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 . Keeping the
membrane . 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 . 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 .
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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 .
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.
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 . 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 . 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 .
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 . 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™) . 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 . 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 . 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 .
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 . 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 . 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 . testosterone replacement therapy . 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
R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 97
trans-oral anesthetic patch . This is similar to a transdermal system crystallizes out from the gelatin strip . 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 . 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 .
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 .
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 . 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 . 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 .
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 . 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 .
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 . Many APIs, which are potential candidates for
of the drug . 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 . 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 . conversion into microparticles/microcapsules, coated particles or coated
Various plasticizers were studied for their plasticization effect on the granules . 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
R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107
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
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
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.
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.
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.
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.
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 . 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 . 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 . 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 .
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 .
neutraceuticals including vitamin B12, chromium picolinate, melatonin Aspartame was used for the preparation of oral strips of valdecoxib .
and possibly CoQ10 . For the oral strip of piroxicam, maltodextrin was employed as
Some of the examples of suitable drug molecule that can be sweetening agent . 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 .
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
R.P. Dixit, S.P. Puthli / Journal of Controlled Release 139 (2009) 94–107 101
Table 3 and stabilizing agents . 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 .
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 . 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 . 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 .
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 . 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.
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 . 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 . 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 .
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 .
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. .
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 . 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 . 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 .
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 . 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 . 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 . 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 .
aspects especially if the product is intended to target the pediatric Similarly, Dyna Tabs has developed OS formulations for delivery of
population . natural products for lifestyle management. The product line includes