Mucosal Drug Delivery System 6d1m7

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 WITH INTESTINAL CELLS. • AVOID FIRST 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: • STAGE: the

•

between the mucoadhesive and the mucous membrane, with spreading and swelling of the formulation, initiating its deep 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 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 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

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 ԑ/L )1/2 E =Young’s modulus of elasticity ԑ = Fracture energy

Adsorption theory: After initial 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 Waal’s 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 ISTRATION. 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. IT’S ORAL BIOAVAILABILITY IS 40% DUE TO EXTENSIVE FIRST 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 PEG400), 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 KORSMEYER–PEPPAS 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 90–100%).

• 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- 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//PHP/S/260_PDF.PDF

• HTTP://WWW.SCIELO.BR/PDF/BJPS/V46N1/02.PDF • HTTP://WWW.IJABPT.COM/PDF/50072-II-AMIT%20ALEXANDER[1].PDF • HTTP://WWW.IJRAP.NET//PHP/S/564_PDF.PDF

• HTTP://WWW.IJPMBS.COM/FILE/2015/0412/20150412031556858.PDF • FILE:///C:/S/DEBJANI/S/1-S2.0-S1319016411000612-MAIN.PDF

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