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Bioadhesive Drug delivery system :

Bioadhesive Drug delivery system RAGHAVENDRA KUMAR GUNDA M.PHARM 1


BIOADHESION:- Bioadhesion can be defined as 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. The two term bioadhesive and the mucoadhesive are similar except in term of the site of adhesion. 2


Bioadhesive Polymer :- A polymer is a substance formed by the linkage of a large number of small molecules known as monomers. A bioadhesive polymer is a synthetic or natural polymer which binds to biological substrates such as mucosal membrane. Such polymers are sometimes referred to as biological ‘glues’ because they are incorporated into drugs to enable the drugs to bind to their target tissues 3


Mucosal membranes:- These are moist membranes that line passageways and structures in the body that lead to the outside environment such as the mouth, respiratory tract, gastrointestinal tract, nose and vagina. They secrete a viscous fluid known as mucus, which acts as a protective barrier and also lubricates the mucosal membrane. The primary constituent of mucus is a glycoprotein known as mucin as well as water and inorganic salts. 4


HISTORY:- Bioadhesive drug delivery formulations were introduced in 1947 when gum tragacanth was mixed with dental adhesive powder. The aim was to deliver Penicillin into the oral mucosa. This later became Orabase ®, a formulation used to treat mouth ulcers. This product is available as a paste which will stick to the wet surfaces of the mouth and form a protective film over the mouth ulcer. Orabase paste contains polymers such as gelatin, pectin and Carboxymethylcellulose. Some examples of Orabase products are shown below 5


BIOADHESIVE POLYMER:- Bioadhesive polymers come from both natural and synthetic sources, some common examples are highlighted below: Acacia gum - This natural polymer is a dried gum obtained from the stem and branches of the tree Acacia senegal. It is used as a thickener in pharmaceuticals. Alginic acid – Is a natural polymer found in the cell walls of brown algae. It is widely used in the manufacture of alginate salts such as sodium alginate which is a constituent of Gaviscon liquid ® . Carbomers – Are polyacrylic acid polymers widely used in the pharmaceutical and cosmetic industries as thickening agents.. Carbomers have a huge advantage in formulation science because they adhere strongly to mucosal membranes without causing irritation, they exhibit low toxicity profiles and are compatible with many drugs. 6


CONT……. Hydroxypropyl methylcellulose (HPMC) – This polymer is included in preparations used to moisten contact lenses and in oral gels. Sodium hyaluronate - A high molecular weight biological polymer made of repeating disaccharide units of glucuronic acid and N-acetyl-D – glucosamine. This polymer is used during intraocular surgery to protect the cornea and also acts as a tear substitute in the treatment of dry eyes. Other examples of polymers include: - pectin - polyvinylalcohol (PVA) - polyvinylpyrrolidone (PVP) - tragacanth 7


MECHANISMS OF BIOADHESION:- The mechanisms responsible in the formation of bioadhesive bonds are not fully known. Most research has focused on analysing the bioadhesive interactions between polymer hydrogel and soft tissue. Wetting and swelling of polymer Interpenetration between the polymer chains and the mucosal membrane Formation of chemical bonds between the entangled chains 8


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 bioadhesive formulation such as a tablet or paste within the oral cavity or vagina. Bioadhesive 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. The image below shows swelling of a polymer 9


Step 2:- The surface of mucosal membranes are composed of high molecular weight polymers known as glycoproteins. In step 2 of the bioadhesive bond formation, the bioadhesive 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. The interpenetration of polymer chains Bioadhesive polymer chains Mucus polymer chains 10


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 Vander Waals Interactions and hydrogen bonds. Both primary and secondary bonds are exploited in the manufacture of bioadhesive formulations in which strong adhesions between polymers are formed. Mechanisms of bioadhesion Step 3 11


Ideal polymer characteristics for Bioadhesion:- Sufficient quantity of the hydrogen binding chemical groups. Anionic surface charges. High molecular weight. High chain flexibility Surface tension. These are helpful in formation of bond which are either… Chemical bonds Mechanical or Physical bond 12




Types of bioadhesive drug delivery system:- 1.Solid Bioadhesive Formulations : Examples of such formulations are given below. Tablets : Dry formulations such as tablets are able to form strong interactions with mucosal surfaces by attracting water from the mucosal surface. An example is Buccastem ® which is used in the treatment of nausea, vomiting and vertigo . It is administered to the buccal mucosa (inside of the cheeks). Inserts: These include ocular inserts such as eye drops and eye gels. An example is Pilogel® which is used in the treatment of glaucoma (raised pressure in the eye). Pilogel ® contains the bioadhesive agent carbomer 940,which minimises irritation and prevents the loss of product by keeping the gel in place. Lozenges: Bioadhesive lozenges containing antibiotics and local anaesthetics can be used topically to treat conditions affecting the mouth. Research has shown that bioadhesive lozenges are able to release drugs in a controlled manner by prolonging the drug release. 14


2. Semi-solid bioadhesive Formulations:- Gels : Bioadhesive polymers that are able to form gels include polyacrylic acid which adheres to mucosal surfaces in a cross-linked form. Gel formulations are used to target several parts of the body including the eye, vagina and oral cavity. An advantage of gels is that they are able to form a very close contact with mucosal membranes and rapidly release drugs at their site of absorption. Films: Bioadhesive films that are flexible in nature can be used to directly deliver drugs to specific mucosal membranes. They form a very close contact with the membrane and are able to deliver an accurate dose of drug to the site of absorption. An example of a bioadhesive film is Zilactin ® which is used in the treatment of cold sores and mouth ulcers. 15


3.Liquid Bioadhesive Formulations:- Viscous liquids: Viscous liquids containing bioadhesive polymers such as carboxymethyl cellulose may be used to protect mucosal membranes from damage and irritation. They can also be used to deliver drugs to specific sites. An example is artificial tears, a carbomer solution used to treat dry eyes. Gel-forming liquids: These formulations are administered as liquids but undergo a change in their form in response to conditions such as temperature and pH. Such formulations are used for the controlled-release of drugs into the eye. 16


Bioadhesive or mucoadhesive formulations have been targeted to various anatomical locations to aid drug delivery and absorption. These structures possess mucous membranes which protect the cell from damage. Drug delivery to each anatomical region is discussed below. Body site Systems Eye Mucoadhesive eye drops / inserts Nasal cavity Nasal drug delivery systems Oral cavity Dental gels / buccal systems Skin Patches, tapes, dressings Vagina Local vaginal delivery systems Rectum Local/systemic rectal delivery systems Targets for Bioadhesive Formulations:- 17

Targets for Bioadhesive Formulations:-:

18 Targets for Bioadhesive Formulations:- 1. The eye:- 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. A brief anatomy of the eye 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.

Some conditions of the eye:-:

Some conditions of the eye:- Conjunctivitis – This is an inflammation of the conjunctivae, which are mucous membranes covering the whites of the eye and the inside of the eyelids. It is caused by bacteria, viruses or allergens and the signs and symptoms displayed by the patient will be dependent on the type of conjunctivitis. The symptoms include: redness of the eye, grittiness or itchy eyes and the presence of a sticky or watery discharge. Dry eye – This occurs when people don’t have enough tears or the adequate composition of tears required to lubricate the eyes. The occurrence of dry eye increases with age and is therefore common in older people. The eyes become itchy, gritty, painful and have a burning sensation. Glaucoma – This disorder is characterised by pressure in the eyeballs and causes excessive amounts of aqueous humour (the fluid that fills the eyeballs). This puts pressure on the optic nerves and compresses the blood vessels in the eye. The resultant effects include abnormalities in vision and total blindness. 19

Ocular Bioadhesive Formulations:-:

Ocular Bioadhesive Formulations:- Various ocular bioadhesive formulations have been designed to treat specific conditions affecting the eye. Such formulations can produce a prolonged or sustained release of drugs into the eye. Drugs containing polymers attach to the mucin on the conjunctival surface by means of non-covalent bonding. The polymer is able to remain in contact with the surface of the eye until mucin replaces itself or until the pressure of blinking removes the drug from the eye. EXAMPLES OF PRODUCTS Hypotears ® and Sno Tears® Eye drops are used for dry eye and tear deficiency and they generally lubricate the eyes. They both contain the polymer polyvinyl alcohol (PVA) which increases tear production and protects the eye from further irritation. The monomer from which PVA is made Vinyl alcohol 20

Ocular Bioadhesive Formulations:-:

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. POLYACRYLIC ACID 21

Targets for Bioadhesive Formulations:-:

Targets for Bioadhesive Formulations:- 2. The Nasal Cavity The nasal cavity is the air passage behind the nose. This is the source of the moisture which is added to air during the breathing process. The nasal cavity has a complex structure and can become inflamed during conditions such as the common cold, nasal allergies and flu. 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. Mucociliary clearance transports mucus from the cells lining the nose and protects the respiratory tract from damage caused by inhaled substances including dirt particles and medicines. 22

Nasal Bioadhesive Formulations:-:

Nasal Bioadhesive Formulations:- By mixing drugs targeted for the nose with bioadhesive polymers, the process of mucociliary clearance of the drug can be overcome. The effects of bioadhesive polymers on mucociliary clearance was examined by Zhou and Donovan (1996). All the polymers examined showed decreases in mucociliary clearance. Methylcellulose exhibited the most reduction in mucociliary clearance whilst Carbopol 934P showed the least reduction in mucociliary clearance in the rats used. EXAMPLES OF PRODUCTS Rhinocort ® Nasal spray is a powdered mixture of the steroid Beclomethasone dipropionate (50 μ g) and 30mg of Hydroxypropyl cellulose(HPC). Patients suffering from nasal allergy administer one spray twice a day into the nasal cavity.The powder sticks to and swells on the cells lining the nose and remains there until approximately six hours after administration. 23

Nasal Bioadhesive Formulations:- :

Nasal Bioadhesive Formulations:- Beconase ® Nasal spray is used to treat nasal inflammation and nasal allergies associated with hay fever. 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. 24

Targets for Bioadhesive Formulations:- :

Targets for Bioadhesive Formulations:- 3. The oral cavity The oral cavity or the mouth comprises of the cheeks, hard and soft palates 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. Some of the common conditions affecting the oral cavity are discussed on the next slide. 25

Common conditions affecting the oral cavity:

Common conditions affecting the oral cavity Mouth ulcers : A mouth ulcer can be described as a breach or break in the mucous membrane that lines the inside of the mouth. The majority of patients suffer from minor aphthous ulcers (MAU). These ulcers are roundish, shallow, grey-white in colour and are painful. They are small and appear in small crops. Oral thrush: This is an infection caused by the fungus Candida albicans in the oral cavity. It can also arise due to risk factors such as diabetes, recent antibiotic therapy and inhaled corticosteroids. Oral thrush presents itself as soft creamy-white patches which can be wiped off. The lesions are painful and can occur anywhere in the oral cavity. Gingivitis: Gingivitis means inflammation of the gums. It is caused by the build-up of plaque (a layer of bacteria) on the teeth. The gums become reddened, swollen and bleed easily with slight trauma such as brushing the teeth. 26

Oral Bioadhesive Formulations:- :

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. 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. For treatment to be successful each pellet or lozenge must be allowed to slowly dissolve in the mouth, close to the ulcer. 27

Oral Bioadhesive Formulations:-:

Oral Bioadhesive Formulations:- Bonjela ® 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® oral gel contains the antifungal agent Miconazole and is used to treat oral thrush. It also contains an adhesive agent known as pregelatinised 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® 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) which helps retain the gel inside the oral cavity. 28

Targets for Bioadhesive Formulations:-:

Targets for Bioadhesive Formulations:- 3a.The Buccal Mucosa 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 layers to the superficial layers. The buccal mucosa is less permeable compared to other oral drug delivery systems and is unable to retain dosage forms at the site of absorption. The use of bioadhesive polymers in buccal drug delivery systems allows a better retention of a dosage form by spreading it over the absorption site. Examples of Products 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). 29

Targets for Bioadhesive Formulations:-:

Targets for Bioadhesive Formulations:- 3b. The sublingual mucosa The sublingual mucosa surrounds the sublingual gland which is a mucin-producing salivary gland located underneath the tongue. This mucosa is relatively permeable and gives a rapid absorption of many drugs due to its excellent blood supply. The sublingual route of drug delivery is convenient, accessible and generally well accepted by patients. Drugs administered via the sublingual route are formulated as tablets, powders, solutions or aerosol sprays. This route is appropriate for many drugs as long as the drug is able to go into solution with saliva in the mouth. Examples of sublingual products include Glyceryl Trinitrate (GTN ) aerosol spray and tablet which is administered under the tongue for the prophylactic treatment of angina. 30

Targets for Bioadhesive Formulations:-:

Targets for Bioadhesive Formulations:- 4.The Skin 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 Cross section of the skin 31

Topical Bioadhesive Formulations:-:

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 Adhesion can be described as the formation of a new mechanical bond between the skin and the adhesive agent. Bioadhesive products targeted to the skin are formulated into different dosage forms which include liquids, powders and semi-solids such as ointments and transdermal patches. Transdermal patches are sustained-release devices that release a specific amount of drug whilst firmly attached to the skin. They must provide a firm, soft contact with the skin but also allow the patch to be easily removed with minor effort. 32

Topical Bioadhesive Formulations:- :

Topical Bioadhesive Formulations:- Examples of Products 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. Evorel®: Is a patch used in hormone replacement therapy (HRT) for oestrogen deficiency. It consists of an adhesive matrix through which the active drug (estradiol) is evenly distributed. The adhesive polymers used are guar gum and polyacrylic acid which holds the patch firmly on the skin surface. 33

Targets for Bioadhesive Formulations:- :

Targets for Bioadhesive Formulations:- 5. The Vagina 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 ) . Histology of the vaginal mucosa The female reproductive System 34

Common conditions affecting the vagina:- :

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. Common vaginal infections Vaginitis : Vaginitis means inflammation of the vagina and it creates discharge, odour, irritation or itching. It has many causes which includes infection with Trichomonas vaginalis, dietary deficiency or poor hygiene. 35

Common conditions affecting the vagina:-:

Common conditions affecting the vagina:- Bacterial vaginosis: The causal organism often implicated in C. albicans this infection is Gardnerella vaginalis , although other bacteria present in the vagina also contribute to the cause. The infection arises due to the overgrowth of these bacteria . About 50% of patients will have a thin white discharge with a strong fishy odour. Candidiasis (Thrush): Is a common yeast infection caused by the organism Candida albicans . The signs and symptoms of thrush are a white cheesy discharge that itches and irritates the vagina. T. vaginalis Trichomoniasis: Is a sexually - transmitted infection caused by the organism Trichomonas vaginalis . The symptoms in women include vaginal itching as well as a frothy, foul-smelling, greenish-yellow discharge. 36

Vaginal bioadhesive formulations:-:

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. Localised application of vaginal formulations enables the spread of these formulations over the target area, which allows an effective therapy. 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 optimises the spread of the formulation over the vaginal epithelium . 37

Vaginal bioadhesive formulations:-:

Vaginal bioadhesive formulations:- Product Function of Product Bioadhesive Agent Dosage Form Aci-Jel ® Maintains vaginal acidity Acacia, Tragacanth Vaginal Gel Crinone ® Used for Progesterone deficiency Carbomer Vaginal Gel Estring ® Restores Oestrogen deficiency Silicone Polymers Vaginal Ring Gynol-II ® Spermicidal Contraceptive Carboxymethyl cellulose Vaginal Gel Zidoval ® Treatment of bacterial vaginosis Carbomer Vaginal Gel Examples of vaginal products:- 38

Targets for Bioadhesive Formulations:-:

Targets for Bioadhesive Formulations:- 6.The Rectum 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. 39

Rectal Bioadhesive Formulations:-:

Rectal Bioadhesive Formulations:- Bioadhesive polymers are incorporated into rectal suppositories to prolong the retention of the active drug in the rectum. Prolonged retention in the rectum increases the chances of reaching a therapeutic outcome. EXAMPLES OF PRODUCTS Anacal ® Is a rectal ointment used to relieve the symptoms associated with hemorrhoids. 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 . Preparation H® Suppositories help shrink the haemorrhoidal tissue which is swollen by irritation. It contains the polymer polyethylene glycol . 40


TECHNIQUES FOR EVALUATING BIOADHESIVE PROPERTIES:- In vitro techniques:- Tensile stress measurement:- 1. 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. 41


2. Electromagnetic force transducer (EMFT): The 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. 3. Texture analyzer:- 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. Adhesion tests based on the shear stress measurement involve two glass slides coated with polymer and a film of mucus. 42


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. 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. The rheological studies provide an acceptable in vitro model representative of the in vivo behaviour of mucoadhesive polymers. Colloidal gold staining method:- This technique employs red colloidal gold particles, which are stabilized by the adsorbed mucin molecule by forming mucin– gold conjugates [55]. Upon interaction with mucin–gold conjugates, bioadhesive hydrogels develop a red colour on the surface. 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. 43


Viscometeric method:- A simple viscometric method was used by Hassan and Gallo 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. Fluorescent probe method:- Park and Robinson studied polymer interaction with the conjunctival epithelial cell membrane using fluorescent probes. 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 44


In vivo 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. Mucoadhesive 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. 45


Case studies:- Design and evaluation of novel pH-sensitive chitosan nanoparticles for oral insulin delivery Chitosan nanoparticles (CS NPs) have been commonly regarded as potential carriers for the mucosal delivery of therapeutic peptides because of their biocompatibility, bioadhesion and permeation enhancing properties. However, they have limited colloidal stability and readily dissociate and dissolve in the acidic gastric conditions CS NPs were formulated by ionic cross-linking with hydroxypropyl methylcellulose phthalate (HPMCP) as a pH-sensitive polymer and evaluated for the oral delivery of insulin. In vitro results revealed a superior acid stability of CS/HPMCP NPs with a significant control over insulin release and degradation in simulated acidic conditions with or without pepsin. Following peroral administration, CS/HPMCP NPs increased the hypoglycemic effect of insulin by more than 9.8 and 2.8-folds as compared to oral insulin solution and insulin-loaded CS/ tripolyphosphate (TPP) NPs, respectively. 46


In vitro release of insulin:- 47


Protection against gastric degradation:- 48


In vivo mucosal adhesion and penetration of the nanoparticles:- 49


In vivo hypoglycemic effects:- 50


CONCLUSION:- Results indicated that the acid stability of CS NPs and their ability to protect the entrapped insulin against gastric degradation were sig- nificantly improved by formulation with HPMCP. Furthermore, the proposed NPs showed a higher degree of mucoadhesion and deeper penetration through the small intestine as compared with CS/TPP NPs. The in vivo data clearly evidenced the ability of CS/HPMCP NPs to enhance the peroral delivery of insulin. 51


Summary:- The concept of bioadhesion involves the binding of a natural or synthetic , bioadhesive polymer to biological substrates such as mucous membranes. Bioadhesive drug delivery systems have been available since the late 1940s and have become an important route of delivering drugs. The earlier applications of bioadhesive formulations mainly involved the oral cavity and the gastrointestinal tract. These days bioadhesive drug delivery systems have been developed to target a wider variety of mucosal and epithelial surfaces, these include the vagina, the skin and the nasal cavity. In most instances bioadhesive formulations are preferred over the conventional methods of drug delivery. This is because Bioadhesion allows the retention of the active drug over the mucosal surface and prolongs the contact time between the polymer and mucosal surface. Bioadhesive drug delivery also offers a controlled release of drugs. From a patient’s point of view this is ideal because the frequency of drug administration is reduced which in turn improves patient compliance. 52





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