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Mucus is a translucent and viscid secretion which gastrointestinal tract. This mucus layer of thickness
forms a thin continues gel adherent to mucosal of about 50-450um in humans actually creates
epithelium surface made up of glycol proteins located adhesive interface for drugs.[10]
various body cavities from respiratory and
This mucus layer performs various functions: cavity. It hydrate the oral mucosa of the dosage
Protective: It protects the epithelium surface from forms.[14]
acid diffusion through lumen. FUNCTIONS OF THE ORAL CAVITY:[15]
Barrier: It allows the selective absorption of the 1) Oral cavity initiate the carbohydrate and fat
drugs. metabolism
Adhesion: Mucus layer with cohesive properties 2) It helps in speech and breating process
allows firm adhesion surface for molecules cell-cell 3) It identifies the ingested material by taste buds of
adhesion. the tongue
Lubrication: Moisture presents in mucus provides 4) To lubricate the food materials and bolus
lubrication to mucosal layer 5) It helps in chewing , mastication, and mixing of
made up of proteins and carbohydrates.[12]. food stuff
SALIVA: 6) As a portal for intake of food materials and water
The saliva with in the oral cavity makes it very ADVANTAGES:[16]
difficult for the drugs to be retained for a significant 1) MDDS offer several advantages over other
amount of the time in oder to facilitate absorption in controlled oral controlled release systems by virtue of
these site.[13] prolongation of residence of drug in GIT
Role of saliva: 2) High drug flux at the absorbing tissue
Saliva continuous mineralization of the tooth enamel 3) MDDS will serve both the purpose of Sustain
and the protective fluid for all tissuses of the oral release and presence of dosage form at the site of
absorption
4) Low Enzymatic activity and avoid the first pass iv) Tissue movement
metabolism v) Concomitant diseases
5) Both hydrophilic and lipophilic drugs can be TYPES OF MDDS:[22]
permeated 1) Buccal drug delivery system
6) These dosage forms are readily localized in the 2) Sub lingual drug delivery system
region applied to improve and enhance bio- 3) Vaginal DDS
availability of drugs 4) Rectal system
7) Extent of perfusion is more therefore quick and 5) Nasal DDS
effective 6) Ocular DDS
8) Some drugs are that are unstable in acidic 7) Gastrointestinal DDS.
environment of stomach can be administrated by MECHANISM OF MUCOADHESION :[23]
buccal delivery Bio adhesion is an adhesion of a synthetic and natural
9) Drug administration can be terminated in case of material to biological surface while muco adhesion is
emergency adhesion of material to mucus and or an epithelial
10) Mucoadhesive systems are known to provide surface muco adhesion occurs in two stages
intimate contact between dosage form and the depending on the nature of dosage form and its
absorptive mucosa,resulting in high drug flux at delivery .
absorbing tissue Contact between a pressure sensitive adhesive
DISADVANTAGES:[17,18]. material and a surface is called as Adhesion which
1) Medications administered orally do not enter the can be defined as the state in which two surfaces or
blood stream immediately after passage through the attached together due to valence interfacial forces are
buccal mucosa interlocking action or both.[24]
2) The absorption of Muco adhesive drugs is Step 1) Contact stage:
adversely affected by the presence of food. One of The first stage is characterized by the contact
the side effects of many antibiotics is the destruction between the muco adhesive and the mucus membrane
of normal GI flora resulting in Diarrhea and with spreading and swelling of the formulation
overgrowth with dangerous organisms initiating its deep contact with the mucus layer .
3) Drugs which are un stable at buccal PH cannot be Sometimes additional forces like mechanical system
administrated in vaginal delivery aero dynamics in nasal delivery
4) Drugs which have a bitter taste or unpleasant taste and peristaltic motions in the intestinal delivery of
or an obnoxious odor, irritate the mucosa cannot be the dosage forms.[25]
administrated by this route Step2) Consolidation stage:
5) Only the small dose is given by this drug delivery In consolidation step the mucoadhesive materials are
6) If formulations contains Antimicrobial agents activated by the presence of moisture plasticizers the
effect the natural Microbial flora of the mouth system allowing the mucoadhesive molecules to
7) Some patients suffers unpleasant feeling to break free and to link up by weak Vander walls and
swallow the tablets hydrogen bonds, electrostatic attractions,
8) Less surface area hydrophobic interactions for complete bioadhesion at
9) Dilution or loss of the drug due to constant attractive forces must overcome repulsive forces.
secretion of the saliva consolidation step was explained by two theories:[26]
FACTORS AFFECTING THE
MUCOADHESIVE DRUG DELIVERY
SYSTEM:[19,20,21]
1) Polymer related factors:
i) Concentration of active polymers
ii) Flexibility of polymer chains
iii) Molecular weight.
2)Environment related factors:
i) PH of the polymer-substrate interface
ii) Initial contact time
iii) Applied strength
iv) Swelling.
3) Physiological factors:
i) Disease state 1) diffusion theory
ii) Mucin turnover 2) dehydration theory
iii) Rate of renewal of mucosal cells. 1) diffusion theory :
Mucus glycol proteins interact with the It analyses the force required to separate to surfaces
mucoadhesive molecules by the interpenetrating their after adhesion is established fraction theory is
chains and forming the secondary bonds. This is a concerned only with the force required to separate the
mechanical as well as chemical interactions. parts, it does not take into account the
2) dehydration theory: interpenetration or diffusion of polymer chains.
After contact with mucus material undergoes vii) The mechanical theory :
dehydration until osmatic pressure balance and gelly It explains the diffusion of the liquid adhesive into
mixture of mucus with material is obtained. solid or the micro-cracks and irregularities present on the
hydrated formulation does not work by this substrate surface thereby forming an interlocked
theory.[27] structure which gives rise to adhesion.
THEORIES OF MUCOADHESION.[28,29] TYPES OF MUCOADHESION
There are seven different theories which explain FORMULATIONS :[34,35]
phenomenom of mucoadhesion : 1) Solid mucoadhesive formulations:
i) The Electronic theory Tablets, inserts , lozenges , matrix tablets ,
ii) The Adsorption theory bioadhesive microparticles .
iii) Wetting theory 2) Semi solid mucoadhesive formulations:
iv) The Diffusion theory Gels , films , patches , ointment .
v) The Dehydration theory 3) Liquid mucoadhesion formulations:
vi) Fracture theory Viscous liquids , gel forming liquid , suspensions .
vii) The Mechanical theory. BASIC COMPONENTS OF BUCCAL DRUG
i) The electronic theory : DELIVERY SYSTEM:[36]
In these both mucoadhesive and biological materials The basic components of buccal drug delivery system
posses opposing electrical charges. when both are
materials come in contact, they transfer electrons 1) Drug substance: drug substance should be
leading to the building of a double electronic layer at selected on the bases of pharmacokinetic properties.
the interface where the attractive forces within these the drug should have the following characteristics:
electronic double layer determines the mucoadhesive The one time dose of the drug should be small (less
strength.[30] than 25mg) the drug should be having short
ii) the adsorption theory: biological half life ranging from 2to8hours.
In these mucoadhesive device adheres to the mucus 2) Bioadhesive polymers: The use of bioadhesion
by secondary chemicals interaction such as in Vander polymers determines the various parameters such as
walls and hydrogen bonds ,electrostatic attraction or mucoadhesive strength, thickness,invitro release and
hydrophobic interactions.[31] the residence time of the drug delivery device. The
iii) the wetting theory: polymers with high molecular weight are preferred
These applies to liquid system which present affinity because they show the effective release rate
to the surface in order to spread over it. this affinity controlling polymers.
can be found by using measuring techniques such as 3) Backing membrane: Backing membrane should
the contact angle. lower the contact angle than the be used for formulations should be impermeable to
greater the affinity.[32] drug as well as the mucus in Oder to prevent the
iv) The diffusion theory : unnecessary drug loss from all sides of the device.
Interpenetration of both polymer and mucin chain 4) Plasticizers: The plasticizer are used in order to
create semiperiment adhesive bond. improve the folding endurance of the delivery device
Adhesion forces increases with increase in .they provide enough flexibility to the dosage form
penetration it depends on diffusion coefficient 0.2- for improving its patient acceptability and patient
0.5micro meter.[33] compliances.
v) The dehydration theory : 4) Permeation enhancers: These are the chemicals
In dehydration theory materials that are able to or the liquids used to improve the permeation of the
readily jellify in an aqueous environment when drug from device into mucus membrane. it works by
placed in contact with the mucous can cause its the following mechanisms:
dehydration due to the difference of osmotic i) By reducing the viscosity of the mucus
pressure. The difference in concentration gradient ii) By increasing the fluidity of lipid bilayer
draws the water into the formulation until the osmotic membrane
balance is reached. iii) By increasing the thermodynamic property of
This process increases the contact time of drug
formulation with the mucous membrane. iv) By countering the enzymatic barrier.
vi) The fracture theory :
EX:Benzalkoniumchloride,Dextransulfate,Fattyacid,SodiumEDTAetc.
samples are weighed and then left to dry for seven the beaker,which is filled with 200ml of phosphate
days in an desiccators over anhydrous calcium buffer ph 6.8.after 2 minutes a 50rpm stirring rate is
chloride at room temperature then the final constant applied to simulate to the buccal cavity environment .
weights are recorded. water uptake percentage is Measurement of mechanical properties:
calculated. Mechanical properties of the patch include tensile
Morphological characterization:[54] strength and elongation at break is evaluated using a
They are determined by using Scanning Electron tensile tester.film strip witj the dimensions of
Microscope(SEM). 60*10mm and without any visual defects cut and
Folding endurance: positioned between two clamps separated by a
It can be done by folding the patches up to 200 times distance of 3cm.force and elongation of the film at
without breaking. the point when the strip break is recorded.
Thermal analysis study: Animal model for permeability measurement:
It was performed by using Differential Scanning The most commonly used animal models are
Calorimeter(DSC). dogs,rabbits, pigs.A general criterion for selecting an
Swelling study: in vivo animal model is the resemblance for the
Weighed the Buccal patches individually and placed animal mucosa to the oral mucosa of human beings in
separately in 2percentage agar gel plates incubated at both ultra structure and enzyme activity which
37degree centigrade and examined for physical represents the physical and metabolic barrier of the
changes. At regular intervals until three hours patches oral mucosa.
are removed for gel patches and excess surface water Moisture absorption studies:
was removed carefully using the filter paper. The The moisture absorption studies for the buccal patch
swollen patches are then reweighed and swelling give an indication about the relative moisture
index were calculated. absorption capacity of the polymers and an idea
Surface pH: whether that the buccal patch maintain their integrity
Buccal patches are left to swell for2hours on the after absorption of the moisture.
surface of an agar plate .the surface pH is measured Determination of tensile strength:
by means of a ph paper placed on the surface of the Tensile stress is also called as maximum stress or
swallon patch. ultimate tensile strength.the resistance of a material
Thickness measurements : to a force tending to tear it a part measured as the
The thickness of each film is measured by five maximum tension the material can withstand without
different locations using an Electron Digital tearing .tensile strength can be defined as the strength
Micrometer. of material expressed as the greatest longitudinal
Ex vivo bioadhesion test: stress. It can bear without tearing apart.it is measured
A piece of gingival mucosa is tied in the open mouth as newtons.
of a glass vial, filled with phosphate buffer .this glass Colloidal gold staining method:
vial is tightly fitted into a glass beaker filled with Park proposed the gold staining technique for the
phosphate buffer. So it is just touched to the mucosal study bioadhesion .These technique employees red
surface. colloidal gold particles which were absorbed on the
Invitro drug release study: mucin gold conjucates which upon interaction with
The dissolution medium consisted of phosphate bio adhesive hydrogels develop a red colour on the
buffer PH 6.8 maintaining a temperature at 37degree surface.
c. with a rotation speed of 50rpm, the disk is Direct staining method:
allocated to the bottom of the dissolution vessel It is a noval technique to evaluate polymer adhesion
.Samples such as 5ml are withdrawn at to human buccal cells following exposure to aqueous
predetermined time intervals and replaced with fresh polymer dispersion an invivo and invitro methods.
medium . The samples filtered through the wattsman The extent of polymer adhesion was quantified by
filter paper and analyzed for drug content after measuring the relative staining intensity of control
appropriate dilution in a UV spectrophotometer . and polymer treated cells by image analysis.
Ex-vivo mucoadhesion time: Shear stress method:
The ex-vivo mucoadhesion time performed after The measurement of the shear stress gives an direct
application of the buccal patch on freshly cut buccal correlation to the adhesion strength in a simple shear
mucosa.the fresh buccal mucosa is tied on the glass stress measurement based methods two
slide ,and a mucoadhesive patch is weteed with one smooth,polished plexi glass boxes were selected one
drop of phosphate buffer PH6.8 and pasted to the block was fixed with adhesive araiditeon a glass
buccal mucosa by applying a light force with a plate with was fixed on level table. The level was
finger tip for 30 seconds.the glass slide is then put in adjusted with the spirit level.to the upper block, a
CURRENTLY USED FORMULATIONS: formulation are better in this respect as they adhere to
Many novel formulations have been advanced to the mucosa increasing exposure time .
various stages of development and approval and have b.Sprays:
met with varying manufacturing and marketing glyceryltrinitrate is a small molecule that can be
successes: rapidly delivered across the sublingual oral mucosa
a.Tablet using a spray for angina relief.the generex
b.Sprays biotechnology corporation as developed a rapid mist
c.Mouth washes spray which is of capable of delivering large
d.Gels molecules such as insulin across the oral
e.Paste mucosa.other applications of the rapid mist system in
f.Patches development include vaccination against cancer and
g.Wafers or films influenza pain management and weight loss.
a.Tablets: c.Mouth washes:
Lozenges,troches and tablets for systemic delivery The current literature on mouth washes and oral
across the oral mucosa are currently commercially rinses predominantly focuses on their use in the local
available for drugs including nitroglycerin and delivery of antimicrobial agents.the substantivity
fentanyl. Solid formulations such as tablets and allows significant antibacterial effect up to 7 hours
lozenges dissolve into the saliva utilizing the whole after the mouth rinse.several naturally occurring
surface area of the oral cavity for absorption. antimicrobials such as lactoperoxidases ,lysoszymes
Drawbacks of the tablet and lozenges include and lactoferrin have also been investigated in a
variations due to the differences in saliva production mouth wash form. The effectiveness of essential oil
and sucking intensity . Muco adhesive tablet containing anti microbial mouth washes is thought to
relate their anti oxidant properties. The management lost to oral cavity .they are better used therefore for
of vesiculoulcerative conditions frequently involves delivery drugs more generally in to the oral cavity
the topical delivery of various steroid preparations than into the oral mucosa to which they are applied .
and anti microbials in mouth wash form. g.Wafers:
d.Gels: Thin strips of polymeric films capable of loading
Gels have been investigated as a means of control upto 20mg of drugs. dissolve on the tongue in less
drug delivery since 1980s.the primary goal of than 30 sec and delivered the drugs which are able to
bioadhesive control drug delivery is to localized a cross the permeability barrier directly to the blood
delivery device with in the body in enhance the drug supply for rapid treatment.
absorption process in a site specific manner . Others
are at the stage of animal or ex-vivo studies .few RECENT APPLICTIONS IN AN ORAL
clinical studies have been performed and those that MUCOADHESIVE DRUG DELIVERY:[56]
have are often small in size for the delivery of Oral muco adhesive drug delivery has widespread
systemic analgesics and antihypertensives and the applications for many drugs which an oral
drug for treating cardiovascular diseases as well as administration results in poor bioavailability and are
the topical delivery of antifungal agents and muco rapidly degraded by the oral mucoadhesive drug
protective agents to the oral mucosa. delivery provides advantages of high accessibility
e.Paste: and low enzymatic activity.
the paste have been utilized in the delivery of anti The hydrophilic polymers like SCMC ,HPC and
microbial agents for improved extractions socket polycarbophil were used for the treatment of
healing after tooth extractions in patients HIV disease periodontal disease but now the trend is shifting
and for the delivery of controlled release triclosan in towards the utilization of effective system to the
oral care formulations .paste are also been used for delivery of peptides, proteins,and polysaccharides.
the local delivery and retension of slow release semisolids offer more ease in administration but
minocycline in the formulation. tablets are also been formulated. tablets include
f.Patches: matrix device or multilayered systems containing a
several different patch systems that adhere to oral muco adhesive agent.the buccal cavity has additional
mucosa and designed to deliver drugs have been advantages of high patient compliance the first
developed. There are basically three different types generation mucoadhesive paste has been used as
oro-adhesive patches.patches with a dissolvable barrier system for mouth ulcers .the tablet is kept
matrix for drug delivery to the oral cavity .they slow under the upper lip to avoid clearance mechanism of
and completely dissolved during use living nothing to the salivary gland.
remove. However significant amounts of drug will be
BUCCOADHESIVE APPROVED UNDER CLINICAL TRAIL FORMULATIONS:[57]
S.NO ACTIVE BRAND COMPANY POLYMER FORMULATION
SUBSTANCE NAME USED
1. Prochorperaxime buccastem Reckitt Xanthangum Tablet
maleate banckiser and povidine
2. Hydrocortisone corlanpelletes UCB pharma acaciagum Pellets
sodium succinate
3. Triamacinolone aphtach Teijin limited HPMC,PAA Tablet
acetonide
4. Testosterone striant Columbia lab HPMC,CP Tablet
5. miconazole daktarin Janssen cilag undisclosed Tablet
LIST OF PATENTS:[58]
S.NO TYPEOF PATENT TITLE OF THE YEAR OF SELECTION OF THE
FORMULATION NO. PATENT PATENT PATENT
1. microspheres US6235313B1 bioadhesiveMicro May2001 to establish the correlation
spheres and there use as between the chemical nature.
DDS.
2. Nano particles US6235313B1 Bio adhesive May2003 Site specific CDS over
microspheres and there extended period of time.
use as DDS.
3. Multi particulate US0281007A1 Mucoadhesive oral December To increase the oral bio
formulations of high 2007 availability of BCS class one.
permeability and
solubility.
4. Multi particulate US5571533A Control release muco November Eliminates diursis peak or
adhesive pharmaceutical 1996 reduces intersubject response
composition oral variability with the
administration of conventional treatment
furosemide
5. Nano composite US0232899A1 Mucoadhesive Sep 2009 Delivery of the drug by adding
nanocomposite delivery with chitoson of silica
system nanocomposite during the in-
situ relation of colloidal silica.
6. Muiti pariculate US0280183A1 Multiparticulate form of November It comprising mucoadhesively
administration 2009 formulated nucleic acid
compresing nucleic acid ingredients and to process for
containing producing the pharmaceutical
mucoadhesive active form
ingredients
7. Tablet USO26824A1 Bio adhesive rate October 2008 Polymers with improved
controlled oral dosages bioadhesive properties and
formulations methods for improving the
release pattern of monolithic
system .
8 Semisolid dosage USO240111A1 Semisolid mucoadhesive October 2006 To improve the technical and
forms formulations organoleptical charecteritics by
vaginal appplications
9 nanoparticles US0323977A9 Mucoadhesive December Chitosin monofatty acids and
nanoparticles for cancer 2010 cancer therapeutics agent based
treatment nanoparticles
10 Nanoparticles US6235313V1 Microspheres and their May2003 Delivery over a extended period
use as drug delivery and of time for active ingredients or
imaging systems sensory markers.
11 Multi particulate USO19643A1 Pentaprazole,multi August 2007 To avoid sticking to nanogastric
particulate formulations and gastronomy.
CONCLUSION: focuses on the preparation of the novel drug delivery
Buccal mucoadhesive drug delivery system is systems which will provide least adverse effects and
becoming popularity .The main objective of using maximal therapeutic response, with advent of new
bioadhesive systems orally would be achieved by molecules especially therapeutic proteins and
obtaining a substantial increase in residence time of peptides there is requirement of specialized delivery
the drug for local drug effect and to permit daily once systems to reach the target sites. This is also evident
dosing. The use of natural polymers is increasing in by the numbers of the products which coming to the
the formulation of buccal tablets and as a carrier for market and there in the pipeline for clinical trials.
buccal drug delivery can be used to improve the MARKETED PRODUCTS:[59]
health of all living things and to minimize the 1) FENTANIL buccal formulations (Fentora and
unwanted effect of synthetic polymers. The area is actiq)are design to adhere in buccal mucosa for
well suited for a retentive device and appears to be certain period of time followed by its swallowing
acceptable to the patient .the mucosa is well supplied .This produces initial rapid absorption when
with both vascular and lymphatic drainage and first formulation is in oral cavity and prolonged
pause metabolism in the liver and pre-systemic absorption when formulation is swallowed and
elimination in the GIT is avoided. This review reaches toGIT.
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