Fast-Dissolving Sublingual Films of Terbutaline Sulfate: Formulation

Jul 8, 2013 - (6, 7) Rapidly dissolving or disintegrating dosage forms and soft gelatin ..... Pressurized metered dose inhalers have the problems of d...
0 downloads 0 Views 303KB Size
Download PDF
Article pubs.acs.org/molecularpharmaceutics

Fast-Dissolving Sublingual Films of Terbutaline Sulfate: Formulation and In Vitro/In Vivo Evaluation Soha Sayed,† Howida Kamal Ibrahim,*,‡ Magdy Ibrahim Mohamed,‡ and Mohamed Farid El-Milligi† †

Department of Pharmaceutics, College of Pharmacy, Misr University for Science and Technology, 6th of October City, Egypt Department of Pharmaceutics, Faculty of Pharmacy, Cairo University, Cairo, Egypt, 11562

‡

ABSTRACT: Terbutaline sulfate fast dissolving sublingual films were prepared using seven drug compatible film formers in different combinations and proportions. The film polymers are maltodextrin, Na alginate, Carpabol 430, xanthan gum, HPMC E5, PVP K-25, and Na CMC. Propylene glycol and sorbitol were used as plasticizers and mannitol as filler. The optimum polymer concentrations and the plasticizer amount were selected on the basis of flexibility, tensile strength, and stickiness of the films. The prepared films were evaluated for their tensile strength, thickness uniformity, disintegration time (in vitro and in vivo), in vitro dissolution, and moisture content. Polymer type rather than total polymer concentration or plasticizer amount showed a significant effect on the tested film properties. A randomized, single dose, crossover study was conducted in four healthy volunteers to compare the pharmacokinetic profile of terbutaline sulfate from the prepared films and the conventional oral tablets. The film formula of choice gave a significantly faster drug absorption rate and recorded a relative bioavailability of 204.08%. Sublingual films could be promising as a convenient delivery system for terbutaline sulfate in patients with swallowing problems. The improved extent of absorption (higher AUC(0−24)) indicates success in improving drug bioavailability, and the faster absorption rate could be promising for the management of acute episodes of asthma. KEYWORDS: terbutaline sulfate, sublingual, fast dissolving film

■

INTRODUCTION

They are of great importance during the emergency cases whenever an immediate onset of action is desired.8 This work aimed to formulate terbutaline sulfate as sublingual films in a trial to improve its bioavailability and to improve patient compliance. A fast dissolving property could help in the management of acute asthmatic attacks.

Terbutaline sulfate is a selective β2 receptor agonist widely used as bronchodilator. Commercially, it is available in formulations for oral intake, inhalation, and injection. In healthy subjects the bioavailability of oral terbutaline sulfate is 14−15%. This low bioavailability is due to various factors, including stereoselective absorption, but the main factor is hepatic first pass metabolism.1 Food impairs the bioavailability by about onethird because of reduced absorption.2 Terbutaline sulfate is available commercially in Egypt as syrup, conventional tablets, and inhalation. Drug delivery via the oral mucous membranes is a promising alternative to the oral route for avoiding presystemic metabolism or instability in the GIT. The relatively less thickness and the higher blood flow of the sublingual area of the oral cavity makes it more permeable than the buccal and palatal areas.3,4 In some cases, the sublingual route provides an alternative to invasive intravenous dosing if rapid delivery to the systemic circulation is required. It is safer and more comfortable for the patient.5 Sublingual pharmaceuticals are acceptable as drug delivery systems for patients with swallowing problems. Furthermore, sublingual drug administration is simple and relatively costeffective.6,7 Rapidly dissolving or disintegrating dosage forms and soft gelatin capsules are suitable for creating high drug concentration in the sublingual region. Fast dissolving films have several advantages over the conventional dosage forms. © XXXX American Chemical Society

■

EXPERIMENTAL SECTION Materials. The materials and suppliers were as follows: terbutaline sulfate (AstraZeneca Company Pharmaceuticals Productions, Sweden); hydroxypropyl methylcellulose (HPMC E5) purchased from Colorcon Limited (Kent, England); sodium carboxymethylcellulose (Na CMC), xanthan gum, guar gum, Carbopol 940, and maltodextrin supplied from Sigma Company for pharmaceuticals (Australia); polyvinylpyrrolidones (PVP K-25) from BDH Chemicals Ltd. (Poole, England); polyethylene glycol (PEG 4000) from Fluka AG Buchs SG (Switzerland); propylene glycol (PG), sodium alginate, sorbitol, and mannitol supplied from El-Nasr Pharmaceuticals Company (Cairo, Egypt). Compatibility Studies of Terbutaline Sulfate with the Suggested Excipients. Differential scanning calorimetry

Received: February 9, 2013 Revised: June 25, 2013 Accepted: July 7, 2013

A

dx.doi.org/10.1021/mp4000713 | Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Molecular Pharmaceutics

Article

Table 1. Composition and Evaluation Parameters for the Prepared Terbutaline Sulphate Sublingual Fast Dissolving Films formula F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

film forming polymer(s) 2.5% HPMC E5 2.5% Na alginate 1.25% xanthan gum 3.125% HPMC−xanthan gum (4:1) 3.75% HPMC−Na CMC (2:1) 3.75% HPMC−PVP-K25 (2:1) 3.125% Na alginate−xanthan gum (4:1) 3.125% Na alginate−Carbopol (4:1) 5% HPMC−maltodextrin (1:1) 5% HPMC−Na alginate−maltodextrin (1:1:2)

plastizicer−H2O ratio

tensile strength (kg/mm2)

3:17 3:17 3:17 1:19 2:18 1:19 3:17 3:17 1:19 1:19

15.45 ± 1.01 24.70 ± 1.54 3.79 ± 0.21 8.20 ± 0.53 4.84 ± 0.31 26.56 ± 1.40 3.86 ± 0.12 5.74 ± 0.44 14.45 ± 1.31 18.28 ± 1.48

in vivo disintegration (min)

release rate (mg/min)

PMAa (%)

± ± ± ± ± ± ± ± ± ±

17.01 ± 1.56 23.10 ± 2.31 6.86 ± 0.64 10.21 ± 0.93 13.27 ± 1.41 17.08 ± 1.53 6.97 ± 0.51 15.85 ± 1.39 20.74 ± 1.87 16.80 ± 1.09

19.29 196.4 142.8 110.9 201.46 21.49 83.28 65.43 8.98 1.871

0.51 0.56 3.45 1.47 1.27 0.56 1.12 1.78 0.54 0.42

0.11 0.26 1.06 0.89 0.76 0.35 1.19 0.97 0.21 0.53

PMA: Percentage moisture absorption after storage at 97% relative humidity for 15 days. The drug amount was fixed at 50 mg and mannitol at 6 mg per 20 mL total preparation volume.

a

obtained solutions were casted onto plastic Petri dishes, previously cleaned, and dried. Plates were kept in oven at 50 °C for 24 h. Dried films were carefully removed, checked for any imperfections, and cut into squares of different dimensions for further characterizations using sharp razor blade. They were individually sealed in airtight packets and stored at 25 °C until use. In Vitro Characterization of the Prepared Films. Visual Inspection. The prepared films were tested visually for their appearance, color, and elegance, as well as for drug precipitation, air bubble entrapment, or cracks. The ease of removal from the Petri dish was also evaluated. Film Thickness Uniformity. The thickness of the prepared films was measured at five places (center and four corners) using Vernier Caliper, China, and the mean thickness and % RSD were calculated.10 Determination of Tensile Strength. The tensile strength of the prepared films was carried out using Chaillon force equipment at speed of 50 mm/min (H1KS, USA) using a constant rate of straining method.11 A specimen film sample of 2 × 8 cm was placed in the grips of the testing machine; the grips were tightened evenly and firmly, and then the maximum force and extension were recorded. In Vitro Disintegration Time. The test was performed using tablet disintegration apparatus (Pharma Test, type PTZ2, Germany) according to the specifications of European Pharmacopeia 5.4 ed. for orodispersible films. Three (4 cm2) film sections of each formula were tested in phosphate buffer of pH 6.8 at 37 °C. The time required for complete film disintegration, where no residue is left on the screen, was recorded using a stop watch. The mean values were calculated.12 In Vivo Disintegration Time. Four healthy male volunteers aging (26−45) years were involved in the determination of the disintegration time of the prepared films in the buccal cavity. One film section of 4 cm2 of each formula was placed under the tongue with 1 h time intervals. Gentle tumbling action on the film without biting was allowed, and the time required for the complete film disintegration was recorded using a stop watch. The subjects were asked to spit out the content of the oral cavity after film disintegration and to rinse their mouths with distilled water. The swallowing of saliva was prohibited during the test. The study protocol was approved by the Research Ethical Committee of Faculty of Pharmacy, Cairo University. Comfort and sensation during and after film administration were evaluated using a score system from 0 to 3, where 0 refers

(DSC) and Fourier transform infrared spectroscopy (FT-IR) studies were conducted to screen excipients commonly used as film forming polymers and plasticizers for drug compatible ones. Solid state characterization was done for terbutaline sulfate, each excipient, and 1:1 physical mixtures of drug− excipient. Samples (2−4 mg) were placed in aluminum pan and heated in the rate of 10 °C/min, to a temperature of 200 °C (differential scanning calorimeter DSC-50, Shimadzu, Kyoto, Japan, connected with thermal analyzer TA-501 and Desk jet 500c printer). The instrument was calibrated with indium, and dry nitrogen was used as a carrier gas with a flow rate of 25 mL/min. The IR spectra were recorded for drug discs after grinding with about 100 mg of dry KBr powder and compression (FT-IR spectrophotometer; Bruker 22, UK). Preliminary Experiments. Experiments were done to determine the optimum concentration of each polymer as well as the optimum plasticizer−distilled water ratio. For each polymer, a series of different concentrations were tested at a fixed plasticizer−H2O ratio of 2:18. The total preparation volume was fixed at 20 mL, and mannitol was added as a filler in amounts of 6 mg/plate. The tested concentrations were 0.25, 0.5, 0.75, 1, and 1.5 g/plate for HPMC E5, PVA, maltodextrin, Na alginate, PEG 4000, and Na CMC. For xanthan gum, Carbopol 940, PVP-K25, and guar gum, the tested concentrations were 0.05, 0.1, 0.125, and 0.25 g/plate. Different polymer combinations were also tried, and the obtained films were evaluated for their appearance, color, elegance, continuity, texture, presence of air bubbles, stickiness to Petri dish, cracks, cuttings, and imperfections. For optimization of plasticizer−H2O ratio for each polymer, sorbitol and propylene glycol were tested as plasticizers. Series of combinations were tried at fixed polymer composition, namely, 19.5:0.5, 19:1, 18.5:1.5, 18:2, 17.5:2.5, and 17:3. The suitable plasticizer and its concentration were selected on the basis of appearance, flexibility, and stickiness of terbutaline sulfate films. Preparation of Terbutaline Sulfate Sublingual Films. Ten fast-dissolving sublingual films of terbutaline sulfate were prepared by the solvent casting method.9 Table 1 shows the detailed composition of the prepared films. Aqueous solutions were prepared by dissolving the specified polymer(s) amounts by magnetic stirring. For films containing Carpobol, neutralization was conducted using triethanolamine. The plasticizer, the filler (mannitol), and the drug were then added and mixed. The B

dx.doi.org/10.1021/mp4000713 | Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Molecular Pharmaceutics

Article

and was used to calculate the AUC(0‑∞). The percentage relative bioavailability (RB) was also calculated as (AUC(0‑∞)(sublingual film)/AUC(0‑∞)(oral tablets)) × 100. Results are expressed as mean values with standard deviation. The pharmacokinetic data between different formulations were compared for statistical significance using a paired t test at P = 0.05 and software package Graph Pad Prism 5 for windows version 5.04 1992−2010 software.

to very satisfied, 1 for quite satisfied, 2 for not satisfied, and 3 for not satisfied at all. Parameters of comfort included convenience of administration, quickness of disintegration, and suitability of pharmaceutical form for taking without water, while sensation was evaluated considering residues left in the mouth after administration.13 In Vitro Dissolution Study. The study was conducted using USP dissolution apparatus I in 300 mL buffer solution of pH 6.8 at 37 ± 0.5 °C and 50 rpm. One film section of 4 cm2 area was placed in each basket, and samples were withdrawn every 2 min up to 30 min for spectrophotometric analysis at λmax = 276 nm (none of the used ingredients interfered with the drug peak). The experiments were conducted in triplicate, and mean values were calculated. The dissolution rate of the drug during the first 4 min (DR4 min) and the dissolution efficiency after 30 min (DE30 min) were calculated for assessment and comparison.14 Determination of Moisture Content and Moisture Absorption Capacity. Moisture content of the freshly prepared and the stored films (at 97% relative humidity for 15 days) was determined using a Karl Fischer Titrator apparatus 787KF Titrino (Metrohom AG, Riverview FL, USA). Films were pulverized, inserted in the titration vessel containing dried Karl Fischer grade methanol, and titrated with Hydranal composite 5 reagent (Riedel deHean Seelze, Germany) after a stirring time of 3 min. Percentage moisture absorption (PMA) in gm/cm2 was calculated according to Alagusundaram et al. and Shivaraj et al.15,16 Bioavailability Studies. A randomized, single dose, crossover study was conducted in four healthy volunteers to compare the pharmacokinetic profile of terbutaline from the selected prepared film and the conventional oral tablets. Volunteers were fasted overnight, and the tested preparations were administered sublingually in a dose of 7.5 mg applying a wash out period of two weeks. The study protocol was approved by the Research Ethical Committee of Faculty of Pharmacy, Cairo University. Blood samples were collected prior to dosing and up to 24 h post administration. The collected blood samples were centrifuged at 2000 × g for 10 min, and the plasma was carefully drawn and collected into sodium-heparinized Venoject sampling tubes. The plasma was stored at −20 °C until the analysis of terbutaline. Terbutaline sulfate was analyzed adapting the method developed by Narendra et al.17 Serum samples were homogenized with the required amount of methanol using a vortex mixer and centrifuged. The supernatant was assayed for terbutaline sulfate by HPLC (AGILENT LC-1200), using hypersil ODS column (4.6 × 150 mm, 5 μm ID, G1316A) with a multiple UV wavelength detector (Germany, G1365B), quaternary pump (G1311A), and auto sampler (G1329A). To assess the bioavailability of terbutaline sulfate, the plasma concentration−time data were evaluated, and different pharmacokinetic parameters were calculated by noncompartmental analysis using WinNonlin standard edition software (Version 1.5, Scientific Consulting Inc., Pharsight Corp., Cary, NC, USA). Cpmax in μg/mL was determined as the highest observed concentration during the study period, and Tmax (h) is the time at which Cpmax occurred. The area under the plasma− concentration−time curve up to the last measured time point (AUC(0−24), μg.h/mL) was calculated by the trapezoidal rule. The residual area was calculated by dividing the concentration of the last measured time point by the elimination rate constant

■

RESULTS AND DISCUSSION Compatibility Studies of Terbutaline Sulfate with the Suggested Excepients. The DSC thermogram of terbutaline sulfate is characterized by one sharp endothermic peak at about 246.08 °C corresponding to its melting point.18 The DSC thermograms of PVP, PVA, HPMC, mannitol, PEG 4000, guar gum, Na alginate, maltodextrin, Carbopol 940, and xanthan gum show characteristic endothermic peaks at about 56.58, 287.76, 323.88, 168.53, 63.2, 84.11, 65.01, 64.51, 106.00, and 269 °C, respectively, which properly corresponds to their melting points. No change in drug melting peak was recorded in any of the DSC thermograms of drug−excipient physical mixtures proving the absence of physical interaction between drug and all the tested excipients. Similarly, the characteristic IR absorption peaks of terbutaline (3330, 2837, 2393, 1679, 839, and 781 cm−1) were persistent in the drug/excipients physical mixtures. No extra peaks were observed in such IR spectra, showing no chemical interaction and indicating good drug excipients compatibility. Preliminary Experiments. Results showed that only HPMC E5 and Na alginate succeed in forming films as single polymers with optimum concentration of 2.5%. The formed films were free from air bubbles, cuttings, or cracks. They were transparent and easily removed from the Petri dishes. Dinge and Nagarsenker13 reported that HPMC E series gave films with the most desired properties at the concentration of 2.2% w/v. The 1.25% xanthan gum gave acceptable but less elegant films, while guar gum, Carbopol 940, Na CMC, PEG 4000, PVP K-25, PVA, and maltodextrin failed to form films when used separately at any of the tested concentrations. The above results suggested the use of polymer combinations. Polymer combinations of HPMC/xanthan gum, HPMC/ PVP, HPMC/Na CMC, HPMC/maltodextrin, Na alginate/ xanthan gum, Na alginate/Carbopol 940, and HPMC/ maltodextrin/Na alginate formed successful films and were considered for further evaluations. The optimum polymer compositions were determined for each formula, and the results are shown in Table 1. Propylene glycol was more efficient as a plasticizer than sorbitol in obtaining acceptable film properties probably due to its more negative heat of solution and less hygroscopicity as compared to sorbitol. In addition, such a negative heat of solution is expected to give more cooling sensation in the mouth, and thus propylene glycol was used in all films. The plasticizer-to-water ratio was determined for each polymer combination, Table 1. In Vitro Characterization of the Prepared Films. Visual Inspection. Visual inspection showed that the 10 prepared films were homogeneous, transparent, and free from air bubbles and cracks. The films were easily handled and removed from the plates. Film Thickness Uniformity. Film thickness values ranged from 0.088 to 0.42 mm. The prepared films showed high C

dx.doi.org/10.1021/mp4000713 | Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Molecular Pharmaceutics

Article

thickness uniformity (the calculated % RSD values were less than 0.045). The films can be arranged according to their thickness values as follows: F7 > F5 > F6 > F10 > F8 > F9 > F4 > F2 > F1 > F3. The increasing polymer concentration increased film thickness values regardless of the plasticizer/ water ratio or film composition. Determination of Tensile Strength. All tested films showed acceptable tensile strength values, as in Table 1. The films can be arranged according to their tensile strength values as follows: F6 > F2 > F10 > F1 > F9 > F8 > F5 > F7 > F3. The best results were recorded with HPMC and Na alginate films. Similarly, ElGendy et al.19 reported that the HPMC E series has a high elongation ability due to its high viscosity and cross-linked structure. The addition of PVP K-25 increased the tensile strength of HPMC, while maltodextrin had no remarkable effect. Similar results about the suitability of PVP for forming flexible films were obtained by Ali and Quadir.20 Xanthan gum, Na CMC, and Carbopol significantly decreased the tensile strength of both Na alginate and HPMC based films. This could be attributed to the interruption of the structure of the polymers. Neither the polymer concentration nor the plasticizer/water ratio had a clear effect on film tensile strength. In Vitro Disintegration Time. All of the prepared films satisfied the requirement of disintegration time for fast dissolving dosage forms except formula F3. The in vitro disintegration time mean values ranged from 1.05 to 3.05 min for all films, while formula F3 recorded a mean disintegration time of 4.2 min. The time required for complete film disintegration was related to the polymer type rather than total polymer concentration, tensile strength or plasticizer amount. Alginate and HPMC based films recorded the fastest disintegration when used alone and in mixtures with PVP-K25 and maltodextrin. It was reported that HPMC E with a high percentage of hydroxypropyl groups (7−12%) are more suitable for formulating films with fast hydration, rapid disintegration, and quick dissolving properties.21,22 Xanthan gum film had the longest disintegration time. Moreover, adding xanthan gum, Na CMC, and Carbopol prolonged the disintegration time of HPMC and alginate films. In Vivo Disintegration Time. Table 1 shows that the in vivo disintegration time mean values ranged from 0.42 to 3.45 min. These results correlates well with the previously discussed in vitro values considering polymer type dependence, but the in vivo values were smaller than the in vitro ones. This may be attributed to the added pressing effect of the tongue in the former case which could help in film disintegration. The involved human subjects were satisfied with the quickness of film disintegration and the convenience of taking it without water. The mean score values of comfort and sensation were 0.5, 0.75, 0.75, and 0.25 for F1, F2, F9, and F10 films, respectively, indicating a high degree of satisfaction with film taste. On the other hand, some subjects reported the presence of residues in the mouth after administration of F3, F4, F5, F6, F7, and F8 films. The score values for those films ranged from 1.75 to 2.25. This unpleasant sensation could be attributed to some undissolved xanthan gum, Carbopol 940, or Na CMC after disintegration. In Vitro Dissolution Study. Figure 1 shows the dissolution profiles of terbutaline sulfate from the prepared films. All films promptly released their entire drug content within 5−25 min except for formula F3, which released only 70% of its loaded drug within the test duration (30 min). A good correlation exists between the calculated dissolution rate (DR4min) of each

Figure 1. In vitro dissolution profiles of terbutaline sulfate from the prepared sublingual fast dissolving films in buffer solution of pH 6.8 (error bars were omitted to facilitate curve interpretation). Dissolution efficiency: DE = ∫ t0(y·dt)/(y100t) × 100.

film and its disintegration time, Table 1. The faster the disintegration, the higher the dissolution rate value of the film. The dissolution efficiencies (DE30min) of the prepared films ranged from 55.28 (±1.2) % to 93.49 (±0.83) %, values between brackets represent the standard deviation. Film formulas could be arranged according to their dissolution efficiency values as F1 > F2 > F9 > F10 > F8 > F6 > F7 > F4 > F5 > F3, Figure 1. The dissolution parameters were a function of polymer type, while no significant effect for the total polymer concentration, film tensile strength, or the plasticizer amount on the dissolution could be figured out of the results. Determination of Moisture Content and Moisture Absorption Capacity. The moisture content values of the freshly prepared films were 8.24 (±0.015), 5.9 (±0.02), 9.62 (±0.05), 10.17 (±0.01), 13.04 (±0.003), 5.75 (±0.05), 4.84 (±0.002), 6.516 (±0.02), 2.72 (±0.076), and 2.78% (±0.019) % for film formulas F1−F10, respectively. The observed results of percentage moisture absorption (PMA) after storage at 97% relative humidity are shown in Table 1. Film formulas F2, F3, F4, and F5 absorbed from 1- to 2-fold their initial moisture content. They softened and lost their resistance to elongation. The percentage moisture absorption ranged from 19.29 to 83.28% for formulas F1, F6, F7, and F8 with a moderate decrease in tensile strength. Formulas F9 and F10 showed the highest resistance against moisture absorption and recoded tensile strength values of 13.21 and 18.00 kg/mm2, respectively after storage. Films based on HPMC alone and in combination with other polymers recorded high resistance against moisture absorption except with Na CMC. Alginate and xanthan gum based films had a higher affinity for moisture absorption. The addition of maltodextrin significantly decreased the percentage moisture absorption after storage at 97% relative humidity. This effect was concentration-dependent. Bioavailability Studies. The aforementioned in vitro evaluations recommended film formula F10, prepared using a 1:1:2 mixture of HPMC−Na alginate−maltodextrin and 1:19 propylene glycol to water, for in vivo evaluation. This film showed fast disintegration (25 s.), high tensile strength (18.28 kg/mm2), and fast release rate (RR4 min = 16.8 mg/min). It recorded the lowest percentage moisture absorption (1.871%) and maintained satisfactory flexibility and resistance to elongation after storage at 97% relative humidity for 15 days. D

dx.doi.org/10.1021/mp4000713 | Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Molecular Pharmaceutics

Article

oral route, while the selection of a suitable inhalation device and the ease of its use for young and elderly patients appear as drawbacks for inhaled terbutaline. Pressurized metered dose inhalers have the problems of decreased ventilator capacity and the need for coordination between actuation and inhalation. The absence of chlorofluorocarbon and surfactants in dry powder inhalers avoids the problem of bronchoconstriction. But such inspiratory flow-driven inhalers necessitate patient ability to produce sufficient peak inspiratory flow rates.23,24 Davies25 and Borgström and Nilsson26 studied the metabolic fate of inhaled terbutaline and showed that less than 10% of the dose was absorbed from the airways to produce the therapeutic effect. The remaining dose fraction was swallowed and largely metabolized (only 6.7% was systemically available via the oral route). Other results indicated considerable intersubject variation in pulmonary absorption.27

The mean plasma concentrations of terbutaline sulfate, after administration of 7.5 mg terbutaline sulfate as sublingual film and as conventional oral tablets, are illustrated in Figure 2. The

Figure 2. Mean plasma concentrations of terbutaline sulfate over 24 h period after single 7.5 mg sublingual and oral dose administration to healthy volunteers, n = 4.

■

CONCLUSION Terbutaline sulfate films were successfully prepared using affordable excipients and an easy reproducible method of preparation. A sublingual route of delivery is promising for avoiding the metabolism of the drug in the gut wall and liver. The fast disintegration and dissolution introduces the optimized film formula as a promising convenient delivery system for the management of acute episodes of asthma. Further investigations in asthmatic patients of different age groups should be conducted to support the obtained results clinically and to optimize the dose.

mean maximum plasma concentration with sublingual film was 12.525 μg·mL−1, Table 2. This was significantly higher than the value observed with the oral tablets 8.143 h (p = 0.001). The obtained absorption rate of the oral tablets was similar to that obtained by Nyberg2 after oral administration of the same dose (Cmax = 7.9 (5.4−10.0) μg/mL and Tmax is 3.3 (2−4) h after fasting conditions).The prepared films significantly shortened the Tmax (2.5 h with a confidence interval of 1.85−3.15 versus 3.5 h for the conventional oral tablets). Similarly, the AUC(0−24) of the films was significantly higher than that of the oral tablets (about 1.5-fold). The mean values of AUC(0‑∞) of terbutaline were similar for the sublingual films and the oral tablets; the paired t test demonstrated no significant difference between the two formulations for this parameter. This statistically nonsignificant difference could be attributed to the small population size. The ratio of mean total area under the curve AUC(0−∞) of sublingual films to oral tablets was 204.08%, which reflects a higher amount of drug absorption over 24 h. This could be due to avoiding the first pass effect. The analysis of pharmacokinetic parameters confirmed that the administration of terbutaline sulfate by sublingual route gave a faster drug absorption rate than with the oral tablets. Indeed, about 1.5-fold greater mean plasma terbutaline sulfate concentration was achieved as soon as 2.5 h after administration of the sublingual films. Considering this faster absorption in addition to the documented limited bioavailability, the side effects and the inconveniencies of using inhalers suggests that sublingual terbutaline could be an acceptable alternative for the management of acute episodes of bronchial asthma. Inhaled therapy has the advantage of direct delivery to the target area with consequent faster onset of action compared to

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: 00201111344459. Fax: 002027001060. Notes

The authors declare no competing financial interest.

■

REFERENCES

(1) Stlhl, E. L.; Ribeiro, B.; Sandahl, G. Dose Response to Inhaled Terbutaline Powder and Peak lnspiratory Flow Through Turbuhalers in Children With Mild to Moderate Asthma. Pediat. Pulmonol. 1996, 22, 106−110. (2) Nyberg, L. Pharmacokinetic parameters of terbutaline in healthy man. An overview. Eur. J. Respir. Dis. Suppl. 1984, 134, 149−60. (3) Keiko, T.; Yasuko, O.; Tsuneji, N.; Thorseinn, L.; Kozo, T. Buccal absorption of ergotamine tartrate using the bioadhesive tablet system in guinea-pigs. Int. J. Pharmaceutics 2002, 238, 161−170. (4) David, H.; Joseph, R. R. Drug delivery via mucous membrane of the oral cavity. J. Pharm. Sci. 1992, 81, 1−10. (5) Malke, M.; Shidhaye, S.; Kadam, V. J. Formulation and evaluation of Oxacarbazine fast dissolve tablets. Ind. J. Pharm. Sci. 2007, 69, 211− 214. (6) Jain, N. K. Controlled and novel drug delivery, 1st ed.; CBS Publishers and Distributors: New Delhi, India; 2004; pp 52−74.

Table 2. Mean and Confidence Intervals of Pharmacokinetic Parameters of Terbutaline Sulphate Sublingual Fast Dissolving Films (Formula F10) and the Conventional Bricanyl Oral Tablets sublingual films

conventional oral tablets parameters

mean

confidence interval

mean

confidence interval

Cpmax (μg·mL−1) Tmax (h) AUC(0−24) (μg·h·mL−1) AUC(0−∞) (μg·h·mL−1)

8.143 ± 1.10 3.5 ± 0.21 40.016 ± 2.34 86.298 ± 5.51

(5.922−10.365) (2.85−4.15) (26.99−53.04) (33.59−139)

12.525 ± 2.04 2.5 ± 0.25 58.96 ± 3.87 176.12 ± 8.45

(6.181−18.869) (1.85−3.15) (41.038−76.885) (28.34−380.88)

E

dx.doi.org/10.1021/mp4000713 | Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Molecular Pharmaceutics

Article

(7) Mashru, R. C.; Sutariya, V. B.; Sankalia, M. G.; Parikh, P. P. Development and evaluation of fast-dissolving film of salbutamol sulphate. Drug Dev. Ind. Pharm. 2005, 31, 25−34. (8) Arya, A.; Chandra, A.; Sharma, V.; Pathak, K. Fast Dissolving Oral Films: An Innovative Drug Delivery System and Dosage Form. Int. J. Chem. Tech. Res. 2010, 2, 576−583. (9) Koland, M.; Sandeep, V. P.; Charyulu, N. R. Fast dissolving sublingual films of ondansetron hydrochloride; Effect of additives on in vitro drug release and mucosal permeation. J. Young Pharm. 2010, 2, 216−222. (10) Attama, A A.; Akpa, P. A.; Onugwu, L. E.; Igwilo, G. Novel bucco adhesive delivery system of hydrochlorothiazide formulated with ethyl cellulose hydroxypropylmethylcellulose interpolymer complex. Ind. J. Pharm. Sci. 2008, 70, 61−65. (11) Khan, T. A.; Peh, K. K.; Ch’ng, H. S. Mechanical bioadhesive strength and biological evaluations of chitosan films for wound dressing. J. Pharm. Pharmaceut. Sci. 2000, 3, 303−311. (12) Zade, P. S.; Kawtikwar, P. S.; Sakarkar, D. M. Formulation, evaluation and optimization of fast dissolving tablet containing tizanidine hydrochloride. Int. J. PharmTech Res. 2009, 134−42. (13) Dinge, A.; Nagarsenker, M. Formulation and Evaluation of Fast Dissolving Films for Delivery of Triclosan to the Oral Cavity. AAPS PharmSciTech 2008, 9. (14) Khan, K. A. The concept of dissolution efficiency. J. Pharm. Pharmacol. 1975, 27, 48−49. (15) Shivaraj, A.; Panner Selvam, R.; Tamiz Mani, T.; Sivakumar, T. Design and evaluation of transdermal drug delivery of ketotifen fumarate. Int. J. Pharm. Biomed. Res. 2010, 1, 42−47. (16) Alagusundaram, M.; Chengaiah, B.; Ramkanth, S.; Angala Parameswari, S.; Madhu, C.; Sudhana, C.; Dhachinamoorthi, D. Formulation and evaluation of mucoadhesive buccal films of ranitidine. Int. J. PharmTech Res. 2009, 1, 557−563. (17) Narendra, C.; Srinath, M. S.; Rao, B. P. Formulation and evaluation of a sublingual tablet containing terbutaline sulphate: Optimization and in vivo studies. Ars. Pharm 2005, 46, 139−58. (18) Pramod kumar, T. M.; Umesh, H. M.; Shivakumar, H. G.; Ravi, V.; Siddaramaiah. Feasibility of Polyvinyl Alcohol as a Transdermal Drug Delivery System for Terbutaline Sulphate. J. Macromol. Sci., Part A: Pure Appl. Chem. 2007, 44, 583−589. (19) El-Gendy, N. A.; Abdelbary, G. A.; EL-Komya, M. H.; Saafan, A. E. Design and Evaluation of a Bioadhesive Patch for Topical Delivery of Gentamicin Sulphate. Curr. Drug Delivery 2009, 6, 50−57. (20) Ali, S.; Quadir, A. High molecular weight povidone polymerbased films for fast dissolving drug delivery applications. Drug Delivery Technol. 2007, 7, 36−43. (21) Sarkar, N. Thermal gelation properties of methyl and hydroxypropyl methyl cellulose. J. Appl. Polym. Sci. 1979, 24, 1073− 1087. (22) ElMeshad, A. N.; El Hagrasy, A. S. Characterization and Optimization of Orodispersible Mosapride Film Formulations. AAPS PharmSciTech 2011, 12, 1384−1392. (23) Engel, T.; Scharling, B.; Skovsted, B.; Heinig, J. H. Effects, side effects and plasma concentrations of terbutaline in adult asthmatics after inhaling from a dry powder inhaler device at different inhalation flows and volumes. Br. J. Clin. Pharmac. 1992, 33, 439−444. (24) Derom, E.; Borgström, L.; Schoor, J. V.; Löfroos, A.; Pauwels, R. Lung Deposition and Protective Effect of Terbutaline Delivered from Pressurized Metered-Dose Inhalers and the Turbuhaler in Asthmatic Individuals. Am. J. Respir. Crit. Care Med. 2001, 164, 1398−1402. (25) Davies, D. S. The fate of inhaled terbutaline. Eur. J. Respir. Dis. Suppl. 1984, 7, 134−141. (26) Borgström, L.; Nilsson, M. A method for determination of the absolute pulmonary bioavailability of inhaled drugs: terbutaline. Pharm. Res. 1990, 10, 1068−70. (27) Abdelrahim, M. E.; Assi, K. H.; Chrystyn, H. Relative bioavailability of terbutaline to the lung following inhalation, using urinary excretion. Br. J. Clin. Pharmacol. 2011, 71, 608−610.

F

dx.doi.org/10.1021/mp4000713 | Mol. Pharmaceutics XXXX, XXX, XXX−XXX