A Seminar on

Bioadhesive site for drug delivery

Keyur Vasava…

Bioadhesion: It is the term that describes the adhesion of a polymer to a biological substrate.
When the adhesion is restricted to the mucus layer lining of the mucosal surface it is termed as mucoadhesion. The mucosa lines a number of regions of the body including the gastrointestinal tract, the urogenital tract, the airways, the ear, nose, and eye. These represent potential sites for attachment of any mucoadhesive system and hence, the mucoadhesive drug delivery system may include the following: 1. Buccal delivery system 2. Nasal delivery system 3. Ocular delivery system 4. Transdermal delivery system

5. Gastrointestinal delivery system 6. Vaginal delivery system 7. Rectal delivery system

1) Buccal delivery system
Structure of oral mucosa: The oral cavity contains four anatomically distinct sites with unique tissue types, which include the palatal, gingival, sublingual and buccal mucosa. The palatal tissue refers to the anatomical sites associated with the roof of the mouth. The gingival tissue surrounds the teeth and holds them in place. The sublingual tissue is composed of the floor of the mouth and ventral tongue, and the buccal mucosa refers to the inside of the cheek, and inside of the upper and lower lip. The oral mucosa is composed of an outermost layer of stratified squamous epithelium. Below this lies a basement membrane, a lamina propria followed by the submucosa as the innermost layer. The epithelium is similar to stratified squamous epithelia found in the rest of the body in that it has a mitotically active basal cell layer, advancing through a number of differentiating intermediate layers to the superficial layers, where cells are shed from the surface of the epithelium. The epithelium of the buccal mucosa is about 40-50 cell layers thick, while that of the sublingual epithelium contains somewhat fewer. The epithelial cells increase in size and become flatter as they travel from the basal layers to the superficial layers. The turnover time for the buccal epithelium has been estimated at 5-6 days , and this is probably representative of the oral mucosa as a whole. The oral mucosal thickness varies depending on the site: the buccal mucosa measures at 500-800 µm, while the mucosal thickness of the hard and soft palates, the floor of the mouth, the ventral tongue, and the gingivae measure at about 100200 µm. The composition of the epithelium also varies depending on the site in the oral cavity. The mucosae of areas subject to mechanical stress (the gingivae and hard palate) are keratinized similar to the epidermis. The mucosae of the soft palate, the sublingual, and the buccal regions, however, are not keratinized . The keratinized epithelia contain neutral lipids like ceramides and acylceramides which have been associated with the barrier function. These epithelia are relatively impermeable to water. In contrast, non-keratinized epithelia, such as the floor of the mouth and the buccal epithelia, do not contain acylceramides and only have small amounts of ceramide. They also contain small amounts of neutral but polar lipids, mainly cholesterol sulfate and glucosyl ceramides. These epithelia have been found to be considerably more permeable to water than keratinized epithelia.

Fig. 1 Buccal mucosa

Advantages of buccal drug delivery:
         Offers an excellent route, for the systemic delivery of drugs with high first pass metabolism, thereby offering greater bioavailability. Quicker onset of action. The buccal mucosa is highly perfused with the blood vessels and offers a greater permeability than skin. The presence of saliva insures relatively large amount of water for drug dissolution unlike in case of rectal and transdermal route. A significant reduction in dose acan be achieved thereby reducing dose related side effects. Drugs which are unstable in the acidic environment are destroyed by enzymatic or alkaline environment of intestine can be administered by this route. Drugs which show poor bioavailability via the oral route can be administered conveniently. This route provides an alternative for the administration of various hormones, narcotic analgesic, steroids, enzymes, cardiovascular drugs, etc. Systemic absorption is rapid

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The buccal mucosa is highly perfused with blood vessels and offers a greater permeability than the skin. Termination of therapy is easy.

Disadvantages:        Not suitable for drugs with unpleasant taste ,odour or which irritate the oral mucosa Only drugs with small dose requirements can be administered. Eating and drinking may become restricted. Drugs which are unstable at buccal pH cannot be administered by this route. Only those drugs, which are absorbed by passive diffusion, can be administered by this route Swallowing of the formulation by the patient may be possible 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.

Bioadhesive dosage forms designed for buccal drug delivery includes: a) b) c) d) Buccal tablets Patches films gels and in-situ gel.

2) Nasal delivery system:
Anatomy and physiology of nasal cavity: The distance from the tip of the nose to the pharyngeal wall is about 10–12 cm. The nasal septum divides the nose into two nasal cavities, each with a 2–4-mm-wide slit opening. Each cavity contains three distinct functional regions. The vestibular region is located closest to the nasal passage opening, contains long hairs, and serves as a filter for incoming particles. The respiratory region, containing the largest surface area, is located between the vestibular and olfactory regions. The respiratory region is considered the most important section for delivering drug systemically. Finally, the olfactory region is located in the uppermost portion of each cavity and opposite the septum.This is the region responsible for functions associated with smell.The epithelium of the respiratory region consists of four different cell types :basal, mucus-containing goblet, ciliated columnar, and nonciliated columnar. The ciliated columnar cell is the most predominant. The cilia beat in a wave-like, coordinated manner to transport mucus and trapped particles tothe pharynx area for subsequent ingestion. Cells in the respiratory region are covered

by approximately 300 microvilli, which greatly increase the surface area of the nasal cavity. The lamina propria, below the epithelium, houses blood vessels, nerves, and both serous and mucus secretory glands. Blood is delivered to the nose from the external and internal carotid arteries. The lamina propia contains a dense network of capillaries. A mucus layer, resulting from nasal and lacrimal gland secretions as well as plasma transudate, is present on the nasal passage epithelium. The pH of secretions ranges from 5.5 to 6.5 and from 5.0 to 6.7 in adults and children, respectively. The mucus consists of an outer viscous layer of mucus (gel) and a watery (sol) layer located along the mucosal surface. Glycoproteins, particularly mucin, are responsible for the gel-like appearance of the mucus. Lysozymes, enzymes, and immunoglobulins in addition to other proteins may also be found in the mucus. Approximately 3% of the mucus consists of these proteins while the remainder is made of 90–95% water and 1–2% salt.

Fig. 2 Nasal mucosa

Advantages of Nasal Drug Delivery System:  Drug degradation that is observed in the gastrointestinal tract is absent.  Hepatic first pass metabolism is absent.  Rapid drug absorption and quick onset of action can be achieved.  The nasal route is an alternative to parenteral route, especially for protein and peptide drugs.

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Rapid onset of action. Ease of administration, non-invasive. Minimal aftertaste Self administration

Disadvantages of Nasal Drug Delivery System:  Nasal administration is primarily suitable for potent drugs since only a limited volume can be sprayed into the nasal cavity.  Drugs for continuous and frequent administration may be less suitable because of the risk of harmful long term effects on the nasal epithelium.

Bioadhesive dosage forms for nasal delivery includes: a) b) c) d) e) Gels Sprays and aerosols Powders In-situ gel Microspheres.

3) Ocular Drug Delivery:
Anatomy and Physiology of eye: The eye is a sensory organ that converts light to an electric signal that is treated and interpreted by the brain. Briefly, the eye ball is covered by three layers: an outer fibrous protective layer(sclera and cornea), a middle vascular layer(choroid),and an inner nervous layer (retina). The cornea is a clear, transparent, thin avascular tissue that is composed of five layers: epithelium, bowmans’s layer, stroma, Descemet’s membrane and endothelium. The stroma is the only hydrophilic layer. The eye is generally divided into two parts: the anterior and the posterior segments. The anterior segment includes the cornea, sclera, ciliary body, and the lens; these structures delimit a cavity: the anterior chamber filled with the aqueous humor. The posterior segment includes all the structures between the lens and the optic nerve that delimit a cavity: the vitreous filled with an aqueous gel (the vitreous humor). The eye possesses efficient protective mechanisms like reflex blinking, lachrymation, and drainage, while lid closure protects the eye from external aggression. Tears permanently wash the surface of the eye and exert an anti-infectious activity through the lysozyme and immunoglobulins they contain. Finally, the lachrymal fluid is drained down the nasolacrimal

pathways. All these protective mechanisms are responsible for te rapis and extensive procorneal loss of topically applied ophtalmic drugs.

Fig 3. Eye Advantages of ocular drug delivery:  Local drug delivery in case of ocular diseases like glaucoma.  Drug delivery for treating the ocular infections.

Disadvantages of ocular drug delivery:  Less capacity of cualdy sac (up to 7.5µlit)  Dilution of drug due to lachrymal secretion.  Nasolachrymal drainage Bioadhesive dosage form designed for ocular drug delivery: a) b) c) d) In-situ gel Ocusert Gels and ointments containing liposomes and nanoparticles Inserts

4) Transdermal Drug Delivery:
Anatomy and Physiology of skin:

The main functions of the skin are protection against dessication and injury an plays an important role in thermo regulation and water balance. Two principal layers are distinguished: the epidermis which is the surface layer and the dermis or cornium, which is a subadjacent connective tissue layer. The principal cell of the skin is the keratinocyte. It is stacked in several layers to form the keratinized squamous stratified epithelium. The layers are stratum basale, stratum spinosum, stratum granulosum, stratum lucidum and stratum corneum. Fig. 4. Skin

The dermis consists of a matrix of connective tissue woven from fibrous proteins(collagen, elastin and reticulin) that are embedded in an amorphous ground substance of mucopolysaccharide. Nerves, blood vessels and lymphatics traverse the matrix and skin appendages (eccrine sweat glands and pilosebaceous glands) pierce it. The dermis needs an efficient blood iarrh to convey nutrients, remove waste products, regulate pressure and temperature and contribute to skin colour. Advantages of topical drug delivery:

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Provides large surface area. It avoids first pass metabolism and gastrointestinal irritation. Non-invasive method of drug administration. Self administration. Suitable in instances like vomiting/ iarrhea where oral route is not desirable. Therapy can be quickly terminated by removal of the patch from the skin. Less chances of over or under dosing as the result of prolonged preprogrammed delivery of drug at the required therapeutic rate.

Disadvantages of topical drug delivery system:    Suitable for drug having sufficiently low molecular weight Onset of action is delayed Transdermal drug delivery systems could be unsuitable for drugs that irritate or sensitize skin

Bioadhesive dosage form designed for transdermal drug delivery includes: a) Metered dose transdermal spray b) Transferosomes, liposomes, etc 5) Gastrointestinal Drug Delivery: Anatomy and Physiology: Basically the entire GIT from mouth to rectum is made up of 4 different layers: serosa, muscularis mucosa, submucosa and mucosa. The pH of gastric fluid varies from 1-3.5 depending on the fasting or fed state. Stomach has 3 parts: fundus, body and pylorus. The epithelium of stomach consists of columnar cells which are covered with the protective mucus layer. The surface of the epithelium is pierced by the openings of gastric glands which are responsible for the secretion of hydrochloric acid and other digestive enzymes.


Fig. 5 Gastrointestinal tract Advantages of gastrointestinal drug delivery:   For the delivery of drugs used in treatment of local diseases of stomach like acidity, H.pylori infection. Improvement in the bioavailability of drugs having absorption window in the stomach or those which are degraded in the intestinal pH.

Disadvantages of gastrointestinal drug delivery:   Due to constant renewal of mucus layer, retention of bioadhesive dosage form is difficult. Not suitable for drugs that might produce gastric lesions like NSAIDs.

Bioadhesive dosage forms for gastrointestinal drug delivery includes: a) In situ floating gels b) Bioadhesive tablets and capsules c) microparticulate systems including microspheres, nanoparticles, pellets, etc


6) Vaginal Drug Delivery:
Anatomy and physiology of vagina: Vagina is a part of female reproductive system. The walls of the vagina are composed of four distinctive layers: the stratified mucosa, submucosa, muscularis, and the tunica adventitia. The stratified mucosa, which offers the main barrier to drug absorption, consists of an epithelium and an underlying lamina propria, with the thickness of the epithelium varying by 200–300 μm as a result of changes in estrogen levels during the menstrual cycle. Therefore, the degree of estrogenization of vaginal epithelium has important consequences for drug permeation through the tissue. The cellular structure of vaginal epithelium consists of five distinct cytological layers: the basal, parabasal, intermediate, transitional, and superficial layers. The basal cells, typically cuboidal in shape and characterized by the presence of microvilli on the surface of the cell membrane, are responsible for the continuous production of squamous cells. Parabasal cells are polygonal in shape and differ slightly from the basal cells in having a substantially greater amount of surface microvilli. The cells of the intermediate layer are of the largest cell type and also exhibit microvilli. The transitional cells that follow may show noticeable signs of involution characterized by the reduction of microvilli and intercellular junctions. The superficial layer, as the name suggests, are the cells of the outermost layer, squamous in shape and normally devoid of keratin. These cells store considerable amounts of glycogen, which is released into the vaginal lumen when the surface cells are exfoliated. All layers of the epithelium consist of living cells that renew continuously as they are stimulated by hormonal action and intracellular communication. The constant loss and renewal of cells is characteristic of epithelial membranes. Epithelial cells are very closely packed and are joined together by junctional complexes. Thus, there is no room for blood vessels between adjacent epithelial cells. The epithelium must therefore receive nourishment from the underlying connective tissue, which has large intercellular spaces that can accommodate blood vessels and nerves. Epithelial membranes are attached to the underlying connective tissue by the basement lamina, consisting primarily of proteins and polysaccharides. Vaginal epithelium is in constant contact with vaginal fluid, formed primarily from transudate that passes through the vaginal wall from the blood vessels. It is mixed with vulval secretions from sebaceous and sweat glands. Vaginal fluid may also contain several enzymes, enzyme inhibitors, proteins, carbohydrates, amino acids, alcohols, hydroxyketones, and aromatic compounds. Vaginal fluid is normally mixed with cervical mucus and sloughed cells from the vaginal epithelia to the extent that this mucus, produced by glandular units within the cervical canal, is the major component of the fluid. The amount, composition, and physical characteristics of cervical mucus change with the menstrual cycle, making its production estrogen-dependent. At the time of ovulation, the amount of cervical secretions further increases, resulting in an increase in the overall volume of vaginal fluid. Consequently, there is an increase in fibrosity, pH, and mucin content and a decrease in the viscosity,

cellularity, and albumin concentration, with potential effects on drug delivery. Since vaginal fluid is aqueous in nature, it follows that any drug intended for systemic absorption via the vaginal epithelium will require a degree of aqueous solubility.

Advantages of vaginal drug delivery:      Large surface area Good blood supply The ability to bypass first pass liver metabolism Permeability to large molecular weight drugs such as proteins and peptides. Prolongs the residence time

Disadvantages of vaginal drug delivery:  Drug absorption is highly dependent on the thickness of the epithelium which in turn is dependent on the phase of menstrual cycle.

Bioadhesive dosage forms designed for vaginal drug delivery includes: a) Mucoadhesive hydrogels b) microspheres formulated using bioadhesive polymers c) SuperVailTM vaginal gels(In SupraVail gels, the phospholipid adopts a liquid crystalline matrix and forms a bilayered translucent gel. On contact with the mucosal surface, the bilayered gel formulation converts readily in vivo to vesicular structures.) d) Bioadhesive vaginal cream based on VagiSiteTM technology( cream containing high internal phase ratio, w/o emulsion. 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).

6) Rectal Drug Delivery:
Anatomical considerations : Unlike the small intestine and upper colon, the vasculature draining the rectal cavity does not totally direct the blood supply to the liver. The lower and middle hemorrhoidal veins of the rectum bypass, at least partially, the portal circulation during their firs pass into the general circulation, allowing absorbed drug to exert systemic effects prior to possible metabolism and

excretion via hepatic mechanisms. The rectal cavity is also drained by extensive lymphatic circulation which facilitates absorption and systemic exposure of absorbed drugs. Although extensive villi and microvill are not present in the rectum and colon, sufficient surface area is present to allow absorption of readily permeable drugs. The lack of motility in the rectum and colon, as opposed to extensive motility in the small intestine, provides and additional advantage in terms of maintaining maximum concentration gradients at the absorptive surface. Together with a limited fluid volume in the lower colon, typically 2-3 ml of inert mucus fluid in the absence of fecal material, the static environment of the rectum and lower colon provides an area for maintaining significantly higher drug concentrations than readily achievable in the small intestine. Advantages of rectal drug delivery:     Large surface area. The ability to bypass first –pass metabolism. Prolongs the residence time Permeability to large molecular weight drugs, such as peptides and proteins.

Bioadhesive dosage forms designed for rectal drug delivery mainly includes: a) Gels and creams b) microspheres

• • • • Michael J. Rathbone, J Hadgraft, M.S. Roberts, Modified-Release Drug DeliveryTechnology, Marcel Dekker, Inc, Pg No:728-729,760-764. James Swarbrick, Encyclopaedia of Pharmaceutical Technology,3rd edition, Informa Healthcare, Pg No: 1300-1301. www.pharmainfo.net Punitha S, Girish Y, Polymers in muchadhesive buccal drug delivery system-A review, Int. J. Res.Pharm.Sci. Vol-1, Issue-2,170-186,2010


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