1. Mucoadhesive Drug Delivery System

2. Bioadhesion / Mucoadhesion: Bioadhesion is the ability of a material to adhere to a biological tissue for an extended period of time.
Bioadhesives / Mucoadhesives: Bioadhesives are the substances that are capable of interacting with biological material and being retained on them or holding them together for extended periods of time.
Mucoadhesive drug delivery system (MDDS):MDDS utilizes the property of bioahesion of certain water-soluble polymers which become adhesive on hydration and hence can be used for targeting a drug to a particular region of the body for extended periods of time

3. INTRODUCTION
Since the early 1980,the concept of Mucoadhesion has gained considerable interest in pharmaceutical technology.
The strategies studied to overcome such obstacles include the employment of the materials that, possibly, combine mucoadhesive , enzyme inhibitory & penetration enhancer properties & improve the patient compliance.
MDDS have been developed for buccal ,nasal, rectal &vaginal routes for both systemic & local effects.
Hydrophilic high mol. wt. such as peptides that cannot be administered & poor absorption ,then MDDS is best choice.

4. What is Mucoadhesive drug delivery system?
Mucoadhesive drug delivery system interact with the mucus layer covering the mucosal epithelial surface, & mucin molecules & increase the residence time of the dosage form at the site of the absorption.
Mucoadhesive drug delivery system is a part of controlled delivery system.

5. Why are we using Mucoadhesive drug delivery system(MDDS)?
MDDS prolong the residence time of the dosage form at the site of application or absorption.
Intimate contact of the dosage form with the underlying absorption .
Improve the therapeutic performance of drug.
Should not cause irritation.
High drug loading capacity.
Controlled drug release(preferably unidirectional
release).

6. Types of Drug delivery systems:
Depending upon the route of administration of the mucoadhesive drugs they are different types .They are
1)Buccal delivery system
2)Sub lingual delivery system
3)Vaginal delivery system
4)Rectal delivery system
5)Nasal delivery system
6)Ocular delivery system
7)Gastro intestinal delivery system

7. ADVANTAGES-
MDDS offer several advantages over other controlled oral controlled release systems by virtue of prolongation of residence of drug in GIT.
Targeting & localization of the dosage form at a specific site.
High drug flux at the absorbing tissue.
MDDS will serve both the purposes of sustain release & presence of dosage form at the site of absorption.
Excellent accessibility.
Painless administration.

8. DISADVANNTAGES-
If MDDS are adhere too tightly because it is undesirable to exert too much force to remove the formulation after use, otherwise the mucosa could be injured.
Some patient suffers unpleasant feeling.
Unfortunately ,the lack of standardized techniques often leads to unclear results.
costly drug delivery system.
Medications administered orally do not enter the blood stream immediately after passage through the buccal mucosa.

9. COMPOSITION OF MUCUS LAYER:
‘Mucus is translucent and viscid secretion which forms a thin continuous gel adherent to mucosal epithelial surface.’
Water %
Glycoprotein and lipids %
Mineral salts %
Free proteins %

10. Mucosal membranes
These are moist membranes that line passageways and structures in the
body that lead to the outside environment such as the mouth, respiratory tract, gastrointestinal tract, nose and vagina

11. Bioadhesion is used to describe the bonding or adhesion
between a synthetic or natural polymer and soft tissues
biological substrate such as epithelial cells, which
allows the polymer to adhere to the biological surface for
an extended period of time . 11

12. Concept The drug can be incorporated into a cross linked
polymer device that would adhere to mucosal membrane in the body .the drug can diffuse from device directly in the tissue.
Adhesion ,anchoring of polymer device result in increase residence time , bioavailability & site specificity.
Decrease in frequency of administration with low dose , rate of elimination.
Can bypass Firstpass metabolisum in route is other than oral 12

13. Pathway to Bypass Oral Delivery Portal Circulation Pharmacological
Response
Oral Delivery
Portal Circulation

14. Theories of mucoadhesion
The Theories include :-
(a) The electronic theory.
(b) The wetting theory.
(c) The adsorption theory.
(d) The diffusion theory.
(e) The mechanical theory.
(f) The cohesive theory.
(g) Fracture theory.
The phenomena of bioadhesion occurs by a complex mechanism .There are seven theories have been proposed till date

15. Electronic theory:
Proposes transfer of electrons amongst the surfaces due to difference in their electrical structure resulting in the formation of an electrical double layer thereby giving rise to attractive forces.

16. 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.

17. Wetting theory calculates the contact angle and work of adhesion (Wa), given by Dupre’seq.
WA = Yb + Yt -- Y bt
Ƴb& Ƴt are surface tension of polymer and substrate respectively and Ƴbtis interfacial tension
The adhesive work done is a sum of the surface tensions of the two adherent phases, less the interfacial tensions apparent between both phases

18. A liquid bioadhesivespreading over a typical soft tissue
Horizontal resolution of the forces gives the Young eq.
Y ta = Ybt + Yba CosƟ
Where, Ƴbt, Ƴba, and Ƴtaare surface tension between tissue and polymer, polymer and air, and tissue and air respectively
If the vector Ƴtagreatly exceeds Ƴbt+ Ƴba, that is:
Yta > Ybt+Yba
then θ will approach zero and wetting will be complete
surface

19. The diffusion theory:
Assumes the diffusion of the polymer chains, present on the substrate surfaces, across the adhesive interface thereby forming a networked , semipermeable structure. The extent depth to which the polymer chain penetrate the mucus depend on diffusion coefficient &time of contact .

20. Fracture theory : Analyze the force required to separate two surface after adhesion.The maximum tensile strength(σm ) produced during detachment can be determined This theory attempts to relete the difficulty of separation of two surfaces after adhesion . Adhesion Strength = (E ԑ/L )1/2 E =Young’s modulus of elasticity ԑ = Fracture energy L = Critical crack length when two surfaces are separated

21. Cohesive theory :proposes that the phenomena of bioadhesion are mainly due to the intermolecular interactions amongst like-molecules.
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. Surface roughness =d/h

22. Adsorption theory:
After initial contact of the material adhere to surface due to forces acting between the atoms in the two surfaces later result in formation of bonds(primary & secondary) due to the presence of intermolecular forces.
hydrogen bonding and Van der Waal’s forces, for the adhesive interaction amongst the substrate surfaces.

23. The image below shows swelling of a polymer
Step 1
The wetting and swelling step occurs when the polymer spreads over the surface of the biological substrate or mucosal membrane in order to develop an intimate contact with the substrate.
Bioadhesives are able to adhere to or bond with biological tissues by the help of the surface tension and forces that exist at the site of adsorption or contact.
Swelling of polymers occur because the components within the polymers have an affinity for water.
The image below shows swelling of a polymer 23

24. Step 2
The surface of mucosal membranes are composed of high molecular weight polymers known as glycoproteins.
In step 2 of the bioadhesive bond formation, the bioadhesive polymer chains and the mucosal polymer chains intermingle and entangle to form semi permeable adhesive bonds. The strength of these bonds depends on the degree of penetration between the two polymer groups.
In order to form strong adhesive bonds, one polymer group must be soluble in the other and both polymer types must be of similar chemical structure.
The interpenetration of polymer chains
Bioadhesive
polymer chains
Mucus

25. Step 3
This step involves the formation of weak chemical bonds between the entangled polymer chains.
The types of bonding formed between the chains include primary bonds such as covalent bonds and weaker secondary interactions such as van der Waals Interactions and hydrogen bonds.
Both primary and secondary bonds are exploited in the manufacture of bioadhesive formulations in which strong adhesions between polymers are formed.
Mechanisms of bioadhesion 25

26. Factor affecting Mucoadhesion
A)Polymer related :-
1)molecular weight –up to and beyond this there is not much effective .
2)Concentration of active polymer –optimum not too high that significantly drops strength.
3)Flexibility of polymer chain –
4)spatial conformation –
B)Environmental related :-
1)PH
2)Applied strength – increase up to optimum level
3)Initial contact time
4)swelling –too greater decrease the adhesion
5)mucus compossion
C)Physiological factors :-
1)Mucin turn over
5)Diseased state

27. Types of intecraction Involved
Physical And Mechanical.
Secondary chemical bond.
Ionic,primary or covalent chemical bonds

28. Classification of Bio(Muco)adhesive polymers
A )Based on Specificity :-
The specific bioadhesive polymers
Are the ability to adhere to specific chemical structures within the biological molecules
e.g. lectins, fimbrin
2) The nonspecific bioadhesive polymers
Are the ability to bind with both the cell surfaces and the mucosal layer.
e.g.polyacrylic acid, cyanoacrylates

29. (I) Synthetic polymers:
B ) Based on Origen
(I) Synthetic polymers:
(a) Cellulose derivatives:-methylcellulose, ethylcellulose, hydroxy-ethylcellulose, Hydroxyl propyl cellulose, hydroxy propyl methylcellulose, sodium carboxy methylcellulose.
(b) Poly (acrylic acid) polymers (carbomers, Polycarbophil, poly(methylacrylate).
(c) Poly (hydroxyethyl methylacrylate).
(d) Poly (ethylene oxide).
(e) Poly (vinyl pyrrolidone).
(f ) Poly (vinyl alcohol).
(II) Natural polymers:
Tragacanth ,Sodium alginate, Karaya gum,
Guar gum ,Xanthan gum ,Lectin ,Soluble starch,
Gelatin, Pectin, Chitosan , Hyaluronic acid .

30. Relative mucoadhesive performance of some polymers :-
Relative mucoadhesive force
Quality of bioadhesion
CMC
193
Excellent
Carbopol
185
Tragacanth
154
Sod. alginate
126
HPMC
125
Gelatin
116
fair
Pectin
100
Poor
Acacia 98
Providone

31. Molecular properties of mucoadhesive :-
1. Strong hydrogen bonding groups (-OH, -COOH).
2. Strong anionic charges.(cellulose derivatives) but some cationic (e.g., Chitosan)
3. Sufficient flexibility to penetrate the mucus network or
tissue crevices.
4. Surface tension characteristics suitable for wetting mucus/ mucosal tissue surface.
5. High molecular weight. 31

32. Characteristics of Bioadhesive polymers
1)Flexibility- important because it controls the extent of the interpenetration between the polymers and mucosal/epithelial surfaces.
2)Hydrophilicity – Polymers that are hydrophilic in nature are able to form strong adhesive bonds with mucosal membranes because the mucus layer contains large amounts of water.
3)Hydrogen bonding – Hydrogen bonding between the entangled polymer chains forms strong adhesive bonds, therefore the presence of hydrogen bond – forming groups such as OH and COOH groups are vital in large quantities.
4)High molecular weight – Polymers with a high molecular weight are desirable because they provide more bonding sites.
5)Surface tensions – Surface tensions are needed to spread the bioadhesive polymer into the mucosal layer epithelial surface. 32

33. Characteristics of an ideal mucoadhesive polymer
1. The polymer and its degradation products should be
nontoxic and should be nonabsorable from the
gastrointestinal tract.
2. It should be nonirritant & non abrasive to the mucous membrane.
3. It should preferably form a strong noncovalent bond with the mucin-epithelial cell surfaces.
4. It should adhere quickly to most tissue and should possess some site-specificity. 33

34. 8.It should get Wash out at desired period.
Continued…
5. It should allow easy incorporation to the drug and offer no hindrance to its release.
6. The polymer must not decompose on storage or during the shelf life of the dosage form.
7. The cost of polymer should not be high so that the prepared dosage form remains competitive.
8.It should get Wash out at desired period.
9.The mucoadhesive should be with high drug-loading capability. 34

35. Types of Bioadhesive Formulations
1.Solid Bioadhesive Formulations :-Tablets , Inserts ,Powders, tapes
2. Semi-solid bioadhesive Formulations:- Gels , Films, solutions,
aerosol sprays
3.Liquid Bioadhesive Formulations:- Viscous liquids ,
Gel-forming liquids 35

36. Oral Bioadhesive Formulations
Oral bioadhesive formulations are topical products designed to deliver drugs to the oral cavity which act by adhering to the oral mucosa and therefore produce localised effects within the mouth
The oral cavity
Important functions which include chewing, speaking and tasting. Some of these functions are impaired by diseases such as ulcers, microbial infections and inflammation. 36

37. In contact with saliva Dosage form become adhesive and render system attached to mucosa
Drug solution rapidly absorbed throug the the reticulated vein which is underneath the oral mucosa & transported through facial vein ,internal jugular vein ,Brachiocephalic vein .
Rapid absorption –peak 1to 2 min
Some of the common conditions - Mouth ulcers , Oral thrush,
Gingivitis.

38. A ) The Buccal Mucosa
The buccal mucosa refers to the inner lining of the lips and cheeks.
The epithelium of the buccal mucosa is about cells thick
The buccal mucosa is less preferable compared to other oral drug delivery systems because of vary short transit time.
The bioadhesive polymers can retention of a dosage form by spreading it over the absorption site. 38

39. B ). The sublingual mucosa
The sublingual mucosa surrounds
the sublingual gland which is a
mucin-producing salivary gland
located underneath the tongue.
Examples :- Glyceryl Trinitrate (GTN) (aerosol spray and tablet in prophylactic treatment of angina.)
Brand name:-Susadrin ,Nitrogard. 39

40. 3 ) The Gingival Mucosa Hardest muscle of body Can retain dosage form
for long duration

41. TECHNIQUES FOR EVALUATING BIOADHESIVE PROPERTIES

42. Techniques utilizing gut sac of rats
A segment of intestinal tissue is removed from the rat, everted, and one of its ends sutured and filled with saline. The sacs are introduced into tubes containing the system under analysis at known concentrations, stirred, incubated and then removed. The percent adhesion rate of the release system onto the sac is determined by subtracting the residual mass from the initial mass

43. Tests measuring mucoadhesive strength

44. Rupture tensile strength
Generally, the equipment used is a texture analyzer or a universal testing machine. In this test, 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 membrane, generally porcine nasal mucus or intestinal mucus from rats.

45. Shear strength.
This test measures the force required to separate two parallel glass slides covered with the polymer and with a mucus film (Bruschi, Freitas, 2005; Chowdary, Rao, 2004). This can also be done using Wilhemy’s model.
In which a glass plate is suspended by a microforce balance and immersed in a sample of mucus under controlled temperature. The force required to pull the plate out of the sample is then measured under constant experimental conditions

46. Wilhemy’s plate technique, or the microforce balance technique, can also be modified in order to measure the specific adhesion force of microparticles (Chowdary, Rao, 2004; Hägerström, 2003). This involves the use of a microtensiometer and a microforce balance (Figure 10) and is specific, yielding both contact angle and surface tension. The mucous membrane is placed in a small mobile chamber with both pH and physiological temperature controlled. A unique microsphere is attached by a thread to the stationary microbalance. The chamber with the mucous membrane is raised until it comes into contact with the microsphere and, after contact time, is lowered back to the initial position

47. Shear stress measurement:The
shear stress technique measures the force that causes a mucoadhesive to slide with respect to the mucous layer in a direction parallel to their plane of contact .
Adhesion tests based on the shear stress measurement involve two glass slides coated with polymer and a film of mucus.
Mucus forms a thin film between the two polymer coated slides, and the test measures the force required to separate the two surfaces

48. Rheological methods
From this test, it is possible to obtain the mucoadhesion force by monitoring the viscosimetric changes of the system constituted by the mixture of the polymer chosen and mucin. The energy of the physical and chemical bonds of the mucin-polymer interaction can be transformed into mechanical energy or work. This work, which causes the rearrangements of the macromolecules, is the basis of the change in viscosity

49. Tests analyzing molecular interactions involved in mucoadhesion
The general problem arising from methods that show the adhesion force and from the rheological methods is that the mucoadhesive response is seen macroscopically while the interactions occur at a microscopic level.
The use of low frequency dielectric spectroscopy represents an attempt to study gel-mucus interactions near the molecular level. It evaluates the possible physicochemical interactions between molecules and glycoproteins of the mucus at the interface, which is considered the step preceding the formation of bonds during the mucoadhesion process.

50. INVIVO TECHNIQUES
GI transit using radio-opaque technique:It involves the use of radio-opaque markers, e.g., barium sulfate, encapsulated in bioadhesive DDS to determine the effects of bioadhesive polymers on GI transit time.
Faeces collection (using an automated faeces collection machine) and x-ray inspection provide a non-invasive method of monitoring total GI residence time without affecting normal GI motility.
Mucoadhesives labelled with Cr-51, Tc-99m, In-113m, or I-123 have been used to study the transit of the DDS in the GI tract .
Gamma scintigraphy technique:It is a valuable tool used in the development of pharmaceutical dosage forms.
With this methodology, it is possible to obtain information non-invasively.

51. This technique gives information in terms of:
oral dosage forms across the different regions of GI tract
the time and site of disintegration of dosage forms
the site of drug absorption
also the effect of food
disease
size of the dosage form on the in vivo performance of the dosage forms.

52. Conclusion
Mucoadhesive dosage forms have a high potential of being useful means of delivering drugs to the body.Current use of mucoadhesive polymers to increase contact time for a wide variety of drugs and routes of administration has shown dramatic improvement in both specific therapies and more general patient compliance. The general properties of these polymers for purpose of sustained release of chemicals are marginal in being able to accommodate a wide range of physicochemical drug properties. Hence mucoadhesive polymers can be used as means of improving drug delivery through different routes like gastrointestinal, nasal, ocular, buccal, vaginal and rectal . 52

53. Reference
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,Marcel Dekker’s Pg .No
2)Yie W. Chaine ,NDDS ,Informa Healthcare USA-2009 ,2nd edition ,pg no
3) S. B. Patil*, R. S. R. Murthy, H. S. Mahajan, R. D. Wagh, S. G. Gattani**,” Mucoadhesive polymers: Means of improving drug delivery” Pharma Times - Vol 38 - No. 4 - April 2006,pg no
4) D r s B h a s k a r a J a s t i , X i a o l i n g L i and G a r y C l e a r y,” Recent Advances in Mucoadhesive Drug Delivery Systems” B U S I N E S S B R I E F I N G : P H A R M A T E C H ,pg no
5) S.E. Harding ,” Mucoadhesive interactions” Biochemical Society Transactions (2003) Volume 31, part 5,pg no
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Polymers in Mucoadhesive Drug Delivery System: A Brief Note “esigned Monomers and polymers 12(2009),pg no
7)Pharmainfonet.com Prof. G.S. Asane “Mucoahhesive anGI DDS ,Vol 5,issu 06,2007. 53

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