Mucoadhesive drug delivery system

MUCOADHESIVE OR BUCCAL DELIVERY SYSTEM

1. Mucoadhesive drug delivery system 10/22/2012 Seminar 1 ABDUL MUHEEM M.PHARM (PHARMACEUTICS) JAMIA HAMDARD Dr.Zeenat Iqbal Dr.sushama Talegaonkar Dr.Yasmin Sultana FACULTY OF PHARMACY JAMIA HAMDARD NEW DELHI

2. 10/22/2012 Seminar 2 What is Mucoadhesive drug delivery system? Mucoadhesive drug delivery system interact with the mucus layer covering the mucosal e pithelial surface, & mucin molecules & increase t he residence time of the dosage form at the s ite of the absorption. Mucoadhesive drug delivery system is a part of controlled delivery system.

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 complaince . MDDS have been devloped 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. 10/22/2012 Seminar 3

4. Why are we using Mucoadhesive drug delivery system(MDDS)? MDDS prolng 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 cause irritation. High drug loading capacity. Controlled drug release(preferably unidirectional release). 10/22/2012 Seminar 4

5. 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

6. 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 & presense of dosage form at the site of absorption. Excellent accessibility. Painless administration. Low enzymatic activity & avoid of first pass metabolism. 10/22/2012 Seminar 6

7. DISADVANNTAGES- If MDDS are adhere too tightlgy because it is undesirable to exert too much force to remove the formulation after use,otherwise the mucosa could be injured. Some patient suffers unpleasent 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. 10/22/2012 Seminar 7

8. Oral cavity: anatomic and physiologic features The oral mucosa presents a surface area of about 100 cm2. Three different types of oral mucosa- 1-Masticatory mucosa- 25% of the total oral mucosa & covers the gingiva and the hard palate. 2-Lining mucosa- (60% of the total oral mucosa) & covers the lips, cheeks, soft palate, lower surface of the tongue and the floor of the oral cavity. 3-The specialized mucosa- (15% of the total oral mucosa) is found on the dorsum of the tongue 10/22/2012 Seminar 8

9. Buccal epithelium- The buccal epithelium is non-keratinized and composed of multiple layers of cells which show different patterns of maturation between the deepest cells and the surface. An intracellular lipid portion is packaged in small organelles called membrane coating granules or lamellar granules. Granules migrate to the apical surface of the cell where their membrane fuse with the cell membrane,&lipid content is extruded in the extracellular space. The buccal epithelium is lacking in tight junctions, common to intestinal and nasal mucosae , and it is endowed with gap junctions, desmosomes and hemidesmosomes , which are loose intercellular links. 10/22/2012 Seminar 9

10. 10/22/2012 Seminar 10 Structure of the mucosa of the oral cavity: 1) mucus layer; 2) epithelium; 3) connective tissue (lamina propria ); 4) smooth muscle layer

11. COMPOSITION OF MUCUS LAYER : ‘Mucus is translucent and viscid secretion which forms a thin continuous gel adherent to mucosal epithelial surface.’ Water - 95% Glycoprotein and lipids - 0.5-5% Mineral salts - 1% Free proteins - 0.5-1%

12. MUCOADHESION THEORY Electronic theory Electronic theory is based on the premise that both mucoadhesive and biological materials possess opposing electrical charges. Thus, when both materials come into contact, they transfer electrons leading to the building of a double electronic layer at the interface, where the within this electronic double layer determines the mucoadhesive strength.

13. Drug transport mechanism Two major routes-(1) Transcellular (Intracellular) (2) Paracellular (intercellular) The transcellular route involves the crossing of the cellular membranes with a polar and a lipid domain. The paracellular essentially implicates the passive diffusion through the extracellular lipid domain. To reach the systemic circulation ,drugs must also overcome an enzymatic barrier represented by the enzymes that are present on the mucosal surface & mucosa. Aminopeptidase,carboxypeptidase & estrase were found in homogenates of human epithelial cell culture. 10/22/2012 Seminar 13

14. Mechanism of Mucoadhesion - Generally divided into two steps- (a)contact stage (b)consolidation stage first is characterized by the contact b/w the mucoadhesive &the mucus membrane ,with spreading & swelling of the formulation, initiating its deep contact with mucus layer. In step (b)the mucoadhesive material are activated by the presence of moisture 10/22/2012 Seminar 14

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16. Formulation design- In case of both mucosal(local) & transmucosal (systemic) adm ., conventional dosage are not able to assure therapeutic level. In MDDS contain the following functional agents- Mucoadhesive agents Penetration enhencers Enzyme inhibitors Mucoadhesive agents- the polymer hydration & consequently the mucus cohesive properties that promote mucoadhesion . Swelling should favour polymer chain flexibility & interpenetration b/w polymer & mucin chains. 10/22/2012 Seminar 16

17. Ex- Polyacrylic acid (PAA) Polyvinyl alcholal (PVA) Sodium carboxymethylcelluose ( NaCMC ) Sodium alginate HPMC HEC HPC Various copolymer of acrylic acid suchas acrylic acid –polyethylene glycol monomethyl ether copolymer have also been studied. Penetration enhancers(PE)- PE are also required when a drug has to reach the systemic circulation to exert its action . Must be non-irritant &have a reversible effect. 10/22/2012 Seminar 17

18. Recently chitosan & its derivatives, polymers already known for MA properties.chitosan help transportion of drug throw paracellular pathway. List of Permeation Enhancer :- Benzalkonium chloride Dextran sulfate Fatty acid Propyleneglycol Menthol Phosphatidylcholine Polysorbate 80 Sodium EDTA 10/22/2012 Seminar 18

19. Enzyme inhibitors- Drug +enzyme inhibitors---->improving the buccal absorption of drugs,particulary peptides. Ex-1-Aprotinin 2 - Bestatin 3-Puromycin bile salts stabilise protein drugs by different mechanism(effecting the activity of the enzymes,altering the conformation of the protein. Chemical modification of chitosan with EDTA produces polymer conjugate chitosan –EDTA that is a very potent inhibitor of metallopeptidases ( carboxypeptidase ) 10/22/2012 Seminar 19

20. FACTORS AFFECTING MUCOADHESION- 1-Mol. Wt.- Mucoadhesive is increase with mol wt above 100,000. 2-Flexibility- Mucoadhesive starts with the diffusion of the polymer chains in the interfacial region. Polymer chains contain a substantial degree of flexibility in order to achieve the desried entanglement with mucus. 3-cross linked density- increse the density of cross linked insufficient of swellingdecrease rate of interpenetration b/w polymer & mucin . 4-hydrogen bonding capacity- desired polymer must have functional grps that are able to form hydrogen bonds & flexibility of the polymer is improve this hydrogen bonding potential. 10/22/2012 Seminar 21

21. 4-Hydration- polymer swelling permits a mechanical entanglement by exposing the bioadhesive sites for hyrogen bonding/ electrostatic interaction b/w polymer &mucus network.eg-HMA,PVA. 5-Concentration- when conc.of the polymer is low ,the number of penetrating polymer chains per unit volume of mucus is small & interaction b/w polymer &mucus is unstable. In general the more concentrated polymer would result in longer penetrating chain length & better adhesion. 10/22/2012 Seminar 22

22. Higher conc.of polymer do not necessarily improve & ,in some cases, actually diminshed mucoadhesive properties. eg -high conc.of the flexible polymeric films based on polyvinyl pyrrolidone as film forming polymer did not further enhance the muco adhesive properties of the polymer. 10/22/2012 Seminar 23

23. Dosage form- most common formulation in MDDS are tablets & patches.various dosage which are given in below- (1)Matrix tablets (2)Patches (3)Films (4)Gels &ointments Matrix tablets-( a)Monolithic (b)two layered tablets In monolithic  mixture of drug+swelling bioadhesive polymer | bidirectional release & outer side coated with impermeable hyrophobic substances. 10/22/2012 Seminar 24

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25. In two layered matrix tablets- Comprises an inner layer based on bioadhesive polymer &an outer non- bioadhesive layer containing the drug for a bi-directional release but only local action . In case of systemic action outer layer is inert & act as a protective layer. Patches- Greater patient complaince compared with tablets owing to their physical flexibility that causes only minor discomfort to the patient. Ex- tyrotropin – releasinghormone (TRH) oxytocin,calcitonin etc. 10/22/2012 Seminar 26

26. Films- may be preferred over adhesive tablets in terms of flexibility &comfort. An ideal film should be flexible,elastic &soft, without breaking due to stress from mouth movements. Gels & ointments- adv.over other dosage form is that they are easily dispersion throughtout the mucosa. But accuracy of drug dosing may not be as accurate. Certain polymer are used such as NaCMC , xanthan,carbopol,hyaluronic acid . They change from liquid to semisolid. HPMC has been used as an adhesive ointment ingredients. 10/22/2012 Seminar 27

27. Dosage form structures Release Effect Active ingredient Matrix tablets Monolithic matrix Sustained/ bidire . Local/ systemic Local- metronidazole;systemic - propanolol , timolol Two-layer matrix Bi direct. Local As above mention Two-layer matrix coated with impermeable layer Monodirect . Local/systemic As above 10/22/2012 Seminar 28

28. Evaluation tests of muco-adhesive tablets Weight variation Friability Hardness Content uniformity Drug release study of Mucoadhesive tablets Swelling index Water sorption studies Mucoadhesive strength

29. CASE STUDY IN EUDRAGIT BASED MUCOADHESIVE BUCCAL PATCHES OF SALBUTAMOL SULFATE Salbutamol (B2 adrenergic receptor agonist ) is used for relief of bronchospasm in case of asthma & COPD. oral bioavailability is 40%(due to 1 st pass effect) ,so salbutamol patches were prepared using Eudragit L-100,HPMC,PVA,& Carbopol934 in various proportions with PEG-400/PG as plasticizers. SS is usually is adm . via inhaled route for direct effect on bronchial smooth muscle,but also have some disadvantages like inaccuracy of dosing,patient complaince due to CFC,cost of the prepration &frequency of administration 10/22/2012 Seminar 30

30. SS Patches were prepared by solvent casting techniques. In which eudragit in ethanol,HPMC in ethanol:acetone mixture (3:1) & PVA in water 5ml of eudragit ,5ml of ethanol & 0.05% of tween 80 mixed well on magnetic stirrer at low rpm. In above mixture added 2ml of PG or PEG was added & mixed low rpm,drug soln must be bubble free. The soln was poured in teflon coated circular dish &hen dried in room temp.for 2hrs & further dried for 18hrs at 4O0C in hot air oven. The patches were laminated on one side with water permeable backing layer. 10/22/2012 Seminar 31

31. EVALUATION TESTS OF PATCHES Mass uniformity & thickness Drug content Swelling index Measurment of surface PH Residence time Bioadhesion test: By tensile strength, shear strength, Fluorescent probe method, Atomic force microscopy (AFM), falling liquid film method, Permeability study: Using different diffusion cells Release rate study: Using USP dissolution test using rotating paddle dissolution test apparatus.

32. CONCLUSION- The mucoadhesive drug delivery offers several advantages for controlled drug delivery. The mucosa is well supplied with both vascular and lymphatic drainage. Mucoadhesive drug delivery is a promising area for systemic delivery of orally inefficient drugs as well as an attractive alternative for noninvasive delivery of potent peptide and perhaps protein drug molecules. A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical properties of the drug and excipients . 10/22/2012 Seminar 33

33. THANK YOU Abdul Muheem