Mucoadhesive Drug Delivery Systems

1. Mucoadhesive Drug Delivery Systems Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. Cell No: 00919742431000 E-mail: nanjwadebk@gmail.com KLE College of Pharmacy, Nipani.

2. CONTENTS • Introduction • Definition • Concepts • Advantages • Disadvantages • Structure of oral mucosa • Trans mucosal permeability • Mimosa membrane • Permeablity enhancers • In-vitro and in-vivo methods for buccal absorption • Nasal and Pulmonary drug delivery system and its applications KLE College of Pharmacy, Nipani.

3. INTRODUCTION • Noninvasive systemic administration .Placing a drug or drug delivery system in a particular region of body for extended period of time • Local targeting / systemic drug delivery • Recent approaches : Bioadhesive polymers • Mucoadhesive dosage forms : Wet adhesives • Mucoadhesion is defined as the interaction between a mucin surface and a synthetic or natural polymer KLE College of Pharmacy, Nipani.

4. BUCCAL CAVITY SITESSublingual / Buccal site HISTORY KLE College of Pharmacy, Nipani.

5. Bioadhesion is the state in which two materials, (at least one of which is biological in nature), are held together for a extended period of time by interfacial forces. The term bioadhesion implies attachment of drug-carrier system to specific biological location. This biological surface can be epithelial tissue or the mucous coat on the surface of tissue. If adhesive attachment is to mucous coat then phenomenon is referred as mucoadhesion. Concept of bioadhesion KLE College of Pharmacy, Nipani.

6. Concept of bioadhesion • These drug delivery system utilize property of bioadhesion of certain water soluble polymers which become adhesive on hydration and hence can be used for targeting particular site. • Definition:- Buccal delivery is the administration of the drug via buccal mucosa (lining of the cheek) to the systemic circulation. KLE College of Pharmacy, Nipani.

7. Advantages • Ease of administration. • Termination of therapy is possible. • Permits localization of drug to the oral cavity for extended period of time. • Avoids first pass metabolism. • Significant reduction in dose can be achieved, thereby reducing dose dependent side effects. KLE College of Pharmacy, Nipani.

8. Advantages • It allows local modification of tissue permeability, inhibition of protease activity or reduction in immunogenic response, thus selective use of therapeutic agents like peptides proteins and ionized species can be achieved. • Drugs which are unstable in acidic environment of stomach or destroyed by the alkaline environment of intestine can be given by this route. • Drugs which show poor bioavailability by oral route can be administered by this route. KLE College of Pharmacy, Nipani.

9. Advantages • It follows passive diffusion, and does not require any activation. • The oral mucosa lacks prominent mucous secreting goblet cells and therefore there is no problem of diffusion limited mucous build up. • The presence of saliva ensures large amount of water for dissolution of drug unlike in case of rectal and transdermal route. • Drugs with short half life can be administered by this method. (2-8 hrs) Eg. Nitroglycerine ( 2 hrs) Isosorbide mononitrate ( 2-5 hrs) KLE College of Pharmacy, Nipani.

10. Advantages • From the formulation point of view a thin mucin film exist on the surface of oral cavity provides opportunity to retain delivery system in contact with mucosa for prolonged period of time with the help of mucoadhesive compounds. • The buccal membrane is sufficiently large to allow delivery system to be placed at different sites on the same membrane for different occasions, if the drug or other excepients cause reversible damage or irritate mucosa. KLE College of Pharmacy, Nipani.

11. DISADVANTAGES • Over hydration may lead to formation of slippery surface & structural integrity of the formulation may get disrupted by the swelling & hydration of the bioadhesive polymer. • Eating and drinking may become restricted • There is possibility that Patient may swallow the tablet • The drug contained in swallowed saliva follows the per oral route & advantages of buccal route is lost. • Only drug with small dose requirement can be administered. KLE College of Pharmacy, Nipani.

12. DISADVANTAGES • Drug which irritate mucosa or have a bitter or unpleasant taste or an obnoxious odour cannot be administered by this route • Drugs which are unstable at buccal pH cannot be administered by this route. • Only those drugs which are absorbed by passive diffusion can be administered by this route KLE College of Pharmacy, Nipani.

13. HUMAN MUCOSAE Physiological characteristic:- • Human nasal mucosa :-Ciliated columnar epithelium and squamous cutaneous epithelium • Human rectal mucosa :-Epithelium, lamina propria, double layer musclaris mocasae • Human vaginal mucosa :- Epithelium, lamina propria, tunica propria, muscularis mucosae, outer fibrous layer KLE College of Pharmacy, Nipani.

14. ANATOMY & PHYSIOLOGY OF ORAL MUCOSA The oral cavity is lined by thick dense & multilayered mucous membrane of highly vascularized nature. Drug penetrating into the membrane passes through net of capillaries & arteries and reaches the systemic circulation. There are mainly three functional zones of oral mucosa:- • Masticatory mucosa :- Covers gingiva/ hard palate regions, keratinized epithelium • Mucous secreting region :- Consist of soft palate, floor of mouth underside of tongue, labial & buccal mucosa. this region shows non-keratinized mucosa. • Specialized mucosa :- consist of lip border & dorsalsurface of tongue with high selective keratinization KLE College of Pharmacy, Nipani.

15. ORAL MUCOSA The oral mucosa consists of :- • Stratified squamous epithelium • Basement membrane • Lamina propria and submucosa • Epithelium :- • Measure 100 cm2 • Protective surface layer • Protective to deeper tissues Important feature of oral mucosa is rapid turnover of the cells(3 – 8 days) KLE College of Pharmacy, Nipani.

16. The average thickness of various regions of the human oral mucosa Epithelium • Basement membrane :-Boundary between basal layer (epithelium) & connective tissue (lamina propria & submucosa) • Submucosa layer :- • Adhesive interface • Mucus : Secreted by goblet cells / special endocrine glands • Connective tissue : Collagen, elastic fibers, cellular components. KLE College of Pharmacy, Nipani.

17. BIOCHEMICAL COMPOSITION • Protein :- Tonofilament (Keratinized & non – keratinised epithelia) • Little known about lipid composition • Keratinized oral epithelium :- Neutral lipids (ceramides) • Non – keratinized epithelium :- Few neutral but polar lipids (cholesterol sulphate & glucosylceramides) • Oral epithelial cell :- Carbohydrate , protein complexes • Role of matrix :- Cell – cell adhesion, lubricant allowing cells to move relative to one another KLE College of Pharmacy, Nipani.

18. SECRETION OF SALIVA • About 1.5 Liters of saliva is secreted daily • Chief secretions by : Parotid, sub maxillary, sublingual glands • Minor salivary glands are situated in buccal, palatal regions The presence of saliva is more important for:- • Drug dissolution • Drug permeation (across mucous membrane). KLE College of Pharmacy, Nipani.

19. VASCULAR SYSTEM OF THE ORAL MUCOSA Table:-Blood flow in the various regions of the oral mucosa • Vascular system have been described by Stablein & Meyer (1984) • Mucous membrane of buccal cavity is highly vascular • Blood supply to mouth : External carotid artery KLE College of Pharmacy, Nipani.

20. Function of oral mucosa. • Provide protection • Acts as a barrier • Provides adhesion • Keep the mucosal membrane moist REGIONAL DIFFERENCES IN MUCOSAL PERMEABILITY • Permeability : Intermediate between epidermis & intestinal mucosa • Galey (1976) estimated permeability of oral mucosa : sublingual > buccal > palatal • Pimlott & Addy (1985) measured the site dependent absorption of Isosorbidedinitrate tablets (Buccal, palatal, sublingual) • Palatal(keratnized), sublingual(thinner & immersed in saliva) KLE College of Pharmacy, Nipani.

21. TRANSPORT OF MATERIAL ACROSS THE ORAL MUCOSA (TRASMUCOSAL PERMEABILITY) • Passive mechanism • Intercellular spaces & cytoplasm (permeability barriers) • Cell membrane ( liphophillic ) FACTORS TO BE CONSIDERED IN THE TRANSMUCOSAL PERMEABILITY • Liphophilicity of drug • Salivary secretion • pH of saliva : Around 6 favours absorption • Binding to oral mucosa • Oral epithelium thickness There are two routes of drug transport :- • Paracellular • Transcellular KLE College of Pharmacy, Nipani.

22. PARACELLULAR ROUTE :- • Primary route for hydrophilic drugs • Intercellular spaces is the preferred route • Disadvantage : Limited surface area TRANSCELLULAR ROUTE :- • Route for lipophiollic compounds • Lipophillic drugs passes through lipid rich plasma membranes of the epithelial cells. MEMBRANE STORAGE DURING BUCCAL ABSORPTION Drug in lymphatic circulation Solid drug powder/ tablet Dissolved drug In buccal fluids Dissolved drug In buccal membrane Drug removed from oral by swallowing Drug in blood circulation KLE College of Pharmacy, Nipani.

23. Mechanism of bioadhesion The bioadhesion is mainly depends upon nature of bioadhesive. First stage involves an intimate contact between a bioadhesive & a membrane. second stage involves penetration of the bioadhesive into tissue. At physiological pH the mucous network may carry negative charge because of presence of sialic acid & sulfate residue & this high charge density due to negative charge contributes significantly to bioadhesion KLE College of Pharmacy, Nipani.

24. Impermeable membrane (1) Drug polymer layer (2) MECHANISM OF ABSORPTION FROM A MUCOADHESIVE BUCCAL DRUG DELIVERY SYSTEM Attachment Bypasses first pass metabolism DRUG RELEASE Mucoadhesive polymer layer (3) Internal jugular vein (1) Systemic circulation (2) Mucous membrane saliva action Results in swelling (1) (2) (3) KLE College of Pharmacy, Nipani.

25. IDEAL CANDIDATES FOR BUCCAL DRUG DELIVERY SYSTEMS • Molecular size 75 – 100 Daltons • Molecular weight 200 – 500 • Drugs should be hydrophilic / lipophilic in nature • Drug should be stable at buccal pH ( 6.4 – 7.2 ) • Drug should be odourless • Drugs which are absorbed only by passive diffusion should be used TYPES OF BUCCAL DRUG DELIVERY SYSTEMS KLE College of Pharmacy, Nipani.

26. Mimosa membrane It has been generally accepted that the biological membrane can be represented by the Fluid mosaic model. This model is proposed by Singer & Nicolson. Fluid mosaic model is two dimentional model, which depicts a biological membrane composed of a fluid state lipid bilayer embeded with globular integral proteins. The integral proteins are either embedded in a portion of lipoidal membrane or spanning throughout its entire thickness. KLE College of Pharmacy, Nipani.

27. Mimosa membrane The amphipathic protein molecules have been hypothesized to minimize the free energy required to for transmembrane permeation by maximizing both hydrophilic & lipophilic interaction in the membrane. it is visualized that ionic & polar portion of the protein molecule remain in contact with the aqueous environment on the membrane surface relatively nonpolar portions interact with the alkyl chains in the lipid bilayer KLE College of Pharmacy, Nipani.

28. Mimosa membrane The integral membrane protein may also exist as sub-unit aggregates, which span through entire thickness of the lipid bilayer to form a continuous water-filled channels. Thus the mucosa as a biological membrane may be considered as composed of lipid rich regions interrupted aqueous channel pores form by subunit aggregates of membrane proteins. KLE College of Pharmacy, Nipani.

29. Fluid mosaic model KLE College of Pharmacy, Nipani.

30. Fluid mosaic model KLE College of Pharmacy, Nipani.

31. FUTURE SCOPE • Management of illness • Peptide based pharmaceuticals • Among the non – oral routes available, i.e. the nasal, intraoral , vaginal & rectal. Major interested route is nasal mucosa (superior permeability) • Peptides drugs ( insulin, oxytocin, protirelin, a vasopressin analog) can effectively permeate the buccal mucosa KLE College of Pharmacy, Nipani.

32. FUTURE SCOPE Various strategies are are being employed to achieve oral absorption of Peptides:- • Manipulation of formulation • Maximizing retention of the delivery system • Alteration of peptide • Chemical & metabolic stability • Maintain balance between lipophilicity & hydrogen bonding potential KLE College of Pharmacy, Nipani.

33. CONCLUSION The buccal cavity provides a highly vascular mucous membrane site for administration of drugs. The main advantages of the buccal route of administration over the traditional routes are that drug degradation in the stomach is avoided, first pass metabolism is avoided & therapeutic drug levels of drug can be achieved rapidly KLE College of Pharmacy, Nipani.

34. Permeability Enhancers • These are the Substances added to pharmaceutical formulation in order to increase the membrane permeation rate or absorption rate of co-administered drug. • Categories of membrane permeation enhancers:- • Bile salts and there steroidal detergents- Sodium glycolate, sodium taurocholate, saponins, etc. KLE College of Pharmacy, Nipani.

35. Permeability Enhancers • Surfactants:- • Nonionic - Polysorbate 80,sucrose ester, etc. • Cationic - Cetyltrimethyl ammonium bromide. • Anionic - Sodium laurylsulfate,fatty acids. • Other enhancers:- • Azone, salisylates, chelating agents, sulfoxides. KLE College of Pharmacy, Nipani.

36. Example of permeability enhancers KLE College of Pharmacy, Nipani.

37. In Vitro Methods For Buccal Absorption • Animals are sacrificed immediately before the start of an experiment. • Buccal mucosa with underlying connective tissue is surgically removed from the oral cavity, the connective tissue is then carefully removed and the buccal mucosal membrane is isolated. KLE College of Pharmacy, Nipani.

38. In Vitro Methods For Buccal Absorption • The membranes are then placed and stored in ice-cold (4°c) buffers (usually Krebs buffer) until mounted between side-by-side diffusion cells for the in vitro permeation experiments. • Preservation of dissected tissue is important, which will directly affect the results and conclusion of the studies. KLE College of Pharmacy, Nipani.

39. In Vivo Methods for Buccal Absorption • In vivo methods were first originated by Beckett and Triggs with the so-called buccal absorption test. • Using this method, the kinetics of drug absorption were measured. KLE College of Pharmacy, Nipani.

40. In Vivo Methods for Buccal Absorption • The methodology involves the swirling of a 25 ml sample of the test solution for up to 15 minutes by human volunteers followed by the expulsion of the solution. • The amount of drug remaining in the expelled volume is then determined in order to assess the amount of drug absorbed. KLE College of Pharmacy, Nipani.

41. Other in vivo methods • It include those carried out using a small perfusion chamber attached to the upper lip of anesthetized dogs. • The perfusion chamber is attached to the tissue. KLE College of Pharmacy, Nipani.

42. Other in vivo methods • The drug solution is circulated through the device for a predetermined period of time. • Sample fractions are then collected from the perfusion chamber to determine the amount of drug remaining in the chamber and blood samples are drawn after 0 and 30 minutes to determine amount of drug absorbed across the mucosa. KLE College of Pharmacy, Nipani.

43. Other in vivo methods • In-vivo method involve use of animals like dog, cat, rabbit, hamster to determine the oral mucosal absorption characteristics of drugs. KLE College of Pharmacy, Nipani.

44. NASAL DRUG DELIVERY SYSTEM KLE College of Pharmacy, Nipani.

45. Anatomy of nose:- The nasal cavity consists of passage of a depth of approximately 12-14cm. The nasal passage runs from nasal vestibule to nasopharynx. INTRODUCTION KLE College of Pharmacy, Nipani.

46. INTRODUCTION • The lining is ciliated, highly vascular and rich in mucus gland. • Nasal secretions are secreted by goblet cells, nasal glands and transudate from plasma. • It contains sodium, potassium, calcium, albumin, enzymes like leucine,CYP450,Transaminase,etc. • The pH of nasal secretion is 5.5-6.5 in adults and 5.0-6.7 in infants. KLE College of Pharmacy, Nipani.

47. Advantages • Large nasal mucosal surface area for dose absorption • Rapid drug absorption via highly-vascularized mucosa • Rapid onset of action • Ease of administration, non-invasive KLE College of Pharmacy, Nipani. Contd..

48. Advantages • Avoidance of the gastrointestinal tract and first-pass metabolism • Improved bioavailability • Lower dose/reduced side effects • Improved convenience and compliance • Self-administration. KLE College of Pharmacy, Nipani.

49. Disadvantages • Nasal cavity provides smaller absorption surface when compared to GIT. • Relatively inconvenient to patients when compared to oral delivery since there is possibility of nasal irritation. • The histological toxicity of absorption enhancers used in the nasal drug delivery system is not yet clearly established. KLE College of Pharmacy, Nipani.

50. Factors affecting nasal absorption • Molecular weight :- • The nasal absorption of drugs decreases as the molecular weight increases. • Martin reported a sharp decline in drug absorption having molecular weight greater than 1000 daltons. KLE College of Pharmacy, Nipani.