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Fast Dissolving Sublingual Strips: a Novel Approach for the Delivery Of Pharmaceutical Sciences December 2019, 25(4), 311-318 doi: 10.15171/PS.2019.34 https://ps.tbzmed.ac.ir/ Research Article Fast Dissolving Sublingual Strips: A Novel Approach for the Delivery of Isosorbide Dinitrate Marziyeh Fathi1 , Mitra Alami-Milani2,3, Sara Salatin1,3, Sharahm Sattari4, Hassan Montazam5, Farhad Fekrat3, Mitra Jelvehgari2,6* 1Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran. 2Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 3Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran. 4Nikookari Ophtalmology Center, Tabriz University of Medical Sciences, Tabriz, Iran. 5Islamic Azad University of Bonab Unit, Bonab, Iran. 6Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. A r t i c l e I n f o A B S T R A C T Article History: Background: Isosorbide dinitrate (ISDN) is used for treating the angina attacks. In Received: 19 November 2018 addition, oral ISDN is available in immediate and sustained release formulations and the Revised: 6 April 2019 Accepted: 12 April 2019 bioavailability of ISDN is about 20-25% when taken orally. Further, the ISDN films are ePublished: 20 December 2019 developed for sublingual drug delivery by improving drug bioavailability. The present study aimed to design and evaluate the physicochemical properties of the film formulation Keywords: for sublingual delivery of ISDN. -Film -Sublingual Methods: In the present study, sublingual films were prepared by the solvent casting -Isosorbide dinitrate technique using the hydroxypropyl methylcellulose (HPMC) polymers (i.e., 100, 150 and -HPMC 200 mg) with a different drug to polymer ratios (i.e., 1:5, 1:7.5 and 1:10). Then, ISDN was -Mucoadhesion evaluated for the film appearance, drug content, surface pH, mucoadhesion force, differential scanning calorimetry (DSC), in vitro drug release, and ex vivo permeability. Results: Based on the results, F3 formulation (1:10 ISDN to HPMC ratio) showed acceptable thickness (0.93 mm), weight (11.14 mg), surface pH (7.82), moisture absorption capacity (6.08%), elasticity (>200), mucoadhesion force (18.05 N/cm2), and drug content (6.22%). Furthermore, the results demonstrated that HPMC polymer improved the characteristics of the films, modified the bioadhesiveness, and finally, enhanced elasticity. However, DSC thermogram failed to show any crystalline drug substance in the films except for F1 (immediate release) and the endothermic peak of ISDN was absent in F2 and F3 films. Therefore, the drug which was entrapped into the film was in an amorphous or disturbed-crystalline phase of the molecular dispersion or dissolved in the melted polymer in the polymeric matrix. Moreover, the drug release from the films was faster compared to the tablet® (P<0.05). Conclusion: In general, the formulation of F1 was observed to be an appropriate candidate for developing the sublingual film for the remedial use. Introduction oromucosal sorption. FDDS fits the drugs which Fast dissolving drug delivery systems (FDDSs) serve as a undertake a high first-pass metabolism and is applied for real benefit over the traditional dosage forms where the improving the bioavailability, along with reducing the drug gets quickly degraded and resolves in the salivation multiplication of drug dosage to mouth plasma peak without using water.1 levels, which itself decreases unfavorable efficacy and Accordingly, a fast dissolving film may be located in order makes FDDS cost-effective.2 to resolve the problems of a fast dissolving tablet. This Oral drug delivery arises several complications as hepatic type of film is very similar to the very elegant strip of first-pass metabolism and enzymatic disintegration in the plastic adhesive tapes in their form, size, and thickness. In gastrointestinal tract.3 These troubles may be dominant for addition, fast dissolving film is readily placed on the some categories of drugs, with their utilization by the tongue of the patient or any oromucosal tissue, which is sublingual tissue. Salivary glands are available on the floor immediately soaked with the saliva and quickly hydrated of the mouth under the tongue and produce salivary mucin. and stuck to the seat of the utilization. Afterward, it is The absorption is defined as the transfer of the drug from quickly degraded and dissolved to release the drug for its site of administration into the systemic circulation, *Corresponding Author: Mitra Jelvehgari, E-mail: [email protected] ©2019 The Authors. This is an open access article and applies the Creative Commons Attribution (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited. No permission is required from the authors or the publishers. Fathi M, et al. therefore, it may be claimed that the absorption is regarded The current study sought to design and assess as the immediate proportional layer thickness (sublingual physicochemical properties of the film formulation for > buccal). The sublingual path may make the quick start sublingual delivery of ISDN. of the function owing to high permeability and rich blood provision, thus, the drug with a short delivery period can Materials and Methods be carried and the dose regimen in this regard would be Materials frequentative.4 ISDN and Hydroxypropyl methylcellulose (HPMC) E15 Upon sublingual administration, the drug immediately were purchased from Toliddaru Company (Iran) and arrives at the blood flow by the ventral surface of the Sigma-Aldrich Company (USA), respectively. Then, tongue and the floor of the mouth. The major mechanism propylene glycol, dichloromethane, acetone, ethanol, for absorbing the drug in the oral mucosa is inactive sodium chloride, aluminium chloride, potassium chloride, diffusion toward the lipoidal membrane. Further, the sodium sulfate, ammonium acetate, urea, and lactic acid absorption of the drug by the sublingual path is 3-10 times were supplied from Merck Company (Darmstadt, larger than the oral path and it alone exceeds through the Germany). All the reagents were of analytical grade. hypodermic injection.5 Basically, thin films are great candidates for targeting the responsive site that cannot be ISDN film preparation method likely targeted by the tablets or liquid formulations. Sublingual films of isosorbide dinitrate (ISDN) were Furthermore, these films have demonstrated the ability to prepared by a solvent casting method using a film forming improve the beginning of the drug function, and the drug a mucoadhesive polymer. Further, HPMC was exactly effect while decreasing the dose repetition.6 Likewise, thin weighed (i.e., 100, 150 and 200 mg) and dissolved in 2.5 films can be beneficial for removing the adverse effects of mL of ethanol and 2.5 mL of dichloromethane and then a drug and decreasing wide metabolism induced by was shocked. Next, one droplet of propylene glycol (30 proteolytic enzymes. Moreover, the desired thin films mg) was poured into the polymer solution. At first, ISDN require displaying favorable aspects including enough drug was exactly weighed (20 mg) and next dissolved in drug loading capacity, quick dissolution rate or long 1.7 mL of acetone and 0.3 mL of water in another beaker residence time at the place of dispersion, and approvable (Table 1). Afterward, both of the polymer and drug formulation stability. Therefore, they should be nontoxic, solution were completely admixed together by a magnetic biocompatible, and biodegradable.7 agitator. The main limitation of FDDSs is related to the mechanical strength of the tablets, high friability, and the dryness of Analytical methods the mouth due to the decreased saliva production and thus Physicochemical properties of films requires a specialized package for physical integrity The physicochemical properties of the prepared films were (under normal condition) and stability. determined in the following order: The fast disintegrating film of loratadine with hydroxypropyl methylcellulose has shown to have good Assessment of thickness and drug content physicochemical properties and solvent casting method Six films were randomly selected from each formulation can be pursued with success for preparing the and their weight, thickness, and mean drug content were formulations. The first oral strips, developed by Pfizer evaluated. The thickness of the films was measured with who named it as Listerine®, were used for mouth the caliper. Furthermore, the films (1x1 cm2) were freshening. Also, Chloraseptic® relief strips were a thin dissolved in ethanol and the drug content was analyzed oral film containing benzocaine that was applied to treat using a UV spectrophotometer at 269.2 nm. sore throat. In the solvent casting method, different natural and Swelling study hydrophilic polymers containing cellulose or cellulose The films including the ISDN were permitted to swell in derivatives are dissolved in a solvent and the drug is the glass plate containing 5 mL of phosphate buffer dissolved in an appropriate solvent with another material (pH=6.8) at 37°C. Moreover, the difference in the primary in order to produce fast dissolving films. Next, both of the and the ultimate diameters was measured at prearranged mixtures are admixed, shocked, and eventually, cast over intervals (i.e., 15, 30, 60, 90 and 120 minutes). 8 the Petri plate, dried, and cut into similar dimensions. Additionally, the excess of phosphate buffer was taken Isosorbide dinitrate (ISDN) is an intermediate-acting away using the filter paper. Finally, the swelling index was nitrate accepted for the inhibition of angina pectoris by the computed using equation A.10 Food and Drug Administration. ISDN has only 20-25% bioavailability in oral intake and is exposed to Dt D0 Swelling index (%) = × 100 Eq. (1) considerable first-pass metabolism. Additionally, the half- D0 life of ISDN is within the range of one hour and the usual dose is 5-80 mg. In addition, ISDN sublingual and where, swelling index denotes the swelling percentage. In chewable tablets are present for the remedy of angina addition, D0 and Dt demonstrate the primary diameter at attacks.9 time t=0 and the diameter at time t=t, respectively.
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