Introduction• Definition : Adhesion can be defined as the bond produced by contact between a pressure - sensitive adhesive and a surface.• Ability to stick,adhere or hold• Bioadhesion is defined as an ability of a material to adhere to a biological tissue for an extended period of time In the case of polymer attached to the mucin layer of a mucosal tissue, the term “mucoadhesion” is used.
Different routes of targeting Bdds They are :1)Buccal delivery system 2)Sub lingual delivery system Depending upon 3)Vaginal delivery the route of system Types of Drug administration of 4)Rectal deliverydelivery systems: the mucoadhesive system drugs they are 5)Nasal delivery different types . system 6)Ocular delivery system 7)Gastro intestinal delivery system
MECHANISM OF MUCOADHESIONMucoadhesive Inner layers called mucosa Inner epithelial Cell lining Covered with viscoelastic fluid.Secreted by Goblet cells Composed of water and mucin (an anionic polyelectrolyte ) Other components include proteins, lipids and mucopolysaccharides ,electrolytesThickness varies from ≈40–50 μm to ≈300 μm Mucus is composed mainly of Water (>95%) Glycoproteins of exceptionally high molecular weight Mineral salts -1 % Free proteins – 0.5 to 1%
Factors affecting Mucoadhesion Polymer related factors: Molecular weight Concentration of active polymer Flexibility of polymer chains Environment related factors : pH of polymer - substrate interface Applied strength Initial contact time Swelling Physiological factors: mucin trun over Disease state
Theories of mucoadhesion The Theories include :-(a) The electronic theory.(b) The wetting theory.(c) The adsorption theory.(d) The diffusion theory.(e) The mechanical theory.(f) The cohesive theory.(g) Fracture theory. The phenomena of bioadhesion occurs by a complex mechanism .There are seven theories have been proposed till date
Electronic theory: Proposes transfer of electrons amongst the surfaces due to difference in their electrical structure resulting in the formation of an electrical double layer thereby giving rise to attractive forces. Wetting theory: Postulates that if the contact angle of liquids on the substrate surface is lower, then there is a greater affinity for the liquid to the substrate surface. If two such substrate surfaces are brought in contact with each other in the presence of the liquid, the liquid may act as an adhesive amongst the substrate surfaces.
The diffusion theory: Assumes the diffusion of the polymer chains, present on the substrate surfaces, across the adhesive interface thereby forming a networked , semipermeable structure. The extent depth to which the polymer chain penetrate the mucus depend on diffusion coefficient &time of contact .
Fracture theory : This theory attempts to relete the difficulty ofseparation of 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
Cohesive theory :proposes that the phenomena of bioadhesion are mainly due to the intermolecular interactions amongst like- molecules. Mechanical theory :explains the diffusion of the liquid adhesives into the micro-cracks and irregularities present on the substrate surface thereby forming an interlocked structure which gives rise to adhesion. Surface roughness =d/h Adsorption theory:After initial contact of the material adhere to surface due to forces acting between the atoms in the two surfaces later result in formation of bonds(primary & secondary) due to the presence of intermolecular forces. hydrogen bonding and Van der Waal’s forces, for the adhesive interaction amongst the substrate surfaces.
Mechanisms of Bioadhesion :The mechanisms responsible in the formation of bioadhesive bonds are not fully known, however most research has described bioadhesive bond formation as a three step process. Step1: Wetting and swelling of polymer Step2: Interpenetration between the polymer chains and the mucosal membrane Step3: Formation of chemical bonds between the entangled chains. Process of bioadhesion can be classified, Chemical (electronic and adsorption theories) Physical (wetting, Diffusion and cohesive theory)
Interdiffusion and Interpenetration of Polymer and Mucus
Bio/muco-adhesive systems: bind to the gastric epithelial cell surface or mucin, which extends the GRT of drug delivery system in the stomach. The ability to provide adhesion of a drug delivery system to the gastrointestinal wall provides longer residence time in a particular organ site, thereby producing an improved effect in terms of local action or systemic effect. Binding of polymers to the mucin/epithelial surface can be divided into three categories: 1. Hydration-mediated adhesion:Certain hydrophilic polymers tend to imbibe large amount of water and become sticky, thereby acquiring bioadhesive properties.
2. Bonding-mediated adhesion:The adhesion of polymers to a mucus/epithelial cell surface involves various bonding mechanisms. Physical-mechanical bonds can result from the insertion of the adhesive material into the folds or crevices of the mucosa. Chemical bonds may be either covalent (primary) or ionic (secondary) in nature. Secondary chemical bonds consist of dispersive interactions (i.e., Vander Waals interactions) and stronger specific interactions such as hydrogen bonds. 3. Receptor-mediated adhesion: Certain polymers bind to specific receptor sites on the cell surfaces, thereby enhancing the gastric retention of dosage forms. Various investigators have proposed different mucin-polymer interactions, such as:
Wetting and swelling of the polymer to permit intimate contact with the biological tissue. Interpenetration of bioadhesive polymer chains and entanglement of polymer and mucin chains. Formation of weak chemical bonds. Sufficient polymer mobility to allow spreading. Water transport followed by mucosal dehydration . The bioadhesive coated system when comes in contact with the mucus layer, various non-specific or specific interactions occurs between the complimentary structures and these interactions last only until the turnover process of mucin the drug delivery system should release its drug contents during this limited adhesion time, in order for a bioadhesive system to be successful.
TYPES OF POLYMERS USED AND THERE BIOADHESIVE NATUREEXCELLENT MODERATE POORCarboxy methyl cellulose Gelatin ++ Pectin ++++Hydroxyl propyl methyl Guar gum ++ Acacia +cellulose +++Carbopol 934 +++ Gum karaya ++ Polyvinyl pyrrolidone +Tragacanth +++Sodium alginate +++Polycarbophil +++Hydroxyl ethyl cellulose+++
Characteristics of Bioadhesive polymers Flexibility- important because it controls the extent of the interpenetration between the polymers and mucosal/epithelial surfaces. Hydrophilicity – Polymers that are hydrophilic in nature are able to form strong adhesive bonds with mucosal membranes because the mucus layer contains large amounts of water. Hydrogen bonding – Hydrogen bonding between the entangled polymer chains forms strong adhesive bonds, therefore the presence of hydrogen bond – forming groups such as OH and COOH groups are vital in large quantities. High molecular weight – Polymers with a high molecular weight are desirable because they provide more bonding sites. Surface tensions – Surface tensions are needed to spread the bioadhesive polymer into the mucosal layer epithelial surface.
CHARACTERISTICS OF AN IDEAL MUCOADHESIVE POLYMER Rapid adherence to mucosa. Exhibit strong interaction with the mucin epithelial tissue. Minimum impact on drug release. Good spreadability, wetting, swelling and solubility and biodegradability properties. Unaffected by the hydrodynamic conditions, food and pH changes. Easy to incorporate in various dosage forms. Possess peel, tensile and shear strengths at the bioadhesive range. Show bioadhesive properties in both dry and liquid state. Demonstrate local enzyme inhibition and penetration enhancement properties.
Bioadhesion and drug absorption Drug absorption is the process by which a drug leaves its site of administration and enters the general circulation. A drug has to cross several cell membranes before reaching its target tissue or organ. These membranes act as barriers which control the transport of drugs and other molecules across cells. The general structure of a cell/plasma membrane consists of a matrix of proteins surrounded by a phospholipid bilayer. Drugs may cross a cell membrane by passive diffusion, facilitated passive diffusion, active transport or pinocytosis. Drug absorption is determined by physicochemical properties of drugs, their formulations (e.g. tablet,capsule,solution) and routes of administration such as oral, parenteral and rectal.
i)Passive Diffusion:Diffusion is the tendency of molecules to spread into an available ii)Facilitated passive diffusion:This is when molecules are transported across membranes cells with the help of carrier proteins. iii)Active Transport:it is the movement of molecules and ions against their concentration gradients, from lower to higher concentrations. iv)Pinocytosis:Pinocytosis (a form of endocytosis) allows a cell to engulf large molecules and fluid that may be present in the extracellular region. Pinocytosis plays a role in the transport of protein drugs.
Passive Diffusion Facilitated passive diffusion Active TransportPinocytosis
TECHNIQUES FOR EVALUATING BIOADHESIVE PROPERTIES INVITRO STUDIES1) Tensile stress measurementa) Wilhelmy plate technique: The Wilhelmy plate technique is traditionally used for the measurement of dynamic contact angles. The instrument measures the bioadhesive force between mucosal tissue and the dosage form . By using the CAHN software system, parameters such as fracture strength, deformation to failure and work of adhesion can be analysed.
b)Electromagnetic force transducer (EMFT): uses a calibrated electromagnet to detach a magnetic loaded polymer DDS from a tissue sample . It has the unique ability to record remotely and simultaneously the tensile force information as well as high magnification video images of bioadhesive interactions at near physiological conditions. EMFT measures tissue adhesive forces by monitoring the magnetic force required to exactly oppose the bioadhesive force.
2)Shear stress measurement:The shear stress technique measures the force that causes a mucoadhesive to slide with respect to the mucous layer in a direction parallel to their plane of contact .o Adhesion tests based on the shear stress measurement involve two glass slides coated with polymer and a film of mucus.o Mucus forms a thin film between the two polymer coated slides, and the test measures the force required to separate the two surfaces.3)Rheological approach:The rheological properties of the mucoadhesive interface (i.e. of the hydrated gel) are influenced by the occurrence of interpenetration step in the process of bioadhesion.
o Chain interlocking, conformational changes and chemical interaction, which occur between bioadhesive polymer and mucin chains, produce changes in the rheological behaviour of the two macromolecular species.4)Colloidal gold staining method:This technique employs red colloidal gold particles, which are stabilized by the adsorbed mucin molecule by forming mucin–gold conjugates .o Upon interaction with mucin–gold conjugates, bioadhesive hydrogels develop a red colour on the surface.o Thus, the interaction between them can easily be quantified, either by the measurement of the intensity of the red colour on the hydrogel surface or by the measurement of the decrease in the concentration of the conjugates from the absorbance changes at 525 nm.
5)Viscometeric method:A simple viscometric method was used to quantify mucin–polymer bioadhesive bond strength Viscosities of 15 %w/v porcine gastric mucin dispersion in 0.1M HCl (pH 1) or 0.1M acetate buffer (pH 5.5) were measured with a Brookefield viscometer in the absence or presence of selected neutral, anionic, and cationic polymers. Viscosity components and the forces of bioadhesion were calculated.6)Fluorescent probe method:Park and Robinson studied polymer interaction with the conjunctival epithelial cell membrane using fluorescent probes . The study was done in an attempt to understand structural requirements for bioadhesion in order to design improved bioadhesive polymers for oral use.
The membrane lipid bilayer and membrane proteins were labelled with pyrene and fluorescein isothiocyanate, respectively. The cells were then mixed with candidate bioadhesive, and the changes in fluorescence spectra were monitored. This gave a direct indication of polymer binding and its influence on polymer adhesion.
INVIVO TECHNIQUES GI transit using radio-opaque technique:It involves the use of radio-opaque markers, e.g., barium sulfate, encapsulated in bioadhesive DDS to determine the effects of bioadhesive polymers on GI transit time. Faeces collection (using an automated faeces collection machine) and x-ray inspection provide a non-invasive method of monitoring total GI residence time without affecting normal GI motility. Mucoadhesives labelled with Cr-51, Tc-99m, In-113m, or I-123 have been used to study the transit of the DDS in the GI tract . Gamma scintigraphy technique:It is a valuable tool used in the development of pharmaceutical dosage forms. With this methodology, it is possible to obtain information non- invasively.
o This technique gives information in terms of:o oral dosage forms across the different regions of GI tracto the time and site of disintegration of dosage formso the site of drug absorptiono also the effect of foodo diseaseo size of the dosage form on the in vivo performance of the dosage forms.
Advantages : Mucoadhesive dosage forms have three distinct advantages when compared to conventional dosage forms. These dosage forms are readily localized in the region applied to improve and enhance the bioavailability of drugs. 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. Mucoadhesive dosage forms also prolong the residence time of the dosage form at the site of application and absorption to permit once or twice a day dosing.
Disadvantages : 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. Many drugs affect liver metabolism and also cause destruction via first pass metabolism of other drugs. One of the side effects of many antibiotics is the destruction of normal GI flora resulting in diarrhea. 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. Mucoadhesive drugs cannot bypass liver metabolism.
CONCLUSIONImprovements in bioadhesive-based drug delivery and, inparticular, the delivery of novel, highly-effective and mucosa-compatible polymer, are creating new commercial and clinicalopportunities for delivering narrow absorption window drugs atthe target sites to maximise their usefulness.Mucoadhesive drug delivery systems are being studied fromdifferent angles, including development of novel mucoadhesives,design of the device, mechanisms of mucoadhesion andpermeation enhancement.
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