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MUCOADHESIIVE DRUG DELIVERY SYSTEM

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MUCOADHESIIVE DRUG DELIVERY SYSTEM

  1. 1. Mucoadesive Drug Delivery System Dr. Gajanan S. Sanap M.Pharm.,Ph.D Department of Pharmaceutics Ideal College of Pharmacy and Research Kalyan 421- 306
  2. 2.  Bioadhesion can be defined as the state in which two materials, at least one of which is biological in nature, are maintained together for a prolonged time period by means of interfacial forces  During the 1980s, this concept began to be applied to drug delivery systems. It consists of the incorporation of adhesive molecules into some kind of pharmaceutical formulation intended to stay in close contact with the absorption tissue, releasing the drug near to the action site, thereby increasing its bioavailability and promoting local or systemic effects INTRODUCTION 2 Purpose of drug delivery :- (a) Local (b) Systemic
  3. 3. Type 1, adhesion between two biological phases, for example, platelet aggregation and wound healing. Type 2, adhesion of a biological phase to an artificial substrate, for example, cell adhesion to culture dishes and biofilm formation on prosthetic devices and inserts. Type 3, adhesion of an artificial material to a biological substrate, for example, adhesion of synthetic hydrogels to soft tissues and adhesion of sealants to dental enamel. CLASSIFICATION OF BIOADHESION 3 For drug delivery purposes, the term bioadhesion implies attachment of a drug carrier system to a specified biological location. The biological surface can be epithelial tissue or the mucus coat on the surface of a tissue. If adhesive attachment is to a mucus coat, the phenomenon is referred to as mucoadhesion
  4. 4. 1. A prolonged residence time at the site of drug action or absorption. 2. A localization of drug at a given target site. 3. An increase in the drug concentration gradient due to the intense contact of particles with the mucosa 4. A direct contact with intestinal cells that is the first step before particle absorption 5. Ease of administration 6. Termination of therapy is easy.{except gastrointestinal} 7. Permits localization of drug to the oral cavity for a prolonged period of time 8. Can be administered to unconscious patients. {except gastrointestinal} 9. Offers an excellent route, for the systemic delivery of drugs with high first pass metabolism, thereby offering a greater bioavailability 10. A significant reduction in dose can be achieved there by reducing dose related side effects ADVANTAGES 4
  5. 5. 11. Drugs which are unstable in the acidic environment or destroyed by enzymatic or alkaline environment of intestine can be administered by this route. Eg. Buccal sublingual, vaginal 12. Drugs which show poor bioavailability via the oral route can be administered conveniently 13. It offers a passive system of drug absorption and does not require any activation 14. The presence of saliva ensures relatively large amount of water for drug dissolution unlike in case of rectal and transdermal routes {buccal mucosa} 15. Systemic absorption is rapid 16. This route provides an alternative for the administration of various hormones, narcotic analgesic, steroids, enzymes, cardiovascular agents etc 17. The buccal mucosa is highly perfused with blood vessels and offers a greater permeability than the skin 18. Less dosing frequency 19. Shorter treatment period 20. Increased safety margin of high potency drugs due to better control of plasma levels 5
  6. 6. 21. Maximum utilization of drug enabling reduction in total amount of drug administered 22. Improved patient convenience and compliance due to less frequent drug administration 23. Reduction in fluctuation in steady state levels and therefore better control of disease condition and reduced intensity of local or systemic side effects 6
  7. 7. 7 1. Drugs, which irritate the oral mucosa, have a bitter or unpleasant taste, odour, cannot be administered by this route 2. Drugs, which are unstable at target site pH cannot be administered by this route 3. Only drugs with small dose requirements can be administered {except GI} 4. Only those drugs, which are absorbed by passive diffusion, can be administered by this route 5. Eating and drinking may become restricted {buccal mucosa} 6. Swallowing of the formulation by the patient may be possible {buccal mucosa} 7. Over hydration may lead to the formation of slippery surface and structural integrity of the formulation may get disrupted by the swelling and hydration of the bioadhesive polymers LIMITATIONS
  8. 8. 8 AVOIDANCE OF FIRST PASS METABOLISM WHY ? INCREASE IN DRUG CONC. GRADIENT BETTER ABSORPTION OF PEPTIDE BY PENETRATION ENHANCER LOCALIZATION OF DRUG AT GIVEN SITE PROLONG RESIDENCE TIME NEED OF MUCOADHESIVE DDS
  9. 9. Mucous membranes are the moist linings of the orifices and internal parts of the body They cover, protect, and provide secretory and absorptive functions Mucosal membranes are relatively permeable and allow fast drug absorption. They are characterized by an epithelial layer whose surface is covered by mucus. MUCOUS MEMBRANE 9 Mucus is a translucent and visco-elastic secretion, which forms a thin, continuous gel blanket adherent to mucosal epithelial surface. The mean thickness of this layer varies from about 50-450 μm in humans. MUCUS
  10. 10. It is secreted by the goblet cells lining the epithelia 10 or by special exocrine glands with mucus cells acini.
  11. 11. The primary constituent of mucus is a glycoprotein known as mucin as well as water and inorganic salts. These units contain an average of about 8-10 monosaccharide residues of five different types. They are: a) L-fructose b) D-galactose c) N-acetyl-D-glucosamine d) N-acetyl-D-galactosamine e) Sialic acid COMPOSITION OF MUCUS 11
  12. 12. Complex-high molecular weight macromolecule consisting of a polypeptide (protein) backbone to which carbohydrate side chains are attached Generic structure of mucin monomer Mucus forms flexible, threadlike strands that are internally cross linked by disulphide bond STRUCTURE OF MUCUS 12
  13. 13. Protective role: The Protective role results particularly from its hydrophobicity and protecting the mucosa from the lumen diffusion of hydrochloric acid from the lumen to the epithelial surface Barrier role: The mucus constitutes diffusion barrier for molecules, and especially against drug absorption diffusion through mucus layer depends on molecule charge, hydration radius, ability to form hydrogen bonds and molecular weight. Lubrication role: An important role of the mucus layer is to keep the membrane moist. Continuous secretion of mucus from the goblet cells is necessary to compensate for the removal of the mucus layer due to digestion, bacterial degradation and solubilisation of mucin molecules. Adhesion role: Mucus has strong cohesive properties and firmly binds the epithelial cells surface as a continuous gel layer Mucoadhesion role: At physiological pH, the mucus network may carry a significant negative charge because of the presence of sialic acid and sulphate residues and this high charge density due to negative charge contributes significantly to the bioadhesion FUNCTIONS OF MUCUS LAYER 13
  14. 14. EXAMPLES OF MUCOSA 14
  15. 15. Stage 1: Contact stage  Stage 2: Consolidation stage STAGES OF MUCOADHESION 15
  16. 16. It is a three step process:- STEP 1: Wetting and swelling of polymer STEP 2: Interpenetration between the polymer chains and the mucosal membrane. STEP 3: Formation of Chemical bonds between the entangled chains. MECHANISM OF MUCOADHESION 16
  17. 17. The wetting and swelling step occurs when the polymer spreads over the surface of the mucosal membrane in order to develop an intimate contact with the substrate. This can be readily achieved by placing a bioadhesive formulation such as a tablet or paste within the oral cavity or vagina.  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. STEP 1 17
  18. 18. The surface of mucosal membranes are composed of high molecular weight polymers known as glycoproteins. In this step interdiffusion and interpenetration take place between the chains of mucoadhesive polymers and the mucous gel network creating a great area of contact. The strength of these bond 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. STEP 2 18
  19. 19. In this step entanglement and formation of weak chemical bonds as well as secondary bonds between the polymer chains and mucin molecules occur 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 STEP 3 19
  20. 20. 1. Electronic theory 2. Adsorption theory 3. Wetting theory 4. Diffusion theory 5. Fracture theory 6. Mechanical theory THEORIES OF MUCOADHESION
  21. 21. 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 attractive forces within this electronic double layer determines the mucoadhesive strength ELECTRONIC THEORY 21 ADSORPTION THEORY It is a surface force where surface molecules of adhesive and adherent are in contact. According to adsorption theory, bioadhesive systems adhere to tissue due to bond formation. * Primary Chemical Bonds Many bioadhesives can form primary chemical covalent bonds with functional chemical groups in mucin: Aldehydes and alkylating agents can readily react with amino groups and sulfhydryl groups. Acylating agents react with amino and hydroxyl groups of serine or tyrosine.
  22. 22. * Secondary chemical bonds: Hydrogen bonding, electrostatic forces or Van-der Waals attractions are sufficient to contribute adhesive joints. The wetting theory applies to liquid systems which present affinity to the surface in order to spread over it. This affinity can be found by using measuring techniques such as the contact angle. The general rule states that the lower the contact angle then the greater the affinity The contact angle should be equal or close to zero to provide adequate spreadability The spreadability coefficient, SAB, can be calculated from the difference between the surface energies γB and γA and the interfacial energy γAB, as indicated in equation (1) WETTING THEORY
  23. 23. The greater the individual surface energy of mucus and device in relation to the interfacial energy, the greater the adhesion work, WA, i.e. the greater the energy needed to separate the two phases 23
  24. 24. Diffusion theory describes the interpenetration of both polymer and mucin chains to a sufficient depth to create a semi-permanent adhesive bond It is believed that the adhesion force increases with the degree of penetration of the polymer chains This penetration rate depends on the diffusion coefficient, flexibility and nature of the mucoadhesive chains, mobility and contact time According to the literature, the depth of interpenetration required to produce an efficient bioadhesive bond lies in the range 0.2-0.5 μm. This interpenetration depth of polymer and mucin chains can be estimated by equation 3: DIFFUSION THEORY where t is the contact time, and Db is the diffusion coefficient of the mucoadhesive material in the mucus 24
  25. 25. The adhesion strength for a polymer is reached when the depth of penetration is approximately equivalent to the polymer chain size In order for diffusion to occur, it is important that the components involved have good mutual solubility, that is, both the bioadhesive and the mucus have similar chemical structures The greater the structural similarity, the better the mucoadhesive bond 25 FRACTURE THEORY •This is perhaps the most used theory in studies on the mechanical measurement of mucoadhesion. •It analyzes the force required to separate two surfaces after adhesion is established.
  26. 26. This force, sm, is frequently calculated in tests of resistance to rupture by the ratio of the maximal detachment force, F m, and the total surface area, A0 , involved in the adhesive interaction 26 the fracture force, sf, which is equivalent to the maximal rupture tensile strength, sm, is proportional to the fracture energy (gc), for Young’s module (E) and to the critical breaking length (c) for the fracture site, as described in equation
  27. 27. Since the fracture theory is concerned only with the force required to separate the parts, it does not take into account the interpenetration or diffusion of polymer chains. Consequently, it is appropriate for use in the calculations for rigid or semi-rigid bioadhesive materials, in which the polymer chains do not penetrate into the mucus layer 27 Mechanical theory considers adhesion to be due to the filling of the irregularities on a rough surface by a mucoadhesive liquid. Moreover, such roughness increases the interfacial area available to interactions thereby aiding dissipating energy and can be considered the most important phenomenon of the process MECHANICAL THEORY
  28. 28.  Polymer  Environment  Physiology 28 FACTORS AFFECTING MUCOADHESION
  29. 29. i. Molecular weight ii.Concentration of active polymer iii.Flexibility of polymer chains iv.Spatial confirmation v.Cross linking density vi.Charge vii.Hydration 29 POLYMERRELATEDFACTORS
  30. 30. The interpenetration of polymer molecules is favorable for low molecular weight polymer Entanglement of polymer chains is favoured for high molecular weight polymer The mucoadhesive strength of a polymer increases with molecular weights above 1,00,000. Direct correlation between the mucoadhesive strength of polyoxyethylene polymers and their molecular weights lies in the range of 2,00,000-70,00,000. 1. MOLECULAR WEIGHT 30
  31. 31. When the concentration of the polymer is too low, the number of penetrating polymer chains per unit volume of the mucus is small and the interaction between polymer and mucus is unstable. In general, the more concentrated polymer would result in a longer penetrating chain length and better adhesion. However, for each polymer, there is a critical concentration, above which the polymer produces an "unperturbed" state due to a significantly coiled structure. As a result, the accessibility of the solvent to the polymer decreases, and chain penetration of the polymer is drastically reduced. Therefore, higher concentrations of polymers do not necessarily improve and, in some cases, actually diminish mucoadhesive properties. 2. CONCENTRATION OF ACTIVE POLYMER 31
  32. 32. One of the studies addressing this factor demonstrated that high concentrations of flexible polymeric films based on polyvinylpyrrolidone or poly(vinyl alcohol) as film-forming polymers did not further enhance the mucoadhesive properties of the polymer 32 Mucoadhesion starts with the diffusion of the polymer chains in the interfacial region. Therefore, it is important that the polymer chains contain a substantial degree of flexibility in order to achieve the desired entanglement with the mucus. In general, mobility and flexibility of polymers can be related to their viscosities and diffusion coefficients, as higher flexibility of a polymer causes greater diffusion into the mucus network 3. FLEXIBILITY 32
  33. 33. Besides molecular weight or chain length, spatial conformation of a molecule is also important Despite high molecular weight of dextran (19,500,000), they have adhesive properties same as PEG having molecular weight 2,00,000 The helical conformation of dextrans shields the adhesive groups PEG polymers have a linear structure. 33 4. SPATIAL CONFORMATION
  34. 34. The average pore size, the number and average molecular weight of the cross- linked polymers, and the density of cross-linking are three important and inter- related structural parameters of a polymer network. Therefore, it seems reasonable that with increasing density of cross-linking, diffusion of water into the polymer network occurs at a lower rate which, in turn, causes an insufficient swelling of the polymer and a decreased rate of interpenetration between polymer and mucin 34 4. CROSS LINKING DENSITY 5. CHARGE •Strong anionic charge on the polymer is one of the required characteristics for mucoadhesion •Nonionic polymers appear to undergo a smaller degree of adhesion compared to anionic polymers.
  35. 35.  Some cationic polymers demonstrate superior mucoadhesive properties, especially in a neutral or slightly alkaline medium. Additionally, some cationic high-molecular-weight polymers, such as chitosan, have shown to possess good adhesive properties. There is no significant literature about the influence of the charge of the membrane on the mucoadhesion but the pH of the membrane affects the mucoadhesion as it can influence the ionized or un-ionized forms of the polymers. 35 6. HYDRATION •Hydration is required for a mucoadhesive polymer to expand and create a proper macromolecular mesh of sufficient size, and also to induce mobility in the polymer chains in order to enhance the interpenetration process between polymer and mucin. •Polymer swelling permits a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding and/or electrostatic interaction between the polymer and the mucus network. However, a critical degree of hydration of the mucoadhesive polymer exists where optimum swelling and mucoadhesion occurs
  36. 36. i.pH of polymer - substrate interface ii.Applied strength iii.Initial contact time iv.Swelling 36 ENVIRONMENTRELATED FACTORS
  37. 37.  The pH at the bioadhesive to substrate interface can influence the adhesion of bioadhesives possessing ionizable groups.  Many bioadhesives used in drug delivery are polyanions possessing carboxylic acid functionalities.  If the local pH is above the pKa of the polymer, it will be largely ionized; if the pH is below the pKa of the polymer, it will be largely unionized.  The approximate pKa for the poly(acrylic acid) family of polymers is between 4 and 5.  The maximum adhesive strength of these polymers is observed around pH 4-5 and decreases gradually above a pH of 6.  A systematic investigation of the mechanisms of mucoadhesion clearly showed that the protonated carboxyl groups, rather than the ionized carboxyl groups, react with mucin molecules, presumably by the simultaneous formation of numerous hydrogen bonds 37 1. pH OF POLYMER - SUBSTRATE INTERFACE
  38. 38. Higher forces lead to enhanced interpenetration and high bioadhesive strength. 38 2. APPLIED STRENGTH 2. INITIAL CONTACT TIME The greater the initial contact time between bioadhesive and substrate, the greater the swelling and interpenetration of polymer chains
  39. 39. It depends on both polymer and environment Interpenetration of chains is easier as polymer chains are disentangled and free of interactions When swelling is too great, a decrease in bioadhesion occurs. Such a phenomena must not occur too early in order to lead to sufficient bioadhesion Swelling later allows easy detachment of the bioadhesive system after complete release of drug 39 4. SWELLING
  40. 40. i. Mucin turnover rate ii. Disease states 40 PHYSIOLOGICALFACTORS
  41. 41. It is important because:  It limits the residence time of the mucoadhesive on the mucus layer  Mucin turnover results in substantial amounts of free mucin molecules which interact with the mucoadhesive before it can reach the mucus layer. Mucin turnover depends on presence of food Mucociliary clearance in the nasal cavity – 5 mm/min Mucociliary clearance in the tracheal region – 4-10 mm/min 41 MUCIN TURNOVER RATE
  42. 42. Physicochemical properties of mucus is known to change in conditions like:  Common cold  Gastric ulcers  Ulcerative colitis  Cystic fibrosis  Bacterial and fungal infections of the female reproductive system  Inflammation of the eye 42 DISEASE STATES
  43. 43. Polymers which adhere to mucin-epithelial surface are broadly classified as: 1.Polymers that become sticky when placed in water and owe their mucoadhesion to stickiness 2.Polymers that adhere through non-specific, non-covalent interactions 3.Polymers that bind to specific receptor sites on the cell surface 43 MUCOADHESIVE POLYMERS
  44. 44. Ideal characteristics of mucoadhesive polymer are as follows: 1.The polymer and its degradation product should be non-toxic and non-absorbable from GIT 2.Non-irritant to mucous membrane 3.Should preferably form strong non-covalent bond with mucin 4.Should adhere quickly to moist tissue 5.Site specific 6.Should allow easy incorporation of drug 7.Should not offer any hindrance to drug release 8.Must not decompose on storage throughout the shelf life of the formulation 9.Should have an optimum degree of cross-linking density, pH and hydration 10.Should be economic 44
  45. 45. 45 CLASSIFICATION OF POLYMERS
  46. 46. These materials are natural or synthetic hydrophilic molecules containing numerous organic functions that generate hydrogen bonds such as carboxyl, hydroxyl and amino groups, which do not adhere specifically. These polymers can be subdivided into three classes: cationic, anionic and nonionic. Cationic molecules can interact with the mucus surface, since it is negatively charged at physiological pH. Eg. Chitosan Mucoadhesion of chitosan occurs because of the electrostatic interactions of their amino groups with the sialic groups of mucin in the mucus layer. 46 FIRST GENERATION POLYMERS
  47. 47. In contrast, synthetic polymers derived from polyacrylic acid (carbomers) are negatively charged but are also mucoadhesive. In this case, mucoadhesion results from physical-chemical processes, such as hydrophobic interactions, hydrogen and van der Waals bonds, which are controlled by pH and ionic composition. Other examples of anionic polymers are carboxymethylcellulose and alginates Nonionic polymers, including hydroxypropylmethylcellulose, hydroxyethylcellulose and methylcellulose, present weaker mucoadhesion force compared to anionic polymers There is a new class of substances being identified as bioadhesive. This class consists of ester groups of fatty acids, such as glyceryl monooleate and glyceryl monolinoleate 47
  48. 48. 48 POLYMER BIOADHESIVE PROPERTY Carboxy methyl cellulose +++ Carbopol 934 +++ Polycarbophil +++ Tragacanth +++ Poly (acrylic acid / divenyl benzene) +++ Sodium alginate +++ Hydroxy ethyl cellulose +++ Gum karaya ++ Gelatin ++ Guar gum ++ +++ :- Excellent ++ :- Fair
  49. 49. 49 POLYMER BIOADHESIVE PROPERTY Thermally modified starch + Pectin + PVP + Acacia + PEG + Psyllium + Amberlite – 200 resin + HPC + Chitosan + Hydroxy ethyl methacrylate + + :- Poor
  50. 50. An ideal polymer should exhibit the ability to incorporate both hydrophilic and lipophilic drugs, show mucoadhesive properties in its solid and liquid forms, inhibit local enzymes or promote absorption, be specific for a particular cellular area or site, stimulate endocytosis and finally to have a broad safety range These novel multifunctional mucoadhesive systems are classified as second generation polymers They are an alternative to non-specific bioadhesives because they bind or adhere to specific chemical structures on the cell or mucus surface. Good examples of these molecules are lectins, invasins, fimbrial proteins, antibodies, and those obtained by the addition of thiol groups to known molecules. 51 SECOND GENERATION POLYMERS
  51. 51. Permeation enhancers are substances added to pharmaceutical formulation in order to increases the membrane permeation rate or absorption rate of a co- administered drug. They are used to improve bioavailability of drugs with normally poor membrane permeation properties without damaging the membrane and causing toxicity. Enhancer efficacy depends on the physiochemical properties of the drug, administration site, nature of the vehicle and whether enhancer is used alone or in combination 52 PERMEATION ENHANCERS
  52. 52. Categories and examples of membrane permeation enhancers A.Bile salts and other steroidal detergents: Sodium glycocholate, Sodium taurocholate, Saponins, Sodium tauro dihydro fusidate and Sodium glycol dihydrofusidate. B. Surfactants: 1. Non- ionic: Laureth-a, Polysorbate-9, Sucrose esters and do-decyl maltoside 2. Cationic: Cetyl trimethylammonium bromide 3. Anionic: sodium lauryl sulfate C. Fatty acids: oleic acid, lauric acid, caproic acid D. Other enhancers: 1. Azones 2. Salicylates 3. Chelating agents 4. Sulfoxides e. g. Dimethyl Sulfoxide (DMSO) 53
  53. 53. Solid Tablets Bioadhesive microparticles Bioadhesive inserts Bioadhesive wafers Lozenges Semisolid Gels Films Liquid Suspensions Gel forming liquids BIOADHESIVE DOSAGE FORMS
  54. 54. POTENTIA L SITES……… .. BUCCAL SUBLINGUAL ORALNASAL OCULAR VAGINALRECTAL Routes
  55. 55. 57 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 cavityThe 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.
  56. 56.  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 ulcersMouth ulcers , Oral thrush,Oral thrush, Gingivitis.Gingivitis.
  57. 57. The buccal mucosa refers to the inner lining of the lips and cheeks.  The epithelium of the buccal mucosa is about 40-50 cells thick and the epithelial cells become flatter as they move from the basal layersbasal layers to the superficial layers. 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. A ) The Buccal MucosaA ) The Buccal Mucosa
  58. 58. B ). The sublingual mucosaB ). The sublingual mucosa The sublingual mucosa surrounds the sublingual gland which is a mucin-producing salivary glandsalivary gland located underneath the tongue. Examples :- Glyceryl Trinitrate (GTNGlyceryl Trinitrate (GTN) (aerosol spray and tablet in prophylacticprophylactic treatment of angina.) Brand name:-Susadrin ,Nitrogard.
  59. 59. 3 ) The Gingival Mucosa Hardest muscle of body Can retain dosage form for long duration
  60. 60. EXAMPLES OF PRODUCTSEXAMPLES OF PRODUCTS . Oral Bioadhesive Formulations CorlanCorlan®® Corlan pellets are used in the treatment of mouth ulcers to reduce the pain, swelling and inflammation associated with mouth ulcers.The active ingredient of the pellet is Hydrocortisone succinate. It also contains the bioadhesive polymer AcaciaAcacia which helps prolong the effect of the drug in the oral cavity. For treatment to be successful each pellet or lozenge must be allowed to slowly dissolve in the mouth, close to the ulcer.
  61. 61. Oral Bioadhesive Formulations  BonjelaBonjela®® This gel is used in the treatment of the soreness associated with mouth ulcers.The gel is applied over the ulcer every three to four hours or when needed. Bonjela® contains hypromellose 4500 which lubricates the ulcers .  Daktarin®Daktarin® oral gel contains the antifungal agent Miconazole and is used to treat oral thrush. It also contains an adhesive agent known as pregelatinised potato starchpregelatinised potato starch which increases the viscosity of the gel and also enables it to stick to the oral mucosa. Patients are advised apply the gel in the mouth and keep it there for as long as possible preferably after food so the gel remains intact for longer.  Corsodyl®Corsodyl® oral gel contains the active ingredient chlorhexidine gluconate and is brushed on the teeth to inhibit the formation of plaque and therefore improve oral hygiene.The gel also contains the bioadhesive polymer Hydroxypropyl cellulose(HPC)Hydroxypropyl cellulose(HPC) which helps retain the gel inside the oral cavity.11111
  62. 62. .The Buccal Mucosa.The Buccal Mucosa Examples of ProductsExamples of Products  BuccastemBuccastem®® Is a drug used in the treatment of nausea, vomiting and vertigo. It contains the bioadhesive agents Polyvinylpyrrolidone and Xanthan gum.  SuscardSuscard®® Is a buccal tablet used in the treatment of angina. It contains the bioadhesive agent Hydroxypropyl methylcellulose (HPMC). The sublingual mucosaThe sublingual mucosa Examples of ProductsExamples of Products Examples of sublingual products include Glyceryl Trinitrate (GTNGlyceryl Trinitrate (GTN) aerosol spray and tablet which is administered under the tongue for the prophylacticprophylactic treatment of angina. 11
  63. 63. RECTAL MUCOSAL DRUG DELIVERY The rectum is the terminal or end portion of the gastrointestinal tract. It is an important route of administration for drugs that have severe gastrointestinal side effects. This route is also suitable for patients who cannot take medicines via the oral route such as unconscious patients and infants. The drugs absorbed from the rectum can escape breakdown by hepatic enzymes. For this reason mucoadhesive suppositories have been developed for the local treatment of diseases such as haemorrhoids and rectal cancer.
  64. 64. FACTORS AFFECTING RECTAL ABSORPTION Formulation (time to liquefaction of suppositories) Volume of liquid Concentration of drug Length of rectal catheter ( site of drug delivery) Presence of stool in the rectal vault pH of the rectal contents Rectal retention of drug(s) administered Differences in venous drainage within the rectosigmoid region Partition coefficient of drug Physical state of medicament Presence of adjuncts in base
  65. 65. RECTAL FORMULATIONS • SUPPOSITORIES - MUCOADHESIVE SUPPOSITORIES - MUCOADHESIVE LIQUID SUPPOSITORIES - THERMO REVERSIBLE SUPPOSITORIES • BIOADHESIVE GEL • HYDROGEL • MICROPARTICULATE -- MICROCAPSULES -- NANOSPHERES
  66. 66. POLYMERS • SUPPOSITORIES - SODIUM ALGINATE AND POLOXAMER - PEG AND POLYCARBOPHIL • GEL - PLURONIC F-127 • HYDROGEL • CARBOPHIL • SODIUM ALGINATE • MICROPARTICULATE
  67. 67. DRUGS • SUPPOSITORY — PROPANOLOL, INSULIN • BIOADHESIVE GEL – INSULIN • HYDROGEL – PROPRANOLOL • MICROSPHERE -- INDOMETHACIN
  68. 68. EVALUATION • FOR SUPPOSITORIES • SURFACE CHARACTERISTICS • DRUG DISSOLUTION OR RELEASE • DISINTEGRATION • MELTING/ SOFTENING OF SUPPOSITORIES • MUCOADHESIVE STRENGTH • FOR GEL AND MICROPARTICULATE SYSTEM --- SAME AS ABOVE.
  69. 69. Flow through cell apparatusFlow through cell apparatus 1. Cell for suppositories1. Cell for suppositories 2. Cell for ointment2. Cell for ointment USP 27-NF 22, The United StateUSP 27-NF 22, The United State
  70. 70. Rectal Bioadhesive Formulations EXAMPLES OF PRODUCTSEXAMPLES OF PRODUCTS  AnacalAnacal®® Is a rectal ointment used to relieve the symptoms associated with haemorrhoids. It contains the bioadhesive agent polyethylene high polymer 1500.polyethylene high polymer 1500.  Germoloids®Germoloids® Is a rectal ointment used to relief the pain, swelling, itchiness and irritation associated with haemorrhoids. It contains the polymer propylene glycolpropylene glycol.  Preparation H®Preparation H® Suppositories help shrink the haemorrhoidal tissue which is swollen by irritation. It contains the polymer polyethylene glycolpolyethylene glycol.
  71. 71. NASAL DRUG DELIVERY SYSTEM
  72. 72. INTRODUCTION 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.
  73. 73. • 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. INTRODUCTION
  74. 74. 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 Contd..
  75. 75. • Avoidance of the gastrointestinal tract and first-pass metabolism • Improved bioavailability • Lower dose/reduced side effects • Improved convenience and compliance • Self-administration. Advantages
  76. 76. 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.
  77. 77. Factors affecting nasal absorption 1. 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.
  78. 78. 2. Lipophilicity :- • Absorption of drug through nasal route is dependent on the lipophilicity of drugs. • E.g. Alprenolol and Propranolol which are lipophilic, has greater absorption than that of hydrophilic Metoprolol. Factors affecting nasal absorption
  79. 79. 3. pH of solution :- • pH should be optimum for maximum absorption. • Nonionised lipophilic form crosses the nasal epithelial barriers via transcellular route and hydrophilic ionized form passes through the aqueous paracellular route. • E.g. Decanoic acid shows maximum absorption at pH 4.5. Beyond this it decreases as solution becomes more acidic or basic. Factors affecting nasal absorption
  80. 80. 4. Drug concentration :- • The absorption of drug through nasal route is increased as concentration is increased. • E.g. 1-tyrosine shows increased absorption at high concentration in rate. Factors affecting nasal absorption
  81. 81. Pathway • In systemic absorption the drugs generally get diffused from epithelial cell into systemic circulation. • It is reported that nasal cavity have alternative pathways of drugs absorption through olfactory epithelium to CNS and peripheral circulation.
  82. 82. Enhancement in absorption • Following approaches used for absorption enhancement :-  Use of absorption enhancers  Increase in residence time.  Administration of drug in the form of microspheres.  Use of physiological modifying agents
  83. 83.  Use of absorption enhancers:- Absorption enhancers work by increasing the rate at which the drug pass through the nasal mucosa. Various enhancers used are surfactants, bile salts, chelaters, fatty acid salts, phospholipids, cyclodextrins, glycols etc. Enhancement in absorption
  84. 84. Various mechanisms involved in absorption enhancements are:- • Increased drug solubility • Decreased mucosal viscosity • Decrease enzymatic degradation • Increased paracellular transport • Increased transcellular transport
  85. 85.  Increase in residence time:- • By increasing the residence time the increase in the higher local drug concentration in the mucous lining of the nasal mucosa is obtained. • Various mucoadhesive polymers like methylcellulose, carboxymethylcellulose or polyarcylic acid are used for increasing the residence time.
  86. 86.  Administration of drug in the form of microspheres:- • Microspheres have good bioadhesive property and they swell when in contact with mucosa. • Microspheres provide two advantages- a. Control the rate of clearance. b. Protect drug from enzymatic degradation. The microspheres of various materials showed increased half-life of clearance. E.g. starch, albumin, gelatin and dextran.
  87. 87.  Use of physiological modifying agents:- • These agents are vasoactive agents and exert their action by increasing the nasal blood flow. • The example of such agents are histamine, leukotrienene D4, prostaglandin E1 and β- adrenergic agents like isoprenaline and terbutaline.
  88. 88. Nasal Delivery Systems • They contain the drug in a liquid or powder formulation delivered by a pressurized or pump system. • Various drug delivery systems are used for nasal drug delivery.
  89. 89.  Liquid formulation :- • These are usually aqueous solutions of the drug. The simplest way to give a liquid is by nose drops. • They are simple to develop and manufacture compared to solid dosage forms but have a lower microbiological and chemical stability, requiring the use of various preservatives. Nasal Delivery Systems
  90. 90.  Squeezed bottles :- • These are used for nasal decongestant and work by spraying a partially atomized jet of liquid into the nasal cavity. • They give a better absorption of drug by directing the formulation into the anterior part of the cavity and covering a large part of nasal mucosa. Nasal Delivery Systems
  91. 91.  Metered-dose pump system :- • They can deliver solutions, suspensions or emulsions with a predetermined volume between 25 and 200 μL, thus offering deposition over a large area. • Particle size and dose volume are two important factors for controlling delivery from metered-dose systems. Nasal Delivery Systems
  92. 92. • The optimum particle size for deposition in the nasal cavity is 10μm. • The volume of formulation that can be delivered is limited by the size of the nasal cavity and larger volumes tend to be cleared faster despite covering a larger area. • Better absorption is achieved by administering two doses, one in each nostril, rather than a single large dose. Nasal Delivery Systems
  93. 93. Applications of Nasal Drug Delivery A. Nasal delivery of organic based pharmaceuticals :- • Various organic based pharmaceuticals have been investigated for nasal delivery which includes drug with extensive presystemic metabolism. • E.g. Progesterone, Estradiol, Nitroglycerin, Propranolol, etc.
  94. 94. B. Nasal delivery of peptide based drugs :- • Nasal delivery of peptides and proteins is depend on:  The structure and size of the molecule.  Nasal residence time  Formulation variables (pH, viscosity) • E.g. Calcitonin, secretin, albumins, insulin, glucagon, etc. Applications of nasal drug delivery
  95. 95. Pulmonary Drug Delivery System
  96. 96. • The lung is the organ of external respiration, in which oxygen and carbon dioxide are exchanged between blood and inhaled air. • The structure of the airways prevent the entry of and promotes the removal of airborne foreign particles including microorganisms. Contd.. Introduction
  97. 97. • The respiratory tract consists of conducting regions (trachea, bronchi, bronchioles, terminal and respiratory bronchioles) and respiratory regions (respiratory bronchioles and alveolar regions). • The upper respiratory tract comprises the nose, throat, pharynx and larynx; the lower tract comprises the trachea, bronchi, bronchioles and the alveolar regions. Contd.. Introduction
  98. 98. Contd.. Anatomy of pulmonary system
  99. 99. • Trachea branches into two main bronchi- the right bronchus is wider and leaves the trachea at the smaller angle than the left. • The conducting airways are lined with ciliated epithelial cells. Anatomy of pulmonary system
  100. 100. Delivery systems • Aerosols are used for the delivery of the drug by this route of administration. • The aerosols are defined as pressurized dosage from containing one or more active ingredients which upon actuation emit a fine dispersion of liquid or solid materials in gaseous medium.
  101. 101. • There are three main types of aerosols generating devices:- i. Pressurized metered dose inhalers. ii. Dry powder inhalers. iii. Nebulizers. Delivery systems
  102. 102. i. Pressurized metered dose inhalers: • In pMDI’s, drug is either dissolved or suspended in liquid propellants together with other excipients and presented in pressurized canister fitted with metering valve. • The predetermined dose is released as a spray on actuation of the metering valve. Delivery systems
  103. 103. • Containers:- Aerosol container must withstand pressure as high as 140-180 psig at 130°F. • Pharmaceutical aerosols are packaged in tin-plated steel, plastic coated glass or aluminium containers. • Aluminium is relatively inert and used uncoated where there is no chemical instability between containers and contents. • Alternatively aluminium containers with an internal coating of chemically resistant organic material such as epoxy-resin or polytetrafluorine can be used Delivery systems
  104. 104. • Propellants: These are liquified gases like chlorofluorocarbons and hydrofluoroalkanes. • These develop proper pressure within the container & it expels the product when valve is opened. • At room temperature and pressure, these are gases but they are readily liquified by decreasing the temperature or increasing pressure. • The vapour pressure of the mixture of propellants is given by Raoult’s law, Contd… Delivery systems
  105. 105. i.e. vapour pressure of the mixed system is equal to the sum of the mole fraction of each component multiplied by it’s vapour pressure. p = pa + pb where p = total vapour pressure of the system, pa & pb = partial vapour pressures of the components a & b. Contd… Delivery systems
  106. 106. • Metering valves: It permits the reproducible delivery of small volumes of product. Depression of the valve stem allows the contents of the metering chamber to be discharged through the orifice in the valve stem and made available to the patient. After actuation the metering chamber refills with liquid from the bulk and is ready to dispense the next dose. Delivery systems
  107. 107. ii. Dry powder inhalers: In this system drug is inhaled as a cloud of fine particles. DPI formulations are propellant free and do not contain any excipients. They are breath activated avoiding the problems of inhalation/actuation coordination encountered with pMDI’s. Delivery systems
  108. 108. iii. Nebulizers: It delivers relatively large volume of drug solutions and suspensions. They are used for drugs that cannot be formulated into pMDI’s or DPI’s. There are three categories :- a. Jet nebulizers b. Ultrasonic nebulizers c. Vibrating-mesh nebulizers Delivery systems
  109. 109. a. Jet nebulizers:- They are also called as air-jet or air-blast nebulizers using compressed gas. The jet of high velocity gas is passed tangentially or coaxially through a narrow venturi nozzle typically 0.3 to 0.7 mm in diameter. e.g. Pari LC nebulizer. Delivery systems
  110. 110. b. Ultrasonic nebulizers: In this the energy necessary to atomize liquids come from the piezoelectric crystal vibrating at high frequency. c. Vibrating-mesh nebulizers: In this device aerosols are generated by passing liquids through a vibrating mesh or plate with multiple apertures. Delivery systems
  111. 111. Applications • Smaller doses can be administered locally. • Reduce the potential incidence of adverse systemic effect. • It used when a drug is poorly absorbed orally, e.g. Na cromoglicate. • It is used when drug is rapidly metabolized orally, e.g. isoprenaline
  112. 112. 114 EVALUATION
  113. 113. 1. IN VITRO / EX VIVO METHODS a. Methods based on measurement of tensile strength. b. Methods based on measurement of shear strength. OTHER IN VITRO METHODS c. Adhesion weight method d. Fluorescent probe method e. Flow channel method f. Falling liquid film method g. Colloidal gold staining method h. Mechanical spectroscopic method i. Thumb test j. Viscometric method k. Adhesion number l. Electrical conductance 2. IN VIVO METHODS a. Use of radio isotopes b. Use of gamma scintigraphy 115
  114. 114. In vitro/ex vivo tests are important in the development of a controlled release bioadhesive system because they contribute to studies of 1. Permeation 2. Release 3. Compatibility 4. Mechanical and physical stability 5. Superficial interaction between formulation and mucous membrane; and 6. Strength of the bioadhesive bond. These tests can simulate a number of administration routes including oral, buccal, periodontal, nasal, gastrointestinal, vaginal and rectal. 116 IN VITRO/ EX VIVO TESTS
  115. 115. 117 DETERMINATION OF BIOADHESION
  116. 116. Depending on the direction in which the mucoadhesive is separated from the substrate, is it possible to obtain the detachment, shear, and rupture tensile strengths 118
  117. 117. The measure the force required to break the adhesive bond between a model membrane and the test polymers Instruments employed: modified balance or tensile testers 119 MEASUREMENT OF DETACHMENT FORCE Mucoadhesion by modified balance method
  118. 118. 120 Measurement of mucoadhesive tensile strength with an automatic surface tensiometer.
  119. 119. Equipment used: Texture analyzer or 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. Based on results, a force-distance curve can be plotted which yields the force required to detach the mucin disc from the surface with the formulation, the tensile work (area under the curve during the detachment process), the peak force etc. This method is more frequently used to analyze solid systems like microspheres, although there are also studies on semi-solid materials 121 MEASUREMENT OF RUPTURE TENSILE STRENGTH
  120. 120. 122
  121. 121. This test measures the force required to separate two parallel glass slides covered with the polymer and with a mucus film Eg: Wilhelmy plate method 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 Although measures taken by this method are reproducible, the technique involves no biological tissue and therefore does not provide a realistic simulation of biological conditions 123 MEASUREMENT OF SHEAR STRENGTH
  122. 122. 124
  123. 123. Adhesion weight method Adhesion number Falling liquid film method Fluorescent probe method Flow channel method Mechanical spectroscopic method Electrical conductance Colloidal gold staining method Thumb test Viscometric method 125 OTHER IN VITRO METHODS
  124. 124. Particles are allowed to come in contact with the mucosal membrane for a short period of time (around 5 mins) The weight of particles retained is then measured Good method for determination of effect of various parameters such as particle size, charge etc on mucoadhesion Limitations: 1. Poor data reproduciblity 2. Rapid degenration of mucosal tissue 126 ADHESION WEIGHT METHOD
  125. 125. Applicable for small particles eg. Mucoadhesive microparticles Particles are allowed to come in contact with the mucosal membrane for a short period of time (around 5 mins) The number of particles retained is then measured 127 ADHESION NUMBER 100 0 X N N Na = Na – Adhesion number N – number of particles attached to the substrate N0 – total number of particles under test
  126. 126. The chosen mucous membrane is placed in a stainless steel cylindrical tube, which has been longitudinally cut. This support is placed inclined in a cylindrical cell with a temperature controlled at 37 ºC. An isotonic solution is pumped through the mucous membrane and collected in a beaker Subsequently, in the case of particulate systems, the amount remaining on the mucous membrane can be counted with the aid of a coulter counter The validation of this method showed that the type of mucus used does not influence the results 128 FALLING LIQUID FILM METHOD
  127. 127. 129
  128. 128. Study polymer interaction with mucosal membrane using fluorescent probes The mucus is labeled with pyrene or fluorescein isothiocyanate It is then mixed with the bioadhesive material The changes in fluorescence spectra is monitored 130 FLUORESCENT PROBE METHOD
  129. 129. It utilises a thin channel made of glass filled with aqueous solution of mucin thermostated at 37°C. Humid air at the same temperature is passed through the glass channel A particle of bioadhesive polymer is placed on the mucin gel Its static and dynamic behavior can be monitored at frequent intervals using a camera 131 FLOW CHANNEL METHOD
  130. 130. Can be used to investigate the interaction between the bioadhesive materials and mucin Can be used to study the effect of pH and chain length But this method shows a very poor correlation with in vivo bioadhesion 132 MECHANICAL SPECTROSCOPIC METHOD
  131. 131. Equipment: modified rotational viscometer capable of measuring electrical conductance Electrical conductance as a function of time is measured In presence of adhesive material, the conductance is low 133 ELECTRICAL CONDUCTANCE METHOD
  132. 132. It employs red colloidal gold particles which were stabilized by adsorbed mucin molecules Upon interaction with these mucin-gold conjugates, bioadhesive materials develop a red colour on the surface This interaction can be quantified by measuring the intensity of the red colour 134 COLLOIDAL GOLD STAINING NUMBER
  133. 133. It is a simple test to identify if the material is mucoadhesive The adhesiveness is quantitatively measured by the difficulty of pulling the adhesive from the thumb as a function of pressure and contact time. This test can be used as most mucoadhesives are not mucin specific It is not a conclusive test but gives useful information on mucoadhesive potential 135 THUMB TEST
  134. 134. Viscosities of mucin dispersion can be measured by Brookfield viscometer Viscosity can be measured in absence or presence of bioadhesive material Viscosity components can give an idea about force of biodahesion 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 136 VISCOMETRIC METHOD
  135. 135. ηb – bioadhesion component ηt - coefficient of viscosity of the system ηm and ηp - coefficients of viscosity of mucin and bioadhesive polymer, respectively All components should be measured at the same concentration, temperature, time and shear gradient. The bioadhesion force, F, is determined by equation: where is the shear gradientσ The main disadvantage of this method is the breakdown of the polymer and mucin network under continuous flow 137
  136. 136. The everted gut sac technique is an example of an ex vivo method It has been used since 1954 to study intestinal transport It is easy to reproduce and can be performed in almost all laboratories. 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 138 USING EVERTED GUT SAC OF RATS
  137. 137. 139
  138. 138. Use of radioisotopes Use of gamma scintigraphy Use of pharmacoscintigraphy Use of electron paramagnetic resonance(EPR) oximetry X ray studies Isolated loop technique 140 IN VIVO METHODS
  139. 139. In vitro drug release In vitro drug permeation – Franz diffusion cell, Keshary Chein cell, modified Franz diffusion cell Histopathological evaluation of mucosa after prolonged contact with bioadhesive material Other tests for that dosage form eg. Tablets, microparticles etc maybe applicable 141 OTHER EVALUATION PARAMETERS
  140. 140. PRODUCT COMPANY BIOADHESIVE AGENT PHARMACEUTICAL FORM Buccastem® Reckitt Benckiser PVP, Xanthum gum Buccal tablet Corlan pellets® Celltech Acacia gum Oromucosal pellets Suscard® Forest HPMC Buccal tablet Gaviscon liquid® Reckitt Benckiser Sodium alginate Oral liquid Orabase® Convatech Pectin, Gelatin Oral paste Corsodyl gel® GalaxoSmithKline HPMC Oromucosal gel Pilogel Alcon Carbomere Eye ge Timoptol Merk, sharpe and Dohme Gallan gum Eye gel forming solution Aci- jel Janssen- cilag Tragacanth Vaginal gel Crinone Serono Carbomer Vaginal gel Gynol Janssen- cilag Sod. CMC & PVP Vaginal gel Zidoval 3M Carbomer Vaginal gel Nyogel® Novartis Carbomer and PVA Eye gel Currently available bioadhesive formulation in U.K. 142
  141. 141. 143 REFERENCES Bioadhesive drug delivery systems fundamentals, Novel approaches, and development: edited by Mathiowitz, Donald E. Chickering III, Claus-Michael lehr, Vol-98, Page no-1-6,131-145,507-541, 541-563,601-641. Roop K Khar, S.P Vyas, Controlled drug delivery concept & advances, 1st edition, page no-250-313. Harris .D, Robinson.J.R. Drug delivery via the mucous membranes of oral cavity,J. Pharma. Sci , vol-81, 1992 Page no-1-8. Ahuja.a, Khar.R.K and Ali.J, Mucoadhesive Drug Delivery Systems, Drug Dev.Ind. Pharm,23, 1997, 489-515. Lee J.W, Park J.H, Robinson J.R, Bioadhesive-Based Dosage Forms: The Next Generation, J Pharm Sci. vol- 89, 2000, 850-861. Chidambaram.N & Srivastava A.K, Buccal drug delivery systems, Drug Dev.Ind. Pharm, 21, 1995, 1009-1036.
  142. 142. 144 Kockisch.S, Rees.G.D, Young.S.A, polymeric microspheres for drug delivery to oral cavity:An in vitro evaluation of mucoadhesive potential, J Phama Sci, Vol-92, 2003, page no-1614. Mizrahi.B, Adhesive tablets effective for treating canker sores in human, J Phama Sci, Vol-93, 2004, page no-2927. M.J Rathbone, J. Handgraft, M.S. Roberts, Modified Drug Delivery, Vol-126, Page no-447,463. H.S Ch’ng, H. Park, P. Kelly, J.R.Robinson,Bioadhesive polymers as a platforms for oral controlled drug delivery II: Sythesis & evaluation of some swelling water insoluble polymers, J Pharma Sci,74, 1985,page no- 399. K.R. Kamath, K. Park, Mucosaladhesive preprations, Encyclopedia of Pharmaceutical Technology,(J. Swarbick, J.C Boylan)Marcel Dekker, 1994, page no 133.
  143. 143. 145 Shah K. U. and. Rocca J. G ,Lectins as Next-Generation Mucoadhesives for Specific Targeting of the Gastrointestinal Tract,Drug delivery tech.com Moes .A.J, Gastric retention system for oral drug delivery, Drug delivery oral, Business Briefings, pharmatech –2003, www.bbriefings.com/pdf/890/Pt04_moes.pdf Batchelor .H, Novel Bioadhesive Formulations in Drug Delivery, The drug delivery companies report autumn/winter2004, Pharma Ventures Ltd 2004, page no-16-19, www.worldpharmaweb.com/ddcr/auto4/article7.pdf Collins .A.E & Deasy. B.D, Bioadhesive lozenges for the improved delivery of cetyl pyridinium chloride, J. Pharm. Sci, Vol-79,1990, Page NO-116-119. James Swarbick, James C Boylan,Encyclopedia of pharmaceutical technology,vol-2, 1994, Page no-189-205.
  144. 144. 146  Give the definitions and importance of BDDS.  Theories of bioadhesion  Which are the factors important to bioadhesion?  Give classifications of BDDS.  Write note on Buccal BDDS with its advantages and limitations.  How will you do the evaluation of bioadhesive drug delivery systems? QUESTIONS
  145. 145. Thank you…!!!Thank you…!!!

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