Concept of mucoadhesive drug delivery

1. MUCOADHESIVE DRUG
DELIVERY SYSTEM

2. INTRODUCTION
 Bioadhesion can be defined as the state in which two materials, at least one
biological in nature, are held together for an extended period of time by
interfacial forces
 When bioadhesion restricted to mucosal surface it is termed as
mucoadhesion.

3.  Mucoadhesive drug delivery system is a part of controlled delivery system.
 Mucoadhesive drug delivery system utilize the property of bioadhesion of certain water
soluble polymer which become adhesive on hydration.
 Hence can be used for targeting a drug to a particular region of the body for extended
periods of time

4. Concept of mucoadhesion
 Step 1: Wetting and swelling of the polymer.
 Step 2: Interpenetration between the polymer chains and the mucosal membrane.
 Step 3: Formation of Chemical bonds between the entangled chains.
Step 1

5. Concept of mucoadhesion
Step 2 Step 3

6. THEORIES OF MUCOADHESION
1. Electronic theory
2. Wetting theory
3. Fracture theory
4. Adsorption theory
5. Diffusion theory
6. Mechanical theory
6

7. 1. Electronic theory
 The theory states that both the mucoadhesive and biological material have
opposite charges.
 When both materials come in contact, they transfer electrons leading to the
formation of double electronic layer at the interface.
 Attractive forces within this electronic double layer determines the
mucoadhesive strength.

8. 2. Wetting theory
 This theory is mainly applicable to liquid or low viscosity muco adhesive
system
 Wetting is the ability to spread and develop intimate contact with mucous
membrane
 Lower the contact angle, then greater this ability(≈0)
 The spreading coefficient of polymers must be positive

10. 3. Adsorption theory
 According to this theory, the adhesive bond is formed due to
 Vander Waals interaction
 Hydrogen bond
 Hydrophobic interactions
 Eventhough, individually these bonds are weak, a greater number of interactions
increases the adhesion

11. 4. Fracture theory
 This theory analyses the force required for the
separation of two 2 surfaces after adhesion
Sm = Fm / Ao
 Sm =maximum tensile strength during detachment
 Fm=maximum force for detachment
 Ao = total surface area

12. 5. Diffusion theory
 This theory states that the
interpenetration and entanglement of
both polymer and mucin chains are
responsible for adhesion.
Interpenetration depth ,L
L = ( t Db ) 1/2
 T=Contact time
 Db =Diffusion coefficient

13. 6. Mechanical theory
 Mechanical theory considers adhesion to be due to the filling of the irregularities on a
rough surface by a mucoadhesive liquid.
 Moreover, such roughness increases the interfacial area available to interactions
thereby aiding dissipating energy and can be considered the most important
phenomenon of the process

14. TRANSMUCOSAL PERMEABILITY
 Transmucosal permeability refers to the transport of materials such as drugs across the mucosa.
 Transmucosal permeability is a unique approach that aims at delivering the drug systemically through
mucosa, rather than delivering drugs that produce a local effect on the oral mucosa, as is the case in
mucosal drug delivery.
DISADVANTAGES:
• absorption via this route is variable.
• unsuitable for delivering potent drugs.
ADVANTAGES:
• less invasive.
• doesn’t require much technical equipment.
• No first pass metabolism

15.  Transmucosal delivery of therapeutic agents is a popular method because mucous membranes are
relatively permeable, allowing for rapid uptake of a drug into the systemic circulation and avoiding the
first pass metabolism.
 Transmucosal products can be designed to be administered
 Via the nasal route by using sprays, pumps and gels,
 Via the oral/buccal route using mucoadhesive,
 Quick dissolve tablets
 Solid lozenge formulations
 Via vaginal or urethral routes using suppositories

16. Transmucosal pathways

17. Transmucosal permeability: methods for
drug absorption
 Drugs traverse through the oral mucosa by different methods of absorption. Some of
the commonly adopted routes are :
 Passive diffusion refers to the non – ionic diffusion of drugs from the high
concentration to the lower concentration and is the major absorption process.
 Facilitated diffusion – This is similar to passive diffusion but differs because it uses
integral transmembrane proteins to facilitate the transport.
 Active transport – This transport requires energy for the drug’s movement across
the oral mucosa. The hydrolysis of ATP often provides the energy.
 Pinocytosis – In this type of transport, the entire drug molecule is engulfed into the
cell as a small vesicle. This process also requires energy in the form of ATP.

18.  After a drug is deposited on the mucosal surface, it may cross the epithelium via the
transcellular (through cells) or paracellular route (between adjacent cells).
 Both routes belong to a passive transport process driven by a local concentration
gradient.

19.  In general, small lipophilic molecules that are non-ionised at their surrounding pH
are favourable for transmucosal absorption.
 Aqueous solubility and dose of drug can also influence its absorption.
 Absorption also relies on the volume of fluid available at the site of administration
for drug dissolution to take place.
 Hence the exact properties of a drug required in order to achieve effective
transmucosal delivery is specific to each route of administration.

20.  Buccal Cavity
 At this site, first-pass metabolism is avoided, and the
non-keratinized epithelium is relatively permeable to
drugs.
 Due to flow of saliva and swallowing, materials in the
buccal cavity have a short residence time and so it is
one of the most suitable areas for the development of
bioadhesive devices that adhere to the buccal mucosa
and remain in place for a considerable period of time.

21.  Vagina
 The vagina is a highly suitable site for a bioadhesive.
 The bioadhesion increases the retention time (up to 72 h) and a smaller amount of
the active ingredient can be used, reducing any adverse effects.
 As a progressive hydration approach to bioadhesive delivery, the product absorbs
moisture, becomes a gel and releases medication in a time-controlled manner.

22.  Nasal cavity
 Alternative route for drugs with poor systemic
bioavailability after oral administration.
 Nasal drug delivery is an attractive alternative to i.v. or i.m.
injections.

23.  Gastrointestinal Tract
 The gastrointestinal tract has been the subject of intense study for the use of
bioadhesive formulations to improve drug bioavailability.
 The disadvantage is that the polymeric bioadhesive formulations bind the intestinal
mucus, which is constantly turning over and are transported down the gut by
peristalsis.
 Another problem is that with conventional formulations such as tablets, the active
ingredient may diffuse relatively rapidly away from the bioadhesive

24.  Oesophagus
 Tablets or capsules lodging in the oesophagus lead to delayed absorption and
therefore delayed onset of action, as the oesophageal epithelial layer is impermeable
to most drugs.
 In addition, adhesion at such a site may cause problems if localization of the drug or
dosage form leads to irritation of the mucosa.
 Development of a DDS that adheres to the oesophagus has implications in both the
protection of the epithelial surface from damage caused by reflux and as a
vehicle to deliver drugs for local action within the oesophagus.
 Bioadhesive dosage forms that adhere to the oesophageal mucosa and prolong
contact have been investigated to improve the efficacy of locally acting agents.

25.  Rectal Drug Delivery
 The lower digestive tract is less harmful to administered drugs than the stomach and
the small intestine due to the lower enzymatic activity and neutral pH.
 Also the rectal route of drug administration is safe and convenient.
 The circumvention of the hepatic first pass metabolism by rectal administration is
only partial and depends on the positioning and / or spreading of the drug
formulation.
 Recent studies have evaluated thermo gelling dosage forms, gels, osmotic mini
pumps, and hard gelatin capsules as rectal drug delivery systems.

26. Factors affecting mucoadhesion
1. Polymer related factors
 Molecular weight
 Concentration of polymer
 Polymer chain flexibility
 Hydrogen bonding capacity
 Presence of functional group
 Spacial conformation
 Cross-linking density

27. 2. Environment related factors
 pH of polymer – substrate interface
 Applied strength
 Initial contact time
 Swelling
3. Physiological factors
 Mucin turn over
 Disease state

28. Factors affecting transmucosal permeation
(buccal)
 Lipophilicity of the drug – The permeability is higher for agents or drugs that are highly lipid-soluble.
 Salivary secretion – Higher the salivary secretion, the higher the drug’s chances of being flushed out.
This can lead to incomplete absorption of the drug.
 The saliva’s pH – Absorption is favored when the pH is around 6.
 Binding to the oral mucosa – Proper binding of the drug carrier to the oral mucosa is essential. It
helps permeates the drug across the mucosa to the systemic circulation.
 Oral epithelium thickness – The permeation rate of the drug from the drug carrier is dependent on
the thickness of the oral epithelium. The thicker this layer, the longer the residence time of the drug.

29. Formulation consideration
 Buccal delivery systems refer to the administration of the drugs via the buccal mucosa.
 The buccal mucosa is the mucosa that lines the inner cheek.
 Formulations are placed in the mouth between the upper gums and the cheek.
 This mucosa is highly vascularized and is relatively easy to access.
 The absorption of drugs in this region mainly occurs by passive diffusion through the lipoidal
membrane.
 The various buccal formulations currently available in the market are buccal tablets, buccal
patches/films, and buccal gels/ointments.

30. 1. Physiological considerations:
 Texture of buccal mucosa
 Thickness of the mucus layer
 Mucus turn over time
 Effect of saliva
2. Pharmacological considerations
 Partition coefficient of drug
 Residence time of drug
 Local drug concentration in mucosa
 Amount of drug transported across mucosa

32. a. Buccal mucosa
 Inner lining of the lips and cheeks.
 Very short transit time.
b. Sublingual mucosa
 It surrounds the sublingual gland located underneath the tongue.
c. Gingival mucosa
 Hardest muscle
 Retain dosage form for loner period.

33.  The novel type buccal dosage forms include:
1. Buccal mucoadhesive tablets,
2. Buccal patches and films,
3. Semisolids (ointments and gels) and powders

34.  Buccal mucoadhesive tablets: Buccal mucoadhesive tablets are dry dosage forms
that have to be moistened prior to placing in contact with buccal mucosa.
 Buccal patches and films: Buccal patches and films consist of two laminates, with
an aqueous solution of the adhesive polymer being cast onto an impermeable
backing sheet, which is then cut into the required round or oval shape.
 Semisolids (ointments and gels): Bioadhesive gels or ointments have less patient
acceptability than solid bioadhesive dosage forms, and most of the dosage forms are
used only for localized drug therapy within the oral cavity.

35.  Structure and design of buccal patches:
 Buccal patches are of two types on the basis of their release characteristics:
i). Unidirectional buccal patches
ii). Bidirectional buccal patches
 Unidirectional patches release the drug only into the mucosa
 Bidirectional patches release drug in both the mucosa and the mouth.

36.  Buccal patches are structurally of two types:
i). Matrix type: The buccal patch is designed in a matrix configuration
contains drug, adhesive, and additives mixed together
ii). Reservoir type: The buccal patch designed in a reservoir system
contains a cavity for the drug and additives separate from the adhesive.
An impermeable backing is applied to control the direction of drug
delivery; to reduce patch deformation and disintegration while in the
mouth; and to prevent drug loss.

37. Composition of buccal patches
1. Drugs
2. Polymers (adhesive layer)
3. Backing layer
4. Permeation enhancer
5. Plasticizers
6. Taste masking agents

38. 1. Drugs
 The conventional single dose of the drug should be small.
 The drugs having biological half-life between 2-8 h are good candidates for controlled drug
delivery.
 Tmax of the drug shows wider-fluctuations or higher values when given orally.
 The drug absorption should be passive when given orally.
 Buccal adhesive drug delivery systems with the size 1–3 cm2 and a daily dose of 25 mg or
less are preferable.

39. 2. Bioadhesive polymer
 Mucoadhesive polymers are water-soluble and water insoluble polymers,
which are swellable networks, joined by cross-linking agents.
 These polymers possess optimal polarity to make sure that they permit
sufficient wetting by the mucus and optimal fluidity that permits the
mutual adsorption and interpenetration of polymer and mucus to take place.
 Bioadhesive system uses polymers as an adhesive component.

40.  Should possess some physicochemical features like
 Hydrophilicity
 Numerous hydrogen bond forming groups
 Flexibility for interpenetration with mucus and epithelial tissue
 Visco-elastic properties

41.  Ideal characters for the bioadhesive polymer
 Inert and compatible
 Non toxic
 Should form strong non covalent bonds
 Shouldn’t decompose on storage
 Easily available
 Should allow easy incorporation of drug in to formulation
 High molecular weight is desirable
 Adhere quickly
 E.g. Agarose, Chitosan, CMC, MC, Amino dextran, Pectin ,Sodium alginate