Mucosal drug delivery system
Learning
Objectives
By the end of this
session, students will be able to:
• Outline the concepts involved in adhesive systems
• State the advantages of mucoadhesive delivery systems
• Explain the various theories to explain mucoadhesion
• Discuss the factors affecting mucoadhesion
• Classify mucoadhesive polymers with relevant examples
• Discuss the mechanism
of drug permeation
across the mucosal barrier
• Outline the role of permeation enhancers in mucoadhesive
dosage form
Introduction
to Mucosal Drug Delivery Systems
Oral route
————-> Preferred route of administration
Drawback of oral route
Hepatic metabolism
or
Extensive pre-
systemic elimination by GIT
↓
Low systemic
bio-availability of the drug
↓
Short duration of
therapeutic activity
Mucoadhesion
Concept
• The molecular force of attraction among two unlike bodies,
which holds them together is called ‘adhesion’
• ‘Bioadhesion’ can be defined as a phenomenon of
interfacial molecular attractive forces amongst the surfaces of the biological
substrate and the natural or synthetic polymers, which allows the polymer to
adhere to the biological surface for an extended period of time
• The term ‘mucoadhesion’ is used when the biological
surface is a mucosal surface
Mucoadhesion
– History
• Various biopolymers show the bioadhesive properties and
have been utilized for various therapeutic purposes in medicine
• 1947- Penicillin
drug delivery system – penicillin delivery to the oral mucosa – gum
tragacanth and dental adhesive powders
• Formulation developed – using finely
ground sodium
carboxymethylcellulose, pectin, and gelatin as mucoadhesive polymers – Marketed
as Orahesive®
• Orabase®- a blend of polymethylene/ mineral oil base
• Various other polymers have been found to exhibit mucoadhesive
properties – e.g. sodium alginate, sodium carboxymethylcellulose, guar gum,
hydroxyethylcellulose, karya gum, methylcellulose, polyethylene glycol (PEG),
retene and tragacanth
• 1980s – Poly (acrylic acid), hydroxypropylcellulose, and
sodium CMC were widely explored
• Various other polymers have been found to exhibit mucoadhesive
properties – e.g. sodium alginate, sodium carboxymethylcellulose, guar gum,
hydroxyethylcellulose, karya gum, methylcellulose, polyethylene glycol (PEG),
retene and tragacanth
Mucoadhesive
Delivery Systems – Advantages
• Bypass hepatic metabolism, increased bioavailability
• Prevents degradation in GIT
• Rapid absorption, rapid onset of action
• Controlled release and prolonged action
• Improved therapeutic performance
• Localized and targeted action
• Prolonged residence time of the dosage form, permit once
or twice a day administration
• Rapid absorption due to good blood flow rate at the
absorption site
• Reduction in fluctuations in steady state plasma levels
• Improved patient compliance
Advantage
of Transmucosal Drug Delivery
Mucoadhesive
Delivery Systems – Disadvantages
• Gastric motility
• Mucous turnover rate
• Irritating drugs cannot be administered
• Lack of a good model for in vitro screening
• Occurrence of local ulcerous effects due to prolonged
contact of the drug
• Patient acceptability in terms to taste, irritancy and
mouth feel
Mucosal
Layer
• Mucus is the viscous slippery gel that covers most of the
mucosal surfaces throughout the GIT
• Mucus membranes (mucosae) line the walls of various body
cavities such as the gastrointestinal and respiratory tracts
• Consist of a connective tissue layer (the lamina propria)
• Above which is an epithelial layer
• Surface epithelium is made moist usually by the presence
of a mucus layer
Single layered
epithelia
• e.g. the stomach, small and large intestines and bronchi
• Contains goblet cells which secrete mucus directly onto
the epithelial surfaces
Multilayered/stratified
epithelia
• e.g. in the esophagus, vagina and cornea
• The multilayerd epithelium contain, or are adjacent to
tissues containing, specialized glands such as salivary glands that secrete
mucus onto the epithelial surface
Mucus
• Mucus is present
either as a gel layer adherent to the mucosal surface or as a luminal soluble
or suspended form
• The major components of all mucus gels are
– Mucin glycoproteins
– Lipids
– Inorganic salts
– Water
• Water accounts for more than 95% of their weight, making
them a highly hydrated system.
• The major functions of mucus – protection and lubrication.
Structure of Mucus
Membrane
Mucoadhesion
Theories
• The process of bioadhesion can be broadly classified into
two categories, chemical and physical methods
Chemical
• Electronic theory
• Adsorption theory
Physical
• Wetting theory
• Diffusion theory
• Cohesive theory
• Mechanical theory
Wetting
theory
The contact angle should be equal or close to zero to provide
adequate spreadability
• The wetting
theory postulates that
if the contact
angle of liquids on
the substrate surface
is lower, then
there is a greater affinity for the liquid to the
substrate surface
• If two such substrate surfaces are brought in contact with
each other in the presence of the liquid, the liquid may act as an adhesive
amongst the substrate surfaces.
• The spreadability coefficient, S can be determined as
follows,
SAB = γB + γA – γAB
γB is Surface tension of the bioadhesive polymer
γA is Surface tension of the substrate
γAB is Interfacial tension between the polymer
and substrate
Diffusion
Theory
• The diffusion theory assumes the diffusion of the polymer chains,
present on the substrate surfaces, across the adhesive interface thereby
forming a networked structure
• Interpenetration of both polymer and mucin chains to a
sufficient depth to create a semipermanent adhesive bond
Cohesive
Theory
• The cohesive theory proposes that the phenomena of bioadhesion
are mainly due to the intermolecular interactions amongst like-molecule
Mechanical
Theory
• Mechanical theory explains the diffusion of the liquid
adhesives into the micro-cracks and irregularities present on the substrate
surface thereby forming an interlocked structure which gives rise to adhesion
The
Electronic Theory
• The electronic theory proposes transfer of electrons
amongst the surfaces resulting in the formation of an electrical double layer
thereby giving rise to attractive forces
The
Adsorption Theory
Primary bonds
• Chemical absorptions
• Ionic, covalent, metallic bonding
• Permanent bonds
• Undesirable
Secondary bonds
• Van der Waals forces, hydrophobic Interactions, hydrogen
bonding
• require less energy to “break”
• Most prominent
• Semipermanent bonds
• Desirable
• The adsorption theory proposes the presence of
intermolecular forces, viz. hydrogen bonding and Van der Waal’s forces, for the
adhesive interaction amongst the substrate surfaces
Mechanisms
of Mucoadhesion
The process of adhesion may be divided into two stages.
1. Contact stage: wetting of mucoadhesive
polymer and mucous membrane occurs
2. Consolidation
stage: physico-chemical interactions prevail
Contact stage
• Characterized by the contact between the mucoadhesive and
the mucus membrane
• Spreading and swelling of the formulation
• Initiating its deep contact with the mucus layer
Consolidation
stage
• The mucoadhesive materials are activated by the presence
of moisture
• Moisture plasticizes the system, allowing the mucoadhesive
molecules to break free and to link up by weak van der Waals and hydrogen
bonds.
• Mucoadhesive device should have features favouring both
chemical and mechanical interactions
• Molecules with
– Hydrogen bond building groups (–OH, –COOH),
– An anionic surface charge
– High molecular weight
– Flexible chains
– Surface active properties
Interaction between mucoadhesive molecules and the
glycoproteins of the mucus
Interpenetration of their chains and the building of
secondary bonds
Factors
Affecting Mucoadhesion
1. Molecular weight
➢ Mucoadhesive strength of a
polymer increases with molecular weights above 100,000
2. Flexibility
➢ The polymer chains should
contain a substantial degree of flexibility in order to achieve the desired
entanglement with the mucus
➢ Higher flexibility of a
polymer causes greater diffusion into the mucus network
3. Crosslinking density
➢ With increasing density of
crosslinking, diffusion of water into the polymer network occurs at a lower
rate
➢ Causes an insufficient
swelling of the polymer and a decreased rate of interpenetration between
polymer and mucin
4. Hydrogen bonding capacity
➢ Polymers must have functional
groups that are able to form hydrogen bonds
5. Hydration
➢ Polymer swelling permits a
mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding
and/or electrostatic interaction between the polymer and the mucus network
➢ critical degree of hydration
of the mucoadhesive polymer exists where optimum swelling and mucoadhesion
occurs
6. Charge
➢ Strong anionic charge on the
polymer is one of the required characteristics for mucoadhesion
7. Concentration
➢ When the concentration of the
polymer is too low, the number of penetrating polymer chains per unit volume of
the mucus is small and the interaction between polymer and mucus is unstable
➢ The more concentrated polymer
would result in a longer penetrating chain length and better adhesion
➢ For each polymer, there is a
critical concentration, above which the polymer produces an “unperturbed” state
due to a significantly coiled structure
Physiological
variables
Mucin turnover
• Limits the residence time of the mucodhesives on the mucus
layer
• Mucin turnover results in substantial amounts of soluble
mucin molecules.
• These molecules interact with mucoadhesives before they
interact with the mucus layer
Disease state
Changes the physiochemical properties of the mucus
Examples: Common cold, gastric ulcers, ulcerative colitis,
cystic fibrosis, bacterial and fungal infections of the reproductive tract
Sites for
Mucoadhesive Drug Delivery Systems
1. Oral
– Buccal
– Sublingual
• The buccal cavity has a very limited surface area of
around 50 cm2
• Easily accessable
• For systemic delivery and local treatment of oral lesions
• Sublingual mucosa is relatively more permeable than the
buccal mucosa
2. Nasal
• Surface area of around 150–200 cm2
• Residence time of a particulate matter in the nasal mucosa
varies between 15 and 30 min
3. Ocular
• Conventional dosage forms are rapidly cleared from site of
application
• This can be minimized by delivering the drugs using ocular
insert or patches
4. Vaginal and the
rectal lumen
• Bypass the hepatic first-pass metabolism
• Helps in reducing the migration within the vaginal/rectal
lumen
5. GIT
• Modulation of the transit time of the delivery systems in
a particular location of the gastrointestinal system
• Has a drawback of acid instability and first-pass effects
Mucoadhesive
Polymers
• Polymers have numerous hydrophilic groups, such as
hydroxyl, carboxyl, amide, and sulfate
• Attach to mucous or the cell membrane by various
interaction such as hydrogen bonding and hydrophobic or electrostatic
interactions
• Cause polymer to swell in water and thus expose the
maximum number of adhesive sites
Ideal characteristics
of mucoadhesive polymers
• Should adhere to the site of attachment for a few hours
• Should release the drug in a controlled fashion
• Should provide a unidirectional drug release – towards the
mucosa
• Should facilitate the rate and extent of drug absorption
• Should not cause any irritation or inconvenience
• Should not interfere with normal functions like talking,
eating, etc
Classification of
Mucoadhesive Polymers
Based on origin
Synthetic – Cellulose derivatives, Polyacrylate,
Polymethacrylate, PVP, Carbopol
Natural – Tragacanth, Sod. Alginate, Karaya gum, Xanthan, Guar
gum, Lectins, Pectin gelatin, chitosan
Based on nature
Hydrophillic – Poloxamer, Methyl cellulose, HEC, Sod. CMC, Carbopol,
Chitosan, PVA, PAA
Hydrogels – Carageenan, Sod. Alginate, Guar gum
Based on charge
Anionic – PAA, Polycarbophil, carbopol
Cationic – Chitosan
Non-ionic-
Second generation
polymers
thiomers
Lectin
• The anionic and cationic polymers exhibit stronger
mucoadhesion
• Anionic polymers are the most widely employed mucoadhesive
polymers within pharmaceutical formulations due to
– Their high mucoadhesive functionality
– Low toxicity
• Examples: PAA and its derivatives, Sodium CMC
• Such polymers are characterised by the presence of
carboxyl and sulphate functional groups that give rise to a net overall
negative charge at pH values exceeding the pKa of the polymer
• Among cationic polymers, chitosan is the most extensively
investigated
• Chitosan is a cationic polysaccharide, produced by the
deacetylation of chitin
• Biocompatible, biodegradable and has favourable toxicological
properties
• Chitosan binds via ionic interactions between primary
amino functional groups and the sialic acid and sulphonic acid substructures of
mucus
Second-generation
polymers
• Less susceptible to mucus turnover rates
• Some bind directly to mucosal surfaces
• More accurately termed “cytoadhesives”
• Furthermore as surface carbohydrate and protein
composition at potential target sites vary regionally, more accurate drug
delivery may be achievable
Examples: lectins and thiomers
• Lectins are naturally occurring proteins
• After initial mucosal cell-binding, lectins can either
remain on the cell surface or in the case of receptor-mediated adhesion
possibly become internalised via endocytosis
• Lectins offer significant advantages in relation to site
targeting
• Many are toxic or immunogenic
• Thiolated polymers (thiomers) are derived from hydrophilic
polymers such as polyacrylates, chitosan or deacetylated gellan gum
• Thiol groups allows the formation of covalent bonds with
cysteine rich sub domains
of the mucus
gel layer leading
to increased residence time and
improved bioavailability
Transmucosal
permeation
Passive diffusion
1.
Paracellular
2.
Transcellular
Facilitated diffusion
1.
Carrier mediated transport
Passive diffusion
• Transport of drugs across the epithelium occurs by passive
mechanisms
• Governed by laws of diffusion
• Two route for simple diffusion of materials across the epithelium
– Transcellular route
– Paracellular route
Transcellular route
• Transport into and across the cells
• Seen with highly lipid soluble molecules
Paracellular route
• Transport of molecules through intercellular spaces
• Water soluble substances and ions
Transmucosal
Permeability
Facilitated diffusion
• Nutrients from mouth are shown to be absorbed by carrier systems
• Exhibits stereospecificity
• Competitive inhibition can be seen in cases of a common carrier
system
Permeation
Enhancers
• They help in enhanced transmucosal absorption of medicament.
• Effective 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:
1. Increasing the
fluidity of the cell membrane
2. Extracting
inters/intracellular lipids
3. Altering
cellular proteins
4. Altering surface
mucin
Permeation enhancers
may be of the following categories
• Surfactants
• Fatty acids and derivatives
• Vehicles and adjuvants
• Chelators
• Enzyme inhibitors
• Cyclodextrin
• Chitosan
Surfactants
Anionic – Sodium
lauryl sulphate, Sodium laurate
Cationic Nonionic –
Cetyl pyridinium chloride
Nonionic –
Poloxamer
Mechanism of action
of surfactants
• Disruption protein domain integrity as well as lipid
structures
• Longer the chain length, greater the permeation effect
Example: Sucrose palmitate (16 carbon chain) is a better permeation enhancer compared
to Sucrose laurate (12 carbon chain)
Fatty acids and
derivatives
Effect of fatty acids depends on the presence and the
position of double bonds, isomer
types (cis or
trans), chain length
and degree of branching
➢ Sodium laurate and myristate –
insulin and calcitonin.
➢ Oleic acid/hydro alcoholic
solutions -lidocaine hydrochloride.
Fatty acids and
derivatives – Mechanism of action
• Insertion between the alkyl chains of membrane lipids
• Disturbance of the lipid packing order in the deep liquid
bilayer and polar head regions
• Increased fluidity of the phospholipids domains.
Vehicles and
adjuvants
➢ 10% lauric acid in propylene
glycol – insulin
➢ Ethanol (15 to 30%) – peptides
➢ Dimethylsulfoxide (DMSO)
➢ N-methylpyrrolidine (NMP)
Mechanism of action
• Increased drug concentration at the mucosal site
• Increase the solubility of the drug in the epithelial
mucosal barrier
• Increasing the partitioning of the drug from the vehicle
to the mucosa
Chelators
➢ EDTA,
➢ Salicylates,
➢ Sodium citrate,
➢ Polyacrylates
Mechanism of action
of chelators
• Interfere with the calcium efflux of the membrane
• Altering the conformation of peptides and making them less
susceptible to enzymatic degradation
Enzyme inhibitors
1. Peptidase
inhibitors.
2. Protease
inhibitors such as aprotinin, bestatin and bile salts
Mechanism of action
Altering the conformation of peptides and making them less
susceptible to enzymatic degradation
Cyclodextrins
➢ α-, β-, and γ cyclodextrins
➢ Methylated β- cyclodextrins
Mechanism of action
• Inclusion of
membrane compounds
Eg. Hydroxypropyl cyclodextrin (HPCD) at a concentration of 10
mM increased the flux of buspirone 35 times
Chitosan
• Positively charged biodegradable polymer
• Interact with the negatively charged mucosal surface
• Interaction with the proteoglycan matrix leading to lead
to widening of intercellular filaments
• Interference with the extracellular lipid and glycolipid contents
Summary
Mucoadhesive Delivery
Systems – Advantages
• Bypass hepatic metabolism, increased bioavailability
• Prevents degradation in GIT
• Rapid absorption, rapid onset of action
• Controlled release and prolonged action
• Improved therapeutic performance
• Localized and targeted action
• Prolonged residence time of the dosage form, permit once
or twice a day administration
• Rapid absorption due to good blood flow rate at the
absorption site
• Reduction in fluctuations in steady state plasma levels
• Improved patient compliance
Mucoadhesive Delivery
Systems Disadvantages
• Gastric motility
• Mucous turnover rate
• Irritating drugs cannot be administered
• Lack of a good model for in vitro screening
• Occurrence of local ulcerous effects due to prolonged
contact of the drug
• Patient acceptability in terms to taste, irritancy and
mouth feel
Mucoadhesion Theories
• The process of bioadhesion can be broadly classified into
two categories, chemical and physical methods
Chemical
• Electronic theory
• Adsorption theory
Physical
• Wetting theory
• Diffusion theory
• Cohesive theory
• Mechanical theory
Mechanisms of
Mucoadhesion
The process of adhesion may be divided into two stages.
1. Contact stage:
wetting of mucoadhesive polymer and mucous membrane occurs
2. Consolidation
stage: physico-chemical interactions prevail
• Factors affecting
mucoadhesion – Polymer related and physiological factors
• Polymer related –
molecular weight, crosslinking density, hydrophilicity etc
• Physiological –
mucin turnover, pathological conditions, etc.
• Mucoadhesive polymers
• ‘Bioadhesion’
can be defined as a phenomenon of interfacial molecular attractive forces
amongst the surfaces of the biological substrate and the natural or synthetic
polymers
• The term ‘mucoadhesion’
is used when the biological surface is a mucosal surface
• Advantages of
mucoadhesive systems – prolonged residence time, controlled drug delivery,
increased bioavailability
• Theories of
mucoadhesion – Wetting theory, diffusion theory, fracture theory,
electronic theory, and adsorption theory
• Mucoadhesive
systems – utilize various mucoadhesive polymers
• Methods of
transmucosal permeability – passive diffusion, tranfollicular route
• Permeation
enhancers used in transmucosal delivery systems – cationic, anionic and
non-ionic surfactants
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