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Bioadhesive drug delivery system


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Bioadhesive drug delivery system

  1. 1. By, Dr. Shreeraj Shah Associate Professor, Dept. of Pharmaceutical Technology L.J. Institute of Pharmacy, Ahmedabad
  2. 2.  Bioadhesion may be defined as the state in which two materials, at least one of which is biological in nature, are held together for extended periods of time by interfacial forces. The rationale being that the formulation will be ‘held’ on a biological surface for localized drug delivery. The API will be released close to the site of action with a consequent enhancement of bioavailability. It is a phenomenon of interfacial molecular attractive forces amongst the surfaces of the biological substrate and the natural or synthetic polymers, which allows the polymer to adhere to the biological surface for an extended period of time For the purpose of drug delivery system Drug carrier system  adhere to biological tissue  increase concentration gradient at the absorption site  increase the bioavailability. Also used for • local target to the mucosal surface • reduce the side effect
  3. 3.  Mucoadhesion is commonly defined as theadhesion between two materials, at least one ofwhich is a mucosal surface. Mucoadhesive dosage forms may bedesigned to enable prolonged retention at thesite of application, providing a controlled rate ofdrug release for improved therapeutic outcome.
  4. 4.  Bioadhesion is defined as an ability of a materialto adhere to a biological tissue for an extendedperiod of time. In the case of polymer attached to the mucinlayer of a mucosal tissue, the term “mucoadhesion”is used.
  5. 5. The ideal characteristics of a Bio/Mucoadhesiveapproach include:The rapid adherence to the mucosal layer without any change in the physical property of the delivery matrix,minimum interference to the release of the active agent,biodegradable without producing any toxicbyproducts, enhance the penetration of the active agent (if the active agent is meant to be absorbed from the delivery site)
  6. 6.  The formulation stays longer at the delivery site improving API bioavailability using lower API concentrations for disease treatment The use of specific bioadhesive molecules allows for possible targeting of particular sites or tissues Increased residence time combined with controlled API release may lead to lower administration frequency The avoidance of first-pass metabolism Dose-related side effects may be reduced due to API localization at the disease site These dosage forms facilitate intimate contact of the formulation with the underlying absorption surface. This allows modification of tissue permeability for absorption of macromolecules ,such as peptides and proteins. Inclusion of penetration enhancers such as Sodium glycocholate, Sodium taurocholate and L-lysophosphotidyl choline and protease inhibitors in the mucoadhesive dosage forms resulted in better absorption of peptides and proteins.
  7. 7.  Medications administered orally do not enter the blood stream immediately after passage through the buccal mucosa. Instead they have to be swallowed and then have to pass through a portion of the GIT before being absorbed. So the action is not very rapid in the GIT as compared when the drug is administered through buccal route. Certain drugs when ingested undergo drug destruction, there are several drugs which are potentially in this category. Many drugs affect liver metabolism and also cause destruction via first pass metabolism of other drugs. Oral ingestions results in more exposure of a drug to the GI tract. One of the side effects of many antibiotics is the destruction of normal GI flora resulting in diarrhea and overgrowth with dangerous organisms such as C. difficile. The absorption of mucoadhesive drugs is adversely affected by the presence of food. Tetracyclines, in particular, complicates the administration of this class of antibiotics via the oral route.
  8. 8.  Mucoadhesive Inner layers called mucosa Inner epithelial Cell lining Covered with viscoelastic fluid. It is secreted by Goblet cells lining the epithelia or by special exocrine glands with mucus cells composed of water and mucin (an anionic polyelectrolyte). Other components include proteins, lipids, electrolytes and mucopolysaccharides Thickness varies from ≈40–50 μm to ≈300 μm
  9. 9. Regions in mucus layer
  10. 10.  General composition of mucus : Water……………………….95% Glycoprotiens and lipids….0.5-5% Mineral salts……………….1% Free proteins………………0.5-1% These units contain an average of about 8-10 monosaccharide residues of five different types. They are: a) L-fucose b) D-galactose c) N-acetyl-D-glucosamine d) N-acetyl-D-galactosamine e) Sialic acid
  11. 11.  Complex-high molecular weight macromolecule consisting of a polypeptide (protein) backbone to which carbohydrate side chains are attached. Generic structure of mucin monomer
  12. 12. Mucus forms flexible, threadlike strands that are internallycross linked by disulphide bond. Disulphide bond present in mucusThe mucus layer which covers the epithelial surface hasvarious roles:• Protective• Barrier• Adhesion• Lubrication
  14. 14.  The mechanisms responsible in the formation of mucoadhesive bonds are not fully known, however most research has described mucoadhesive bond formation as a three step process. Step 1 : Wetting and swelling of polymer (the contact stage) Step 2 : Interpenetration between the polymer chains and the mucosal membrane Step 3 : Formation of chemical bonds between the entangled chains (both known as consolidation stage)
  15. 15. Step 1 The wetting and swelling step occurs when the polymer spreads over the surface of the biological substrate or mucosal membrane in order to develop an intimate contact with the substrate. This can be readily achieved for example by placing a mucoadhesive formulation such as a tablet or paste within the oral cavity or vagina. Swelling of polymers occur because the components within the polymers have an affinity for water.
  16. 16. Step 2 The surface of mucosal membranes are composed of high molecular weight polymers known as glycoproteins. In step 2 of the mucoadhesive bond formation, the mucoadhesive polymer chains and the mucosal polymer chains intermingle and entangle to form semi permeable adhesive bonds. The strength of these bonds 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.
  17. 17. Step 3 This step involves the formation of weak chemical bonds between the entangled polymer chains. 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 mucoadhesive formulations in which strong adhesions between polymers are formed.
  18. 18.  The Theories include :-(1) The electronic theory.(2) The wetting theory.(3) The adsorption theory.(4) The diffusion theory.(5)The Fracture theory(6) The mechanical theory.(7) The cohesive theory. The phenomena of bioadhesion occurs by a complex mechanism. There are seven theories have been proposed till date
  19. 19. 1) The 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 attractive forces within this electronic double layer determines the mucoadhesive strength2) The wetting theory 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
  20. 20. 3) The Adsorption theory According to the adsorption theory, the mucoadhesive device adheres to the mucus by secondary chemical interactions, such as in van der Waals and hydrogen bonds, electrostatic attraction or hydrophobic interactions. For example, hydrogen bonds are the prevalent interfacial forces in polymers containing carboxyl groups. Such forces have been considered the most important in the adhesive interaction phenomenon because, although they are individually weak, a great number of interactions can result in an intense global adhesion
  21. 21. 4) The diffusion theory 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
  22. 22. 5) The Fracture theory This theory attempts to relate the difficulty of separation of two surfaces after adhesion It analyzes the force required to separate two surfaces after adhesion Adhesion Strength = (E ԑ/L )1/2 E =Young’s modulus of elasticity ԑ = Fracture energy L = Critical crack length when two surfaces are separated
  23. 23. 6) The mechanical theory 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 process7) The cohesive theory It proposes that the phenomena of bioadhesion are mainly due to the intermolecular interactions amongst like-molecules.
  24. 24.  Polymer related factors: Molecular weight Concentration of active polymer Flexibility of polymer chains Hydrogen bonding capacity Presence of functional group Spatial conformation Cross linking density Charge on polymer Hydration Hydrophilicity Environment related factors : pH of polymer – substrate interface Applied strength Initial contact time Swelling Physiological factors: mucin trun over
  25. 25. POLYMER RELATED FACTORS:- 1) Molecular weight Bioadhesion is maximum at certain molecular weight. Low molecular weight  interpenetration is more High molecular weight  entanglement is more Bioadhesive force of polymers is increase up to molecular weight 10000, beyond which there is no further gain. 2) Concentration of active polymer In high concentration coiled molecules of polymer become solvent poor and chains available for bioadhesion are less. In low concentration bioadhesion of polymer also decreases.
  26. 26. 3) Degree of hydration Depending on the degree of hydration adhesive properties are different. It is maximum at a certain degree of hydration. High degree of hydration  formation of slippery, non- adhesive mucilage due to large amount of water leads to loss of adhesiveness. 4) Charge on polymer Mucosal surface is negatively charged. So positively charged polymer might facilitate the mucoadhesive process. Chitosan have bioadhesion due to electrostatic attraction between positively charged D- glucosamine residue of chitosan and negatively charged sialic acid residues.
  27. 27. 5) Presence of functional group Due to immobilization of thiol groups on polymers like chitosan & polyacrylic acid their permeation enhancement, enzyme inhibitory & mucoadhesive properties are improved. The immobilization of thiol groups on microparticles improves mucoadhesive properties.6) Spatial conformation Besides molecular weight or chain length, spatial conformation of a polymer is also important. Despite a high molecular weight of 19,50,0000 for dextrans, they have adhesive strength similar to that of polyethylene glycol (PEG), with a molecular weight of 2,00,000. The helical conformation of dextran may shield many adhesively active groups, primarily responsible for adhesion, unlike PEG polymers, which have a linear conformation.
  28. 28. ENVIRONMENT RELATED FACTORS:-(1) pH• pH influences the charge on the surface of both mucus and the polymers.• Mucus will have a different charge density depending on the pH because of the difference in the dissociation of the functional groups on the carbohydrate moiety and amino acids of the polypeptide backbone.• Polyacrylic acid polymers  degree of hydration increase upto pH 4 to 5  slightly increase at pH 6 to 7  decreasing at more alkaline pH. (2) Applied strength• To place a solid bioadhesive system, it is necessary to apply a defined strength. The adhesion strength increases with the applied strength or with the duration of its application, up to an optimum level.
  29. 29. (3) Initial contact time The initial contact time between the mucoadhesives and the mucus layer determines the extent of swelling and the interpenetration of the polymer chains. The mucoadhesive strength increases as the initial contact time increases. (4) Swelling Interpenetration of chains is easier when polymer chains are disentangled and free of interactions. When swelling is too great, a decrease in the bioadhesion occurs, such phenomena must not occur too early, in order to lead to a sufficient time for action of the bioadhesive system.
  30. 30. PHYSIOLOGICAL FACTORS:-(1) Mucin turnover The natural turnover of the mucin molecules from the mucus layer is important for at least two reasons-  The mucin turn over is expected to limit the residence time of mucoadhesive dosage form on the mucus layer.  Mucin turnover results in substantial amount of soluble mucin molecules. These mucin molecules interact with mucoadhesive dosage form before they have a chance to interact with the mucus layer.(2) Disease states The physiological properties of the mucus are known to change during disease conditions such as the common cold, gastric ulcers etc. The exact structural changes taking place in mucus under these conditions are not yet clearly understood.
  31. 31.  They are water soluble and water insoluble polymers which are swellable networks joined by cross linking agents. Characteristic of ideal polymer Degradation products should be non toxic and non absorbable from GIT Good spreadability, wetting, swelling, solubility and biodegradability properties Optimum molecular weight Non irritant to mucous membrane Form a strong non covalent bond with mucin epithelial cell surfaces
  32. 32.  Adhere quickly to moist tissue Allow easy incorporation of the drug Not decompose on storage or during shelf life of dosage form Should possess site specificity Cost effective Should approved by regulatory authorities
  33. 33. According to sourceNatural and modified natural SyntheticAgaros CarbopolChitosan PolycarbophilGelatin Polyacrylic acidHyaluronic acid PolyacrylatesCarrageenan Methacrylic acidPectin Poly Vinyl AlcoholSodium alginate Poly Vinyl PyrollidineCarboxy Methyl Cellulose EthylhexaacrylateThiolated CMC Thiolated polymer, etc.Sodium CMCHECHPCHPMCMethylhydroxyethylcellulose, etc.
  34. 34. According to water solubilityWater soluble Water insolubleCMC, Thiolated CMC, Sodium Carbopol,Polycarbophil,CMC, HEC, HPC,HPMC, MC, Polyacrylic acid, PolyacrylatesHPMC,PVA,PVP, etc. Methacrylic acid, PEG, etc. According to chargeCationic and Anionic UnchargedAminodextran, Chitosan, Hydroxyethylated starch,Chitosan-EDTA, Carbopol HPC, PEGPolycarbophil, Sodium alginate, PVA, PVP, etc.Pectin, Sodium CMC, CMC, etc.
  35. 35. Route/site Bioadhesive formulationOral cavity (Buccal Tablet, Patch, Gel, Ointment,and Sublingual) Chewing gum, Hollow fibersNasal Gel, Microspheres, Dry powdersOcular Insert, gelGastro intestinal Gel, Tablet, Microspheres, Capsule, Hollow fibersSkin/Transdermal Patch, LiposomesVaginal Gel, Microspheres, TabletRectal Gel
  36. 36.  Bioadhesive tablets are immobilized drug delivery systems Formulated as monolithic, partially coated or multilayered matrices Formulation ingredients1) API 6) Sweetening agent2) Mucoadhesive polymer 7) Flavoring agent3) Permeation enhancer 8) Coloring agent4) Diluent 9) Buffering agent5) Lubricant 10) Backing layer polymers
  37. 37. Designs of bioadhesive tablets
  38. 38.  Small surface of contact with mucosa Lack of physical flexibility Difficult to obtain high release rate, which is required for some drugs The extent and frequency may cause irritation to mucosa
  39. 39. 1)Weight variation2) Thickness3) Hardness4) Friability5) Drug content6) Surface pH7) In vitro drug release8) In vitro drug permeation9) Swelling study10) Measurement of residence time / retention time11) Adhesive strength determination
  40. 40. Measurement of residence time / retention time Provides quantitative information on mucoadhesive properties. The GI transit time of many mucoadhesives have been examined using radioisotopes . e.g. 51Cr and the time dependent distribution of the radioactivity in the GIT is measured. Esophageal bioadhesive property porcine oesophageal tissue is used. tissue is washed at a rate of 1ml/min with simulate saliva flow. 1.5 mL of formulation was mixed with ~0.2 MBq Tc99m as a radioactive substance. Eluate is collected upto 30 min. fig : In-vitro apparatus used to measure the residence time to perticular tissue. 41
  41. 41. Measurement of mucoadhesive strengthThree different types of stress, tensile, shear and peel stress are measuredA) Tensile strength
  42. 42. B) Shear and Peel strengthC) Thumb test The adhesiveness is qualitatively measured by the difficulty of pulling the thumb from the adhesive as a function of the pressure and the contact time. It provides useful information on mucoadhesive potential
  43. 43. Dissolution of Buccal tablet:- fig : Mumtaz and Chang model for the dissolution of the buccal tablet. From the inlet dissolution medium is poured and from outlet it is collected and assayed.  45
  44. 44.  Gels includes bioadhesive gels and in situ forming gels Bioadhesive gels These gels highly viscous semisolids prepared by using mucoadhesive polymers Formulated for various sites like buccal, nasal, vaginal, rectal,etc
  45. 45.  Formulation ingredients of bioadhesive gel1) Active pharmaceutical ingredient2) Mucoadhesive polymer3) Permeation enhancer4) Preservative5) Solvent
  46. 46.  In situ gels are in solution form and formed gels upon administration to particular site due to phase transition in environment of that site Gel formation is due to various mechanisms includes, Thermal change pH change change in electrolyte composition combination of any 2 mechanisms
  47. 47. Thermo sensitive gel forming system Thermo sensitive polymer systems are formed fromaqueous polymer solutions with temperature changes Thermo sensitive polymers are copolymers of N-isopropylacrylamide (PNiPAAM), polaxamer, etc. pH sensitive gel forming system pH sensitive gel forming systems, which swell or shrinkin response to changes in the pH Carbopol (polyacrylic acid) is mostly used as pHsensitive polymer
  48. 48.  Ion sensitive gel forming system Ion sensitive gel forming system is new type of gel, in which solution of polymer containing drug triggered to gel form when contact with specific ion at specific site Ion sensitive polymer includes sodium alginate, gellan gum, xyloglucan, carrageenan In situ gels formulate for various sites including nasal, ophthalmic, oral, vaginal, rectal
  49. 49. 1) Drug content2) Viscosity3) pH4) In vitro drug release5)Adhesion properties: Adhesive strength is measured as described in tablets and the other methods are,A)Membrane viscosity The interaction between polymers and cell membranes was examined by labeling the cell membranes with fluorescent probes
  50. 50.  The lipid bilayer and proteins of cell membranes were labeled with pyrene and fluorescein isothiocyanate The fluorescence spectrum of pyrene and the fluorescence depolarization of fluorescein isothiocyanate were used to examine the change in membrane viscosity after interaction with polymer It was assumed in this study that affinity of polymers to cell membranes is linearly related to the increase in membrane viscosity
  51. 51. B) Electrical conductance The adhesion of orabase, carbopol, guar gum, and methyl cellulose to artificial biomembrane in artificial saliva was studied by using a modified rotational viscometer capable of measuring electrical conductance In presence of adhesive material the conductance was comparatively low. As the adhesive was removed the value increased to final corresponding to conductance of saliva, which indicate the absence of adhesion
  52. 52.  Patches are designed for buccal delivery and transdermal delivery of drugs Buccal patches Designed either for unidirectional release or bidirectional release Use of impermeable backing layer will maximize the drug concentration gradient and prolong adhesion because the system is protected from saliva Typically size of such polymeric patches would be 1-3 cm 2 but may have dimensions as large as 10-15 cm2 depending on the site of administration
  53. 53.  Patch contains mucoadhesive polymer and supportive material Matrix system Reservoir system
  54. 54.  Formulation ingredients of Buccal patch1) API2) Mucoadhesive polymer3) Supporting material4) Plasticizer Evaluation of Buccal patch1) Thickness uniformity2) Folding endurance3) Uniformity of weight4) Drug content uniformity5) Swelling study6) Surface pH7) In vitro release study8) Adhesive strength
  55. 55.  Transdermal patches Transdermal patch is a medicated adhesive placed on the skin to deliver a specific dose of medication through the skin and into bloodstream Formulation is same as buccal patches Evaluation of Transdermal patches1) Thickness uniformity2) Moisture content3) Uniformity of weight4) Drug content uniformity5) Flatness study6) Surface pH7) In vitro release study8) Adhesive strength
  56. 56. Mucoadhesion measurement by Modified balance method
  57. 57.  Chewing gums are mobile drug delivery systems The main target mucosa for drug absorption is sublingual mucosa Drug release is generally rapid but not as immediate as in case of fast dissolving tablets Commercially available medicated chewing gums are currently available for pain relief, smoking cessation, travel illness, and freshening of breath Medicated chewing gum offers advantages in comparison to conventional oral mucosal and oral dosage forms both for (a) local treatment of mouth diseases and (b) systemic effect after absorption through the buccal and sublingual mucosa or from the gastrointestinal tract
  58. 58.  Components of chewing gum Component Concentration (%) Drug Max. approximately 50 Gum base 20–40 Bulk sweeteners 30-75 Softeners 0-10 Flavoring agents 1-5 Coloring agents ˂1
  59. 59.  Manufacturing process of chewing gum The most common method comprises mixing the gum base with the other ingredients in a mixer with Z formed blades. The gum base can either be added in a solid form and softened through heating from the jacket of the mixer or from the frictional heat generated during the mixing process, or it can be added in a melted form. Chewing gum can also be manufactured by compression of powders or granulates on a conventional tablet machine (compression technique).
  60. 60.  The release into saliva and disappears rapidly from the oral cavity because of involuntary swallowing The concentration drug in the oral cavity always tends to decrease as a result of salivary dilution The drug is not protected from the environment found in oral cavity Administration of such dosage form is restricted to short time periods because the delivery system in the oral cavity causes disturbance in drinking, eating and speaking
  61. 61.  Films are used for buccal bioadhesive drug delivery Both degradable and non-degradable forms of films have been developed The major method of polymeric film manufacture is the solvent evaporation process Formulation ingredients1) API2) Mucoadhesive polymer3) Plasticizer
  62. 62.  Evaluation of film1) Weight uniformity2) Thickness3) Swelling study4) folding endurance5) Drug content uniformity6) Surface pH7) In vitro drug release8) Mucoadhesion study
  63. 63.  Solid ophthalmic delivery devices (inserts) are thin disks or small cylinders made with appropriate polymeric materials and fitting into the lower or upper conjuctival sac Their long persistence in the perocular area can result in a greater drug bioavailability with respect to liquid and semisolid formulations Mucoadhesive polymers can be profitably used as constituents of inserts to achieve prolonged contact with the conjuctival tissue
  64. 64.  Alternative approach for chewing gum formulations The design of micro porous hollow fiber of polysulphone intended for the delivery of histerelin, a LHRH agonist was reported (Burnside et al.) This fiber is intended to be placed in the buccal cavity for oral mucosal drug delivery The fiber may also prepare for periodontal application
  65. 65.  Multiparticulate system includes microspheres, liposomes and nanoparticlesMicrospheres Bioadhesive microspheres include micro particles and microcapsules(size 1–1000µm in diameter) They have the potential to be used for targeted and controlled release drug delivery; but coupling of bioadhesive properties to microspheres has additional advantages, Efficient absorption and enhanced bioavailability of the drugs due to a high surface to volume ratio A much more intimate contact with the mucus layer Specific targeting of drugs to the absorption site
  66. 66.  Bioadhesive microspheres can be tailored to adhere to any mucosal tissue including those found in eye, nasal cavity, urinary and gastrointestinal tract, thus offering the possibilities of localized as well as systemic controlled release of drugs Their formulation contains API and mucoadhesive polymer Liposomes Liposomes are coated with mucoadhesive polymers and remain for longer period of time and improved the drug therapy Ocular route is widely used for mucoadhesive liposomal preparation Nanoparticles Nanoparticles prepared for mucoadhesive drug delivery by either consisting entirely of a bioadhesive polymer or having an outer coating of it
  67. 67.  Evaluation of multiparticulate system1) Drug entrapment efficiency2) Particle size analysis3) In vitro release study4) Mucoadhesion study Mucoadhesion studyIn microspheres adhesion number is determined The adhesion number (Na) is, Na = (N/No)*100Where, No = total no. of applied particles N = no. of particles attached to the substrate Two methods for measurementA)Falling liquid film methodB) Mucin gold staining
  68. 68. A)Falling liquid film methodThe adhesion of particles to this surface is measured by passing the particle suspension over the surface and by comparing the fraction of particles adhered to the tissue
  69. 69. B) Mucin gold staining In this technique, colloid gold particles, which are red in solution, are stabilized by mucin molecules The interaction between mucin and adhesive particles is monitored by appearance of red color on surface.
  70. 70. EVALUATION OF BDDS IN VITRO / EX VIVO METHODSa. Methods based on measurement of tensile strength.b. Methods based on measurement of shear strength. OTHER IN VITRO METHODSc. Adhesion weight methodd. Fluorescent probe methode. Flow channel methodf. Falling liquid film methodg. Colloidal gold staining methodh. Mechanical spectroscopic methodI. Thumb testj. Viscometric methodk. Adhesion number
  71. 71.  IN VIVO METHODS a. Use of radio isotopes b. Use of gamma scintigraphy In vivo evaluation methods In vivo methods used for evaluation are based on administration of polymers to a laboratory animal and tracking their transit through the GI system. Administration methods include forced oral gavage, surgical stomach implantation and infusion through a loop placed in situ in the small intestine. Tracking generally followed with the help of X-ray studies, radio opaque markers and radioactive elements etc. For e.g. X- ray studies for monitoring GI transit time for bioadhesive tablet made of BaSO4 and radiolabelled microspheres and nanoparticles. 73
  72. 72.  Ocular (Eye) Nasal cavity Oral (Buccal and Sublingual) Skin/Transdermal Gastro-intestinal and Colorectal (Colon+ Rectum) Vaginal
  73. 73.  The eye is one of the most important and complex organs of the body, because of its complicated anatomy many things can go wrong with the eye. Topical drug delivery systems to the eye can be very difficult to achieve because the eye has several protective mechanisms in place to get rid of foreign substances. An effective ocular drug delivery system must be easy to use, comfortable to the patient and maintain substantial concentrations of the drug in the eye to produce therapeutic effects. Problems associated with eye include conjunctivitis, Glaucoma and dry eye.
  74. 74. Ocular Bioadhesive Formulations GelTears® and Viscotears® Liquid gel eye drops are used for dry eye conditions and contain carbomer 980 (polyacrylic acid). Carbomers lubricate the eye by clinging to the surface of the eye. This can help reduce the frequency of their application into the eye. Pilogel® is an eye gel used in the treatment of glaucoma. It contains the high molecular weight polymer polyacrylic acid. The polymer increases the viscosity of the gel which provides a prolonged retention of the gel in the eye.
  75. 75.  Drugs such as antihistamines and steroids are administered as nasal drops or nasal sprays to treat conditions affecting the nose. However nasal mucociliary clearance affects the retention and therefore the effects of the drugs in the nose. The effects of bioadhesive polymers on mucociliary clearance was examined by Zhou and Donovan (1996). Methylcellulose exhibited the most reduction in mucociliary clearance whilst Carbopol 934P showed the least reduction in mucociliary clearance in the rats used.
  76. 76. Bioadhesive formulations for Nasal cavity Rhinocort® Nasal spray is a powdered mixture of the steroid Beclomethasone dipropionate(50μg) and 30mg of Hydroxypropyl cellulose(HPC). Used for patients suffering from nasal allergy. The powder sticks to and swells on the cells lining the nose and remains there for about 6 hrs. Beconase® Nasal spray is used to treat nasal inflammation and nasal allergies associated with hayfever. It contains the active ingredient Beclometasone dipropionate and the bioadhesive polymers carboxymethyl cellulose and microcrystalline cellulose. Nasacort® Nasal spray is used to treat allergies that result in inflammation of the nose. The active ingredient in this product is Triamcinolone acetonide as well as the bioadhesive polymer microcrystalline cellulose. The polymer swells in the presence of water and is able to spread across the nasal mucosa thus helping the distribution of the drug over the mucosal surface.
  77. 77.  The oral cavity or the mouth comprises of the cheeks, teeth and the tongue. It is an entrance of the digestive system and plays many important functions which include chewing, speaking and tasting. Some of these functions are impaired by diseases such as ulcers, microbial infections and inflammation.Examples of products Corlan®: 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 Acacia which helps prolong the effect of the drug in the oral cavity.
  78. 78. The Buccal Mucosa Buccastem® is a drug used in the treatment of nausea, vomiting and vertigo. It contains the bioadhesive agents Polyvinylpyrrolidone and Xanthan gum. Suscard® is a buccal tablet used in the treatment of angina. It contains the bioadhesive agent Hydroxypropyl methylcellulose (HPMC).The sublingual mucosa Drugs administered via the sublingual route are formulated as tablets, powders, solutions or aerosol sprays. Examples of sublingual products include Glyceryl Trinitrate (GTN) aerosol spray and tablet which is administered under the tongue for the prophylactic treatment of angina.
  79. 79.  The skin is the outer covering of the body and consists of different layers. It performs several functions which include:  Protecting the body from injury and invasion by pathogens  Preventing the body from becoming dehydrated  Regulating body temperature  Production of Vitamin D Topical Bioadhesive Formulations The drug delivery systems used in this case are required to adhere to the skin for the purpose of:  Collecting body fluids  Protecting the skin  Providing local or systemic drug delivery
  80. 80. Transdermal Bioadhesive formulations Voltarol Emulgel: This is a gel which provides a local relief from pain and inflammation in the tendons, muscles and joints. It contains the bioadhesive polymer carbomer which aids the absorption of the active drug by spreading it into the affected area. Feldene: This gel is used in the treatment of conditions which are characterised by pain, inflammation and stiffness. The active ingredient in this formulation is piroxicam but the gel also contains two bioadhesive agents to increase its retention at the absorption site. These agents are Carbopol 980 and hydroxyethyl cellulose.
  81. 81.  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.
  82. 82. Rectal Bioadhesive Formulations Anacal® is a rectal ointment used to relieve the symptoms associated with haemorrhoids. 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 haemorrhoids. It contains the polymer propylene glycol.
  83. 83.  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)Common conditions affecting the vagina The epithelium of the vagina contains glycogen, which is broken down enzymes and bacteria into acids such as lactic acid. This maintains a low vaginal pH which is normally between 4 and 5. Such a pH is desirable because it makes the vagina inhospitable to pathogens. Decreased levels of glycogen in the vagina leads to an increase in vaginal pH and makes the vagina more susceptible to infection such as Vaginitis, Bacterial vaginosis, Candidiasis (Thrush), Trichomoniasis etc..
  84. 84. Vaginal bioadhesive 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. Polymers also increase the retention of the active drug in the vagina and also optimise the spread of the formulation over the vaginal epithelium.
  85. 85.  S-DBMP-T(Slowly Disintegrating Buccal Mucoadhesive Plain-Tablet) BCTS (Buccal Covered-Tablet System) VagiSiteTM Bioadhesive Technology
  86. 86.  Iga et al. developed this system S-DBMP-T are prepared by incorporating a relatively large amount of hydroxypropylcellulose in a tablet formulation An example of a typical composition is a tablet composed of 20 mg of drug, 20 mg of hydroxypropylcellulose, 20 mg of carboxymethylcellulose (ECG-505, disintegrating agent), and 60 mg of lactose The S-DBMP-T technology was originally developed for increasing the bioavailability of oxendolone (a steroidal anti-androgen)
  87. 87.  To maintain the tablet shape for as long as possible, Iga et al. developed a method to restrict disintegration from the sides of the tablets The method involved sandwiching a S-DBMP-T tablet between two polyethylene sheets. The upper sheet contained a hole that allowed the tablet to absorb water and disintegrate only through the hole. The lower sheet contained adhesives to allow the delivery system to adhere to the gingiva for a long time.
  88. 88.  Developed by KV Pharmaceutical Company, St. Louis, Missouri, U.S.A. The VagiSiteTM technology comprises a high-internal-phase- ratio, water-in-oil emulsion The internal phase of the emulsion acts as the carrier of the active drug. The drug-laden internal-dispersed phase globules serve a dual purpose for both the sequestering and the controlled release of the active agent, butoconazole nitrate After introduction of the drug-containing emulsion to a mucosal surface, in this case the vaginal mucosa, a thin bioadhesive film of contiguous drug-laden internal-phase globules forms on the mucosal surface
  89. 89.  Rathbone MJ et al., Modified Release Drug Delivery Technology, Marcel Dekker, Inc., 2002, 349-81, 801-6 Vyas SP, Khar RK., Controlled Drug Delivery: Concepts and Advances, Vallabh Prakashan, First Edition: 2002, 257-314 Methiowitz E et al., Bioadhesive Drug Delivery System, Marcel Dekker, Inc., 1999, 551-3, 621-31 Andrews GP et al., Mucoadhesive polymeric platforms for controlled drug delivery, European Journal of Pharmaceutics and Biopharmaceutics 71 (2009) 505–18 Salamat-Miller N et al., The use of mucoadhesive polymers in buccal drug delivery, Advanced Drug Delivery Reviews 57 (2005) 1666– 91