Online Available at www.thepharmajournal.com
`
`THE PHARMA INNOVATION
`
`
`
`A Review on Oral Mucosal Drug Delivery System
`Rakesh Hooda*, Mohit Tripathi and Prof. Kiran Kapoor
`
`Submitted 2011.07.14. Accepted for publication 2011.11.17.
`Buccal controlled drug delivery system has been developed since the environment of the oral
`cavity provides potential sites for drug delivery. The acid hydrolysis and first pass effects can be
`avoided. The release of drug can be affected by continuous secretion of saliva. The mucin film
`exists in oral mucosa offers an opportunity to develop mucoadhesive system, which retain at
`absorption site for prolonged time by mucoadhesive binding. The administration of drugs by the
`buccal route has several advantages over per oral administration such as QWICK ACTION,
`improved patient compliance particularly with pediatric & geriatric patient. It is the objective of
`this article to review the oral mucosal drug delivery by discussing briefly the structural feature of
`mucosa as drug delivery such as buccoadheshive film & tablet, medicated chew gum, fast
`dissolving tablet, film & capsule etc.
`Keyword: Buccal Drug Delivery, NDDS, Quick Action, Absorption via buccal mucosa
`
`and rectum. In general, the higher up a drug is
`absorbed along the alimentary tract, the more
`rapid will be its action, a desirable feature in most
`instances. A drug taken orally must withstand
`large fluctuation in pH as it travels along the
`gastrointestinal
`tract, as well as resist
`the
`onslaught of the enzymes that digest food and
`metabolism by micro flora that live there. It is
`estimated that 25% of the population finds it
`difficult to swallow tablets and capsules and
`therefore do not
`take
`their medication as
`prescribed by their doctor resulting in high
`incidence of non-compliance and ineffective
`therapy. Difficulty is experienced in particular by
`pediatrics and geriatric patients, but it also applies
`to people who are ill bedridden and to those
`active working patient who are busy or travelling,
`especially those who have no access to water. In
`these cases oral mucosal drug delivery is most
`preferred.
`
`
`
`
`INTRODUCTION:
`A drug can be administered via a many different
`routes to produce a systemic pharmacological
`effect. The most common method of drug
`administration is via per oral route in which the
`drug is swallowed and enters the systemic
`circulation primarily through the membrane of
`the small intestine. The oral route of drug
`administration is the most important method of
`administering drugs for systemic effect. The
`parenteral route is not routinely used for self–
`administration of medication. It is probable that at
`least 90 % of all drugs used to produce systemic
`effects are administered by the oral route.
`Absorption of drugs after oral administration may
`occur at the various body sites between the mouth
`
`
`Corresponding Author’s Contact information:
`Rakesh Hooda*
`Department of Pharmacy, Maharshi Dayanand
`University, Rohtak, Haryana, India
`E-mail: voltas169@yahoo.com
`
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`Rakesh Hooda*, Mohit Tripathi and Prof. Kiran Kapoor
`
`It has been known for centuries that buccal and
`sublingual administration drug solutes are rapidly
`absorbed into the reticulated vein, which lies
`underneath the oral mucosa and transported
`through the facial veins, internal juglar vein, and
`braciocephalic vein and are then drained into the
`systemic circulation. Therefore the buccal and
`sublingual routes of administration can be utilized
`to bypass the hepatic first-pass elimination of
`drugs. Within the oral mucosal cavity, the buccal
`region offers an attractive route of administration
`for systemic drug delivery. The mucosa has a rich
`blood supply and it is relatively permeable. The
`oral cavity is highly acceptable by patients, the
`mucosa is relatively permeable with a rich blood
`supply and the virtual lack of langerhans cells
`makes the oral mucosa tolerant to potential
`allergens.
`
`Structural Features of Oral Mucosa:
`Buccal mucosa Structure: The total area of the
`oral cavity is about 100cm2 1. Out of this about
`one third is the buccal surface, which is lined
`with an epithelium of about 0.5mm thickness
`(Fig. 1). The keratinized and non keratinized
`regions of the oral epithelium differ from each
`other in terms of lipid composition of the cells.
`The keratinized epithelium has predominantly
`neutral lipids (e.g., ceramides) while the non
`keratinized epithelium has few but polar lipids,
`particularly
`cholesterol
`sulphate
`and
`2. Buccal membrane has
`glucosylceramides
`numerous elastic fibers in the dermis, which is
`another barrier for diffusion of drug across the
`buccal membrane. Drug that penetrates this
`membrane enters the systemic circulation via
`network of capillaries and arteries. The lymphatic
`drainage almost runs parallel to the venous
`vascularization and ends up in the jugular ducts.
`The oral mucosal surface is constantly washed by
`the saliva (daily turn out is about 0.5 to 2 liters).
`The drug absorption across the oral mucosa
`occurs
`in
`the non-keratinized sections
`for
`protein/peptide delivery buccal
`route offers
`distinct benefits over other mucosal routes like
`nasal, vaginal, rectal, etc.
`Permeability: The oral mucosa in general is
`somewhat leaky epithelia intermediate between
`
`that of the epidermis and intestinal mucosa. It is
`estimated that the permeability of the buccal
`mucosa is 4-4000 times greater than that of the
`skin 3. As indicative by the wide range in this
`reported value, there are considerable differences
`in permeability between different regions of the
`oral cavity because of the diverse structures and
`functions of the different oral mucosa. In general,
`the permeability’s of the oral mucosa decrease in
`the order of sublingual greater than buccal and
`buccal greater than palatal 4. This rank order is
`based on the relative thickness
`
`
`and degree of keratinization of these tissues, with
`the sublingual mucosa being relatively thin and
`on-keratinized,
`the buccal
`thicker and non-
`keratinized, and
`the palatal
`intermediate
`in
`thickness but keratinized. It is currently believed
`that the permeability barrier in the oral mucosa is
`a result of intercellular material derived from the
`so-called ‘membrane coating granules’ (MCG) 5.
`When cells go through differentiation, MCGs
`start forming and at the apical cell surfaces they
`fuse with
`the plasma membrane and
`their
`contents are discharged into the intercellular
`spaces at the upper one third of the epithelium.
`This barrier exists in the outermost 200μm of the
`superficial layer. Permeation studies have been
`performed using a number of very
`large
`molecular weight tracers, such as horseradish
`peroxides 6 and lanthanum nitrate 7.
`the
`When applied
`to
`the outer surface of
`epithelium, these tracers penetrate only through
`outermost layer or two of cells. When applied to
`the sub mucosal surface, they permeate up to, but
`not
`into,
`the outermost cell
`layers of
`the
`epithelium. According to these results, it seems
`
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`Rakesh Hooda*, Mohit Tripathi and Prof. Kiran Kapoor
`
`apparent that flattened surface cell layers present
`the main barrier to permeation, while the more
`isodiametric cell layers are relatively permeable.
`In both keratinized and non-keratinized epithelia,
`the limit of penetration coincided with the level
`where the MCGs could be seen adjacent to the
`superficial plasma membranes of the epithelial
`cells. Since the same result was obtained in both
`keratinized
`and
`non-keratinized
`epithelia,
`keratinization by itself is not expected to play a
`significant role in the barrier function 6. The
`components of the MCGs in keratinized and non-
`keratinized epithelia are different, however 8. The
`MCGs of keratinized epithelium are composed of
`lamellar lipid stacks, whereas the non-keratinized
`epithelium contains MCGs that are non-lamellar.
`The MCG lipids of keratinized epithelia include
`sphingomyelin, glucosylceramides, ceramides,
`and other nonpolar lipids, however for non-
`keratinized epithelia,
`the major MCG
`lipid
`components are cholesterol esters, cholesterol,
`and glycosphingolipids 8. Aside from the MCGs,
`the basement membrane may present some
`resistance to permeation as well, however the
`outer epithelium is still considered to be the rate
`limiting step
`to mucosal penetration. The
`structure of the basement membrane is not dense
`enough
`to exclude even
`relatively
`large
`molecules.
`
`Environment: The cells of the oral epithelia are
`surrounded by an intercellular ground substance,
`mucus, the principle components of which are
`complexes made
`up
`of
`proteins
`and
`carbohydrates. These complexes may be free of
`association or some maybe attached to certain
`regions on the cell surfaces. This matrix may
`actually play a role in cell-cell adhesion, as well
`as acting as a lubricant, allowing cells to move
`relative to one another 9. Along the same lines,
`the mucus is also believed to play a role in
`bioadhesion of mucoadhesive drug delivery
`systems 10. In stratified squamous epithelia found
`elsewhere in the body, mucus is synthesized by
`specialized mucus secreting cells like the goblet
`cells, however in the oral mucosa; mucus is
`secreted by the major and minor salivary glands
`as part of saliva 9, 11. Up to 70% of the total mucin
`
`found in saliva is contributed by the minor
`salivary gland 9, 11. At physiological pH the
`mucus network carries a negative charge (due to
`the sialic acid and sulfate residues) which may
`play a role in mucoadhesion. At this pH mucus
`can form a strongly cohesive gel structure that
`will bind to the epithelial cell surface as a
`layer 12. Another feature of
`gelatinous
`the
`environment of the oral cavity is the presence of
`saliva produced by the salivary glands. Saliva is
`the protective fluid for all tissues of the oral
`cavity. It protects the soft tissues from abrasion
`by rough materials and from chemicals. It allows
`for the continuous mineralization of the tooth
`enamel after eruption and helps
`in
`re-
`mineralization of the enamel in the early stages of
`dental caries 13. Saliva is an aqueous fluid with
`1% organic and inorganic materials. The major
`determinant of the salivary composition is the
`flow rate which in turn depends upon three
`factors: the time of day, the type of stimulus, and
`the degree of stimulation 9, 11. The salivary pH
`ranges from 5.5 to 7 depending on the flow rate.
`At high flow rates, the sodium and bicarbonate
`concentrations increase leading to an increase in
`the pH. The daily salivary volume is between 0.5
`to 2 liters and it is this amount of fluid that is
`available to hydrate oral mucosal dosage forms.
`A main reason behind the selection of hydrophilic
`polymeric matrices
`as vehicles
`for oral
`transmucosal drug delivery systems is this water
`rich environment of the oral cavity.
`
`Absorption via buccal mucosa: There are two
`permeation pathways for passive drug transport
`across the oral mucosa: Para cellular and Tran
`cellular routes. Permeants can use these two
`routes simultaneously, but one route is usually
`preferred over
`the other depending on
`the
`physicochemical properties of the diffusant. Since
`the
`intercellular spaces and cytoplasm are
`hydrophilic in character, lipophilic compounds
`would have low solubilities in this environment.
`The cell membrane, however, is rather lipophilic
`in nature and hydrophilic solutes will have
`difficulty permeating through the cell membrane
`due to a low partition coefficient. Therefore, the
`intercellular spaces pose as the major barrier to
`
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`
`Rakesh Hooda*, Mohit Tripathi and Prof. Kiran Kapoor
`
`permeation of lipophilic compounds and the cell
`membrane acts as the major transport barrier for
`hydrophilic compounds. Since the oral epithelium
`is stratified, solute permeation may involve a
`combination of these two routes. The route that
`predominates, however, is generally the one that
`provides
`the
`least amount of hindrance
`to
`passage.
`
`Promoting buccal absorption: Absorption
`enhancers:
`Absorption enhancers have demonstrated their
`effectiveness in delivering high molecular weight
`compounds, such as peptides, that generally
`exhibit low buccal absorption rates. These may
`act by a number of mechanisms, such as
`increasing the fluidity of the cell membrane,
`extracting
`inter/intracellular
`lipids,
`altering
`cellular proteins or altering surface mucin. The
`most common absorption enhancers are azone,
`fatty acids, bile salts and surfactants such as
`sodium dodecyl
`sulfate. Solutions/gels of
`chitosan were also found to promote the transport
`of mannitol and fluorescent-labeled dextrans
`across a tissue culture model of the buccal
`epithelium while Glyceryl monooleates were
`reported to enhance peptide absorption by a co-
`transport mechanism.
`
`Prodrugs: Hussain et al., delivered opioid
`agonists and antagonists in bitter less prodrug
`forms and found that the drug exhibited low
`bioavailability as prodrug. Nalbuphine and
`naloxone bitter drugs, when administered to dogs
`via the buccal mucosa, causes excess salivation
`and swallowing. As a result, the drug exhibited
`low bioavailability. Administration of nalbuphine
`and naloxone in prodrug form caused no adverse
`effects, with bioavailability ranging from 35 to
`50% showing marked improvement over the oral
`bioavailability of these compounds, which is
`generally 5% or less 12.
`pH: Shojaei et al., evaluated permeability of
`acyclovir at pH ranges of 3.3 to 8.8, and in the
`presence of the absorption enhancer, sodium
`glycocholate. The
`in vitro permeability of
`acyclovir was found to be pH dependent with an
`increase in flux and permeability coefficient at
`
`both pH extremes (pH 3.3 and 8.8), as compared
`to the mid-range values (pH 4.1, 5.8, and 7.0) 12.
`
`for drug delivery:
`Buccal mucosa-site
`Controlled drug delivery systems specifically
`designed for buccal cavity, where the drug
`releases in a controlled manner. The drug can be
`administered for local or systemic action. These
`systems are generally based on the polymers
`including bioadhesive polymers.
`
`
`
`
`
`including buccal
`The various dosage forms
`bioadhesive tablets, laminated film, hydrogels,
`buccal patches, chewing gums and hollow fibers
`have been designed to extend the time of drug
`release from buccal cavity.
`The absorption of drug through buccal mucosa
`can be
`increased using
`some absorption
`enhancers. Different peptides including insulin
`can be delivered to or through buccal cavity using
`control drug delivery systems. Particulate systems
`such as microspheres and nanoparticles have also
`been tried for the buccal control drug delivery.
`Buccal control drug delivery can be achieved in
`three ways; delivery through buccal mucosa,
`delivery through sublingual mucosa and local
`delivery to mouth. Local delivery includes the
`systems designed mainly to deliver drugs to
`periodontal pocket. Bioadhesion
`is a major
`approach involved in the designing of buccal
`controlled drug delivery systems. Theoretically,
`
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`
`Rakesh Hooda*, Mohit Tripathi and Prof. Kiran Kapoor
`
`maximum buccal residence time can be in the
`order of several days. But it has been observed
`that usually it does not exceed several hours,
`possibly due interference with drinking, eating
`and talking.
`
`Factors Affecting Buccal Absorption: The oral
`cavity
`is a complex environment for drug
`delivery, as there are many interdependent and
`independent factors which reduces the absorbable
`concentration at the site of absorption.
`
`Membrane Factors: This involves degree of
`keratinization,
`surface
`area
`available
`for
`absorption, mucus layer of salivary pellicle,
`intercellular
`lipids of epithelium; basement
`membrane and lamina propria. In addition, the
`absorptive membrane thickness, blood supply/
`lymph drainage, cell renewal and enzyme content
`will all contribute to reducing the rate and amount
`of drug entering the systemic circulation.
`
`Environmental Factors:
` Saliva: The thin film of saliva coats
`throughout the lining of buccal mucosa
`and is called salivary pellicle or film. The
`thickness of salivary film is 0.07 to 0.10
`mm. The
`thickness, composition and
`movement of this film effects buccal
`absorption.
` Salivary glands: The minor salivary
`glands are located in epithelial or deep
`epithelial region of buccal mucosa. They
`constantly secrete mucus on surface of
`buccal mucosa. Although, mucus helps to
`retain mucoadhesive dosage forms, it is
`potential barrier to drug penetration
` Movement of oral tissues: Buccal region
`of oral
`cavity
`shows
`less
`active
`movements. The mucoadhesive polymers
`are to be incorporated to keep dosage
`form at buccal region for long periods
`while withstanding
`tissue movements
`during talking and if possible during
`eating food or swallowing.
`
`
`Advantage and Limitation: The administration
`of drugs by
`the buccal route has several
`
`advantages over per oral administration such as;
`13, 14
` The drug is not subjected to destructive
`acidic environment of the stomach.
` Therapeutic serum concentration of the
`drug can be achieved more rapidly.
` The drug enters the general circulation
`without first passing through the liver.
` With the right dosage form design and
`formulation, the permeability and the
`local environment of the mucosa can be
`controlled and manipulated in order to
`accommodate drug permeation.
` Delivery can also be terminated relatively
`easily if required.
`
`
`considerable barrier
`a
`some drugs
`For
`contribution arises as a result of presystemic
`metabolism. The enzymatic activity of the buccal
`mucosa is relatively low, and drug inactivation is
`neither
`rapid nor extensive. Nevertheless,
`enzymes existing in the oral cavity could degrade
`some drugs, particularly peptide or protein drugs.
`Co- administration of enzyme inhibitors such as
`aprotinin, bestatin, puromycin and bile salts
`reduces the activity of proteolytic enzymes,
`altering the conformation of the peptide drug or
`forming micelles, and/or rendering the drug less
`accessible to enzymatic degradation. The main
`obstacles that drugs meet when administered via
`the buccal
`route derive
`from
`the
`limited
`absorption area and the barrier properties of the
`mucosa. The mucin film may act as a barrier,
`although unless the drug binds specifically with
`the mucin or are large molecules, the diffusion
`through the mucus is not a rate limiting step.
`Rapid removals of conventional delivery system,
`primarily through copious salivary flow are also
`clear impediments to successful use of this route.
`Bioadhesive polymer can overcome the removal
`issue.
`
`Oral Mucosal Dosage Forms: Various drug
`delivery systems are their which uses the oral
`mucosa as a drug delivery site such as – fast
`dissolving tablets, orodissolving films, fast caps,
`
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`
`Rakesh Hooda*, Mohit Tripathi and Prof. Kiran Kapoor
`
`buccoadheshive film and tablets, chewing gums
`etc.
`
`(a) Fast Dissolving Tablet (FDT): Recently fast
`dissolving drug delivery systems have started
`gaining popularity and acceptance as new drug
`delivery system, because
`they are easy
`to
`administer and lead to better patient compliance.
`They also impart unique product differentiation
`thus enabling use as line extension for existing
`commercial products. FDTs can be prepared by
`various
`techniques
`like direct compression,
`sublimation, melt
`granulation, moulding,
`volatilization and freeze drying. Some of patented
`technologies are zydis, orasolve, durasolv, flash
`dose, wowtab, flash tab etc. some drugs which
`are poorly water soluble and have a variable
`bioavailability and bio-inequivalence related to
`its poor water solubility. The solubility of drug
`was increased by various methods to make a fast
`dissolving tablet like solid dispersion technique,
`by cogranulation with beta – cyclodextrin.
`Because fast dissolving systems dissolves or
`disintegrate in patient’s mouth, thus the active
`constitute come in contest with the taste buds and
`hence taste masking of the drugs become critical
`to patient compliance. Taste masking can be done
`by various methods like addition of sweeteners,
`or by mass extrusion technique using eudragit
`E100. Recently various comparative studies were
`done between fast dissolving and conventional
`formulations. In an acceptance survey of FDT in
`allergic patients it is observed that if given the
`choice 93 % would choose FDT formulations
`
`(b) Fast Dissolving Films: However, the fear of
`taking solid tablets and the risk of choking for
`certain patient population still exist despite their
`short dissolution/disintegration
`time. Recent
`development in novel drug delivery system aims
`to enhance safety and efficacy of drug molecules
`by formulating a convenient dosage form for
`administration. One such approach is rapidly
`dissolving film. It consists of a very thin oral
`strip, which
`releases
`the active
`ingredient
`immediately after uptake into the oral cavity.
`Rapid film combines all the advantages of tablets
`(precise dosage, easy application) with those of
`
`liquid dosage forms (easy swallowing, rapid
`bioavailability).
`The delivery system is simply placed on a
`patient’s tongue or any oral mucosal tissue.
`Instantly wet by saliva, the film rapidly hydrates
`and dissolves to release the medication for
`oromucosal absorption. One or a combination of
`the following processes can be hot melt extrusion,
`solid dispersion extrusion, rolling, semisolid
`casting, and solvent casting. Spence S.H. et al
`disclosed orally consumable films that include
`pullulan as a water soluble film forming agent. A
`film is also developed that may deliver rotavirus
`vaccine to infants in improvised area. Mashru R.
`C. et al also developed a fast dissolving film of
`salbutamol sulphate using PVA as a polymer. A
`taste masked film was developed by Renuka
`Sharma et al. using Eudragit EPO and HPMC.
`Various patents are also assigned for water
`soluble films for oral administration.
`
`(c) Fast Caps: A new type of fast dissolving drug
`delivery system based on gelatine capsules was
`developed. In contrast to conventional hard
`capsules, the fast caps consist of gelation of low
`bloom strength and various additives to improve
`the mechanical and dissolution properties of the
`capsule shell. The advantage of
`these fast
`disintegrating capsules are high drug loading,
`possible solid and liquid filling, no compression
`of coated taste-masked or extended release drug
`particles/pellets, good mechanical properties,
`simple manufacturing, mechanical stability and
`requirement of special packaging.
`
`(d) Buccoadheshive Film and Tablets: Recent
`years have seen an increasing interest in the
`development of novel muco- adhesive buccal
`dosage forms. These are useful for the systemic
`delivery of drugs as well as for local targeting of
`drug to a particular region of the body. Water
`soluble drugs are considered difficult to deliver in
`the form of sustained or controlled release
`preparations due to their susceptibility to “dose
`dumping phenomena “. Attempts have been made
`to regulate their release process by use of
`mucoadhesive polymers in order to achieve a
`once- a- day dose treatment.
`
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`
`Rakesh Hooda*, Mohit Tripathi and Prof. Kiran Kapoor
`
`
`(e) Medicated Chewing Gums: Medicated
`chewing gum is an attractive alternative for drug
`delivery
`system with
`several
`advantages
`including
`convenience
`for
`administration,
`individually controlled release of active substance
`and effective buccal drug administration for the
`treatment of local oral disease and systemic
`action. Mainly chewing gum is used to promising
`controlled
`release
`drug
`delivery
`system.
`Medicated chewing gums are currently available
`for pain relief, smoking cessation, travel illness
`and freshening of breath. A hydrophobic gum
`was used for the formulation of chewing gum. A
`new chewing gum device in the form of a three
`layer tablet has been also developed. In vitro
`release study of chewing gum requires special
`apparatus and instrumental setting.
`
`
`CONCLUSION: Beside delivery drug to the
`body, a drug delivery system with a aim to
`improve patient compliance and convenience are
`more important. Now days there is huge work
`going in developing to novel dosage form to
`satisfy
`increased patient demand of more
`convenient dosage forms. These dosage forms are
`expected to become more popular oral mucosal
`delivery offers a convenient way of dosing
`medication, not only to special population group
`with swallowing difficulties, but also to general
`population. They also provide opportunity for the
`product line extension in the market place and
`extension of patent term of innovator.
`
`
`
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`Rakesh Hooda*, Mohit Tripathi and Prof. Kiran Kapoor
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`Corresponding Author: Rakesh Hooda
`Journal: The Pharma Innovation
`Website: www.thepharmajournal.com
`Volume: 1
`Issue: 1
`Year: 2012
`Page no.: 14- 21
`
`
`Vol. 1 No. 1 2012 www.thepharmajournal.com Page | 21
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`Dr. Reddy's Labs. v. Indivior UK Ltd, IPR2016-01113
`INDIVIOR EX. 2017 - 8/8