Buccal drug delivery systems

What is BDDS???
 Delivery of drug through Buccal mucosa of oral
cavity is called BDDS. Buccal mucosa lines the
inner region of cheeks.
 In biological term, the product is placed between
upper gingiva (gums) & cheek to treat local &
systemic conditions.
Department of Pharmaceutical Technology,
LJ Institute of Pharmacy, Ahmedabad4/10/2013 1

Advantages
 Avoids 1st pass metabolism
 Avoids acid/Enzyme metabolism
 Permeation is faster with respect to Skin & TDDS (4-
4000)
 Large surface area with respect to sub-lingual mucosa
 Good patient compliance with respect to parental
 Easy administration & removal in case of toxicity.
 For unconscious or comatose patients

Disadvantages
 Drugs with bitter taste or irritant to mucosa or having
noxious smell
 Not for children
 Eating & drinking difficulty
 Salivary erosion & it may enter GIT & choke esophagus
 Less surface area than skin
 Drugs unstable at Buccal pH(6.5 to 7)

Anatomy/Physiology of Buccal
Cavity

Buccal Environment
 It has four parts & is 500-800um thick & 150Cm^2
approx
 Epithelium: 40-50 cell thick & is major barrier for
lipophilic drug. It has initially square shaped cells which
further grows in the elliptical cells which are permeable
for hydrophilic drugs. It may be Keratinized (having High
MW) or non-keratinized (Low MW).
 Mostly, non-keratinized epithelium is permeable to drug
very easily due to absence of acylceramides & only
small amounts of ceramides. Also they contain small
amounts of neutral but polar lipids (Cholesterol Sulfate&
Glucosyl ceramides). Hence more permeable to
formulation

Cont…
 Lamina propria: Barrier for hydrophilic drug
 Hence highly hydrophilic & highly lipophilic drug
are not suitable for BDDS.
Salivary Secretions: It is secreted by Parotid,
Sub-maxillary & Sub-lingual glands
99 % Aq liquid
1% Solute
{Na, K, Ca, Mg,
Mucin, Albumin,
Enzymes(Amylas
e, lipase) }

Mucin Biochemistry
 The pH of saliva is due to Mucin (6.2-7.4).
 Mucins are synthesized by the goblet cells and
special exocrine glands & secreted by sialic cells
& Mucus cells
 It is gylcorylated glycoprotein having large peptide
backbone & oligosaccharides side chains & 14
side chains made up of oligosaccharide.
 End part of side chains has negative charge due
to sialic acid, sulphonic grp & fructoic grp which
attract cationic polymers.

Factors affecting…
FACTORS…
Polymer related factors MW of polymer
Flexibility
H-bond capacity
Cross-linking density
Charge
Concentration
Drug related factors Mw of Drug,
Lipophilicity
Patient Related factors Salivary secretion rate
pH of Buccal Cavity
Eating/Drinking habit

POLYMER RELATED FACTORS
MW of polymer MW increases, chain & ultimately
adhesion increases Eg PEG4000
Flexibility Should be high
H-bond Capacity HPMC, Carbopol, PVA, PMA
Cross-linking density Should be low as possible
Charge Charged
adhere
molecule will be highly
Concentration 0.5-2 % optimum, because it will
directly increase the cross linking &
hence binding decreases
DRUG RELATED FACTORS
MW of Drug Mw of drug increases, the Absorption
decreases
Lipophilicity Should be high
PATIENT RELATED FACTORS
Salivary secretion rate
pH of Buccal Cavity
Eating/Drinking habit

Mechanism of Adhesion
 The term bioadhesion is commonly defined as adhesion
between two materials where at least one of the
material is of biological origin.
 When adhesion is restricted to mucus layer lining of the
mucosal surface, then it is known as Mucoadhesion.
 Generally such adhesion occurs in four different steps…
 Wetting & Swelling
 Interpenetration of polymer chains in mucin chains
 Formation of chemical bonds between Entangled
chains

1. Wetting and swelling of polymer to permit
intimate contact with biological tissue.
2. Inter-penetration of bioadhesive polymer(BP)
chains and entanglement of polymer and
mucin chains.

3. Formation of chemical bonds between Entangled
chains.
Chemical bonds may be primary(covalent) or
secondary(ionic, van dervaals, H-bonds)

Theories of Adhesion
Adsorption theory: Polymer/groups form covalent/non-covalent
bonds which will bind very strongly (also H-bonds,
vanderwaal’s bonds).
Wetting theory: Polymer with positive spreading co-efficient will
have good binding.
Diffusion theory: Permeability is good in mucin due to chain
flexibility.
Fracture Theory: Irregular surface of polymer & mucin give
good physical entanglement.
Electronic theory: Electric bilayer between polymer & mucin is
responsible.

Formulation of BDDS
SolidDosageforms
• Tablets
• Patches/films
• Wafers
• Lozenges
• Powders
Semi-SolidDasageforms
• Gels
• Ointments
LiquidDosageforms
• Sprays

Basic Formulation components
Muco-adhesive Polymers Permeation enhancers
Diluents Plasticizer
Preferred Drug
Candidate

Selection of DRUG for BDDS
I. MW should be less than 1000da
II. It should be having both nature i.e. hydro-lipophilic type
III. Should be potent {low dose so that formulation is not
bulky}
IV. Non-irritant to mucosa
V. Drugs that degrades in GIT.

List of API’s delivered via Buccal
route
API
Acyclovir Metronidazole
Buprenorpine Metoprolol tartrate
Carbamazepine Morphine sulphate
Chlorpheniramine maleate Nifedipine
Danazol Omeprazole
Diclofenac sodium Pentazocine
Diltiazem Pindolol
Flurbiprofen Piroxicam
Hydrocortisone acetate Rh EFG
Insulin Testosterone
Lignocaine Terbutaline sulphate
LHRH Theophyline
Zinc sulphate Triamcinolone acetate

Mucoadhesive Polymers
 These are the main component for adhesion.
 They attract water from the biological surrounding, get
swells & adhere to the membrane.
 Normally they should be having hydrophilicity, numerous
H-bonding groups, flexibility, interpenetration with
mucus & tissues

Ideal features…
 Non-toxic, non-irritant & pure.
 Good spreadibility, wetting, swelling, solubility &
biodegradable if possible.
 Adhesion should be quick & with sufficient mechanical
strength.
 Should have peel,tensile,shear strength.
 Should easily incorporate drug in formulation & it should
not be obstacle in drug release.
 Cost effective.

 Examples
 Hydrogels:
Polyacrylates, carbopol, polycarbophils
PVA, Ethylene Vinyl alcohol, cellulose derivatives,
alginates
 Thiolated Polymers
Hydrophilic macromolecules exhibiting free thiol groups
on the polymeric backbone.
Eg: Thiomers of chitosan and polyacrylic acid etc
4/10/2013 23
Department of Pharmaceutical Technology, LJ
Institute of Pharmacy, Ahmedabad

Permeation Enhancers
 Permeation is very limiting factor in BDDS.
 Substances that facilates permeation through Buccal
mucosa are called PE.
 Epithelium & Lamina Propria are very effective barrier to
absorption.
 They should be used with very care & in optimum
concentration(<1%), above this concentration toxicity
due to membrane damage may occur &
histopathological study should be done.

Mechanisms of PE’s
 Increasing fluidity & integrity of cell membrane.
 Extracting inter/intra cellular lipids.
 Altering cellular proteins.
 Altering mucus rheology.
 Acting at the tight junctions.
 Increasing thermodynamic activity of drugs.
 Surface tension decreasing.

Permeation Enhancers
Types Examples
Chelators EDTA, Citric acid, Sodium salicylate,
methoxy salicylates
Surfactants SLS, Polyoxyethylene,
Benzalkonium chloride,
Cetylpyridinium chloride,
Cetyltrimethyl ammonium bromide.
Bile salts sodium glycocholate,
sodium deoxycholate,
sodium taurocholate,
sodium glycodeoxycholate,
sodium taurodeoxycholate
Fatty acids Oleic acid, Capric acid, Lauric acid,
PG, methyloleate,
Phosphatidylcholine.
Non-surfactants Unsaturated cyclic ureas.
Inclusion complexes: Cyclodextrins

Important formulation
 Tablets
 Is small, flat, generally oval shape with 5-8mm diameter.
 It is directly placed onto mucosal surface & adheres to
it.
 DC/WG may be used to formulate.

 We can get
 Unidirectional Release
 Multidirectional release (as with conventional product)
Generally for unidirectional release, a backing
membrane is applied, which is impermeable to liquid,
to one side so that no drug release is observed form
that side & non-coated surface adheres to the Buccal
mucosa. Ethyl Cellulose is used as backing
membrane.

 Different marketed Buccal tablets…
 Prochlorperazine maleate tab (BuccastemR M)
 Glycerl trinitrite Buccal tab (Suscord)
 Fentanyl Buccal tab (Fentora)
 Miconazole Buccal tab (Oravig)
 Testosterone (Striant) patented product

Buccal Patches/films
 They are long, flat, thin thickness, transparent with high
surface area.
 They can be prepared by two methods
 Solvent casting method
 Direct milling method

Solvent Casting Method
 Here drug & all excipients are weighed and dispersed in
the suitable organic solvent & coated on the release
liner.
 The organic solvent is allowed to evaporate & after
evaporation the thin layer of the backing material is
laminated on to the sheet of coated release liner to form
laminate.
 After that the whole patch is ready to cut into required
size (almost 2*2 cm2 )

Direct Milling Method
 Here, drug & excipients are mixed mechanically
by milling or kneading.
 After mixing the resultant material is rolled on
the release liner till desired thickness is
achieved.
 Finally as the previous method, backing
material is laminated.
 Though there is no difference in the patch
performance manufactured by either of the
method but with the SOLVENT method there
are chance of residual solvent.
 Hence this Solvent free method is highly used

 What does backing layer does…
Control the direction of drug release
Also prevent drug losses
Minimize deformation during handling &
transportation
Reduces the disintegration of device during the
application
Examples
Nitroglycerin patches
Fentanyl patches (Onsolis)

Evaluating the BDDS
Dosage forms Tablets Patches Semi-solids Sprays
In-vitro test
Weight Variation Y Y
Assay Y Y Y Y
Thickness Y Y
Friability Y
Disintegration time Y Y
Residence time Y Y Y
Tensile strength Y
Folding endurance Y
Viscosity Y
Droplets size Y
Dissolution Y Y Y
Mucoadhesion
Strength
Y Y Y
Permeability test4/10/2013
Y Department of P
LJ Instituteof
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Pharmacy, Ahmedaba
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35

Some important in-vitro test
 Disintegration time:
 Slide frame method: film on slide + drop of water in it.
Note the time when hole is observed in the film.
 Petri dish method: film in Petri plate + 2 ml of water in it.
Check time till film dissolves.
 Residence time:
Take a slide, stick a mucosa on it with gum. Place
our dosage form on it with few droplets of PBS 6.8,
allow it to stick on it. Now make it inclined at 30 C
& at constant rate add PBS 6.8 drop wise on it
without moving the slide. Note the time till dosage
form detaches from mucosa.
Permeation Study: Franz diffusion cell

Residence time
 Locally modified USP disintegration apparatus
was used. DT media: 800 mL PBS pH 6.8 at 37
°C. The buccal tissue was glued to the surface of a
glass slab, vertically attached to the apparatus.
The buccal tablet was hydrated from one surface
using 0.5 mL of PBS pH 6.8, and then the
hydrated surface was brought into contact with the
mucosal membrane. The glass slab was vertically
fixed to the apparatus and allowed to run in such a
way that the tablet was completely immersed in
the buffer solution at the lowest point and was out
at the highest point. The time necessary for
complete erosion or detachment of the tablet from
the mucosal surface was recorded.

Muco-adhesive strength

Shear Force (for various
polymers)
The shear test measures the
force required to separate two
polymer-coated glass slides
joined by a thin film of natural
or synthetic mucus. The
results of this technique often
correlate well with in vivo test
results.

Muco/bio adhesion test
 Modified physical balance. Here lighter pan had replaced
the right pan and the left pan had been replaced by a
glass slide. The height of the total set-up was adjusted to
accommodate a glass container of 6.6 cm height. Buccal
tablet was stacked to the glass slide with the help of the
knob, which was situated at the base of the physical
balance. Five grams weight from the right pan was then
removed. This lowered the glass slide along with the
tablet over the membrane with a weight of 5.0 g. This was
kept undisturbed for 5 min. Then, the weights on the right-
hand side were slowly added in increments of 0.1 g till the
tablet just separated from the membrane surface. By
using this weight calculate the bio-adhesive force using
following equation
Bio adhesive force (N) = weight in grams × G/1000

Modified Balance Method

Block Diagram of Modified
Balance Method

TEXTURE ANALYZER:
 Here the force required to remove the formulation from
a model membrane is measured, which can be a disc
composed of mucin , a piece of animal mucous

In-vivo test
 Buccal Absorption study: Assay of drug solution,
after mouth gargles.
 Perfusion study
 Kinetic study

Chien Diffusion Cell

Recent Innovations
4/10/2013 LJ Institute of Pharmacy, Ahmedabad 46
 Gel Forming Liquids:
 This type of a formulation is liquid upon instillation
and undergoes a phase transition to form a
viscoelastic gel in response to stimulus such as
temperature, ionic strength or ph
 Carbomers become more viscous upon increased
pH.
 Gellan gum and alginate both form gel in response
to increased ionic strength (particularly with Ca+2
ions).
medical solution)
 Poloxamers and smart hydrogel®( Advanced
gel at approximately body
temperature. Department of Pharmaceutical Technology,

Slowly disintegrating buccal
mucoadhesive plain tablet (SDBMPT)
• Prepared by incorporating large amount of HPC.
e.g. tablet having 20mg drug, 20mg HPC, 20mg CMC &
60mg lactose – mixed & compressed with a flat faced
die that is 8mm in diameter.
the control of
• Limitation:
 softens on extended period and
 lose its shape which hinders
disintegration over long time periods

BCTS (Buccal Covered Tablet System)
• Sandwiched S-DBMP-T system between two
polyethylene sheets
• Upper sheet contains hole to absorb water and lower
sheet is made of adhesives

OraVescent technology
• System which transports drug through across the mucosal
membrane.
• Based on effervescent technology and administered buccally
or sublingually by Cima labs Inc
• Principle:
 pH < pKa of weak base –
ionization and solubilization

Marketed products
 Striant®, developed by Columbia Labs, is a testosterone
extended-release buccal tablet that delivers
testosterone systemically for hormone replacement in
hypogonadal men.
 Asftach® is a buccal tablet containing triamcinolone
acetonide for treatment of apththous ulcers, and
contains a bioadhesive layer and a dissolvable lactose
nonadhesive backing layer
 DentiPatch® has been developed by Noven, which is a
lidocaine extended-release buccal patch that adheres
to the gingival tissue to provide for local analgesia, and
was approved in the United States in May 1996.

 Cydot® is an example of a patch technology where the
patch adheres to the buccal mucosa for a period of up
to 24 hours to slowly release melatonin for normalizing
circadian rhythms.
 Buccal Methyltestosterone
Brand name-Metandren, Ciba;
Avoids first-pass hepatic metabolism
 Prochlorperazine
Brand name -Oreton ,Schering Buccastem,
Alternative to enteral tablet

Department of Pharmaceuti

PRODUCT COMPANY BIOADHESIVE
AGENT
PHARMACEUTICA
L FORM
Buccastem® Reckitt Benckiser PVP, Xanthum
gum
Buccal tablet
Corlan pellets® Celltech Acacia gum Oromucosal
pellets
Suscard® Forest HPMC Buccal tablet
Gaviscon liquid® Reckitt Benckiser Sodium alginate Oral liquid
Orabase® Convatech Pectin, Gelatin Oral paste
Corsodyl gel® GlaxoSmithKline HPMC Oromucosal gel

 Administering the drug via membrane located below the
tongue is called Sublingual DDS(SLDDS) generally
called floor of mouth.
 The SLDDS is almost similar to the BDDS having some
more advantages than Buccal drug delivery system.
 Generally factors affecting the SLDDS are almost similar
to factors related with the BDDS.

SLDDS vs BDDS
SLDDS BDDS
The absorption via sub lingual
route is faster than buccal mucosa
due to the thickness of the
sublingual mucosa.
It is 100-200 µm thick
Here, in BDDS, the thickness of
buccal mucosa is 500um
approximately, hence permeation
is slow in compare to sublingual
route
Hence, in emergency conditions, like angina pectoris/asthmatic attack,
SLDDS in preferred than BDDS due to faster permeation of drug
Sub lingual mucosa has rapid
absorption and has higher blood
levels due to very high
vascularization of the region than
Buccal mucosa
It has less vascularization than
sublingual mucosa.

Drug administered
 Antianginal like nitrites and nitrates
 Anti hypertensive like nifedipine
 Analgesics like morphine
 Bronchodilators like fenoterol
 Certain steroids like estradiol
 Peptides like Oxytocin can also be administered

Various formulations
 Sublingual tablets
 Fast-disintegrating sublingual tablets
 Bioadhesive sublingual tablet
 Thin film drug delivery
 Lipid matrix sublingual tablet
 Sublingual immunotherapy
 Sublingual vitamin tablet

Evaluating SLDDS
 Surface pH of the tablet
 Uniformity of weight
 Content uniformity
 Hardness
 Thickness
 Diameter
 Disintegration time
 Wetting time
 Friability
 Dissolution test
 Folding endurance
 Bioadhesion strength
 Permeation studies
 % Elongation

Marketed Products

Buccal drug delivery systems

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