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PHYSIOLOGY OF MUCOSAE AND MECHANISM OF TRANSMUCOSAL PERMEATION

Prepared by : Ms Arpita Patel Guided by: Mr Ravish Patel Ramanbhai Patel of college of pharmacy

INTRODUCTION TO MUCOSA
Mucosa is moist tissue that lines some organs and body cavities throughout the body, including your nose, mouth, lungs, and digestive tract. Glands along the mucosa release mucus (a thick fluid). Mucus is a translucent and viscid secretion which forms a thin, continuous gel blanket adherent to the mucosal epithelial surface.

It has the following general composition:  Water 95%  Glycoprotiens and lipids 0.5-5%  Mineral salts 1%  Free proteins 0.5-1%

TRANSMUCOSAL ROUTES OF DRUG DELIVERY

The various routes of transmucosal delivery includes the mucosal linings of the Nasal, Rectal, Vaginal, Ocular, and Oral cavity

Advantages of Transmucosal Routes
Possible bypass of first pass metabolism

Avoidance of presystemic elimination within the GI tract,
Depending on the particular drug, a better enzymatic flora for drug absorption. Because of dual biophysical and biochemical nature of these mucosal membranes drugs with hydrophilic and /or lipophilic characteristics can be readily absorbed.

Disadvantages of transmucosal routes For buccal route:  The tablet must be kept in place and not chewed or swallowed.  Excessive salivary flow may cause a very rapid dissolution and absorption of the tablet and wash it away.  A bad tasting tablet will have a low patient acceptability. .

For nasal route: Disease conditions of the nose may result in impaired absorption. Time available for absorption is limited. Not applicable to all the drugs. Polar drugs and some macromolecules are absorbed in sufficient concentration because of poor membrane permeability. Little is known of the effect of the common cold on transmucosal drug delivery and it is likely that instilling a drug into a blocked nose or a nose with surplus of watery rhinorrhea may expel the medication from the nose. . rapid clearance and enzymatic degradation into nasal cavity. Dose is limited because of relatively small area available for absorption.

For rectal route: Some hydrophilic drugs such as antibiotics and peptide drugs are not easily absorbed from the rectum and absorption enhancers are needed. Drugs may cause rectal irritation and sometimes proctitis with ulceration and bleeding. .

In the intercellular spacings there exists a composition of homogenous mucoprotein-like substances. and squamous cutaneous epithelium. which covers the nasal septum and turbinates. Within the mucosa there exist goblet cells. On the surface of each goblet cell there are hundreds of club like microvilli. which produce nasal secretions with a pH of 7. Beneath the ciliated epithelium and goblet cells several layers of flat polygonal basal cells. The basement membrane is composed of parallel and transverse reticulum. fibres and connective tissues. exist.Human mucosa NASAL MUCOSA : The surface of human nasal mucosa is lined with both ciliated columnar epithelium.4. which have microvilli-like processes. . An individual cilium on the columnar epithelial surface is approximately 5 microns in length and 0.2 microns in width.

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while that of the sublingual epithelium contains somewhat fewer. Para keratinized epithelium. The human oral mucosal epithelium shows several distinct patterns of maturation that may be related to the different functions of the mucosa at the various regions of the oral cavity. or be replaced by. The major function of the oral epithelium is to provide a protective surface layer between the oral environment and the deeper tissues. The epithelium of the buccal mucosa is about 40-50 cell layers thick.ORAL MUCOSA: It consists of two parts: the underlying epithelium and the connective tissues. . The epithelial cells increase in size and become flatter as they travel from the basal layers to the superficial layers. The epithelium is of the stratified squamous type and varies in its thickness and the extent of keratinized epithelium may coexist with.

held in place firmly to bone and does not move. It consists of a thin. Keratinized tissue has a horny. has a dense. . and functions to withstand the active process of chewing and swallowing food. A) Masticatory Mucosa: Masticatory mucosa is comprised of the tissue that covers the hard palate and the gingiva. Lining mucosa is brighter red in color than masticatory mucosa. It lies apical to the mucogingival junction and is loosely attached. soft palate. cheeks.The oral cavity also consists of specialized epithelial tissues that surround the teeth and serve as a lining. and under the tongue. lining mucosa. B) Lining Mucosa:  Lining mucosa is found on the inside of the lips. fragile tissue that is very vascular. Also included in the lining mucosa is alveolar mucosa. hard covering. and specialized mucosa. tough. Characteristics of masticatory mucosa are: no submucosa lies under the masticatory mucosa. These tissues are: masticatory mucosa. protective outer layer of tissue.  Masticatory mucosa is usually light pink in color and is keratinized. vestibule.

Healthy gingiva under normal flossing and brushing activities does not bleed. and protects the alveolar process and periodontal ligament from bacterial invasion. It aids in the support of the teeth. The color of healthy gingiva can range from pale pink to darker shades (purple to black) depending on each individual's pigmentation.C) Specialized Mucosa: GINGIVA. The gingiva is specialized masticatory mucosa covering the alveolar process. gingiva is firmly in place encircling the necks of the teeth. Healthy gingiva is firm and resilient. In a healthy mouth. .

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which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa) Local delivery. . Buccal delivery. which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth. Within the oral mucosal cavity. which is drug delivery into the oral cavity. delivery of drugs is classified into three categories: Sublingual delivery.      Some advantages of oral route: Highly acceptable by patients The mucosa is relatively permeable with a rich blood supply Shows short recovery times after stress or damage The virtual lack of Langerhans cells makes the oral mucosa tolerant to potential allergens.

spread over a total surface area of approximately 300cm2. the lamina propria.5.  The epithelial surface consists of closely packed columnar cells with some areas interrupted by crypt regions. eosinophils. The pH of the mucous layer is reported approximately 7. Within the crypt regions there are mucus producing goblet cells. and lymphocytes  The muscularis mucosa contains smooth muscle cells and larger blood vessels. and the double –layer muscularis mucosae.  The lamina propria consists of two layers: a dense acellular collagen layer and a loose connective tissue layer. . Within the lamina propria there exist superficial blood vessels and inflammatory cells. The total volume of mucous is estimated as approximately 3 ml. including macrophages.RECTAL MUCOSA: The human rectal mucosa is composed of the epithelium.

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 The human vaginal epithelium is composed of noncornified. 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).  The vaginal epithelium is composed of five different cell layers: Superficial (about 10 rows of cells): large polygonal cells with a high degree of proliferation. stratified squamous cells.VAGINAL MUCOSA  The vagina is the lower part of the female reproductive tract. similar to those of the buccal mucosa and somewhat similar to the skin epithelium.  Transitional (about 10 rows of cells)  Intermediate (about 10 rows of cells)  Parabasal (2 rows of cells)  Basal (single row of cells) .

lymphocytes. ground substance.  It is through the blood vessels in the lamina propria that drugs can gain entry to the systemic ciruculation.  Lymph drainage from the vagina takes place to the iliac sacral. macrophages. and cells such as fibroblasts. plasma cells. . and eosinophils . neutrophils. and a network of nerve fibres. consisting of collagen fibres. and inguinal lymphatic nodes. langerhans cells. rectal. a lymphatic drainage system. gluteal. The lamina propria is composed of dense connective tissue.  It contains a blood supply. mast cells.

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The palpebral portion lines the eyelids. tarsal. and is then reflected forwards on the eye. that portion joining the eyeball is the bulbar conjunctiva and that forming the conjunctival sac and reflecting on the eye is called the fornix. The palpebral conjunctiva is subdivided into marginal. and orbital zones. The marginal zone transitions between skin and conjunctiva and shows minimal keratinization. It is made of epithelial tissue. transparent mucous membrane that lines the posterior surface of the lids.OCULAR MUCOSA: Conjunctiva (named because it conjoins the eyeball to the lids) is a thin. The tarsal conjunctiva is a fairly flat layer. The orbital zone shows more numerous Goblet cells . The conjunctiva is a clear mucous membrane consisting of cells and underlying basement membrane that covers the sclera (white part of the eye) and lines the inside of the eyelids.

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.  The tarsal conjunctiva (4) covers the tarsus. The limbus (1) is the junction of the conjunctiva and cornea.  The punctum (5) is also shown.  The bulbar conjunctiva (2) covers the eyeball and extends into the recess created by forniceal conjunctiva (3).  The marginal conjunctiva (6) is at the eyelid margin where the epithelium will begin to be keratinized.

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The bulbar conjunctiva is relatively less undulating and contains fewer Goblet cells. . In this electron micrograph the microvilli cover the superficial layer of the epithelium (arrow 1) and the mucin granules (2) of the Goblet cell are captured in a plane lacking contiguity with the surface.The histology of the conjunctiva varies according to its topographic location. The Goblet cells produce gel forming mucins called MUC5AC that may be critical to provide lubrication to the ocular surface.

Meibomian glands are embedded in the tarsus .The tarsal conjunctiva shows a stratified squamous epithelium (1) that has few Goblet cells (none seen here) overlying a very dense fibrous stroma. tarsus (2).

and vaginal mucosal homogenates. may add both enzymatic and diffusional barriers to the mucosal absorption of drugs. either in the mucosal surface microenvironment or in the mucosal membrane.g. . These secretions. which contain proteolytic enzymes and immunoglobulins. including nasal. Vaginal secretions also contain both glucose and glycogen. both are converted by enzymes and bacteria to lactic acid. by the presence of mucus secreted by the goblet cells. Drugs may be subject to metabolism during the course of transmucosal permeation. Peptidases have been noted to be present in the nonoral mucosae.Biochemical and Metabolic characteristics of Mucosa The surface environment of the nasal. to a great extent. For e. rectal and vaginal mucosae is influenced. rectal. resulting in mucus with pH of 4-5.

e. several phase II conjugating enzymes. in particular CYP3A4). cytochromeP450s. .. This includes brush border metabolism and intracellular metabolism. although it could serve as a key site for targeted delivery of ester or amide prodrugs.  Furthermore.  The intracellular metabolism occurs in the cytoplasm of enterocytes and involves the major class of phase I metabolizing enzymes (i.  It is obvious that intestinal epithelium as a site of preabsorptive metabolism may significantly contribute to the low bioavailability of therapeutic peptides and ester type drugs like aspirin. sucrase. and a considerable number of peptidases.Intestinal mucosa:  First-pass intestinal metabolism. the brush border activity is generally greater in the proximal small intestine (duodenum _ jejunum > ileum _ colon) and involves enzymes such as alkaline phosphatase. isomaltase. The former occurs at the surface of the enterocytes by the enzymes present within the brush border membrane. and others such as esterases.

carbonic anhydrase and various phase II conjugative enzymes. but nasal mucosa does possess enzymatic activity as a protective mechanism against a protective mechanism against exogenous chemicals. Examples include dehydrogenases. such as nasal decongestants and anaesthetics There are many other types of enzymes in the nasal mucosa which can act on conventional drugs. carboxylesterases. Nasal first pass metabolism may be a significant factor in the absorption of some drugs. . P450 monooxygenases can oxidize many nasally administered drugs.Nasal mucosa: The nasal route of drug administration avoids the first pass metabolism in liver. hyroxylases. For example there is a high content of cytochrome P450 enzymes.

it was demonstrated that Trans mucosal delivery high systemic bioavailability. For e. Peptide/protein drugs are increasingly becoming a very important class of therapeutic agents.g. which has bioavailability 510 times greater than that by oral administration. . for organic based pharmaceuticals. especially the nasal route. including organic and peptide based pharmaceuticals. such as progesterone.Transmucosal systemic delivery of drugs: Trans mucosal drug delivery has the potential to achieve greater systemic bioavailability for orally metabolized drugs. These drugs are easily degraded by proteolytic enzymes in the gastrointestinal tract and thus are generally not suitable for oral administration.

However. . repeated injections are often required. buccal and transdermal. the transmucosal delivery of peptide-based pharmaceuticals. such as insulin. The lower extent of transmucosal absorption of insulin and many other peptidebased pharmaceuticals is probably due to a combined effect of poor mucosal permeability and extensive metabolism at the absorption site. there was an urgent need to search for non-parenteral routes of administration as well as to develop formulations with controlled delivery features Routes of administration that have been widely investigated for this purpose include nasal. ocular. has achieved a much lower systemic bioavailability than parenteral administration. rectal. they are mostly delivered by parenteral administration.Currently. Because they are extremely short-acting. To minimize the health hazard by constant injection.

TRANS CELLULAR ROUTE. .Mechanisms of Transmucosal Permeation: There are two permeation pathways for passive drug transport across the oral mucosa: PARA CELLULAR ROUTE.

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The Para cellular route: Low molecular weight. The major junctional attachment between the epithelial cells is the desmosome. which displays minimal impedance to intercellular diffusion. water soluble compounds may transverse the mucosa via the Para cellular route. drug absorption for small hydrophilic moieties is thought to occur via Para cellular penetration. moving between the cells. as claimed for drug transport through the epidermis of the skin. Thus in the majority of the cases. . moving between the junctions of the epithelial cells.

The stratified nature of epithelium means that lipophilic moieties must permeate across several layers of cells to reach the underlying blood capillaries. movement occurs down a concentration gradient. lipophilic drugs may be absorbed transcellularly. . by passive diffusion across the cells of the epithelium.The Transcellular route: Transcellular passive diffusion:  Low molecular weight. according to Fick’s Law.  Again.

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Carrier mediated processes The oral mucosa contains active or carrier mediated systems for small molecules such as monosaccharides and amino acids. these processes have not been fully characterized in terms of location. transport capacity or specificity . However.

However.  These are presently poorly characterized in the oral mucosa.Endocytic processes:  Endocytosis means a process of cellular ingestion by which the plasma membrane folds inward to bring substances into the cell. as the oral cavity becomes increasingly important as a potential site for systemic absorption. particularly for high molecular weight drugs which are generally thought to cross epithelial cells endocytically .

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EFFECT OF pH AND PARTITION CO-EFFICIENT: More lipophilic drugs are likely to travel probably by partitioning across the mucosal cell membranes and diffusing through the cells (Transcellular route) at a slower rate than through the paracellular route. as peptides have a large number of ionizable groups of either charge. The effect of pH on peptide drugs is more complex than on conventional drugs.Factors affecting Transmucosal Permeation MOLECULAR SIZE AND WEIGHT: The absorption of small compounds is high at around 80%. . Most drugs can be ionized and their partition co-efficients are dependent upon environmental pH. the pH at which they have no net charge and where their solubility is often lowest. Peptides are characterized by their isoelectric point. but it decreases as molecular weight increases.

 Vascularity of the nose: increase of blood flow increases the absorption of drugs. .SOLUBILITY OF DRUG AND DISSOLUTION RATE: This is quite important when drug is give as solid dosage form (e. powder). as it must be able to cross the mucous layer before it can be absorbed by the epithelial cells. the lesser the bioavailability of drug. SPECIFICALLY FOR NASAL ROUTE:  The rate of nasal secretion: the greater the rate of secretion. Ability of compound to form hydrogen bond with the component of the membrane. In addition.g. the lesser the bioavailability of drug. powder morphology and particle size influence the deposition of the drug inside the cavities.  Ciliary movement: the greater the ciliary movement.

. Exampleinclusion of viscosity increasing additives like colloidal silicon oxide or aluminium monostearate will create gel like system with a slower rate of the drug. more will be the absorption.DISEASE CONDITION: example common cold. conjunctivitis. etc. OTHER ADDITIVES: The inclusion of variety of additives to the formulation also affects the transmucosal permeation. keratitis. SURFACE AREA OF MEMBRANE: the greater the surface area.

Mucociliary clearance acts to remove foreign bodies and substances from the nasal mucosa as quickly as possible. MC. 2) Modify the structure of the drug to change the physicochemical properties. . E. However this task requires the regulatory approval. which increase the viscosity of the formulation and act as bioadhesives with the mucus.g. increasing the aqueous solubility or improving the partitioning characteristics. therefore its too costly and time consuming.g.Permeation Enhancers:  1) For increasing the transmucosal permeability we can do the following: Improve the residence time of drug in the respective cavities: e. The preparation can be formulated with polymers like HPMC. or polyacrylic acid (carbopol).

3) Enhancement of Absorption: absorption enhancers work by increasing the rate at which drugs pass through the mucosa.  General requirements of an ideal absorption enhancer are:  It should be pharmacologically inert  Non irritating. Non allergic  Its effect on the mucosa should be reversible  Compatible with the drug  Should remain in contact with the mucosa long enough to achieve maximal effects  Should not have any offensive odor or taste  Readily available and inexpensive . Many act by altering the structure of the epithelial cells in some way. Non toxic. but they should accomplish this while causing no damage or permanent change.

Commonly studied bile salts include sodium cholate. .  Forming intercellular aqueous pores by opening the tight junctions between cells. and glycodeoxycholate. because their size leads to a relatively poor bioavailability. sodium glycocholate.  Mechanisms by which the increase in permeation occurs by bile salts are:  Increasing cell membrane permeability by forming temporary channels through the lipid structure. sodium deoxycholate. The major reason for developing enhancers is to increase the absorption of peptides and proteins. Various permeation enhancers: BILE SALTS: Bile salts have greater potential as they appear to possess much of enhancing activity but less of damaging potential of surfactants. sodium taurocholate and taurodeoxycholate.

 Increasing the lipophilicity of charged drugs by forming ion pairs.  Inhibition of proteolytic enzymes. It has good aqueous solubility and stability and is surface active. forming micelles at a critical micelle concentration of 2.  Another group of surface active materials is the phosphatidylcholines example lysophosphatidylcholine.  Opening of intercellular channels is most likely than increasing cell permeability. They disrupt the cell membranes and increase its permeability. SURFACTANTS: Sodium tauro-24. as the latter would cause massive disruption of cell. They may also inhibit the proteolytic enzymes and lysophosphatidylcholine is also mucolytic. 25-dihydrofusidate (STDHF) is an enhancer with similar structure to bile salts.5Mm. .

sodium caprate and esters like gylceryl monostearate. FATTY ACIDS AND THEIR SALTS AND ESTERS:  Oleic acid.  The unsaturated fatty acids such as oleic acid acts by decreasing lipid order and increasing fluidity due to their kinded molecular conformation arising from the double bond in the hydrocarbon chain. Azone (laurocapram) is used for transdermal as well as for buccal drug delivery. These are predominantly water soluble and can form associations in aqueous solution. and cod liver extract and their salts like sodium laurate. polysorbates. diethylene glycol monoethyl ether and various sucrose fatty acids esters are widely used. benzalkonium chloride. lauric acid. It is a lipophilic surfactant. Other surfactants include sodium dodecyl sulfate. .

potential for central nervous system delivery. The mucosa offers numerous benefits as a target issue for drug delivery.CONCLUSION: Interest in TRANSMUCOSAL DRUG DELIVERY as a non-invasive route for drug delivery continues to grow rapidly. A wide variety of therapeutic compounds can be delivered. rapid drug onset. such as a large surface area for delivery. and no first-pass metabolism. including relatively large molecules such as peptides and proteins. particularly in the presence of permeation enhancers .

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