass metabolism and very low bioavailability pointing towards development of sublingual immediate release drug delivery system that avoids first pass metabolism and provides immediate drug delivery as well as quicker onset of action for better patient compliance. In order to solubilize the poorly water soluble drug molecules, cyclodetrins are very well recommended in oral drug delivery. *Corresponding author. Megha G. Kakde Plot no. 114, Kamgar nagar, Near ramna maroti temple Nagpur. Dist.: Nagpur (M.S.) 44 9, India. Thus, the objective of present research work was to prepare inclusion complex of poorly water soluble drug raloxifene hydrochloride to enhance its aqueous solubility and to develop drug delivery system that lowers dissolution as well as disintegration time and act as immediate release dosage form to avoid hepatic first pass metabolism and formulate, optimize and evaluate sublingual immediate release films of raloxifene hydrochloride. Hence, it was envisaged to solubilize drug and developed by sublingual drug delivery system. MATERIALS AND METHODS Materials Raloxifene hydrochloride was obtained as gift sample from Alkem Laboratories Ltd., Mumbai (India). ß-cyclodextrin was obtained from Concept Pharmaceuticals Ltd., Aurangabad (India). All the other chemicals were of analytical grade. Drug and polymer characterization by FT- IR spectroscopy 5 Drug was triturated with potassium bromide in 1:5 ratio and compressed at pressure of 5 tons in a hydraulic press. Thirty scans were obtained at a resolution of 2 cm -1 from 4 to 5 cm -1. UV spectroscopy studies A solution containing 5 (µg/ml) of raloxifene hydrochloride in.1

2 %w/v tween 8 solution in water was prepared. A series of dilutions were made and scanned over range of 2 to 4 nm against blank solution. Phase solubility studies 6, 7 1. Saturation solubility studies of raloxifene hydrochloride Phase solubility studies of raloxifene hydrochloride with ß- cyclodextrin (-25 mm) were performed. Excess amount of raloxifene hydrochloride was added to 1 ml distilled water containing -25 mm ß-cyclodextrin in a series of 25 ml screw capped vials and mixture was shaken for 24 hours at room temperature on water bath shaker. After 24 hours of shaking, solutions were filtered through Whatman # 1 filter paper. Filtered samples were diluted suitably and assayed. Similar process was carried for phosphate buffer ph 6.8 and 7.4. Inclusion complex of raloxifene hydrochloride with ß-CD and sweetners (mannitol and xylitol) were finely dispersed in 1 ml of distilled water. Dispersion was added to polymeric solution with continuous stirring to form a clear solution. Solution was casted on 9 cm diameter petridish and dried in oven at 45 C for 24 hours. Film was carefully removed from petridish and checked for any imperfection and cut according to 2x2 cm size. Samples were stored in glass container maintained at temperature 3 C in oven. Evaluation of sublingual immediate release films 1 1. Thickness and weight Thickness of film was measured by digital vernier caliper at five different locations. Average thickness and standard deviation was measured. This is essential to ascertain uniformity of film as this is directly related to accuracy of dose in film. Weight determinations were conducted for three films. 2. Saturation solubility studies in presence of co-solvent ethanol Similarly, effect of co-solvent ethanol on saturation solubility was studied by using increasing concentration of co-solvent from -5 ml. Preparation and characterization of inclusion complex Inclusion complex of raloxifene hydrochloride with ß-cyclodextrin in 1:2 and 1:4 ratios were prepared by kneading method and optimized spectrophotometrically at wavelength of 29.5 nm and characterized by FT-IR spectroscopy. To the slurry of ß-cyclodextrin (ß-CD: water 1:3) calculated quantity of raloxifene hydrochloride was added step wise with continuous triturating in same direction. Slurry was then dried at 4 o C for 24 hours in hot air oven and resulted complex was ground and passed through sieve # 15. Formulation and evaluation of sublingual immediate release films of raloxifene hydrochloride 8, 9 Formulation batches of sublingual immediate release films of raloxifene hydrochloride composed of inclusion complex (1:4), 4:1, 3.5:1.5, 3:2 ratios of HPMC K4M and PVP K3, propylene glycol, mannitol and xylitol as shown in table 1. Preparation of sublingual immediate release films Sublingual immediate release films were prepared by solvent casting method. Polymers were dissolved in water and plasticizer propylene glycol was incorporated and mixed thoroughly with help of magnetic stirrer a homogeneous mixture was formed and kept for 24 hours. 2. Drug content and content uniformity Specified area of film (2x2 cm 2 ) was dissolved in 2 ml methanol and shaken continuously for 24 hours. Then whole solution was sonicated for 15 min. After filtration and dilution with water, drug was estimated spectrophotometrically at wavelength of 29.5 nm and drug content was determined. To determine drug content uniformity, three samples of film from each batch were taken and per cent drug content was determined individually by spectrophotometric method. 3. In vitro dispersion time In vitro dispersion time gives an indication about disintegration characteristics and dissolution characteristics of the film. Film as per dimensions (2 x 2 cm) required for dose delivery was placed on a stainless steel wire mesh placed in a petridish containing 1 ml distilled water. Time required for film to disperse was noted as dispersion time. Mechanical properties Tensile strength Tensile strength is property of film that requires a load to cause load deformation failure of film. Tensile strength was measured by sticking film using an adhesive (feviquick) to steel plate attached to stand and other end of film was attached to other plate having a pan to apply load. Mercury was used to apply load. Tensile strength was calculated as Table 1: Formulation composition of sublingual immediate release film of raloxifene hydrochloride Sr. Formulation Raloxifene HPMC K4M PVP Propylene Mannitol Xylitol No. Code hydrochloride + (mg) K3 glycol (mg) (mg) ß-cyclodextrin (mg) (%w/w) complex(mg) 1 F F F

3 2. Per cent elongation Per cent elongation is measured when film snaps as sufficient force applied so as to exceed elastic limit. Per cent elongation break was determined by noting length just before break point, per cent elongation was determined by below mention formula. 3. Folding endurance Folding endurance was determined by repeated folding patch at 18 o angle of plan at same place till it breaks or folded up to 3 times manually, which was considered satisfactory to reveal good film property. Number of time film folds without breaking is computed as folding endurance value. Test was done on randomly selected three films from each batch. Ex vivo mucoadhesive strength Mucoadhesive strengths of sublingual immediate release films were determined at room temperature using two-arm balance method. Fresh goat sublingual mucosa was obtained from a local slaughterhouse. Membrane was separated by removal of underlying fat and loose tissues. Membrane was washed with phosphate buffer solution and fixed to the bottom of a smaller beaker attached to a larger beaker. Phosphate buffer solution was then added to beaker up to upper surface of mucosa to keep it moist. Test film was glued with same adhesive to bottom of small glass vial hanging on left hand side. Two sides of balance were balanced with a 5 g weight on right hand side. Balance beam raised with 5 g weight on right pan was removed off the weight. This lowered glass vial along with film over mucosa with a weight of 5 g. Balance was kept in this position for 3 minutes and then slowly water was added to plastic container in right pan by pipette until film detached from mucosa. Total weight of water was measured and expressed as force required for detachment. At least three replicates of each formulation were analyzed at room temperature, and in each case, a fresh sample was used. Mean and standard deviations were calculated. Ex vivo diffusion study These are carried out in Franz diffusion cell of internal diameter of 2 cm. Fresh goat sublingual mucosa was used as a model membrane. It was obtained from local slaughter house. Mucosa was excised and trimmed evenly from sides and then washed in isotonic phosphate buffer of ph 6.6 and used immediately. Membrane was stabilized before mounting to remove soluble components. Mucosa was mounted between donor and receptor compartment. Receptor compartment was filled with 2 ml isotonic phosphate buffer of ph 7.4 which was maintained at 37±.2 o C and hydrodynamics was maintained by stirring with magnetic bead at 5 rpm. One previously weighed film of dimension 2x2 cm was placed in intimate contact with mucosal surface of membrane that was previously moistened with a few drops of simulated saliva. Donor compartment was filled with 1 ml of simulated saliva of ph 6.8. Samples were withdrawn at suitable interval replacing the same amount with the fresh medium. Percentage of drug diffused was determined by spectrophotometrically at 29.5 nm. In vitro drug release studies Cumulative % drug release of drug from sublingual immediate release films of raloxifene hydrochloride was determined using the USP type I dissolution test apparatus (Basket). Dissolution test was performed using 3 ml.1 %w/v tween 8 in water at 37±2 C and rotational speed of 1 rpm. The 5 ml aliquots were withdrawn at an interval of 5 minutes for 45 minutes. Samples were replaced by their equivalent volume of dissolution medium. Samples were suitably diluted and analyzed at 29.5 nm by UV spectrophotometer. Cumulative % drug release was calculated using calibration curve. Stability studies of optimized batch Stability studies on the optimized formulation batch was carried out to determine effect of presence of formulation additives on stability of drug and also to determine physical stability of formulations under accelerated storage conditions. Films were stored in an aluminium foil and placed in oven maintained at temperature and humidity condition of 4±2 o C/ 75±5 % RH and at room temperature. Samples were withdrawn on 3 th day and analyzed for physical evaluation, mucoadhesive strength and in vitro drug release. Table 2: Effect of ß-CD on saturation solubility of raloxifene hydrochloride in water Sr. No. ß-CD Absorbance Solubilization Conc. at 29.5 nm (%) (mm) RESULTS AND DISCUSSIONS FT-IR spectrum of drug, excipients and their mixture revealed that no interaction was observed between drug and polymers. Hence, it was good to formulate sublingual immediate release films as shown in figure 1 and 2. Calibration curve was obey Beer Lambert s law within concentration range of -24 (µg/ml) in.1 %w/v tween 8 in water with correlation coefficient (R 2 ) of.999. Phase solubility studies of raloxifene hydrochloride with ß-CD (-25 mm) were performed. Per cent solubilization of drug into ß-CD was increased from 4.29 to % as shown in table 2 and figure 3. This is due to more solubility of ß- CD in water. Effects of basic ph, ph 6.8, ph 7.4 and co-solvent ethanol on solubilization of raloxifene hydrochloride by ß-CD were studied. Results indicated that solubility of raloxifene hydrochloride was increased from distilled water to ph 7.4 as shown in table 3 and figure

4 Table 3: Effect of ph on solubilization of raloxifene hydrochloride by ß-CD Concentration of raloxifene hydrochloride (mm) Sr. Conc. Distilled Phosphate Phosphate No. of ß-CD water buffer ph 6.8 buffer ph 7.4 (mm) (Mean ± S. D) (Mean ± S. D) (Mean ± S. D) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±.16 Figure 1: FT-IR spectrum of raloxifene HCI HPMC 4M and PVP K3 mixture Table 4: Effect of co-solvent ethanol on solubilization of raloxifene hydrochloride using ß-CD Sr. Conc. Conc. of raloxifene hydrochloride (mm) No. of ethanol Drug Drug + (% v/v) ß-cyclodextrin 1.58± ± ± ± ± ± ± ± ± ± ± ±.38 Figure 2: FT-IR spectrum of raloxifene HCI Table 5: Evaluation of physicochemical parameters for sublingual immediate release films Sr. Formulation Weight(mg) Thickness Drug content (mg)drug content uniformity (%) In vitro dispersion No. Batches (Mean ±S.D) (mm)(mean ±S.D) (Mean ± S.D) Mean ± S.D time(minutes) 1 F ± ± ± ± ±.18 2 F ± ± ± ± ± F ± ± ± ± ±.14 Table 6: Evaluation of mechanical parameters and ex vivo mucoadhesive strength Sr. Formulation Tensile strength Per cent Folding Ex vivo No. Batches (N/mm 2 ) elongation endurance mucoadhesive (Mean ± S.D) (Mean ± S.D) (Mean ± S.D) strength(g) 1 F ±.6 3 ± ± ± F ± ± ± ± F3.939 ± ± >3 ± ± 1.48 Figure 3: Phase solubility diagram of drug and ß-CD Table 7: Comparative ex vivo diffusion of batch F2 and raloxifene hydrochloride Sr. Time Diffusion of raloxifene Diffusion for No. (min) hydrochloride from raloxifene batch F2 (%) hydrochloride (%) ± ± ± ± ± ± ± ±.631 Concentration of raloxifene hydrochloride (mm) b -cyclodextrin concentration (mm) Figure 4: Effect of ph on solubilization of drug and ß-CD Water Buffer 6.8 Buffer 7.4

5 Raloxifene Hydrochloride (mm) Ethanol(%v/v) 4 5 Without β -CD With β -CD Figure 5: Effect of ethanol on solubilization of drug and ß-CD Absorbance Complex (1:2) Complex (1:4) Table 1: Cumulative % drug release of formulation batch F2 at room temperature and at 4 o C/75 %RH Time Cumulative % drug released Min At room temperature At 4 o C/75 %RH day 3 days 3 days ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± Concentration (mg/ml) Figure 6: Ratio optimization of inclusion complex at 29.5 nm Table 8: Cumulative % drug release of sublingual immediate release films of raloxifene hydrochloride Time Cumulative % drug release (min) (Sublingual Immediate release film ) F1 F2 F ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±.517 Table 9: Drug content, in vitro dispersion time and ex vivo mucoadhesive strength of batch F2 at room temperature and 4 o C/ 75 %RH Parameters At room temperature 4 o C/75 %RH day 3 days 3 days Drug content(mg) 31.4± ± ±.18 In vitro dispersion time 2.48± ± ±1.24 Ex vivo Mucoadhesive strength (g) 27.65± ± ± So, it can be concluded that basic ph help in formation of inclusion complex between raloxifene hydrochloride and ß-CD. Result indicated that solubility of raloxifene hydrochloride was increased up to 2.49±.82 mm in presence of ethanol but more solubility was found in presence of ß-CD, up to 3.93±.38 mm as shown in table 4 and Figure 7: FT-IR spectrum of inclusion complex of drug and ß-CD Mucoadhesive Strength (g) Form ulation Code Figure 8: Ex vivo mucoadhesive strength of formulation batches Drug diffused (%) Time (min) % Drug diffused of film % Drug diffused of Raloxifene Figure 9: Comparative ex vivo diffusion of batches F2 and drug figure 5 which indicates synergistic effect of ethanol with ß-CD on solubalization of raloxifene hydrochloride was observed. Inclusion complex of raloxifefene hydrochloride and ß-CD were prepared in1:2 and 1:4 ratios by kneading method and optimized spectrometrically

6 Cumulative % drug release Time(mins.) Figure 1: In vitro drug release profile of formulation batches Cumulative % drug release Time(minutes) day RT 3 days RT F1 F2 F3 3 days 4 o C/75 %RH Figure 11: In vitro drug release profile of batch F2 stored at room temperature and at 4 o C/ 75 %RH which concluded that inclusion complex 1:4 gives more prominent solubility than 1:2 in water as shown in figure 6. In order to characterness was found in range of ± 1.53 to ± 1.39 and ± ize inclusion complex formation between drug and ß-CD (1:4) in solid state, FT-IR spectrum was recorded which showed that all characteristic peaks of raloxifene hydrochloride at and cm -1 were disappeared except peak for carbonyl group but it is shifted towards higher wave number as shown in figure 7. It shows complex has been formed between raloxifene hydrochloride and ß-CD. Sublingual immediate release films of raloxifene hydrochloride were prepared by solvent casting method and evaluated for various physicochemical and mechanical parameters. Average film weight and thick to ±1.37 respectively. This variation in thickness and weight of films may be observed because of change in concentration of polymers. Drug content and content uniformity was found to be not affected by type of polymer and all batches showed uniform drug content in range of ± 2.89 to ± 5.2 mg which indicated that drug is uniformly distributed throughout film prepared by solvent casting method. In vitro dispersion time of batch F1 was found to be 2.53 ±.18 min than other batches due to presence of mannitol and xylitol as shown in table 5. Tensile strengths of batches were found to be sufficient and in range of.939 ±.5 to ±.6. Results indicated that as concentration of HPMC K4M increased tensile strength increased. Per cent elongation depends upon both polymer and plasticizer concentration. 4 % plasticizer concentration had been given most promising results. Per cent elongation of different formu lation batches was found in range of 3 ± 1. to ± Results indicated that as concentration of HPMC K4M increased tensile strength was decreased. Results of folding endurance indicated that 4% w/v of plasticizer showed more optimum results for folding endurance. Formulation batch F3 had been given folding endurance of >3. Hence, it has been observed that as HPMC K4M concentration increased, folding endurance subsequently decreased. Mucoadhesive strength values shown by formulation batches were found between ± 1.48 g to 3.53 ±.879 g as shown in table 6 and figure 8. Sublingual immediate release film containing HPMC K4M and PVP K3 in 4:1 ratio exhibited strongest mucoadhesive strength while film containing HPMC K4M and PVP K3 in 3:2 ratio showed weakest mucoadhesive strength amongst all batches. This might be due to formation of stronger mechanical interlocking between HPMC K4M and mucus membrane. Results were indicated that as HPMC K4M concentration increases, mucoadhesive strength increases. In ex vivo drug diffusion studies, it was found that optimized formulation batch F2 gives more diffusion of drug in 45 minutes i.e ±.426 % which was found to be more than raloxifene hydrochloride which diffused ±.631 % in saline phosphate buffer ph 6.6 as shown in table 7 and figure 9. Cumulative per cent drug release of sublingual films of raloxifene hydrochloride were performed using.1% w/v of tween 8 solution in water as dissolution medium for 45 minutes and drug concentrations were analyzed spectrophotometrically at 29.5 nm. Observed cumulative per cent drug release of all batches of sublingual immediate release films was found to be ±.224, ±.531 and ±.517 in 45 minutes as shown in table 8 and figure 1 respectively. These results indicated that batch F2 showed more drug release than F1 and F3. This may be due to formation of more viscous diffusion layer in case of F2 which contain 3.5:1.5 ratio of HPMC K4M and PVP K3 as compared to other ratios. It showed immediate release within 45 minutes. The formulation F2 was optimized batch. Stability studies were conducted on optimized formulation batch F2 under accelerated storage conditions of temperature and humidity to ensure that formulation remains stable over its designed period of shelf-life.no significant reduction in drug content, in vitro dispersion time, ex vivo mucoadhesive strength and in vitro drug release occurred a period of 3 days when stored at room temperature and at 4 o C/75 %RH as shown in table 9, 1 and figure 11. CONCLUSION From various phase solubility studies, it can be concluded that ß- cyclodextrin helps in enhancing solubility of raloxifene hydrochloride. 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