Insights into Polymers: Film Formers in Mouth Dissolving Films

Drug Invention Today ISSN: 0975-7619 Review Article www.ditonline.info Insights into Polymers: Film Formers in Mouth Dissolving Films Priyanka Nagar, Iti Chauhan, Mohd Yasir* Department of Pharmaceutics, ITS Pharmacy College, Muradnagar, Ghaziabad- 201206 (UP), India Mouth dissolving films is a new drug delivery system for oral route. This delivery system consists of a very thin oral strip, which is simply placed on the patients tongue or any oral mucosal tissue, instantly wet by saliva, film rapidly hydrates and then disintegrates and/or dissolve to release the medication. In the formulation of oral film, the most important ingredient is polymer which helps in film formation. Mainly hydrophilic polymers are used in mouth dissolving films. The present article highlights various natural and synthetic polymers, their properties and applications in oral film delivery system. Keywords: Fast dissolving oral film, polymers, patient compliance, disintegrates, strip etc. INTRODUCTION Should have good wetting and spread ability property 6. Should exhibit sufficient peel, shear and tensile strength 7. Readily available 8. Inexpensive 9. Should have sufficient shelf life 10. Should not aid in causing secondary infections in the oral mucosa or dental regions 5. Oral route is the most preferred and acceptable route due to ease of ingestion, pain avoidance, versatility and most importantly, the patient compliance [1]. Mouth dissolving films, a new drug delivery system for the oral route, was developed based on the technology of the transdermal patch. This delivery system consists of a very thin oral strip, which is simply placed on the patients tongue or any oral mucosal tissue, instantly wet by saliva, film rapidly hydrates and then disintegrates and/or dissolve to release the medication [2]. Oral film includes various ingredients for its formulation which includes polymers, active pharmaceutical ingredient, film stabilizing agents, sweeteners, flavors, colors, saliva stimulating agents, preservatives, surfactants etc but the first and far most a very essential ingredient which helps in film formation is a Polymer. Film is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity, delivering the drug to the systemic circulation via dissolution when contact with liquid is made [3]. A variety of polymers are available for preparation of fast dissolving oral films. The use of film forming polymers in oral films has attracted considerable attention in medical and nutraceutical applications. The selection of polymer, is one of the most important and critical parameter for the successful development of the film formulation. The polymers can be used alone or in combination to obtain the desired film properties. The film obtained should be tough enough so that there won't be any damage while handling or during transportation. The robustness of the strip depends on the type and amount of polymer in the formulation [4]. As the strip forming polymer (which forms the platform for the oral film) is the most essential and major component of the film, at least 45%w/w of polymer should generally be present based on the total weight of dry film [5] but typically 60 to 65%w/w of polymer is preferred to obtain desired properties [6]. The polymers employed in the oral film preparation should be: [7] 1. Non-Toxic and Non-Irritant 2. Devoid of leachable impurities 3. Should not retard disintegration time of film 4. Tasteless Presently, both natural and synthetic polymers are used for preparation of fast dissolving oral film. Table 1 represents various natural & synthetic polymers which are nowadays used in MDF preparation. Table 4 and 5 represents quality parameters of different natural and synthetic polymers respectively. Table 6 represents a patent review on different polymers used for the preparation of MDF. Table: 1 Polymer Available Preparation of MDF S.No. Polymer Examples 1. Natural Polymers 2. Synthetic Polymers Pullulan, Starch, Gelatin, Pectin, Sodium alginate, Maltodextrins, Polymerized Rosin Hydroxy propyl methyl cellulose, Sodium Carboxy methyl cellulose, Poly ethylene oxide, Hydroxy propyl cellulose, Poly vinyl pyrrolidone, Poly vinyl alcohol Reference [7] [7] NATURAL POLYMERS 1. Pullulan Pullulan is a unique biopolymer with many useful traits and hundreds of patented applications. It is a water soluble, neutral linear polysaccharide consisting of α–1, 6-linked maltotriose residues. It is a fungal exopolysaccharide produced from starch by Aureobasidium pullulan. [8] Commercially pullulan is made from fermentation process. Other microbial sources of pullulan include Tremella mesenterica [9], Cytaria harioti [9], Cytaria darwinii [9], Cryphonectria parasitica [10], Teloschistes flavicans [11], Rhodototula bacarum [12]. Corresponding Author: Mohd Yasir, Department of Pharmaceutics, ITS Pharmacy College, Muradnagar, Ghaziabad- 201206 (UP), India Received 27-09-2011; Accepted 21-11-2011 December, 2011 Drug Invention Today, 2011, 3(12), 280-289 280 Priyanka Nagar, et al. : Insights into Polymers: Film Formers in Mouth Dissolving Films Pullulan has following properties [13]  It is impermeable to oxygen, non-hygroscopic and non-reducing.  It is easily soluble in hot and cold water to make clear and viscous solution and also has high adhesion and film forming abilities.  The principal advantages of pullulan are that it is a nonionic polysaccharide and is blood compatible, biodegradable, non-toxic, non immunogenic, nonmutagenic and non carcinogenic. Bender et al. (1959) studied the novel glucan and named it "pullulan." During the 1960s, the basic structure of pullulan was resolved [14]. The unique linkage pattern of pullulan endows the polymer with distinctive physical traits, including adhesive properties and the capacity to form fibers, compression moldings, and strong oxygen impermeable films. Fig. 1 depicts the chemical structure of pullulan. Fig. 1: Chemical structure of pullulan Bender and Wallenfels (1961) discovered the enzyme pullulanase, which specifically hydrolyzes a (1, 6) linkages in pullulan and converts the polysaccharide almost quantitatively to maltotriose. Pullulan can be considered to be a polymer of panose or isopanose subunits, which may reflect more accurately the biosynthetic origins of the molecule. Catley and coworkers subsequently established the occurrence of a minor percentage of randomly distributed maltotetraose subunits in pullulan [15]. The regular occurrence of alpha-(l, 6) linkages in pullulan interrupts what would otherwise be a linear amylase chain. This unique linkage pattern is believed to be responsible for the structural flexibility and solubility of pullulan, resulting in distinct film and fiber-forming characteristics which is not exhibited by other polysaccharides. Pullulan films are thermally stable and possess anti-static and elastic properties and can be developed into compression mouldings [16]. Films made from pullulan are highly water soluble, colorless, tasteless, odorless, transparent, flexible and heat sealable. Films made up of pullulan are clear and highly oxygen-impermeable with excellent mechanical properties. The oxygen resistance of pullulan films is suitable for protection of readily oxidized fats and vitamins in food. Pullulan film has 300 times stronger oxygen barrier than HPMC film and 9 times stronger than gelatin film of the same thickness [17]. 2. Starch / Modified Starches Starch is the major carbohydrate reserve in plant tubers and seed endosperm where it is found as granules, each typically containing several million amylopectin molecules accompanied by a much larger number of smaller amylose molecules. Amylose is responsible for the film-forming capacity of starch [18]. The largest source of starch is corn (maize) with other commonly used sources being wheat, December, 2011 potato, tapioca and rice. Genetic modification of starch crops has recently led to the development of starches with improved and targeted functionality. Starch is used to produce biodegradable films to partially or entirely replace plastic polymer. The films are transparent or translucent, flavorless, tasteless and colorless [19]. However, starch film application is limited by poor mechanical strength and its efficient barrier against low polarity compound. Many research reported that film forming conditions have an effect on crystallinity of the starch films and, therefore, their properties [20]. Films of high-amylose corn starch or potato starch was more stable during aging, lost little of their elongation and had not or a slight increase in tensile strength [20]. Films from cassava starch were found to have good flexibility and low water permeability, indicating the potential application as edible film former [21]. Plasticizer is generally required for starch-based edible films to overcome film brittleness. The most commonly used plasticizers for starch films are glycerol and sorbitol [21]. Recently, Hu et al have developed starch films from oxidized potato starch (OPS) with glycerol as a plasticizer. The OPS films were transparent and flexible with interesting mechanical properties. Starches used in forming oral films are: 1. Pre gelatinized starch includes lycoat 2. Modified starch 3. Amylase rich starch Modified starch is also used for preparation of oral film. Due to low cost of this excipient it is used in combination of pullulan to decrease the overall cost of the product. Fig. 2 depicts the chemical structure of starch. Fig. 2: Chemical structure of starch New film-forming polymer Lycoat NG 73 Lycoat NG 73 is an excellent film forming polymer from pea starch prepared by chemical and physical treatments [22]. Lycoat is a novel granular hydroxypropyl starch polymer that has been designed especially for orodispersible films. Lycoat disperses easily in cold water without formation of lumps. Simple cooking by heating will develop its film-forming ability. It gives a homogenous solution as viscosity develops progressively by cooking thus preventing formation of lumps and agglomerates. It can be used as the sole film forming polymer to formulate ODF with excellent functionality without the need of additional film forming agent [22]. 3. Sodium Alginate Chiefly sodium alginate consists of sodium salt of alginic acid, which is a mixture of polyuronic acids composed of residues of D-mannuronic acid and L-guluronic acid. Alginate is an indigestible biomaterial produced by brown seaweeds (Phaeophyceae, mainly Laminaria). It is present in the Drug Invention Today, 2011, 3(12), 280-289 281 Priyanka Nagar, et al. : Insights into Polymers: Film Formers in Mouth Dissolving Films cell walls of brown algae as the calcium, magnesium and sodium salts of alginic acid [23]. Fig. 3 depicts the chemical structure of sodium alginate. Fig. 3: Chemical structure of sodium alginate Alginate has a potential to form biopolymer film or coating component because of its unique colloidal properties, which include thickening, stabilizing, suspending, film forming, gel producing, and emulsion stabilizing property [23]. Edible films prepared from alginate are strong and exhibit poor water resistance because of their hydrophilic nature. The water permeability and mechanical attributes can be considered as moderate compared to synthetic films. Mechanical properties of alginate film can be improved by addition of starch [24]. 4. Pectin Pectin is a high-molecular-weight, complex anionic polysaccharide composed of β-1, 4-linked d-galacturonic acid residues, wherein the uronic acid carboxyls are either fully (HMP, high methoxy pectin) or partially (LMP, low methoxy pectin) methyl esterified. Pectin is found in fruit and vegetables and mainly prepared from citrus peel and apple pomace [25]. Fig. 4: Chemical structure of pectin Pectins are good film formers with good capacity to carry drugs and are particularly suitable for low pH applications. Solubility of the films depends on molecular weight of the polymer, but generally it dissolves slowly in the oral cavity. In a study, it was found that degradation of pectin reduces its intrinsic viscosity from 4.9dl/g to 2.5dl/g making it more suitable for use in oral films [25]. Fig. 4 shows the chemical structure of pectin. 5. Gelatin Gelatin is a generic term for a mixture of purified protein fractions obtained either by partial acid hydrolysis (type A gelatin) or by partial alkaline hydrolysis (type B gelatin) of animal collagen and/ or may also be a mixture of both. The protein fractions consist almost entirely of amino acids joined together by amide linkages to form linear polymers. Gelatin is prepared by the thermal denaturation of collagen, isolated from animal skin, bones and fish skins [26]. It is readily soluble in water at temperatures above 40ºC, forming a viscous solution of random-coiled linear polypeptide chains. December, 2011 Mammalian gelatins commonly have better physical properties and thermo stability than most fish and this has been related mainly to their higher amino acid content [26]. The use of mammalian gelatin in the elaboration of edible film or coatings was very well studied until the sixties, which resulted in many patents mainly in the pharmaceutical area [27]. The properties and film forming ability of gelatin is directly related to the molecular weight, i.e., the higher the average molecular weight, the better the quality of the film. The molecular weight distribution depends mainly on the degree of collagen cross-linking and the extraction procedure [27]. However, in the year 2000, the gelatin films formed principally with fish gelatin have returned to the attention of researcher. Gelatin films were found to dissolve rapidly, excellent carriers for flavors and produce a smooth mouth feel [27]. Fig. 5 depicts the chemical structure of gelatin. Fig. 5: Chemical structure of gelatin 6. Polymerized Rosin Rosin, formerly called colophony or Greek pitch (Pixgraeca), is a solid form of resin obtained from pines and some other plants, mostly conifers, produced by heating fresh liquid resin to vaporize the volatile liquid terpene components [28]. Rosin and its esters are reported to have excellent film forming properties and can be used for enteric coating and delayed release of drugs [29]. Being natural in origin, rosin and its derivatives are expected to be biodegradable In-vivo. Polymerized rosin is made from gum rosin by polymerization via catalyst. It has many excellent properties including high softening point, anti-oxidation, non-crystallizing and good compatibility with film-forming agent [29]. 7. Maltodextrin It is a non-sweet nutritive saccharide polymer. It is produced from starch by partial hydrolysis and is usually found as a creamy-white hygroscopic spray dried powder. Maltodextrin consists of D-glucose units connected in chains of variable length. The glucose units are primarily linked with α (1→4) glycosidic bond. Maltodextrin is typically composed of a mixture of chains that vary from three to nineteen glucose units [30]. Maltodextrins are classified by DE (dextrose equivalent) and have DE between 3-20. Higher the DE value, shorter the glucose chains, higher the sweetness and higher the solubility. It is used as film forming agent. Table 2 represents a brief review on natural polymers which are used for preparation of mouth dissolving film. Table 2 represents literature review on natural polymers used for the preparation of MDF. Drug Invention Today, 2011, 3(12), 280-289 282 Priyanka Nagar, et al. : Insights into Polymers: Film Formers in Mouth Dissolving Films Table 2: Literature Review on Natural Polymers Used for Preparation of MDF S.No. 1. Polymer Pullulan Drug Cetrizine HCl Pilocarpine HCL 2. Starch Benzocaine Tianeptine Sodium 3. Sodium alginate 4. Gelatin 5. Maltodextrin Medicinal carbon Levocetrizine HCl Salbutamol Sulfate Montelukast sodium Piroxicam Nicotine Description Used as film forming polymer in order to formulate the oral film and the film shows satisfactory thickness, good mechanical properties, good disintegration time, even distribution and uniformity in the film. Used as film forming material and film was easy to swell and quickly disintegrate. Lycoat RS720 (25%w/w) was used to formulate oral film. This form offered dose homogeneity with fast dissolution. It allowed hydrophilic, hydrophobic as well as temperature sensitive API’s incorporation. Lycoat NG73 was used as new film forming agent and its various physico- mechanical properties were compare with HPC, HPMC, HEC, and PVA. Lycoat NG73 showed greatest dissolution, satisfactory disintegration and desired physico-mechanical properties. Used as film base material. The addition of sorbitol or manitol in it caused improvement in adsorption ability of medicinal carbon film as compared to its powder form along with sufficient strength and disintegration time. Sodium alginate used as film forming polymer Sodium alginate used in formulation of film Montelukast sodium fast dissolving film was prepared by solvent casting method using gelatin as film base with different concentrations of superdisintegrants like microcrystalline cellulose and crospovidone using PEG 400 as plasticizer. It was demonstrated that 4% crospovidone and 10% MCC with 4% gelatin as a film base was suitable for developing fast dissolving films of Montelukast sodium Maltodextrin with a low dextrose equivalent as film forming material was used to formulate oral film by both casting and extrusion method. Homogenous film was obtained by loading a large amount of water insoluble powders more than 15%w/w. Two different dextrose equivalents namely DE 6 and DE12 were selected in order to evaluate the effect of polymer molecular weight on film tensile properties. It shows that decreasing the DE value of Maltodextrin the tenacity of the film improved. SYNTHETIC POLYMERS 1. Hydroxypropyl Cellulose Hydroxypropyl cellulose (HPC) is non-ionic water soluble thermoplastic polymer. Hydroxypropyl cellulose as partially substituted poly (hydroxypropyl) ether of cellulose. It may contain NMT 0.6% of silica or another suitable anticaking agent. HPC is commercially available in a number of different grades that have various solution viscosities [40]. It is known that films formed with polymers having very high glass transition temperature values are stiff. Because of relatively high glass transition temperatures (compared to other film forming polymers) of HPC [41], the formed films were shown to exhibit brittle fracture and were found to be stiff, with a high elastic modulus and a very low percent elongation (less than 5%). Typically slow dissolving, the films have good carrying capacity and reasonable clarity. HPC has December, 2011 Reference [31] [32] [22] [33] [34] [35] [36] [37] [38] [39] a good film forming property. It was chosen as the primary matrix-forming polymer since it is the only water soluble cellulose derivative that is thermoplastic. HPC has a softening temperature in the range of 100–1500C, depending on its molecular weight. It imparts low surface and interfacial tension to its solution and thus can be used for the preparation of flexible films alone or in combination with Hypromellose [41]. Fig. 6 depicts the chemical structure of hydroxypropyl cellulose. R is H or [CH2CH(CH3)O] nH Fig. 6: Chemical structure of hydroxypropyl cellulose Drug Invention Today, 2011, 3(12), 280-289 283 Priyanka Nagar, et al. : Insights into Polymers: Film Formers in Mouth Dissolving Films 2. Hydroxypropyl Methyl Cellulose Hydroxypropyl Methyl Cellulose (HPMC) or hypromellose is a partly O- methylated and O-(2-hydroxypropylated) cellulose. It is known for its good film forming properties and has excellent acceptability. Lower grades of HPMC like Methocel E3, E5, and E15 are particularly used for film formation because of their low viscosity. Fig. 7 depicts the chemical structure of hydroxypropyl methyl cellulose. 4. Polyvinyl Alcohol Polyvinyl alcohol is produced by the polymerization of vinyl acetate to poly vinyl acetate followed by hydrolysis of poly vinyl acetate to poly vinyl alcohol. Commercial PVA grades are available with high degree of hydrolysis [45]. Fig. 9 depicts the chemical structure of polyvinyl alcohol. Fig. 9: Chemical structure of polyvinyl alcohol Fig. 7: Chemical structure of hydroxypropyl methyl cellulose HPMC polymer has a high glass transition temperature and is classified according to the content of substituent’s and its viscosity which affects the solubility– temperature relationship. HPMC forms transparent, tough and flexible films from aqueous solutions [42]. Additives are often incorporated to improve specific properties of formulated films. Several studies have been focused on the influence of additives on physico-chemical properties of HPMC films. It is known that lipid compounds such as waxes, triglycerides (e.g., tristearin), fatty acids (e.g., Stearic and palmitic acid), frequently incorporated into HPMC films, lead to a decrease the water affinity and moisture transfer due to their high hydrophobic properties caused by their high content of longchain fatty alcohols and alkanes. 3. Sodium Carboxy Methyl Cellulose Sodium carboxy methyl cellulose (Na CMC) is prepared from cellulose by treatment with alkali and mono-chloro-acetic acid or its sodium salt. Na CMC is non-ionic cellulose ether commonly used in controlled release hydrophilic matrix systems. It is non-toxic and has the ability to accommodate high drug loadings [43]. Na CMC is also a good film former. Formulations comprising Na CMC or other hydrophilic polymers such as HPMC and xanthan have great potential for delivery of drugs to moist surfaces. The enzymatically modified carboxymethyl cellulose has good film forming property. It is reported for use in combination with other film forming polymers for preparation of oral films [43]. Fig. 8 depicts the chemical structure of Sodium carboxy methyl cellulose. 5. Polyethylene Oxide Polyethylene oxide (PEO) or POLYOX is a synthetic polyether or water soluble resins that is readily available in a wide range of molecular weights. Materials with MW