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Oral Strip Technology Overview & Future Potential (1) Document Transcript

  • 1. Journal of Controlled Release 139 (2009) 94–107 Contents lists available at ScienceDirect Journal of Controlled Release j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j c o n r e l Review Oral strip technology: Overview and future potential R.P. Dixit, S.P. Puthli ⁎ Drug Delivery Division, Panacea Biotec Ltd., Samarpan complex, Chakala, Andheri (East), Mumbai-400 099, Maharashtra, India a r t i c l e i n f o a b s t r a c t Article history: Over the recent past, many of the research groups are focusing their research on this technology. Amongst Received 10 April 2009 the plethora of avenues explored for rapid drug releasing products, Oral Strip Technology (OST) is gaining Accepted 16 June 2009 much attention. The advantages of OST are the administration to pediatric and geriatric patient population Available online 24 June 2009 where the difficulty of swallowing larger oral dosage forms is eliminated. This technology has been used for local action, rapid release products and for buccoadhesive systems that are retained for longer period in the Keywords: Oral delivery oral cavity to release drug in controlled fashion. OST offers an alternate platform for molecules that undergo Strip first pass metabolism and for delivery of peptides. The review article is an overview of OST encompassing Buccal materials used in OST, critical manufacturing aspects, applications, commercial technologies and future Buccoadhesive business prospects of this technology. Formulation © 2009 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 2. Formulation considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 2.1. Strip forming polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 2.2. Plasticizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 2.3. Active pharmaceutical ingredient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 2.4. Sweetening agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 2.5. Saliva stimulating agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 2.6. Flavoring agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 2.7. Coloring agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 2.8. Stabilizing and thickening agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 3. Manufacture and production of oral strips . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 3.1. Thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3.2. Dryness test/tack tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3.3. Tensile strength . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3.4. Percent elongation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3.5. Tear resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3.6. Young's modulus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3.7. Folding endurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3.8. Disintegration time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3.9. Dissolution test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 3.10. Assay/drug content and content uniformity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 3.11. Organoleptic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 3.12. Clinical and regulatory aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 3.13. Commercial technologies and marketed products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 1. Introduction Among the delivery routes, the oral route is the most acceptable ⁎ Corresponding author. Tel.: +91 22 28386987; fax: +91 22 28386955. from patient compliance aspects. Many pharmaceutical firms have E-mail address: drugdel@rediffmail.com (S.P. Puthli). directed their research activity in reformulating existing drugs into 0168-3659/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2009.06.014
  • 2. R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 95 new dosage forms. One such relatively new dosage form is the oral Developing formulations for children has been a challenging task. strip, a thin film that is prepared using hydrophilic polymers that Amongst other factors, palatability of formulations of pediatric oral rapidly dissolves on the tongue or buccal cavity. medications is one of the most significant factors influencing compli- The surface of buccal cavity comprises of stratified squamous ance to therapeutic regimens [22,23]. Although solid dosage forms are epithelium which is essentially separated from the underlying tissue widely accepted by elders and adolescents, younger children tend to of lamina propria and submucosa by an undulating basement prefer liquid formulations that are easier to swallow [24]. Keeping the membrane [1]. It is interesting to note that the permeability of buccal ease of administration and swallowing in mind, pharmaceutical mucosa is greater than that of the skin, but less than that of the intestine research has led to the development of Oral Disintegrating Tablets [2–4]. It is also reported that the permeability of the buccal mucosa is (ODTs). ODTs have been defined as “A solid dosage form containing approximately 4–4000 times greater than that of the skin [5]. Hence the medicinal substances which disintegrates rapidly, usually within a buccal delivery serves as an excellent platform for absorption of matter of seconds, when placed upon the tongue”. United States Food molecules that have poor dermal penetration. However, the primary and Drug Administration further defines ODTs as solid oral preparations barrier to permeability in the oral mucosa is the result of intercellular that disintegrate rapidly in the oral cavity, with an in-vitro disintegration material derived from the so-called ‘membrane coating granules’ time of approximately 30 s or less, when based on the United States present at the uppermost 200 micron layer [6,7]. Pharmacopeia (USP) disintegration test method or alternative [25]. The epithelia of oral cavity are also composed of an intercellular Research and development in the oral drug delivery segment has ground substance called as mucus which basically consists of proteins led to transition of dosage forms from simple conventional tablets/ and carbohydrates. It maintains hydrated condition of the oral cavity, capsules to modified release tablets/capsules to oral disintegrating provides adequate lubrication, concentrate protective molecules such as tablet (ODT) to wafer to the recent development of oral strip (OS). secretory immunoglobulins, and reduces the attachment of microorgan- Basically the OS can be considered as an ultra-thin strip of postage isms. The negatively charged mucin contains sulfhydryl groups and sialic stamp size with an active agent or active pharmaceutical ingredient acid residues that are responsible for mucoadhesion phenomena [8]. The and other excipients. The advantages of convenience of dosing and saliva and salivary mucin contribute to the barrier properties of oral portability of OS have led to wider acceptability of this dosage form by mucosa [9]. While the major salivary glands consist of lobules of cells pediatric as well as geriatric population equally. that secrete saliva; parotids through salivary ducts near the upper teeth, The introduction of ODT in market was accompanied by educating submandibular (tongue regions), and the sublingual ducts, the minor the mass about the proper way to administer the product like giving salivary glands are located in the lips, buccal mucosa, and in linings of the instructions “do not swallow” or “do not chew”. The process of mouth and throat [10]. Total turnover rate of the total whole saliva manipulating the ODT in oral or buccal cavity was also important. (output from the major and minor salivary glands) at normal physiolog- However since the OST derived products were readily popular in the ical conditions has a flow rate of 1–2 ml/min [11]. Drug absorption market in the form of breath-freshening strips, no further efforts were through the buccal cavity can take place either by the transcellular route needed to re-instruct the populace about the technique of adminis- (or intracellular route, crossing across the cell membrane and entering tration of this dosage form. OST was already popular amongst the the cell) or paracellular pathway (passing between the cells). The people in the early 2000 year with the introduction and widespread mucosa in sublingual region is relatively more permeable leading to use of Listerine pocket strips, a new launch in the mouthwash range. rapid absorption with improved bioavailability [12]. Technology Catalysts forecasts the market for drug products in oral In view of the systemic transmucosal drug delivery, the buccal thin film formulations to be valued at $500 million in 2007 and could mucosa is the preferred region as compared to the sublingual mucosa. reach $2 billion by 2010 [26]. However only a few products consisting One of the reasons is that the buccal mucosa is less permeable and is thus bitter molecules have been able to be commercialized because of the not able to elicit a rapid onset of absorption and hence better suited for complexity associated with the OST. formulations that are intended for sustained release action. Further, the This dosage form enjoys some distinct advantages over other oral buccal mucosa being relatively immobile mucosa and readily accessible, formulations such as- it makes it more advantageous for retentive systems used for oral transmucosal drug delivery. The primary disadvantage associated with 1. Availability of larger surface area that leads to rapid disintegrating buccal delivery route is the low flux that in turn results in low drug and dissolution in the oral cavity. bioavailability. To overcome this hurdle, various buccal penetration 2. The disadvantage of most ODT is that they are fragile and brittle enhancers have been studied which improve the absorption pattern of which warrants special package for protection during storage and the molecules (this has been discussed in details in future sections of transportation. Since the films are flexible they are not as fragile as this article). The constant salivary secretion within the oral cavity makes most of the ODTs. Hence, there is ease of transportation and during it quite difficult for dosage forms to be retained for long periods of time. consumer handling and storage. Accidental swallowing of dosage forms and salivary scavenging is 3. As compared to drops or syrup formulations, precision in the another limitation in buccal delivery systems. It is documented that the administered dose is ensured from each of the strips. maximum duration of buccal delivery is 4–6 h [13]. 4. The advantage of ease of swallowing and no need of water has led An ideal buccoadhesive system is the one that adhere to the site of to better acceptability amongst the dysphagic patients. The diffi- attachment for a few hours, releases the drug in a controlled fashion, culty encountered in swallowing tablets or capsules is circum- facilitates the rate and extent of drug absorption, does not cause any vented. The large surface area available in the strip dosage form irritation or inconvenience to the patient, does not interfere with the allows rapid wetting in the moist buccal environment. The dosage normal functions such as talking, drinking etc. and that provides form can be consumed at anyplace and anytime as per convenience of unidirectional drug release toward the mucosa. the individual. In spite of these challenges the buccal route is still the preferred route 5. The oral or buccal mucosa being highly vascularized, drugs can be for delivery of active pharmaceutical ingredients (API) that are prone to absorbed directly and can enter the systemic circulation without high level of degradation in the gastrointestinal tract. Different buccal undergoing first-pass hepatic metabolism. This advantage can be delivery products have been marketed or are proposed for certain exploited in preparing products with improved oral bioavailability diseases like trigeminal neuralgia, Meniere's disease, diabetes, addiction of molecules that undergo first pass effect [27]. etc. [14–21]. The buccal cavity can be a platform for mucoadhesive 6. Since the first pass effect can be avoided, there can be reduction in the (buccoadhesive) systems, gingival dosage forms, local delivery into the dose which can lead to reduction in side effects associated with the oral cavity and buccal delivery systems. molecule.
  • 3. 96 R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 7 Patients suffering from dysphagia, repeated emesis, motion replaced by starch in the production of OS without loss of required sickness, and mental disorders prefer this dosage form as they properties of Pullulan. Typically 60 to 65%w/w of water soluble are unable to swallow large quantity of water. polymer is preferred for preparation of OS with desired properties [39,40]. Many times, mixtures of polymers are used to improve A number of molecules can be incorporated into this delivery hydrophilicity, flexibility, mouth-feel and solubility characteristics of system. They may include cough/cold remedies (antitussives, expec- OS. Polyvinyl pyrrolidone films are brittle in nature and therefore torants), sore throat, erectile dysfunction drugs, antihistaminics, copovidone is mixed with poly vinyl pyrrolidone for preparation of antiasthmatics, gastrointestinal disorders, nausea, pain and CNS (e.g. flexible fast disintegrating strips [41]. Combination of microcrystalline anti-parkinsons disease). Other applications comprise caffeine strips, cellulose and maltodextrin has been used to formulate OS of snoring aid, multivitamins, sleeping aid etc. piroxicam made by hot melt extrusion technique. In this case, The OS technology continues to be viewed as an alternative for microcrystalline cellulose is used to render the film non-sticky and ODT products that would afford a superior barrier to generic entry and smooth [42]. Microcrystalline cellulose was also used to decrease the product differentiation to over-the-counter brands. From the market- disintegration time and improve the dissolution of drug from the OS ing perspective, a patented OS technology would be beneficial. The [43]. grant of marketing exclusivity to the new dosage form would help to The polymer employed should be non-toxic, non-irritant and devoid gain more revenue. As compared to the other ODTs such as tablets; the of leachable impurities. It should have good wetting and spreadability product is robust. From the patient point of view OS offers ease of property. The polymer should exhibit sufficient peel, shear and tensile administration and improved compliance. The manufacturing of this strengths. The polymer should be readily available and should not be dosage form is cost-effective with affordable end-products. From very expensive. Various polymers can be employed to modulate the clinical aspect, the improved bioavailability can be advantageous in disintegration property of the oral strip. This is especially used in case of reducing the dose of the formulation. This would lead to product with slowly disintegrable oral bioadhesive strips or patches that need to be minimized side effects. The product can be a substitute with more retained in intact form for longer duration in the oral cavity. The clinical advantage. However, not all drugs can be incorporated into bioadhesive polymer used in such formulations imparts the adhesive this dosage form. The disadvantage of OS is that high dose cannot be property to the strip such that it adheres to buccal mucosa to deliver the incorporated into the strip. However, research has proven that the drug for prolonged period. Bioadhesive polymer should ideally adhere concentration level of active can be improved up to 50% per dose quickly to the buccal mucosa and should have sufficient mechanical weight. Novartis Consumer Health's Gas-X® thin strip has a loading of strength. Polymers used for OS should have good shelf life and they 62.5 mg of simethicone per strip [28]. should not aid in causing secondary infections in the oral mucosa or This article endeavors to review the general aspects of OST, some dental regions. It would be ideal to have a polymer that would have local polymeric materials employed for preparation, the critical aspects of enzyme inhibition action along with penetration enhancing property. manufacturing processes and intricacies of preparing the product, The details of properties of bioadhesive or mucoadhesive polymers and commercial technologies and future prospects in this area. their applications are discussed elsewhere [44–51]. Mucoadhesive polymers include polycarbophil, cellulose derivatives like hydroxypro- 2. Formulation considerations pyl methylcellulose, poly(acrylic acid) derivatives, sodium carboxy- methyl cellulose, hydroxylethyl cellulose, hyaluronic acid, xanthan gum, Formulation of OS involves the intricate application of aesthetic locust bean gum, guar gum, carrageenan, sodium alginate, chitosan, poly and performance characteristics such as taste masking, fast dissolving, (ethylene oxide), poly (ortho esters), poly (hydroxyl butyrate), poly physical appearance, mouth-feel etc. The excipients used in formula- (cyano acrylates), polyphosphazenes, poly (vinyl alcohol) etc. Second tion of OS are given below as per their categories. From the regulatory generation mucoadhesive polymers include thiolated polymers. They perspectives, all excipients used in the formulation of OS should be are multifunctional polymers consisting of hydrophilic macromolecules Generally Regarded as Safe (i.e. GRAS-listed) and should be approved having free thiol groups on the polymer backbone. The polymer forms for use in oral pharmaceutical dosage forms. disulfide bonds with cysteine-rich subdomains of mucus glycoproteins. Corium International has developed a new class of adhesive hydrogels 2.1. Strip forming polymers (Corplex™) [52]. The polymer has properties of both hydrophobic pressure sensitive adhesives and hydrophilic bioadhesives. This is A variety of polymers are available for preparation of OS. The prepared by non-covalent (Hydrogen bond) cross-linking of film- polymers can be used alone or in combination to obtain the desired strip forming hydrophilic polymer (like polyvinyl pyrrolidone) with a properties. The film obtained should be tough enough so that there short-chain plasticizer (typically; polyethylene glycol) bearing comple- won't be any damage while handling or during transportation. The mentary reactive hydroxyl groups at the chain ends. robustness of the strip depends on the type of polymer and the amount There are a number of marketed products available that are based on in the formulation [29]. On the other hand, fast dissolving strip dosage mucoadhesion phenomena. Oramoist® is a Timed Release oral disk that form should have the property to disintegrate in seconds when placed in adheres to the roof of the mouth and has a moisturizing effect for about mouth and deliver the drug to the oral cavity instantaneously. A list of 4 h [53]. It is recommended for dry mouth syndrome (xerostomia). polymers and their properties are given in Table 1 [30–36]. As the strip Compeed® is another formulation that is intended to treat cold sore [54]. forming polymer (which forms the platform for the OS) is the most This system is similar to transdermal formulation wherein the patch has essential and major component of the OS, at least 45%w/w of polymer to be applied onto the affected area. The disadvantage is that since it should generally be present based on the total weight of dry OS [37]. Of does not contain biodisintegrating ingredients, the patch has to be the various polymers available, pullulan, gelatin and hypromellose are removed after use. Canker Cover® is a tablet-like patch that is used in the most commonly used for preparation of OS. Pullulan is a natural polymer treatment of canker sore [55]. It adheres to the canker sores and lasts for obtained from non-animal origin and does not require chemical 8–12 h. It forms a clear gel patch after application. The patch once modification. This polymer provides highly clear and homogenous applied needs careful manipulation using water for its removal and at films. It has low oxygen permeability and low water content which times may cause pain. Striant® is a bioadhesive delivery system for makes it most suitable for production of OS [38]. testosterone replacement therapy [56]. It is a small monoconvex tablet Modified starches are also used for preparation of OS. Due to low that rapidly adheres to the buccal mucosa, gets hydrated due to saliva to cost of this excipient it is used in combination of pullulan to decrease form gel like form that remains in the region of where the gum meets the the overall cost of the product. About 50 to 80%w/w of pullulan can be upper lip above the incisor teeth for a period of 12 h. Dentipatch® is
  • 4. R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 97 trans-oral anesthetic patch [57]. This is similar to a transdermal system crystallizes out from the gelatin strip [76]. Maltodextrin can also be and the formulation has to be retrieved after its use. BioErodible plasticized and converted into OS with incorporation of glycerin and MucoAdhesive (BEMA™) technology, which is designed to deliver propylene glycol as plasticizer in the concentration range of 16–20%w/w. either local or systemic levels of drugs across mucosal tissues [58]. It In this case, glycerin was found to be better than propylene glycol when consists of a small, bioerodible polymer film for application to the the strips were manufactured by solvent casting as well as hot melt mucosal membranes (inner lining of cheek). As compared to the OS, extrusion methods. However, PEG has miscibility problems with most of the above marketed disk formulations have higher thickness. maltodextrins and do not act as good plasticizers [42]. Hence this might cause inconvenience to the individual when the Certain drug molecules themselves can act as plasticizer. For system is residing in the buccal cavity. Additionally there is a risk of example, Ibuprofen interacted with Eudragit RS 30 D and played the inadvertent detachment of the system leading to loss of clinical role of a plasticizer. In this case, the glass transition temperature of response. Eudragit RS 30 D decreased and smooth film formation was observed Thus, Oral mucosal patches can be categorized into three types due to the hydrogen bonding between the drug and the polymer. Also, namely; patches with a dissolvable matrix, patches with a non- the dissolution rate of ibuprofen decreased when its concentration in dissolvable backing, and patches with a dissolvable backing. Patches the formulation was increased [77]. with a dissolvable matrix are designed to release drug into the oral There are two mechanisms propagated of how the plasticization cavity. The mucoadhesive layer (either in drug matrix or attached to takes place namely internal plasticization (involving chemical inter- drug matrix) would prolong the duration of drug matrix in the oral action) and external plasticizing effect. Formulators prefer to adopt cavity. Hence, in comparison to other dosage forms, these systems are the latter mechanism as it does not involve chemical interactive longer acting and can potentially deliver more drug quantities. Patches alterations in the product. An example of internal plasticization is with non-dissolvable backing are usually designed for systemic delivery. where PEG 4000 was used as plasticizer for phenobarbital where the Being closed systems the formulations are protected from saliva, the drug release was reduced to considerable extent [78]. The chemical drug concentrations are controlled and drug is continuously delivered structure and concentration of plasticizers play an important role in for few hours. However, the disadvantages with these patches are that alleviating the glass transition temperature of the polymers. Cellulosic they use only a small mucosal area and the backings have to be removed hydrophilic polymers were easily plasticized with hydroxyl containing by the patient after drug administration. Patches with dissolvable plasticizers like PEG, propylene glycol, glycerol and polyols. In backing have the advantage of the entire patch being dissolved in the contrast, less hydrophilic cellulosic polymers were plasticized with oral cavity. Patches with dissolvable backings are shorter acting as esters of citric acid and phthalic acid [79]. Glycerol acts as a better compared to those with non-dissolvable backing membranes. plasticizer for polyvinyl alcohol while diethylene glycol can be used for both Hypromellose as well as polyvinyl alcohol films [75]. 2.2. Plasticizers 2.3. Active pharmaceutical ingredient Plasticizer is a vital ingredient of the OS formulation. It helps to improve the flexibility of the strip and reduces the brittleness of the The OS technology has the potential for delivery of variety of APIs. strip. Plasticizer significantly improves the strip properties by However since the size of the dosage form has limitation, high dose reducing the glass transition temperature of the polymer. The molecules are difficult to be incorporated in OS. Generally 5%w/w to selection of plasticizer will depend upon its compatibility with the 30%w/w of active pharmaceutical ingredients can be incorporated in polymer and also the type of solvent employed in the casting of strip. the OS [40]. Multivitamins up to 10%w/w of dry film weight was The flow of polymer will get better with the use of plasticizer and incorporated in the OS with dissolution time of less than 60 s [41]. enhances the strength of the polymer [59,60]. Glycerol, Propylene While water soluble APIs are present in the dissolved state in the OS glycol, low molecular weight polyethylene glycols, phthalate deriva- or in the solid solution form, the water insoluble drugs are dispersed tives like dimethyl, diethyl and dibutyl phthalate, Citrate derivatives uniformly in the strip. The distribution of water insoluble molecules in such as tributyl, triethyl, acetyl citrate, triacetin and castor oil are some water miscible polymer becomes important from the large scale of the commonly used plasticizer excipients. Typically the plasticizers manufacture point of view. APIs can also be added as milled, micronized are used in the concentration of 0–20%w/w of dry polymer weight or in the form of nanocrystals or particles depending upon the ultimate [61–69]. However inappropriate use of plasticizer may lead to film release profile desired. It is always useful to have micronized API which cracking, splitting and peeling of the strip [70–72]. It is also reported will improve the texture of the film and also for better dissolution and that the use of certain plasticizers may also affect the absorption rate uniformity in the OS [79]. Many APIs, which are potential candidates for of the drug [73]. OS technology, have bitter taste. This makes the formulation unpalatable The Plasticizer employed should impart the permanent flexibility to especially for pediatric preparations. Thus before incorporating the API the strip and it depends on the volatile nature plasticizer and the type of in the OS, the taste needs to be masked. Various methods can be used to interaction with the polymer. It should be noted that the properties of improve the palatability of the formulation [80]. Among the techniques plasticizer are important to decrease the glass transition temperature of employed, the simplest method involves the mixing and co-processing polymer in the range of 40–60 ºC for non aqueous solvent system and of bitter tasting API with excipients with pleasurable taste. This is often below 75 ºC for aqueous systems [72,74]. Plasticizer should be termed as obscuration technique. Barrier technologies that can be used compatible with drug as well as other excipients used for preparation to mask the bitter taste include complexation, polymeric coating, of strip [75]. conversion into microparticles/microcapsules, coated particles or coated Various plasticizers were studied for their plasticization effect on the granules [79]. However, in the cases where the drug is encapsulated, the gelatin strips. In these studies it was observed that malic acid was found instantaneous release of medicament will not be achieved. Depending to be better plasticizer as compared to citric acid, oleic acid and tartaric on the material employed in encapsulation and the manufacturing acid as it did not crystallize out when the strips were dried. Amongst the technique, the rate of drug release varies. Hence, the issue of palatability different grades of polyethylene glycol (PEG); PEG 300 was found to be and drug response needs to be balanced to achieve maximum advantage better plasticizer for gelatin as compared to higher molecular weight of the developed OS formulation. PEG. This is because lower molecular weight PEG formed visually Complexation technology involves use of cyclodextrins, resins superior films and had low water vapor permeation rate. When sugars which surround the bitter API and prevents the direct contact with like mannitol and sorbitol were tested as plasticizers for gelatin strips, saliva [81–85]. Matrixing of the bitter drug or coating of drug with sorbitol was found to be better as compared to mannitol since mannitol water insoluble polymer has been used widely for taste masking of
  • 5. 98 R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 Table 1 List of polymers used in development of strip formulations. Property Hydoxy propyl methyl Hydroxy propyl cellulose Starch and modified starch Pullulan Pectin Gelatin Carboxy methyl cellulose cellulose (Hypromellose) Synonym HPMC, Methocel, Metolose, Hydroxyl propyl ether, Amido, amylum, PharmGel, Pullulane, 1, 6 α linked Citrus pectin, Methopectin, Byco, cryogel, Instagel, Akulell, Blanose, Aquasorb, Benecel hyprolose, Klucel, Nisso HPC. Fluftex W, Instant pure-Cote, maltotriose pectin, pectinic acid. Solugel CMC sodium Melogel etc. Description It is a odorless, tasteless and It is a white to slightly yellow It is an odorless, tasteless, It is available as white, It occurs as a yellowish- It occurs as light amber to It is white, odorless powder white or creamy white colored, odorless and fine, white powder. odorless tasteless, stable white, odorless powder with faintly yellow colored, fibrous or granular powder tasteless powder. It is stable powder mucilaginous taste. vitreous, brittle solid. It is material ordorless, tasteless. Molecular weight 10,000–1,500,000 50,000–1,250,000 50,000–160,000 8000–2,000,000 30,000–100,000 15,000–250,000 90,000–700,000 Solubility Soluble in cold water, It is freely soluble in water Starch is insoluble in cold It is soluble in hot as well as It is soluble in water but Soluble in glycerin, acid and It is easily dispersed in water forming a viscous colloidal below 38 °C forming a water and ethanol. It swells in cold water. insoluble in most of the alkali. Swells in water and to form a clear or colloidal solution, insoluble in smooth, clear, colloidal water by about 5 to 10% at organic solvents. softens. It is soluble in hot solution. chloroform, ethanol. solution. Hydroxypropyl 37 °C water. cellulose is soluble in many cold and hot polar organic solvents such as absolute ethanol, methanol, isopropyl alcohol and propylene glycol. Film forming It has a film forming ability in It has a good film forming Modified starches have a 5–25%w/w solution forms It has a film forming ability. It has a very good film The enzymatically modified capacity 2–20%w/w concentrations. property and 5%w/w solution property to form quick flexible films. Films are low forming ability. carboxymethyl cellulose has is generally used for film dissolving films. permeable to oxygen, stable. good film forming property. coating. Viscosity A wide range of viscosity A wide range of viscosity types 2%w/v aqueous dispersion of The viscosity (10%w/w, – 4.3–4.7 mPa s for a 6.67%w/v The 1%w/w aqueous solution grades are commercially are commercially available. starch provides 13 mPa s 30 °C) of pullulan was 100– aqueous solution at 60 °C. has viscosities in the range of available. Viscosity of various The viscosity of solutions viscosity. 180 mm2/s. 5–13,000 mPa s. grades ranges from 3 mPa s– ranges from 75 mPa s– 100,000 mPa s 6500 mPa s depending upon the polymer grade. Melting point Browns at 190–200 °C. glass It softens at 130 °C; chars at It decomposes at 250 °C 107 °C 152° in dry state. – Browns at 227 °C and chars at transition temperature is 260–275 °C 252 °C. 170–180 °C
  • 6. Moisture content It absorbs moisture from the It absorbs moisture from the Starch is very hygroscopic It contains less than 6%w/w It is hygroscopic in nature. 9–11%w/w Moisture content of the air. The amount of moisture air. Typical equilibrium and readily absorbs moisture. of moisture. polymer is less than 10%. absorption depends on initial moisture content values at Commercial grades are moisture content, 25 °C/50% RH are 4%w/w and having moisture content in temperature and humidity of 12%w/w at 84%RH. the range of 10–14%w/w. surrounding air. Application/s Hypromellose is widely used Hydroxypropyl cellulose acts Starch is used widely in the It is used extensively in food Pectin is used as a gel forming It is widely used in an It is used widely in oral and in oral, ophthalmic and as a tablet binder in the range solid oral dosage forms as a industry to provide bulk and agent for sustained release of implantable delivery system. topical formulation. It is used topical formulations. of 2–8% of tablet weight. The binder, diluents and texture. The hydrophobic drugs. It has been used in It is used for the preparation mainly as a viscosity Hypromellose is primarily polymer is also used for disintegrant. Starch is used grades of pullulan are used combination with other of hard and soft gelatin increasing agent. It is used as used as a tablet binder, film preparation of modified extensively in topical for preparation of polymers for colon drug capsule. It is used for a stabilizer for preparation of coating agent, film forming release dosage form. Hydroxy preparation such as dusting nanoparticles for targeted delivery. Pectin mixed with microencapsulation of drugs. suspensions and emulsions. It agent and as a matrix for use propyl cellulose is most powders, ointments. It is delivery. Pullulan can be used polymers for preparation of It is used topically in wound can be utilized as a binder or in extended release suitable for water soluble used therapeutically for the as a replacement to dextran controlled release dressing. Absorbable gelatin disintegrant depending on formulations. Hypromellose drugs. It is also used for the treatment of iodine as a plasma expander. microparticles. It is used as is available as sterile film, the grade and concentration is also used as a suspending preparation of microcapsules. poisoning. Modified starches Pullulan films are strong adsorbent, emulsifying agent, ophthalmic film, sterile used in the formulation. It is and thickening agent. It is used as a thickening are used for coating of therefore used for decoration stabilizing agent. It is used as sponge etc. also reported as a Hypromellose is also used as agent in the oral and topical immediate release dosage of food products, in a bulk forming agent in the cryoprotective agent. It has a an emulsifier, suspending formulations. Due to its non forms. These are the aqueous confectionaries. It acts as an preparations for the mucoadhesive property R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 agent and stabilizing agent in ionic nature, it is used as an preparations used for ideal carrier system for management of diarrhea and which is utilized in some of gels and ointments. emulsifier in the cosmetic aesthetic purpose, light and flavors, colors and drugs. constipation. the topical as well as oral Hypromellose is also used to formulations. It imparts low moisture barrier. It is also Pullulan is used in coating for preparation. It is reported for manufacture capsules, as an surface and interfacial used in the treatment of immediate release tablets use in combination with adhesive in plastic bandage tension to its solution and dehydration. and it is also used for other film forming polymers and as a wetting agent in thus can be used for the preparation of capsule shells. for preparation of oral films contact lenses preparation of flexible films or for coating the tablets. It alone or in combination with can be used for preparation of Hypromellose. microparticles as it forms complex coacervates with gelatin and pectin. Safety and GRAS listed and included in Generally regarded as a non- Generally regarded as a non- GRAS listed. GRAS listed and included in Included in FDA Inactive GRAS listed and included in regulatory FDA Inactive Ingredient toxic and non-irritant toxic and non-irritant FDA Inactive Ingredient Ingredient Guide. the Inactive Ingredients status Guide. material. It is GRAS listed and material. It is GRAS listed and Guide. Guide. included in the FDA Inactive included in the FDA Inactive Ingredient Guide. Ingredient Guide. 99
  • 7. 100 R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 drugs. The bitter taste of paracetamol was masked with the use of Table 2 lipidic excipients like hard fat and lecithin [84,85]. Particulate List of molecules eligible for incorporation in strip delivery dosage forms. technology has studied widely for the taste masking of APIs. Molecule Therapeutic category Dose Microparticulates of Famiotidine and Eudragit EPO were prepared Nicotine Smoking Cessation 1.0–15.0 mg by spray drying technique. The results rendered a good taste masked Nitroglycerin derivatives Vasodilator 0.3–0.6 mg product which did not affect the bioavailability of the drug confirming Zolmitriptan Anti migraine 2.5 mg Loratidine Antihistaminic 5–10 mg the potential of the developed technology [86–88]. Desloratidine Antihistaminic 5.0 mg MonosolRx technology utilizes particulate technology approach Diphenhydramine hydrochloride Antihistaminic 25.0 mg for preparation of taste masked product to be incorporated in the OS. Loperamide Antidiarroheal 2.0 mg The limitation of barrier technologies is the dose of the API since the Famotidine Antacid 10.0 mg dose of the drug will ultimately decide the amount of microparticles Flurazepam Anxiolytic, Anticonvulsant 15.0–30.0 mg Chlorpherinamine maleate Antihistaminic 4.0 mg or complex powder to be accommodated in the OS [79]. Acrivastine Antihistaminic 8.0 mg Chemical modification of API was used successfully by GlaxoS- Oxycodone Opoid Analgesic 2.5–10.0 mg mithKline Beecham for the taste masking. Due to low solubility of Diclyclomine Muscle Relaxant 25.0 mg ondansetron base than its salt form, base was used to prepare orally Omeprazole Proton pump inhibitor 10.0–20.0 mg Cetrizine Antihistaminic 5.0–10.0 mg disintegrating tablets. The conversion of the salt of the base can be Ketoprofen Anti–inflammatory 12.5–25.0 mg done in situ by addition of buffering agent in the OS. These agents alter Azatidine maleate Antihistaminic 1.0 mg the pH of the saliva and thus convert the salt form of the drug into the Sumatriptan succinate Antimigraine 35.0–70.0 mg low soluble base form leading to taste masking of drug [79,89]. Chlorhexidine gluconate Antimicrobial 0.12% Recently a novel salting out technology was developed for the taste Tiprolidine hydrochloride Antihistaminic 2.50 mg masking of API. The technology involved coating of drug substance with salting out layer consisting of salt and water soluble polymer. The salt reduced the dissolution of water soluble polymer and drug from used widely as a sweetener. Polyhydric alcohols such as sorbitol, the system resulting into taste masking of the drug. As the mannitol, isomalt and maltitol can be used in combination as they concentration of salt decreases in the system, the polymer and drug additionally provide good mouth-feel and cooling sensation. Poly- was released and resulted into immediate release of the drug. This hydric alcohols are also less carcinogenic and do not have bitter after salting-out taste-masking system generates lag time with subsequent taste which is a vital aspect in formulating oral preparations. The immediate release. The technology was successfully utilized for the sweetness property of most of the polyols is less than half of that of taste masking of paracetamol used as model drug [90]. Other methods sucrose except xylitol and maltitol which have similar sweetness as involve the obstructing of taste receptors. Nucleotide containing that of sucrose (scale of 0.8–1.0). However it should be noted that the purine or pyrimidine group derivatives which are bound to ribose or use of natural sugars in such preparations need to be restricted in deoxy ribode sugar moiety inhibits the bitter or unpleasant taste. people who are on diet or in the case of diabetic patients [93,94]. These compounds can be included in the OS to mask the bitter taste of Due to this reason, the artificial sweeteners have gained more drug substances. Adenosine 5′ mono phosphate, inosine 5′ monopho- popularity in food and pharmaceutical preparations. Saccharin, sphate, adenosine 3, 5′ cyclic monophosphate are few examples which cyclamate and aspartame are the first generation of the artificial can be utilized in the concentration of 10.0–20.0%w/w in the sweeteners followed by acesulfame-K, sucralose, alitame and neotame formulation [91]. which fall under the second generation artificial sweeteners. The OS technology offers advantages in certain critical clinical Acesulfame-K and sucralose have more than 200 and 600 time situations. For drugs that are projected as local anesthetic or pain killer, sweetness. Neotame and alitame have more than 2000 and 8000 time the OS has demonstrated improved clinical benefits. Certain pathologies sweetening power as compared to sucrose. Rebiana which is a herbal require instantaneous release of the medicament for prompt relief. For sweetener, derived from plant Stevia rebaudiana (South American instance, in the case of migraine a rapid clinical effect is desired by the plant) has more than 200–300 time sweetness [95]. individual. Regiospecific delivery of the medicament would be required The disadvantage of these artificial sweeteners is the after taste in the cases of sore throat, cough, allergy and other local oral effect. This disadvantage of artificial sweeteners can be reduced by manifestations. Breath strips also offer superior consumer compliance. mixing or blending the natural and artificial sweetener. Similarly, cases of motion sickness need immediate attention. Also since The flavor quality of these artificial sweeteners is different than the OS technology does not require water during administration as natural sweeteners and may not be acceptable to the patients who are compared to the regular tablet dosage forms; it is very handy during accustomed to the natural sugars. The amalgamation of sweeteners may travel. This dosage form can also be used for natural extracts and lead to synergism and improvement in the taste of the formulations [94]. neutraceuticals including vitamin B12, chromium picolinate, melatonin Aspartame was used for the preparation of oral strips of valdecoxib [96]. and possibly CoQ10 [92]. For the oral strip of piroxicam, maltodextrin was employed as Some of the examples of suitable drug molecule that can be sweetening agent [40]. Generally sweeteners are used in the concentra- incorporated in the OS are listed in Table 2. tion of 3 to 6 %w/w either alone or in combination [97]. 2.4. Sweetening agents 2.5. Saliva stimulating agent Sweeteners have become the important part of the food products The purpose of using saliva stimulating agents is to increase the as well as pharmaceutical products intended to be disintegrated or rate of production of saliva that would aid in the faster disintegration dissolved in the oral cavity. The sweet taste in formulation is more of the rapid dissolving strip formulations. Generally acids which are important in case of pediatric population. Natural sweeteners as well used in the preparation of food can be utilized as salivary stimulants. as artificial sweeteners are used to improve the palatability of the Citric acid, malic acid, lactic acid, ascorbic acid and tartaric acid are the mouth dissolving formulations. The classical source of sweetener is few examples of salivary stimulants, citric acid being the most sucrose (derived from cane or beet in the form of liquid or dry state), preferred amongst them. These agents are used alone or in dextrose, fructose, glucose, liquid glucose and maltose. The sweetness combination between 2 to 6%w/w of weight of the strip. Other OS of fructose is perceived rapidly in the mouth as compared to sucrose ingredients such as sweeteners also act as salivary stimulants. Food and dextrose. Fructose is sweeter than sorbitol and mannitol and thus grade sugars as well as synthetic sugars are useful salivary stimulants
  • 8. R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 101 Table 3 and stabilizing agents [97]. Other ingredients such as surfactants and Data on comparison between the salivary stimulation using citric acid and other sugars. emulsifying agents are also added in small amount to improve the Stimulant Molarity Flow rate (ml/min) Time required for returning strip properties. to initial flow rate (min) Citric acid 0.26 1.68 7.3 3. Manufacture and production of oral strips Glucose 1.17 0.52 6.7 Fructose 1.17 0.97 8.7 Films can be prepared either by hot melt extrusion method or Sucrose 1.17 0.74 6.3 Aspartame 0.034 0.82 6.8 solvent casting technique. In the extrusion process the API and other Sodium saccharin 0.42 1.04 10.5 ingredients are mixed in dry state, subjected to heating process and The resting salivary flow rate was 0.34 ml/min [98]. then extruded out in molten state. In this process, solvents are completely eliminated. The strips are further cooled and cut to the desired size. The high temperature used in this process may degrade along with acidulents. Glucose, fructose, xylose, maltose, lactose are thermolabile APIs. Hence, generally the solvent cast method is few examples of such sweeteners [98]. employed for manufacture of strips (Fig. 1). The stimulation of salivation can be measured by comparing the Typically it includes the preparation of the base material which amount of resting flow and stimulated flow at equal time under same involves the mixing of strip forming excipients and the API mixed conditions. The comparison between the salivary stimulation using together in a suitable solvent or solvent system. The selection of citric acid and other sugars is given in Table 3. solvent essentially depends on the API to be incorporated into the The stimulant action of sweeteners is dependent on the sweetness strip. The physicochemical properties of the API like heat sensitivity, value. Fructose has the sweetness value of 1.1 as compared to 0.7 of shear sensitivity, the polymorphic form of the API employed, glucose and 1.0 of sucrose. The artificial sweetener is preferred over compatibility of the API with solvent and other strip excipients are natural sugars because lower concentration is required and multiple to be critically studied. The significant elements in this are liquid uses don't result in dental caries in individuals [98]. rheology, desired mass to be cast and content or dosage uniformity. Solvents used for the preparation of solution or suspension should 2.6. Flavoring agents ideally be selected from ICH Class 3 solvent list [102]. Heating process may be included at this stage for the complete Perception for the flavors changes from individual to individual dissolution of materials. At this point the important point to be depending upon the ethnicity and liking. It was observed that age considered is the air bubbles that may have entrapped during the plays a significant role in the taste fondness. The geriatric population solution preparation. Entrapped air may tend to produce uneven like mint or orange flavors while younger generation like flavors like strips. Deaeration step is imperative to get a strip with uniform fruit punch, raspberry etc. The selection of flavor is also dependant on thickness. Vacuum assisted machines can be employed to remove the the type of drug to be incorporated in the formulation. For example, entrapped air. Many firms adopt bubble-free mixing using suitable mint flavor is generally added in products used for gastric related type of specialized stirring systems. Another important aspect is the ailments like indigestion. The acceptance of the oral disintegrating or moisture present in the solution. It is observed that moisture can dissolving formulation by an individual by and large depends on the cause changes in the mechanical properties of the strips such as initial flavor quality which is observed in first few seconds after the tensile strength, flexibility, folding endurance, Young's modulus, product has been consumed and the after taste of the formulation elongation etc. Hence care should be exercised by using suitable which lasts for at least about 10 min [99]. humidity controls in the manufacturing production area. The solution Flavoring agents can be selected from synthetic flavor oils, oleo is subjected to continuous mixing process in order to keep the resins, extract derived from various parts of the plants like leaves, viscosity and concentration unchanged. The solution or suspension fruits and flowers. Flavors can be used alone or in the combination. may be kept under controlled temperature condition to achieve the Peppermint oil, cinnamon oil, spearmint oil, oil of nutmeg are desired viscosity of the material. Once this solution is prepared, the examples of flavor oils while vanilla, cocoa, coffee, chocolate and film casting process is performed wherein a strip of desired thickness citrus are fruity flavors. Apple, raspberry, cherry, pineapple are few is cast onto a moving inert substrate. Suitable rollers are employed for examples of fruit essence type. The amount of flavor needed to mask guiding the solution onto the substrate. The clearance or tolerance the taste depends on the flavor type and its strength. Preferably up to between the roller and the substrate determines the required 10%w/w flavors are added in the OS formulations. Cooling agents like thickness of the strip. The formed strip is then subjected to drying monomethyl succinate can be added to improve the flavor strength process to remove the solvent. In R&D for small scale production, film and to enhance the mouth-feel effect of the product. Other cooling strips are usually cast using applicators. Adjustable film applicators agents like WS3, WS23 and Utracoll II can also be used in conjunction allow the user to modulate the film thickness by changing the distance with flavors [91,97]. 2.7. Coloring agents Pigments such as titanium dioxide or FD&C approved coloring agents are incorporated (not exceeding concentration levels of 1%w/w) in OS when some of the formulation ingredients or drugs are present in insoluble or suspension form [100,101]. 2.8. Stabilizing and thickening agents Fig. 1. Schematic representation of a typical OST manufacturing unit. A – Formation of The stabilizing and thickening agents are employed to improve the medicated film takes place. The rollers can be adjusted to get the desired film thickness. viscosity and consistency of dispersion or solution of the strip After formation of film, it is dried. a – Reservoir for the film forming materials, b – deaerator and film applicator, c – rollers. B – The dried medicated film is slit and cut into little strips of preparation solution or suspension before casting. Natural gums like desired size. C – Strips are placed into lower packaging web. D – Laser printer prints on upper xanthan gum, locust bean gum, carragenan and cellulosic derivatives packaging web. E – Sealing head seals the strips into single dose sachets. F – Introduction of can be used in the concentration up to 5%w/w as thickening agents tear-notch/slit/cut off to sachet. G – Quality control conveyer to final packaging.
  • 9. 102 R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 between the applicator head and the substrate using micrometer tenacity with which the strip adheres to an accessory (a piece of gauge. Glass or Teflon plates are used as the inert base for casting the paper) that has been pressed into contact with the strip. Instruments film. are also available for this study. Most challenges are encountered when the formulation is scaled up from the bench scale to production scale. The critical step is the 3.3. Tensile strength film casting and the drying process. Optimization of speed of casting and drying time are important from the commercial scale output. The Tensile strength is the maximum stress applied to a point at which thickness of wet strip cast and the physicochemical properties of the the strip specimen breaks [105]. It is calculated by the applied load at coating solution affect scale-up by limiting the drying speed of rupture divided by the cross-sectional area of the strip as given in the product and final thickness of the dried strip. In the continuous equation below: coating line the proper selection of dryers (for instance; bow-type or horizontal-nozzle, or hot-flue type dryer) and also the number of on- Load at failure × 100 line dryers improves the processing times [103]. Tensile strength = ð1Þ Strip thickness × Strip width The current trend is that many of the companies are using similar type of dryers in their R&D scale to mimic the process so that the translation to higher scale becomes easier. This is advantageous from the scale-up point of view. High dosing accuracy essentially depends 3.4. Percent elongation on micrometer accuracy of film casting and accuracy in cutting of the strip. Many a times, during the optimization trials in small scale R&D When stress is applied, a strip sample stretches and this is referred trial, the strip is cut and weighed in an endeavor to estimate the to as strain. Strain is basically the deformation of strip divided by accurate dose per strip. original dimension of the sample. Generally elongation of strip Once the strips are dried, it is cut into suitable shape and size as per increases as the plasticizer content increases [106]. the required dosage and thickness of the formed strip and intended application. Many a times the strips are rolled and kept for certain Increase in length of strip × 100 % elongation = ð2Þ duration before cutting. This is referred in industry as ‘rollstock’. Initial length of strip However, this should be avoided since the properties of the strip may alter during this period. It essentially should be cut and packed immediately after the preparation. The medicated strip then is 3.5. Tear resistance subjected to packaging. In the primary package, the strips are placed into individual lower packaging web. Packaging of strips is very Tear resistance of plastic film or sheeting is a complex function of important. The pack should be robust enough to give mechanical its ultimate resistance to rupture. Basically very low rate of loading protection to the strip. Further, moisture barrier property is equally 51 mm (2 in.)/min is employed and is designed to measure the force important aspect for the selection of pack. Aluminium foils are ideal to initiate tearing. The maximum stress or force (that is generally and most preferred for packaging strips. Tamper proof packaging is found near the onset of tearing) required to tear the specimen is achieved by using suitable lidding foil. Next the laser printed upper recorded as the tear resistance value in Newtons (or pounds-force) packaging web is placed onto it and is subjected to sealing process. A [107]. multi-track sealing unit may be employed for getting accurate air- tight seal between the lower and upper pack foils. Thus the strips are 3.6. Young's modulus now available as single dose sachets (referred to as pocketpaks™ for cool mint Listerine strips manufactured by Pfizer consumer health- Young's modulus or elastic modulus is the measure of stiffness of care). Multiple-unit dispenser and multi-unit blisters are also other strip. It is represented as the ratio of applied stress over strain in the packaging options. In the next stage, a tear notch/slit/cut-off is region of elastic deformation as follows: introduced for convenience of the consumer to peel-off the pack. The entire production process is automated and computer control driven 0 Slope × 100 process. Young s modulus = ð3Þ Strip thickness × cross À head speed The final product is then critically examined by the quality control department before it is finally packed into the secondary pack. Medicated strips are generally characterized by the quality control Hard and brittle strips demonstrate a high tensile strength and tests stated below. Young's modulus with small elongation. 3.1. Thickness 3.7. Folding endurance The thickness of strip can be measured by micrometer screw gauge Folding endurance is determined by repeated folding of the strip at at different strategic locations. This is essential to ascertain uniformity the same place till the strip breaks. The number of times the film is in the thickness of the film as this is directly related to the accuracy of folded without breaking is computed as the folding endurance value dose in the strip. [108]. 3.2. Dryness test/tack tests 3.8. Disintegration time About eight stages of film drying process have been identified and The disintegration time limit of 30 s or less for orally disintegrating they are set-to-touch, dust-free, tack-free (surface dry), Dry-to-touch, tablets described in CDER guidance can be applied to fast dissolving dry-hard, dry-through (dry-to-handle), dry-to-recoat and dry print- oral strips [25]. Although, no official guidance is available for oral fast free. Although these tests are primarily used for paint films, most of disintegrating films/strips, this may be used as a qualitative guideline the studies can be adapted intricately to evaluate pharmaceutical OS for quality control test or at development stage. Pharmacopoeial as well [104]. The details of evaluation of these parameters can be disintegrating test apparatus may be used for this study. Typical checked elsewhere and are beyond the scope of this review. Tack is the disintegration time for strips is 5–30 s [109].
  • 10. R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 103 3.9. Dissolution test Oral mucosa irritation testing is carried out in both animal models and humans. In case of animal studies, the most appropriate model is Dissolution testing can be performed using the standard basket or the hamster cheek pouch it is a reliable model for predicting irritation paddle apparatus described in any of the pharmacopoeia. The criteria prior to testing in humans. In clinical trials, the clinical dissolution medium will essentially be selected as per the sink endpoint is significant. Primary and secondary outcome measures are conditions and highest dose of the API [110]. Many times the to be noted. The objective is to demonstrate the superiority and dissolution test can be difficult due to tendency of the strip to float advantage of the newly developed oral strip as against the existing onto the dissolution medium when the paddle apparatus is employed. traditional conventional dosage forms. The International Conference on Harmonization (ICH) has laid guidance on product development. 3.10. Assay/drug content and content uniformity According to the ICH Q8 guideline on pharmaceutical development, companies may choose either an empirical approach or a more This is determined by any standard assay method described for the systematic approach towards product development. This document is particular API in any of the standard pharmacopoeia. Content an integral part of the regulatory document for USA, EU and Japan. uniformity is determined by estimating the API content in individual Clinical study protocol should define a clear objective; different strip. Limit of content uniformity is 85–115%. problems should be tackled in separate well-defined studies. The planned study should have sufficient resolution power to pick up 3.11. Organoleptic evaluation critical adverse health effect (including supporting rationale). Calcu- lation of the study size(s) is dependent on type of study (e.g. effects on Since the OS are intended to disintegrate rapidly or reside for more soft tissues and/or on hard tissues). Specification of all endpoints duration of time in the oral cavity, the product needs to have should be determined. Description of usage pattern(s) (single/multi- acceptable organoleptic palatable characteristics. The product should ple application) is to be included. Follow-up during a relevant period possess the desired features of sweetness and flavor which is after treatment (e.g. single application with follow-up periods of 1, 3, 6 acceptable to a large mass of population. For evaluation of psycho- and 12 months; multiple applications with longer follow-up, etc.) physical evaluation of the product, special controlled human taste should be mentioned. There should be an inclusion of confounders panels are used. In-vitro methods of utilizing taste sensors, specially and effect modifiers along with description of subject source(s), designed apparatus and drug release by modified pharmacopoeial selection criteria, and methodology with appropriate analytical methods are being used for this purpose. These in-vitro taste details. assessment apparatus and methodologies are well suited for high- Due to the modified drug dissolution characteristics, the clinical throughput taste screening of oral pharmaceutical formulations [111]. effect and drug bioavailability may be very different than conventional Experiments using electronic tongue measurements have also been dosage forms. Being a non-invasive delivery system, it bypasses the reported to distinguish between the sweetness levels in taste-masking first-pass effect to a large extent which can alter the clinical profile. formulation [112]. The safety profiles can be improved as the toxic metabolites that result from hepatic metabolism can be lower in the case of drug being 3.12. Clinical and regulatory aspects majorly absorbed from the buccal mucosa. Another aspect is its faster onset of action which leads to rapid signs of clinical end-point. Since In the product approval process (other than the New Drug every strip ideally contains precise amounts of the drug, and the Application procedure) in the US Food and Drug Administration, if dosage form is independent of physiological variability of gastro- the product is intended to be bioequivalent to that of the existing oral intestinal tract, the inter-subject variability in clinical response is fairly product of the drug, an Abbreviated New Drug Application route is reduced. On the other hand, the absorption of drugs through the oral followed. In this, in-vitro dissolution studies and therapeutic mucosa would be much rapid than the conventional counterparts that equivalence (bioequivalence study in which the 90% confidence have to disintegrate and then solubilize the active, there is a possibility interval of the log transformed ratio of Test and Reference product of dose dumping phenomena. Its clinical implications need to be pharmacokinetic parameters AUC0-t, AUC0-inf and Cmax should be studied. Due to this rapid response characteristic, the safety aspects of within the acceptable limits of 80% to 125%). There are no clinical the dosage form should be closely monitored. studies associated in this generic approval process (section 505(j) of the Food, Drug, and Cosmetics Act). The example of such a case would 3.13. Commercial technologies and marketed products be a comparative bioequivalence between and ODT formulation and OS product. However, developed oral strip product may also exhibit a Over-the-counter and nutraceuticals market was the first to move different target pharmacokinetic profile compared to the existing into OST after breath fresheners with a range of fast dissolving strip marketed product. The OS product is categorized as ‘new dosage form’ products which incorporated actives such as vitamins, herbal extracts and the section 505(b)(2) approval process needs to be followed. In and non herbal extracts. Pfizer had introduced Listerine® pocketpaks® this case, a new clinical study would be required. The advantage of a in 2001 for bad breath and Novartis had introduced their famous new clinical study is that it would award three years of marketing Triaminic and Theraflu brands in OS form [114,115]. The detailed exclusivity to the product. Pre-clinical toxicity studies are not required information of the various OS products is given in Table 4. Since then a to be demonstrated if the molecule is same as that of the approved large number of OS products have been introduced. Biofilm is utilizing product. Generally a randomized double-blinded placebo-controlled OST for the brand extension of the existing products in pharmaceu- clinical trial is recommended. Safety, tolerability and efficacy features ticals as well as nutraceuticals focusing on the population of particular are to be demonstrated in such trials. In Europe, Marketing age group with a range of aphrodisiac, energy boosters, vitamins and Authorization approval (Abridged Application) is essential as per appetite suppressor. Biofilm has developed and commercialized OS for the European Medicines Evaluation Agency guidelines. Either of the various applications in the area of neutraceuticals and improvement two modes i.e. the decentralized procedure or the mutual recognition in the life style of consumers. Variety of energy booster OS products route can be adopted. The Ministry of Health, Labor and Welfare is has been developed and commercialized for specific population such primarily responsible for product approvals in Japan. Many of the as students, drivers etc. The energy booster OS contain a mixture of regulatory agencies lay special emphasis on the taste and palatability caffeine, green tea extract and guarana to maintain energy levels [116]. aspects especially if the product is intended to target the pediatric Similarly, Dyna Tabs has developed OS formulations for delivery of population [113]. natural products for lifestyle management. The product line includes
  • 11. 104 R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 Table 4 Marketed products of oral strips. Product category Ingredient/s Indication/applications Biofilm Energy boosters Caffeine, green tea extract and guarana The product maintains the energy levels. Detoxification strip Green tea extract which is high in polythenols Green tea has been used as a traditional medicine and rich in anti-oxidants. Spearmint flavor. to help everything from wound healing, regulating body temperature, blood sugar and promoting a healthy digestion Male vitality strip Maca root extract and Siberian ginseng extract, It acts as an aphrodisiac and improves the libido in males. herbs which enhance libido, Cinnamint flavor. Female vitality strip Botanical ingredients like damiana and passion flower It is used to improve general well-being, increase energy and enhance mood Appetite suppressant fucus vesiculosus and guarana extract, garcinia cambogia These are top selling natural ingredients associated with weight loss. Cambogia helps to reduce the food intake by suppressing appetite. Vitamins and food supplements Various vitamins, minerals and supplements It is useful for the people who do not like to pop up the tablets or soluble supplements Breath freshener strip, Contain mint flavor and antibacterial agent, It is used as mouth freshener and to stop bad breath. (Antibacterial strip) cetylpyridinium chloride Saliva promoting strips Fruit acid extracts, range of flavors It is used in the dry mouth as a side effect of the other medications. Labtec GmbH Ondansetron Rapidfilm® Ondansetron 4 mg and 8 mg. It is used in the prevention of chemotherapy and radiation-induced nausea and vomiting and prevention of postoperative nausea and vomiting. Donezepil Rapidfilm® Donepezil Hydrochloride 5 mg and 10 mg. Treatment of mild to moderately severe dementia of the Alzheimer's type. Paladin Labs (Bioenvelop) Smoking cessation Nicotine To reduce the smoking habit Multivitamin for kids and adults B6, B12, C; D3 for kids, D3 for adults Multi vitamin supplement, Teeth whitening – Lifestyle improvement product Food supplements Benzocaine, Caffeine, Melatonin, MentholOmega, Nutraceuticals Hoodia, Protein, Vinpocetine Minerals Chromium Mineral supplements Natural products Ginseng, Guarana Aphrodisiac, Appetite reducer. Innozen Inc Chloraseptic® Relief Strips™ Benzocaine 3 mg, BHT, corn starch, erythritol, FD&C Occasional minor irritation, pain, sore throat and sore Red 40, hydroxypropyl methylcellulose, malic acid, mouth menthol, monoammonium glycyrrhizinate, cherry flavors, polyethylene oxide, sucralose ® Chloraseptic Kids Sore Throat Benzocaine 2 mg and menthol, grape flavor, BHT, corn Occasional minor irritation, pain, sore throat and sore Relief Strips starch, erythritol, FD&C Blue 1, FD&C Red 40, mouth hydroxypropyl methylcellulose, malic acid, menthol, monoammonium glycyrrhizinate, polyethylene oxide, sucralose Suppress™ Cough strips Dextromethorphan hydrobromide 2.5 mg, Temporarily suppresses coughs due to minor throat and with Dextromethorphan Asulfame potassium, FD&C Blue 1, glycerin, menthol, bronchial irritation associated with cold or inhaled irritants. natural and artificial flavors, pectin, peppermint oil, sucralose, sugar, water Suppress™ Cough strips with menthol Artificial flavors, ascorbic acid, aspartame, asulfame Temporarily suppresses coughs due to minor throat and potassium, carrageenan, diglycerides, fatty acid ester, bronchial irritation associated with cold or inhaled irritants. FD&C yellow 5 (tartrazine), glycerin, menthol, monoglycerides, pectin, sodium alginate, sorbitan monolaurate, sorbitol, spices, starch, water Hughes Medical Corporation Methylcobalamin 1 mg Peripheral neuropathy, Diabetic neuropathy Dextromethorphan 2.5 mg–5.5 mg–15 mg Anti-tussive agent used to prevent cough. Folic Acid 1 mg–5 mg Required for formation of healthy red blood cells and used in anemia. Loratidine 10 mg–20 mg It is a non sedative antihistaminic agent used to treat the allergy. Caffeine 2.5 mg It is used as a stimulant Diphenhydramine HCl 2.5 mg–5 mg It is used as antihistaminic, sedative, hypnotic and antiemetic Novartis Pharmaceuticals Night Time Triaminic Thin Strips® Diphenhydramine HCl 12.5 mg, Phenylephrine Antihistamine/cough suppressant, Nasal decongestant. Cold & Cough HCl 5 mg, acetone, FD&C blue #1, FD&C red #40, flavors, It temporarily relieves cough due to minor throat and hypromellose, maltodextrin, mannitol, polyethylene bronchial irritation as may occur with a cold. glycol, polypropylene glycol, purified water, sodium Nasal and sinus congestion. polystyrene sulfonate, sucralose, titanium dioxide. Itchy and runny nose Triaminic Thin Strips® Long Dextromethorphan 5.5 mg (equivalent to 7.5 mg It temporarily relieves cough due to minor throat and Acting Cough Dextromethorphan HBr), acetone, alcohol, dibasic sodium bronchial irritation as may occur with a cold. phosphate, FD&C red #40, flavors, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, maltodextrin, microcrystalline cellulose, polacrilin, polyethylene glycol, pregelatinized starch, propylene glycol, purified water, sodium phosphate, sorbitol, sucralose, titanium dioxide.
  • 12. R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 105 Table 4 (continued) Product category Ingredient/s Indication/applications Novartis Pharmaceuticals Triaminic Thin Strips® Cough & Diphenhydramine HCl 12.5 mg, acetone, alcohol, FD&C It reduces cough due to minor throat and bronchial irritation Runny Nose blue #1, FD&C red #40, flavors, hydroxypropyl cellulose, as may occur with a cold. It relieves itchy, watery eyes due hypromellose, isopropyl alcohol, maltodextrin, to hay fever. microcrystalline cellulose, polyethylene glycol, pregelatinized starch, propylene glycol, purified water, sodium polystyrene sulfonate, sorbitol, sucralose, titanium dioxide Day Time Triaminic Thin Strips® Dextromethorphan 3.67 mg (equivalent to 5 mg It is used as nasal decongestant. Cold & Cough Dextromethorphan HBr), Phenylephrine HCl 2.5 mg, acetone, alcohol, FD&C blue #1, FD&C red #40, flavors, hypromellose, isopropyl alcohol, microcrystalline cellulose, polacrilin, polyethylene glycol, propylene glycol, purified water, sodium polystyrene sulfonate, sucralose, titanium dioxide Triaminic Thin Strips® Cold with Phenylephrine HCl 2.5 mg, acetone, alcohol, FD&C blue #1, FD&C It temporarily relieves nasal and sinus congestion as may Stuffy Nose red #40, flavors, hypromellose, isopropyl alcohol, maltodextrin, occur with a cold. microcrystalline cellulose, polyethylene glycol, propylene glycol, purified water, sodium polystyrene sulfonate, sucralose and titanium dioxide Theraflu® Daytime Thin Strips Dextromethorphan 14.8 mg (equivalent to 20 mg It temporarily relieves nasal and sinus congestion as may Dextromethorphan HBr), Phenylephrine HCl 10 mg, acetone, occur with a cold. It reduces cough due to minor throat and alcohol, FD&C red #40, flavors, Hypromellose, mannitol, bronchial irritation as may occur with a cold. polyethylene glycol, polystyrene sulfonate, polacrilin and sucralose Theraflu® Nighttime Thin Strips Diphenhydramine HCl 25 mg, Phenylephrine HCl 10 mg, acetone, It is used for nasal congestion, runny nose, sneezing, alcohol, FD&C blue #1, flavors, Hypromellose, mannitol, polyethylene itchy nose and throat etc. glycol, polystyrene sulfonate, polacrilin and sucralose Theraflu® Thin Strips®–Multi Symptom Diphenhydramine HCl 25 mg, acetone, alcohol, FD&C red #40, It temporarily relieves nasal and sinus congestion as may flavors, Hypromellose, hydroxyl propyl cellulose, maltodextrin, occur with a cold. It reduces cough due to minor throat and microcrystalline cellulose, polyethylene glycol, pregelatinized bronchial irritation as may occur with a cold. starch, polystyrene sulfonate, sorbitol and sucralose. Titanium dioxide. Pfizer Inc Listerine® pocketpaks® Available in cool mint®, Fresh Citrus, Cinnamon, and These strips dissolve instantly and kill 99% of bad breath germs. fresh burst®. Pullulan is used as a film forming polymer. Prestige Brands Little cold sore throat strip Ascorbic acid, pectin Cold/allergy Chloraseptic relief strip Benzocaine, menthol Sore throat BioDelivery Sciences International Onsolis™ Fentanyl buccal soluble film Pain in opioid-tolerant patients BEMA™ Buprenorphine Buprenorphine Therapeutic alternative for patients with incomplete pain relief or those unable to tolerate the side effects of non-narcotic analgesics green tea extract oral strips for anti oxidant activity, aloe vera Out of these, ondansetron hydrochloride had been successfully containing OS for digestive tract cleansing, bromelain extract and incorporated into the monosolRx technology and has been proven to papain for better digestion, ginkgo biloba extract for improvement in be bioequivalent with the innovator Zofran ODT®. A unique product the memory, panax ginseng to improve the energy levels amongst was developed and marketed for prevention of snoring by Passion for others. Life Healthcare. Snoreeze® OS coats the back of the throat throughout RapidFilm® is a patented technology developed and commercia- the night and reduces the vibrations of the soft tissues, helping to stop lized by German based Labtec GmBH. The proprietary RapidFilm® snoring [120]. It essentially contains peppermint oil which improves technology is a novel, non-mucoadhesive, fast dissolving oral dosage airflow and tone the tissues, vitamin E, sodium hyaluronate and guar form. It is a fast disintegrating strip which releases the drug rapidly in gum to moisturize, tone the throat tissues for added comfort and for the mouth and leads to fast systemic absorption of drugs. RapidFilm® lubrication. Aridis pharmaceuticals has devised oral thin film delivery can accommodate maximum 30 mg of the drugs. The films can be system, that utilizes pre-stabilized powder drugs and a pH responsive either packaged in boxes or in the RapidCard® which is designed in the polymer system to generate stable thin films that can protect the format of credit-card [117]. Thinsol™ is another OST developed by sensitive active moiety against inactivation during transit through the BioEnvelop (Paladin Labs) which contains enzymatically digested gut. The product is quick-dissolving delivery system incorporating carboxy methyl cellulose. As the films can be dried at low enteric protection. Rotavax™ vaccine is based on this technology and temperature, it can be a good platform for heat sensitive drugs. The was found to be stable for more than one year at room temperature OS prepared by this technology can accommodate up to 60% of drug and able to withstand temperatures excursions above 45 °C [121]. Dr. (more than 100 mg of drug) [118]. Similar types of products are Katzs New Oral Strips contain Zinc, vitamin C and Echinacea Purpurea developed by Hughes Medical Corporation for delivery of neutraceu- (herb that acts as immunostimulant). Meldex International has a ticals and pharmaceuticals. MonosolRx technology is an OS that has technology of edible film strips (Soluleaves™). The patented technol- size similar to a postage stamp [119]. It is more stable, robust and fast ogy that uses vegetable based polymer film has applications in a range dissolving than other conventional dosage forms. This OST can of vitamins, flavors, and pharmaceutical actives. Another technology is accommodate doses up to 80 mg of actives. The technology enables WaferTab™ that incorporates pharmaceutical actives into an inges- buccal and sublingual delivery. This platform technology is under tible film strip. The active ingredient is integrated into the body of a consideration for delivery of drugs like escitalopram oxalate, doneze- fused XGel™ film. This technology is also patented and can be used for pil hydrochloride, zolpidem tartarate and ondansetron hydrochloride. unstable pharmaceutical forms, particularly salt forms [122].
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