FORMULATION AND EVALUATION OF FELODIPINE ORODISPERSIBLE FILMS

Abstract

Orodispersible films (ODF) are the most innovative form of oral solid dosage forms because of their flexibility and comfort. Felodipine (FD) is a dihydropyridine calcium-channel blocker used in the management of hypertension and angina pectoris, it have poor bioavailability (15%) after oral administration because it is undergo extensive first pass metabolism. The effect of different type and concentrations of polymers, plasticizers, surfactants and CPV on mechanical properties, the in-vitro evaluation parameters was evaluated. HPMC E5 films show higher cumulative % drug release than films of other film forming polymers at the same concentration of polymer, plasticizer and surfactant. Hence, Formula (F14) containing 25 mg HPMC E5, 15 mg glycerin, 3.75mg Poloxamer 407 and 2 mg CPV showed the highest cumulative % drug release of 78 % at the end of 2 min and other excellent film characteristics. It was concluded that the Orodispersible films of Felodipine can be made by solvent casting technique with enhanced dissolution rate, better patient compliance and effective therapy.

Headnote

ABSTRACT

Orodispersible films (ODFs) are the most innovative form of oral solid dosage forms because of their flexibility and comfort. It enhance the efficacy of active pharmaceutical ingredient (API) by dissolving within second in the oral cavity after it come in contact with less amount of saliva as compared to orodispersible tablets. Felodipine (FD) is a dihydropyridine calcium-channel blocker used in the management of hypertension and angina pectoris, it have poor bioavailability (15%) after oral administration because it is undergo extensive first pass metabolism. Felodipine ODFs were prepared by solvent casting method using different film forming polymers (HPMC E5, HPMC E15, Polyvinyl alcohol (PVA), and Methylcellulose (MC)), different plasticizer (glycerin and PEG 400), different surfactant (Poloxamer 407 and tween 80) and using Crosspovidone (CPV) in different concentration. The compatibility between Felodipine and excipients was established by FTIR study and DSC. The effect of different type and concentrations of polymers, plasticizers, surfactants and CPV on mechanical properties, the in-vitro evaluation parameters was evaluated. HPMC E5 films show higher cumulative % drug release than films of other film forming polymers at the same concentration of polymer, plasticizer and surfactant. Hence, Formula (F14) containing 25 mg HPMC E5, 15 mg glycerin, 3.75mg Poloxamer 407 and 2 mg CPV showed the highest cumulative % drug release of 78 % at the end of 2 min and other excellent film characteristics. It was concluded that the Orodispersible films of Felodipine can be made by solvent casting technique with enhanced dissolution rate, better patient compliance and effective therapy.

Keywords: Felodipine (FD); Orodispersible films (ODFs); Poloxamer 407; HPMC E5.

INTRODUCTION

Oral route is the most convenient and preferred route of administration from the other various route of drug delivery. More than 70% of drugs are available in the market in the form of oral drug delivery system due to ease of ingestion, patient compliance, pain avoidance and versatility (to accommodate various types of drug candidates) and accurate dosing1. Approximately 60% of all dosage forms available are the oral solid dosage form. The decrease in bioavailability, long onset time of action and difficulty to swallowing patients turned the manufacturer to the parenteral and liquid orals. But the liquid orals have the drawback of accurate dosing and parenteral are painful route of drug delivery, so decrease patient compliance2. Drug delivery by the oral mucosa is a promising route, when one hopes to achieve a rapid onset of action or enhance bioavailability for drugs that have high first-pass metabolism, i.e. orally fast dissolving film, which permit a rapid dissolving drug to absorb directly into the systemic circulation through the oral mucosa. These types of dosage forms are also convenient for children, elderly patients having problem in swallowing3. Orodispersible films (ODFs) give quick absorption and instant bioavailability of drugs due to high blood flow and permeability of oral mucosa. The ODFs plays as an alternative over conventional tablets or capsules. ODFs combine all the advantages of tablets with those of liquid dosage forms. It has reduced hepatic first pass effect, dose accuracy and site specific action4.

Felodipine (FD) is a dihydropyridine calcium-channel blocker used in the management of hypertension and angina pectoris. Felodipine has the benefit it is more selective as vasodilator and less cardiac effects than non-dihydropyridine calcium-antagonists. This benefit is excluded by the poor bioavailability of the drug, which (in spite of the drug is absorbed completely from the gastrointestinal tract) is only 15% bioavailable after oral administration. The poor oral bioavailability of Felodipine is because it is undergo extensive first-pass metabolism and also it had low solubility in water5. The aim of this study is to prepare Felodipine as orodispersible films using solvent casting and to improve patient compliance.

MATERIALS & METHODS

Fourteen formulations (F1-F14) were prepared (table 1) by solvent casting method using different percentage of polymer and each film with surface area approximately 4 cm2 is loaded with 2.5mg Felodipine. The calculated amount of film forming polymer was dispersed in 20 ml of solvent (distilled water) with continuous stirring using magnetic stirrer for 3 hrs to form homogenous polymeric solution. To this polymeric solution 25% of plasticizer is added. In the next step the drug (Felodipine), surfactant, saliva stimulating agent (Ascorbic acid) and sweetener (Saccharin) were dissolved in 10 ml of water and ethanol as co-solvent (5ml water + 5ml ethanol) in another beaker to form clear solution. The two medium were mixed using magnetic stirrer for 1 h, the solution was kept in sonicator for degassing. Then the bubble free solution was casted onto petridishs and kept in hot air oven (50°C). Dried film is then removed and cut into the desired shape and size (2cm × 2cm) for the intended application. Cuts or imperfections were excluded from the study6.

Evaluation of Felodipine ODFs

Visual inspection: Properties such as homogeneity, color, transparency and surface of the oral films were estimated for all the prepared oral films. This parameter was tested simply by visual examination of films and evaluation of quality by feel or touch7.

Weight variation: Weight variation test confirms the uniformity of the film formed. Ten randomly selected films from each patch (each of 2 × 2 cm2) are cut and weighed individually and compared with the average weight for deviation8.

Thickness: The thickness of films was measured by using digital vernier caliper at 5 different positions (center and four corners) and the mean thickness was calculated. This is essential to establish uniformity in the thickness of the film as it is directly correlated to the accuracy of dose in the film9.

Drug content: Three films (2 × 2 cm2) are cut randomly from each formulation batch; these films were placed in 50 ml phosphate buffer pH 6.8 (0.5 % Brij 35) solutions and kept on magnetic stirrer for 1h. Then the solution was filtered, diluted suitably and absorbance was measured spectrophotometrically at λmax 362 nm, so the drug content was determined by the standard calibration curve of drug in phosphate buffer pH 6.810.

Surface pH measurement: The surface pH of oral film was determined so as to study the chance of any side effects in-vivo, because an acidic or alkaline pH may cause irritation to the oral mucosa. The pH value was determined by dissolving one oral film in 2 ml of distilled water and determining the pH of the obtained solution. The pH was measured by using pH-meter. Differences were expected because various polymers were used along with the addition of (API)11.

In-vitro disintegration time (DT): The disintegration time was determined by using petridish method, and it is defined as the time at which a film starts to break or disintegrate (in second). Film was placed into a petridish, after adding 2 ml of distilled water, the petridish was shaken continuously, then measure the time at which a film starts to break or disintegrate. The determination of disintegration time was carried out in triplicate for all the formulations12.

Folding endurance: Folding endurance measures the elastic properties or the flexibility of films. Folding endurance of films was measured by repetitively folding a small strip of films at the same place until broken or folded up to 300 times. The number of times films could be folded at the same place without breaking gives the value of folding endurance13.

Tensile strength: Tensile strength is the maximum stress applied to a point at which the film breaks. It was determined by holding a film of 5 × 2 cm2 (which must be free from air bubbles or physical imperfections) longitudinally in the Universal strength testing machine. Then the film was pulled by the clamp at a rate of 10 mm/min. Tensile strength is calculated by the applied load at rupture divided by the cross sectional area of the strip as given in the equation below14;

...

Percentage elongation (%E): When stress is applied on the film it will stretched and is referred to as strain. Strain is principally the deformation of the film divided by the original length of the film. Normally elongation of the film increases as the plasticizer concentration increases. Percentage elongation was calculated by measuring the increase in length of the film after tensile strength measurement by using the following equation15;

...

Where; L = Final length, Lo = initial length.

Young's modulus (YM): Young's modulus or Elastic modulus is the measure of stiffness of films. Hard and brittle films exhibit a high tensile strength and Young's modulus with small elongation. It is represented as the ratio of applied stress over strain in the region of elastic deformation as follows16;

...

In-vitro dissolution study: The in-vitro dissolution of Felodipine ODFs was studied by using USP type II dissolution apparatus (i.e. Paddle). Two films corresponding to 5 mg Felodipine allowed to dissolve in 500 ml of 6.8 phosphate buffer (0.5 % Brij-35) as the dissolution medium. The stirrer was adjusted to rotate at 50rpm. The temperature of the dissolution medium was maintained at 37±0.5 °C during the experiment with the film of 2 × 2 cm2. Samples of dissolution medium (5 ml) were withdrawn by means of a syringe at regular intervals (1, 2, 3, 4, 5, 10, 15 and 20 min). The aliquots were filtered through Whatman filter paper (0.45µm), and were analyzed for drug release at 362 nm spectrophotometrically. The volume withdrawn each time was replaced with fresh 6.8 phosphate buffer (0.5 % Brij-35) in order to maintain sink conditions. Cumulative percent Felodipine released was calculated and plotted against time17. The time required for 80% of drug to be released (T80%) and percent drug dissolved in 2 minutes (D2min) were considered for comparing the dissolution results18.

Drug polymer compatibility study

Fourier Transform Infrared Spectroscopy (FTIR): Drug polymer interactions were studied by FTIR spectroscopy. The spectrum was recorded for the drug, blank polymer, physical mixture of polymer and the drug in a ratio (1:1). Samples were mixed with potassium bromide (KBr) and pressed into the form of disc. The disc was analysed by FTIR spectroscopy from 4000-400 cm -1 19.

Differential Scanning Calorimetric Studies (DSC): DSC scans were recorded for the drug, physical mixture of drug - polymer in a ratio (1:1) and Felodipine ODFs. The samples (3-5 mg) was hermetically sealed in aluminum pans and heated at a constant rate of 10°C/min, over a temperature range of 25 °C to 300 °C. Thermograms of the samples were obtained using differential scanning calorimetry20.

Statistical Analysis

The results of the experiments are given as a mean of triplicate samples ± standard deviation and were analyzed according to the one way analysis of variance (ANOVA) at the level of (P<0.05) for significant results and (p>0.05) for non-significant results.

RESULTS AND DISCUSSION

Visual inspection

All the prepared films were opaque white to yellow, homogenous, thin and soft.

Weight variation

The results expose that: the average weights for all the prepared formulas were uniform and conform with referred values which range from 47.4±2.1 to 53.1±2.78 mg (table 2). The weight of the patches were determined using digital balance, all patches shows uniformity.

Thickness

Table 2 gives the average thickness values of films of all the formulation. The thickness was found to vary between 0.09±0.018 to 0.13±0.02 mm. A very low standard deviation value is indicating that the method used for the formulation of films is reproducible and give films of uniform thickness and hence dosage exactness in each film can be ensured.

Drug content

The result (table 2) showed that all the prepared films were found to contain a nearly even quantity of the drug approximately from 94.3±4.72 to 101±8.2 % the content uniformity studies indicating reproducibility of the technique used. The preparations met the standards of British Pharmacopeia content uniformity (85-115) % of the label claim. On this basis, it was found that the drug was spread uniformly throughout the 4 cm2 constant area of the film.

Surface pH measurement

The surface pH of all the films was found to be within (5.8±0.2 - 6.3±0.2) as shown in (table 2), which is within the range of salivary pH. No significant difference (p<0.05) was found in surface pH of different films.

Mechanical properties

Mechanical properties of the films are important for film casting on release liners, punching and packaging. Orally dissolving films should possess moderate tensile strength (TS), high % elongation (%E), and low elastic modulus (EM), in addition folding endurance values were considered satisfactory (>100 times) or folded maximum 250 times21. The result (table 2) shows that all the formulations have acceptable mechanical properties.

Effect of type and concentration of film forming polymer

Results shows that films containing HPMC E5 (F1), HPMC E15 (F2), PVA (F3) and MC (F4) had good mechanical properties as represented in (table 3). But, the prepared HPMC E5 oral films have the faster disintegration time than HPMC E15, PVA and MC formulations.

Also the results of tensile testing shown in table 4 reveal that increasing the polymer concentration produced films with higher tensile strength. The in-vitro release of Felodipine from formulation (F1- F2) is shown in figure 1. The value of DT of (F1) and (F2) were 44 s and 56.3 s respectively (table 2); While the values of T80% for (F1) and (F2) was 4.8 and 9 min respectively (table 3).

The difference in dissolution may be attributed to the differences in viscosity grade of HPMC film forming polymer. It was observed that the drug release rate decreases significantly (p < 0.05) as the concentration of HPMC E5 was increase from 52.36% (w/w) in formula (F5) to 57.14% (w/w) in formula (F6) (figure 2). This might be due to that higher concentration of polymer, results in creation of high viscosity gel layer produced by more close contact between the particles of HPMC E5 results in a reduced movement of drug particles in swollen matrices, which leads to a decrease in release rate22. Therefore, HPMC E5 (52.36% w/w) was considered the best concentration and was chosen for the design of the subsequent formulas through the study.

Effect of the type and concentration of plasticizer

The result (table 2) showed that both changing the plasticizer types and concentration had non-significant difference (p>0.05) on the disintegration time of oral films. This may be due to that the two plasticizers are water soluble and they will diffuse out from films in aqueous media making void places in the film through which diffusion of fluid occurs, facilitating film disintegration, the same result were reported by Abd-Alhammid SN et al23. While table 4 showed that the increase in the plasticizer concentration 22.2 % (F8), 26.3 % (F6) and 30 % (F9) produced a significant (p<0.05) decrease in elastic modulus, and the tensile stress. Decrease in tensile strength as a function of plasticizer concentration may be due to weakening of the intermolecular forces between polymer chains, thus leading to decrease the rigidity of three-dimensional structure formed upon drying the film24. The effect of plasticizer type and concentration on release profile are shown in figure 3 and figure 4, that there is no significant (p>0.05) effect by altering the type of plasticizer (figure 3), while increase the concentration of plasticizer have significant (p<0.05) effect on Felodipine release (figure 4).

Effect of type and concentration of surfactant

The results also discovered that the increase in concentration of Poloxamer 407 significantly (p<0.05) reduces the DT (table 2), being that the surfactant accelerates the diffusion of fluid into the film giving quicker disintegration of the film. Hence the formula (F11) formulated with high Poloxamer 407 content disintegrated faster (31.7±1.5 s) as compared to the films prepared with low Poloxamer 407 content (F12), Similar result were reported by Patel R J et al25. The release of Felodipine from formulas (F9) and (F10) which contain (5% w/w) of Poloxamer 407 and tween 80 respectively is shown in (figure 5). It was observed that the drug release was faster (p < 0.05) in case of hydrophilic surfactant Poloxamer 407 (HLB value of Poloxamer 407 is 22 while HLB value of tween 80 is 1526). The T80% values for formulas (F9) and (F10) are (3.3±0.17 and 7±0.43 min) respectively (table 3), This is due to the hydrophilic nature of the surfactant, Poloxamer 407 acts by decreasing drug surface tension and increased drug wettability; thus, the dissolution rate of Felodipine was improved noticeably27. The release of Felodipine from formulas (F9, F11 and F12) which contain (5, 7.3 and 2.56% w/w) respectively of Poloxamer 407 is shown in (figure 6). It was shown that as the concentration of Poloxamer 407 increases the rate of release of Felodipine improve significantly (p < 0.05), similar results were reported by Radhi A A et al28.

Effect of Crosspovidone (CPV)

The results (table 2) indicated that there is a significant changes (p>0.05) on the in-vitro DT, by the addition of CPV (F13 and F14). It was observed that DT of the film decreased from 31.7 to 20.7 s with increase in the concentration of CPV from 0.0 to 3.75%, further increase in the concentration of CPV (>6%) lead to increase the disintegration time due to blockade of capillary pores which prevents the entry of fluid into the film, The same results were recorded by Ghorwade V et al29. Other characteristics of Felodipine oral Films were mechanically examined and results explained that the addition of CPV has no significant changes (p>0.05) for all related parameters (tensile strength, % elongation) as shown in table 4). Similar result was found with Montelukast fast dissolving films30. In the other hand there is a significant difference (p>0.05) in the release profiles between formula prepared without CPV (F12) and the formulas with CPV (F13 and F14), as shown in table 3 in which the T80% for (F14) is (2.1 ± 0.17min) and the D2 min (%) is about (78 ± 6.2 %). Figure 7 show the effect of addition of CPV on release profile of Felodipine ODFs.

Drug polymer compatibility study

Fourier Transform Infrared Spectroscopy (FTIR): Fourier transform infrared (FTIR) spectral study was done to discover the chemical stability or interaction of the drug with the other component of formulation. The FTIR spectra of pure Felodipine, HPMC E5 and physical mixture (drug + polymer) are shown in figure 8, 9 and 10 respectively.

FTIR spectra of pure drug Felodipine (figure 8) show characteristic absorption peaks at (3370 cm-1 is due to N-H stretching, 2947.66 cm-1 is due to stretching of C-H bond, the peaks at 1697.05 cm-1 is due to C=O bonds (carbonyl group), peak at 1620.88, 1496.49 and 1430.92 cm-1 are due to C=C bond of benzene ring, 1206.26 cm-1 is due to C-N stretching, 1099.23 cm-1 is due to C-O-C stretching of ester, 727.03, 800.31 cm-1 are due to substituted benzene ring and 565.04 cm-1 is due to Cl stretching). Similar characteristic absorption peak were observed by Upendra K et al31 and Raghavendra RNG et al32. The presence of these characteristic peaks of the drug and polymer in the IR spectrum of physical mixture (drug + polymer) indicates that there is no interaction between the drug and polymer of the formulation.

Differential Scanning Calorimetric Studies (DSC)

Felodipine peak was clear in its DSC thermogram representing a sharp characteristic endothermic peak around its melting point; such sharp endothermic peak indicates that Felodipine used is in pure state as compared with reference31. A single endothermic peak corresponding to melting point of FLD was observed at 148.8C° (figure 11).

Endothermic peak of mixture containing FLD and HPMC E5 was observed at 145.39 °C (figure 12), it indicate no interaction between drug and polymer.

Upon scanning the DSC thermogram of Felodipine ODFs a complete disappearance of the drug fusion peaks (figure 13) suggesting that Felodipine was molecularly dispersed in an amorphous form in ODFs and/or homogeneous dissolution of the drug in the polymer matrix, similar results were observed by Shubhrajit M et al33.

CONCLUSION

Based on the results, it can be concluded that the best formula (F14) which contain 46.95% HPMC E5, 30% Glycerin, 7.3% Poloxamer 407 and 3.75% Crosspovidone in terms of showing the fastest in-vitro disintegration time. In addition, an acceptable mechanical properties and dissolution behavior achieved. An increasing the concentration of HPMC E5 resulted in lowering disintegration and drug release rates of Felodipine ODFs. As the concentration of Poloxamer 407 is increased, both the disintegration and the drug release rates increased. Successful enhancement of dissolution of Felodipine ODFs was done by using superdisintegrant (Crosspovidone) at 3.67 % w/w (F14). Finally, the overall results suggest that Felodipine could be prepared as an orodispersible film utilizing the suitable prepared formulation.

CONFLICT OF INTERESTS

The authors report no conflict of interests.

ACKNOWLEDGMENT

We extend our appreciation to the University of Baghdad, Collage of pharmacy for granting this research project.

References

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