MUCOSAL DRUG DELIVERY

SYSTEM
SUBMITTED TO PRESENTED BY
V.B. POKHARKAR DEBJANI BAIDYA
HOD OF PHARMACEUTICS M.PHARM(2ND SEM)
 INDEX

INTRODUCTION
BIOLOGICAL MEMBRANE
STAGES
MECHANISM
THEORIES
BIOADHESIVE POLYMERS
RESEARCH ARTICLE
REFERENCES
 INTRODUCTION

ADHESION: THE MOLECULAR FORCE OF ATTRACTION BETWEEN UNLIKE BODIES.

BIOADHESION: WHEN ONE OF THE ADHERENTS IS OF BIOLOGICAL NATURE.
MUCOADHESIVE: WHEN THE BIOLOGICAL ADHERENT IS MUCOSAL SURFACE.
ADVANTAGES:
PROLONGED RESIDENCE TIME.
LOCALISATION OF THE DRUG DELIVERY SYSTEM
INCREASE N THE DRUG CONCENTRATION GRADIENT
DIRECT CONTACT WITH INTESTINAL CELLS.
AVOID FIRST PASS METABOLISM.
PREVENTION FROM ENZYMATIC DEGRADATION.
INCREASE BIOAVAILABILITY.
 BIOLOGICAL MEMBRANE

ALL BIOLOGICAL MEMBRANES ARE COVERED WITH THICK GEL LIKE STRUCTURE KNOWN AS
MUCIN.
IT POSSESSES CONSIDERABLE BINDING PROPERTIES.
MUCUS IS A NETWORK OF MUCIN GLYCOPROTEINS.
AT PHYSIOLOGICAL PH IT HAS NEGATIVE CHARGE DUE TO THE PRESENCE OF SIALIC
ACID(PKA_-2.6)
HIGHLY HYDRATED
CROSS LINKED
LINEAR AND FLEXIBLE
THICKNESS VARY FROM 50-450 MICROMETRE TO 1 MICROMETRE.
STAGES INVOLVED IN BIOADHESION:

CONTACT STAGE: the contact between the mucoadhesive and the mucous membrane,
with 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
 MECHANISM
The mechanisms responsible in the formation of bioadhesive bonds are not
fully known, however most research has described bioadhesive bond
formation as a three step process:-
STEP1: Wetting and swelling of polymer

STEP2: Interpenetration between the polymer chains and the mucosal

membrane.

STEP3: Formation of Chemical bonds between the entangled chains.

 THEORIES OF BIOADHESION

(A) THE ELECTRONIC THEORY

(B) THE WETTING THEORY
(C) THE ADSORPTION THEORY
(D) THE DIFFUSION THEORY
(E) FRACTURE THEORY
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.
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.
Diffusion theory: Diffusion theory describes that polymeric chains from the bioadhesive
interpenetrate into glycoprotein mucin chains and reach a sufficient depth within the opposite
matrix to allow formation of a semi permanent bond.
The existence of concentration gradients will drive the polymer chains of the bioadhesive into
the mucus network and the glycoprotein mucin chains into the bioadhesive matrix until an
equilibrium penetration depth is achieved .
The extent depth to which the polymer chain penetrate the mucus depend on diffusion
coefficient &time of contact
Fracture theory : This theory describes the force required for the separation
of two surfaces after adhesion. This theory is useful for the study of bioadhesion by
tensile apparatus.
Adhesion Strength = (E /L )1/2
E =Youngs modulus of elasticity
= Fracture energy
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 i.e.
hydrogen bonding and Van der Waals forces, for the adhesive interaction amongst
the substrate surfaces.
Oral mucosa:
The oral mucosa is composed of an outermost layer of stratified squamous
epithelium (about 40-50 cell layers thick), a lamina propria followed by the submucosa as the innermost
layer
Components of Buccal Bioadhesive Drug Delivery System
 Mucoadhesive drug delivery system in Nasal cavity

By mixing drugs targeted for the nose with bioadhesive

polymers, the process of mucociliary clearance of the
drug can be overcome. The effects of bioadhesive
polymers on mucociliary clearance was examined by
Zhou and Donovan (1996)
 The Vagina

The vagina is the lower part of the female reproductive tract. It is a muscular tube lined with mucous
membrane which is covered with a layer of stratified squamous epithelium with an underlying layer of
connective tissue (lamina propria) .
 Vaginal Mucoadhesive Formulations:

The intravaginal route has been used to deliver contraceptives as well as anti-infective agents such as
antifungal drugs to exert a local effect

Agents targeted for the vaginal route have been formulated into various dosage forms including creams,
gels and vaginal tablets.

Bioadhesive polymers are incorporated into vaginal formulations to aid the adhering of the dosage form to
its target site
 Rectal Mucoadhesive Formulation :

Bioadhesive polymers are incorporated into rectal suppositories to prolong the

retention of the active drug in the rectum. Prolonged retention in the rectum
increases the chances of reaching a therapeutic outcome.

Examples of Products
Anacal Is a rectal ointment used to relieve the symptoms associated with hemorrhoids. It contains the
bioadhesive agent polyethylene high polymer 1500.

Germoloids Is a rectal ointment used to relief the pain, swelling, itchiness and irritation associated with
hemorrhoids. It contains the polymer propylene glycol.
 Bioadhesive Polymer
Characteristic of Bioadhesive polymer:
Flexibility- The flexibility of bioadhesive polymers is important because it controls the
extent of the interpenetration between the polymers and mucosal/epithelial surfaces.

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.

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.

High molecular weight Polymers with a high molecular weight are desirable because
they provide more available bonding sites.
Degree of cross linking- it influences chain mobility and resistance to dissolution
Long chain polymers-chain length must be long enough to promote the
interpenetration and it should not be too long that diffusion becomes a problem
Concentration of the polymer-an optimum concentration is required to promote
the muco adhesive strength. It depends however, on the dosage form.
Charge and degree of ionization-mucoadhesive strength can be attributed as
anion>cation>non-ionic
Optimum hydration- excessive hydration leads to decreased mucoadhesive
strength due to formation of a slippery mucilage.

Optimum pH mucoadhesion is optimum at low pH conditions but at higher Ph.

change in the conformation occurs into a rod like structure making them more
available for inter diffusion and interpenetration.
Natural:-A) Protein based polymers: collagen, albumin, gelatin
B) Polysaccharides: Alginates, Cyclodextrines, Chitosan, Dextran, Agarose,
Hyaluronic acid, Starch, Cellulose

Synthetic:
I) Biodegradable polymers
A) Polyesters: Polylactic acid, Polyglycolic acid, Polyhydroxyl butyrate,
Polycaprolactone, Poly Doxanones
B) Polyanhydride: Polyadipic acid,Polyterphthalicacid,Polysebacic acid and Various
copolymers
C) Polyamides: Poly iminocarbonates, Poly amino acids.
D) Phosphorous Based polymers: Polyphosphates, Polyphosphonates,
Polyphosphazenes.
E) Others: Poly cyanoacrylates, Poly urethanes, Poly ortho esters, Polyacetals.
II) Non biodegradable polymers
A)Cellulose derivatives: Carboxymethylcellulose, Ethyl cellulose, Cellulose acetate
HPMC.
B) Silicones: Polydimethyl siloxanes, Colloidal silica, Polymethacrylates
C) Others: PVP, EVA, Poloxamines

Thiolated Polymers*
Derived from hydrophilic polymers such as chitosan
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

Polyox WSRA: Class of high molecular weight polyethylene molecular weight

polyethylene oxide homo polymers
 KING SAUD UNIVERSITY
SAUDI PHARMACEUTICAL JOURNAL
WWW.KSU.EDU.SA
WWW.SCIENCEDIRECT.COM
DEVELOPMENT AND CHARACTERIZATION OF EUDRAGIT BASED MUCOADHESIVE
BUCCAL PATCHES OF SALBUTAMOL SULPHATE

PRASANTH VISWANADHAN VASANTHA (A) , AYARIVAN PURATCHIKODY (B), *, SAM THOMARAYIL

MATHEW (C) , ASHOK KUMAR BALARAMAN (D)
(A) DEPARTMENT OF PHARMACEUTICS, GAUTHAM COLLEGE OF PHARMACY, SULTANPALYA, BANGALORE
560 032, KARNATAKA, INDIA
(B) DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY AND DIRECTOR ACADEMIC COURSES, ANNA
UNIVERSITY OF TECHNOLOGY, TIRUCHIRAPPALLI 620 024, TAMILNADU, INDIA
(C) ACCENTURE PHARMACEUTICAL SERVICES, BANGALORE 560 072, KARNATAKA, INDIA
(D) DEPARTMENT OF PHARMACEUTICAL CHEMISTRY, JADAVPUR UNIVERSITY, KOLKATA 700 032, INDIA
 ABSTRACT
FOR SYSTEMIC DRUG DELIVERY, THE BUCCAL REGION OFFERS AN ATTRACTIVE ROUTE OF DRUG ADMINISTRATION. SALBUTAMOL
SULPHATE IS A SHORT-ACTING B2-ADRENERGIC RECEPTOR AGONIST USED FOR THE RELIEF OF BRONCHOSPASM IN CONDITIONS
SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. ITS ORAL BIOAVAILABILITY IS 40% DUE TO EXTENSIVE FIRST
PASS METABOLISM. SALBUTAMOL SULPHATE PATCHES WERE PREPARED USING EUDRAGIT L-100, HPMC, PVA AND CARBOPOL 934 IN
VARIOUS PROPORTIONS AND COMBINATIONS USING PEG-400/PG AS PLASTICIZERS. PATCHES WERE LAMINATED ON ONE SIDE
WITH A WATER IMPERMEABLE BACKING LAYER FOR UNIDIRECTIONAL DRUG RELEASE. THE THICKNESS OF MEDICATED PATCHES WERE
RANGED BETWEEN 0.23 0.008 AND 0.59 0.007 MM AND MASS VARIED BETWEEN 65.23 3.3 AND 117.92 4.2 MG.
PATCHES SHOWED AN INCREASE IN MASS AND SWELLING INDEX WITH PEG-400 WHEN COMPARED WITH PG. THE SURFACE-PH OF
PATCHES RANGED BETWEEN 6 AND 7. FORMULATIONS E7 (7.5 ML EUDRAGIT L-100, 15 ML HPMC K4M, 7.5 ML PVA AND 2 ML PEG-
400), E12 (7.5 ML EUDRAGIT L-100, 7.5 ML PVA, 15 ML CARBOPOL AND 2 ML PEG-400), F7 (7.5 ML EUDRAGIT L-100, 15 ML HPMC
K4M, 7.5 ML PVA AND 2 ML PG), AND F12 (7.5 ML EUDRAGIT L-100, 7.5 ML PVA, 15 ML CARBOPOL AND 2 ML PG) SHOWED HIGH
FOLDING ENDURANCE. RESIDENCE TIME OF THE TESTED PATCHES RANGED BETWEEN 101 AND 110 MIN. THE MAXIMUM IN VITRO
RELEASE WAS FOUND TO BE 99.93% OVER A PERIOD OF 120 MIN FOR FORMULATION F12. DATA OF IN VITRO RELEASE FROM
PATCHES WERE FITTED TO DIFFERENT KINETIC MODELS SUCH AS HIGUCHI AND KORSMEYERPEPPAS MODELS TO EXPLAIN THE
RELEASE PROFILE. FORMULATIONS E7 AND F7 WERE BEST FITTED TO THE NON-FICKIAN, WHERE AS FORMULATIONS E12 AND F12
SHOWED FICKIAN/ANOMALOUS DRUG RELEASE. STABILITY STUDIES INDICATED THAT THERE WAS NO CHANGE IN THE CHEMICAL
AND PHYSICAL CHARACTERISTICS DURING THE TEST PERIOD.
 MATERIALS
SALBUTAMOL SULPHATE
HPMC
PVP
CARBOPOL
EUDRAJIT L-100 (POLYMER)
AGAR
METHANOL (SOLVENT)
SODIUM SACCARINATE
SODIUM HYDROXIDE
POTASIUM DIHYDROGEN PHOSPHATE
POLYETHELENE GLYCOL (PLASTICIZER)
PROPYLENE GLYCOL (PLASTICIZER)
TWEEN-80 (SURFACTANT)
BIAXIALLY-ORIENTED POLYPROPYLENE (BAKING MEMBRANE)
PIG BUCCAL MUCOSA
 METHOD
FORMULATION OF MUCOADHESIVE BUCCAL PATCHES BY SOLVENT CASTING TECHNIQUE.
EUDRAGIT L-100 (95%) WAS DISSOLVED IN ETHANOL, HPMC IN ETHANOL: ACETONE MIXTURE (3:1 V/V) AND, PVA IN WATER.
TO 5 ML OF EUDRAGIT DISPERSION (95%), 5 ML OF ETHANOL AND 0.05% OF TWEEN 80 WERE ADDED AND MIXED WELL ON A
MAGNETIC STIRRER
TO THE ABOVE SOLUTION KNOWN QUANTITIES OF PVA (2% M/V) AND HPMC (5% M/V) OR CARBOPOL (1% M/V) WERE
ADDED AND MIXED THOROUGHLY.
TO THIS MIXTURE, 2 ML OF PG OR PEG WAS ADDED AND MIXED WELL ON A MAGNETIC STIRRER, AT LOW RPM, FOR A PERIOD
OF 1 H TO GET A HOMOGENOUS CLEAR, BUBBLE FREE SOLUTION.
TO THIS MIXTURE, A DRUG SOLUTION CORRESPONDING TO 230.4 MG WAS ADDED AND MIXED THOROUGHLY TO OBTAIN
UNIFORM DISTRIBUTION OF THE DRUG.
THIS SOLUTION WAS THEN POURED INTO A SPECIALLY FABRICATED TEFLON COATED CIRCULAR DISH (9.6 CM DIAMETER).
PATCHES WERE THEN DRIED AT ROOM TEMPERATURE FOR 2 H AND WERE FURTHER DRIED FOR 18 H AT 40 C IN A HOT AIR
OVEN. FINALLY, THE PATCHES WERE VACUUM DRIED FOR 4 H AT ROOM TEMPERATURE IN A VACUUM DESICCATOR.
CUT INTO 2 CM DIAMETER PATCHES USING A SPECIALLY FABRICATED CIRCULAR STAINLESS STEEL CUTTER. THE PATCHES WERE
LAMINATED ON ONE SIDE WITH A WATER IMPERMEABLE BACKING LAYER (PIDILITE BOPP FILM).
 EVALUATION OF PATCHES

MASS UNIFORMITY, THICKNESS, AND FOLDING ENDURANCE

DRUG CONTENT
MEASUREMENT OF SURFACE PH.
SWELLING STUDIES.
RESIDENCE TIME
IN VITRO DRUG DISSOLUTION
IN VITRO DRUG PERMEATION
STABILITY STUDIES
 RESULTS AND DISCUSSION

THE PREPARED PATCHES WERE SMOOTH, UNIFORM IN THICKNESS, MASS AND DRUG CONTENT. PATCHES
SHOWED NO VISIBLE CRACKS OR FOLDS.
THE THICKNESS OF THE MEDICATED PATCHES RANGED BETWEEN 0.23 0.008 AND 0.59 0.007 MM AND
THE MASS VARIED BETWEEN 65.23 3.3 AND 117.92 4.2 MG,
PATCHES WITH PEG-400 AS A PLASTICIZER SHOWED INCREASED MASS
THIS OBSERVATION COULD BE CORRELATED TO THE HIGH MOLECULAR WEIGHT OF PEG-400 WHEN COMPARED
TO PG
THE SURFACE PH OF THE PATCHES RANGED BETWEEN 6 AND 7 AND NO MUCOSAL IRRITATION WAS EXPECTED.
PATCHES SHOWED FAVOURABLE DRUG LOADING WHICH VARIED BETWEEN 9.0 0.3 AND 10.05 0.82
MG/2 CM2 PATCHES (I.E. DRUG LOADING EFFICACY OF 90100%).
ALL THE PATCHES HAD SATISFACTORY FOLDING ENDURANCE OF >240. FORMULATIONS E7, E12, F7 AND F12
SHOWED HIGH FOLDING ENDURANCE OF OVER 300, AND HENCE WERE SELECTED FOR FURTHER EVALUATION
AND CHARACTERIZATION.
Swelling behaviour of selected SS patches. Values
presented as mean SD, n = 3.

The swelling indices of the selected patches were in the following

order E12 > E7 > F12 > F7
 The residence time of the tested patches
ranged between 101 and 110 min.

none of the patches were detached from

the mucosal membrane over the study
period, which indicated that the
bioadhesion of all patches was
satisfactory to retain the patch on the
buccal mucosa

Ex vivo mucoadhesion time. Values presented

as mean SD, n = 3.
 CONCLUSION

NOVEL MUCOADHESIVE BUCCAL PATCHES OF SS WITH UNIDIRECTIONAL DRUG

DELIVERY WERE DEVELOPED TO OVERCOME THE FIRST-PASS METABOLISM
AND SUBSEQUENT LOW BIOAVAILABILITY OF THE DRUG. THE IN VITRO STUDIES
HAVE SHOWN THAT THIS IS A POTENTIAL DRUG DELIVERY SYSTEM FOR SS
WITH CONSIDERABLY GOOD STABILITY AND RELEASE PROFILE.
 REFERANCES

HTTP://WWW.NOTTINGHAM.AC.UK/NCMH/HARDING_PDFS/PAPER143.PDF
HTTP://WWW.IJRAP.NET/ADMIN/PHP/UPLOADS/260_PDF.PDF
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HTTP://WWW.IJABPT.COM/PDF/50072-II-AMIT%20ALEXANDER[1].PDF
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THANK
YOU