An Introduction to Fast Dissolving Oral Thin Film Drug Delivery Systems: a Review
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Muthadi Radhika Reddy /J. Pharm. Sci. & Res. Vol. 12(7), 2020, 925-940 An Introduction to Fast Dissolving Oral Thin Film Drug Delivery Systems: A Review Muthadi Radhika Reddy1* 1School of pharmacy, Gurunanak Institute of Technical Campus, Hyderabad, Telangana, India and Department of Pharmacy, Gandhi Institute of Technology and Management University, Vizag, Andhra Pradesh, India INTRODUCTION 2. Useful in situations where rapid onset of action Fast dissolving drug delivery systems were first developed required such as in motion sickness, allergic attack, in the late 1970s as an alternative to conventional dosage coughing or asthma forms. These systems consist of solid dosage forms that 3. Has wide range of applications in pharmaceuticals, Rx disintegrate and dissolve quickly in the oral cavity without Prescriptions and OTC medications for treating pain, the need of water [1]. Fast dissolving drug delivery cough/cold, gastro-esophageal reflux disease,erectile systems include orally disintegrating tablets (ODTs) and dysfunction, sleep disorders, dietary supplements, etc oral thin films (OTFs). The Centre for Drug Evaluation [4] and Research (CDER) defines ODTs as,“a solid dosage 4. No water is required for the administration and hence form containing medicinal substances which disintegrates suitable during travelling rapidly, usually within a matter of seconds, when placed 5. Some drugs are absorbed from the mouth, pharynx upon the tongue” [2]. USFDA defines OTFs as, “a thin, and esophagus as the saliva passes down into the flexible, non-friable polymeric film strip containing one or stomach, enhancing bioavailability of drugs more dispersed active pharmaceutical ingredients which is 6. May offer improved bioavailability for poorly water intended to be placed on the tongue for rapid soluble drugs by offering large surface area as it disintegration or dissolution in the saliva prior to disintegrates and dissolves rapidly swallowing for delivery into the gastrointestinal tract” [3]. 7. Leaves minimal or no residue in the mouth after OTFs are coming into their own as mainstream administration pharmaceutical products. The first approved prescription 8. Has ability to provide advantages of liquid medication OTF was Zuplenz (Ondansetron hydrochloride- 4 mg, 8 in the form of solid preparation mg) which was approved in 2010. The second approval 9. Adaptable to existing processing and packaging followed quickly Suboxone (Buprenorphine and machinery Naloxone). Statistics have shown that four out of five 10. Cost-effective patients prefer orally disintegrating dosage forms over 11. Gives accurate dosing as compared to liquids conventional solid oral dosages [4]. These factors, coupled 12. Provides good chemical stability with convenience and compliance advantages, have been 13. Free of need of measuring, which is an essential (and will continue to) pave the way for ODT and OTF drawback in liquids [5] drug product growth. 14. Offers market expansion and product differentiation This review highlights the various types of polymers, the 15. Can be developed and launched within 12-16 months, different types of manufacturing techniques and evaluation thus provides improved product development life- tests for the oral films. cycle time [4] Need for preparing fast dissolving oral thin films Disadvantages of OTF Pediatric, geriatric, bedridden, emetic patients and those 1. Dose uniformity is difficult to maintain with Central Nervous System disorders, have difficulty in 2. Only those active pharmaceutical ingredients having swallowing or chewing solid dosage forms. Many of these small dose can be incorporated [6] patients are non-compliant in administering solid dosage Research has proven that concentration level of active forms due to fear of choking. Even in the case of ODTs, pharmaceutical ingredient (API) can be improved up fear of choking is associated which can behazardous.Fast to 50% w/w. Novartis Consumer Health's Gas-X® thin dissolving oral thin film drug delivery system is a better strip has 62.5 mg of Simethicone per strip [4]. alternative to ODTs. OTFs when placed on the tip or the 3. Require expensive packaging floor of the tongue, instantly wet by saliva. As a result, 4. Since OTFs dissolve quickly, dose termination is OTFs rapidly hydrate and then disintegrate and/or dissolve impossible to release the medication for local and/or systemic 5. OTFs are not official in any pharmacopoeia absorption. ODTs are friable and may break during transport and handling. Thus, fast dissolving oral thin film FORMULATION OF FAST DISSOLVING ORAL drug delivery systems are being developed. THIN FILMS Formulation includes consideration regarding mechanical Advantages of OTF properties, taste masking, fast dissolving, physical 1. Ease of administration for mentally ill and non- appearance, mouth feel. Fast dissolving oral thin films are compliant patients generally with an area of 5-20 cm2. APIs can be 925 Muthadi Radhika Reddy /J. Pharm. Sci. & Res. Vol. 12(7), 2020, 925-940 incorporated upto 30 mg [7]. From the regulatory point of Water soluble APIs exist in the dissolved state or as solid view, all the excipients used should be generally regarded solution and there is no problem of uniformity of as safe (GRAS) listed and should be used as per Inactive distribution. But water insoluble APIs have to be Ingredients Limit (IIG limit). Various components of fast homogenously distributed so as to have an acceptable drug dissolving oral thin films are shown in Table 1 content uniformity. Water insoluble APIs can also be added as milled, micronized or in the form of nanocrystals Table 1: Composition of fast dissolving oral thin films [8]. or microcapsules [10] in order to maintain smooth texture Components % w/w of the film and also for fast dissolution. Active pharmaceutical ingredient 5-30 Lou et al. formulated Chlorpheniramine maleate Film forming polymers Upto45 microparticles by encapsulating Chlorpheniramine maleate Plasticizers 0-20 into Eudragit EPO by spray drying of water-in-oil Surfactants q. s. emulsion method. The optimized microparticles were Sweetening agents 3-6 incorporated into OTF with satisfactory weight and drug Saliva stimulating agents 2-6 content uniformity and acceptable physical strength. OTFs Superdisintegrants Upto 8 disintegrated immediately (in less than 40 seconds) in Coloring agents Upto 1 simulated saliva solutions [11]. Flavoring agents Upto 10 Sievens-Figueroa et al. formulated OTFs of hydroxypropyl methyl cellulose (HPMC) by incorporating Active pharmaceutical ingredients (APIs) API in the form of nanosuspension. They transformed Since the size of the thin films has to be small enough to nanosuspension produced from wet stirred media milling be conveniently placed on the tongue, those active (WSMM) into polymer films containing drug loaded pharmaceutical ingredients with high dose are not suitable nanoparticles by mixing with HPMC E15 LV solution candidates for incorporation into fast dissolving oral thin containing glycerin followed by film casting and drying films [9]. [12]. Ideal characteristics of APIs to be incorporated into fast As the thin film formulation is to be placed on tongue, dissolving oral thin films those drugs having bitter and unpleasant taste may cause 1. Low dose vomiting sensation and may be inacceptable by the patient. 2. Palatability Hence, various taste masking technologies for the drug 3. Small molecular weight like coating with polymers, inclusion complexation with 4. Solubility and stability in saliva cyclodextrins, microencapsulation, complexation ()eg Some of the suitable candidates for incorporation into thin with ion-exchange resins are being practiced which are as film formulation are given in Table 2. shown in Table 3. Table 2: Suitable candidates for incorporation into thin Table 3: Taste masking technologies for bitter APIs. film formulation. Active Taste masking Active pharmaceutical pharmaceutical Material used Category Dose (mg) technology ingredients ingredient Levocetrizine 5, 10 Hydroxypropyl Anti-histaminic Loratadine 10 methyl cellulose, Ketorolac 10 Famotidine [13] Coating with Hydroxyl propyl Indomethacin 25 Terfenadrine [14] polymers cellulose NSAIDs Valdecoxib 10, 20 Sodium alginate, Piroxicam 10, 20 Carageenan Zolmitriptan 2.5, 5 Inclusion Anti-migraine Hydroxylpropyl-β- Sumatriptan succinate 35, 70 Ibuprofen [15] complexation with cyclodextrin Mirtazapine Anti-depressant 15, 30, 45 β-cyclodextrins Sulphathiazale Solid dispersion Buspirone Anxiolytic 5, 15, 30 Povidone 3.125, 6.25, [16] systems Carvedilol β-blocker 12.5, 25 Beclamide [17] Microencapsulation Gelatin Pseudoephedrine Ion-exchange Glipizide Anti-diabetic 2.5, 5 Amberlite CG 50 Galantamine 4, 8, 12 [18] resins Anti-Alzheimer Chloroquine Egg phosphatidyl Donepezil 5, 10 Liposomes Nitroglycerine phosphate [19] choline Vasodilator 0.3, 0.6 derivatives Chloramphenicol, Clindamycin Palmitate ester Oxycodone Opioid analgesic 2.5-10 Prodrugs Famotidine Antacid 10 Triamcinolone Diacetate ester Anti- [16] Ketoprofen 12.5, 25 inflammatory Dextromethorphan Anti-tussive 15, 30 Film forming polymers Ondansetron Anti-emetic 8-24 Since the film formulation rapidly disintegrates and Loperamide Anti-diarrheal 2 dissolves in oral cavity, the film forming polymers used Bupre must be water soluble. The polymers can be used alone or 926 Muthadi Radhika Reddy /J. Pharm. Sci. & Res. Vol. 12(7), 2020, 925-940 in combination with others in order to obtain the desired 2. Gelatin film which should be tough enough so that there won't