Oro Mucosal Delivery Is A Promising Drug Delivery Route Biology Essay

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Among the various routes of drug delivery, oral route is mostly preferred to the patients and the clinicians alike. However, peroral (Jain. et al., 2003) administrations of drugs have disadvantages such as hepatic first-pass metabolism and enzymatic degradation within the GI, which thus prohibits oral administration of certain classes of drugs.

A rapid onset of pharmacological effect is often desired from drugs, especially in the treatment of acute disorders. This can effectively be achieved by parenteral administration, but this method may not always be convenient for the patient. Therefore, there is growing interest in developing new, non-parenteral, reliable and convenient dosage forms using administration routes where a rapidly dissolved drug is immediately absorbed into the systemic circulation. Tablet formulations are generally the first choice for drug administration because of the relative ease of both production and usage. However, for acute disorders, the time to onset of action for a conventional oral tablet is generally not acceptable; this is usually attributable to gastric emptying causing a highly variable lag time between drug administration and onset of intestinal absorption ( Christer Nystrom et al., 2003).

Oro-mucosal delivery , especially that utilizing the buccal and sublingual mucosa as absorption site, is a promising drug delivery route which promotes rapid absorption and high bioavailability, with subsequent almost immediate onset of pharmacological effect. These advantages are the result of the highly vascularized oral mucosa through which drugs enter the systemic circulation directly, by passing the gastrointestinal tract and the first pass effect in the liver (Moffat et al., 1971).

There are several aims of systemic oral mucosal drug delivery. These include: to increase patient compliance, improve drug bioavailability, decrease pulsed entry and control drug appearance in the systemic circulation and reduce the side effects and ineffectiveness associated with other routes of drug administration. Therefore the aims of the pharmaceutical scientist working in this area are to manufacture efficient, effective and economical delivery systems which optimize the systemic delivery of drugs via oral mucosal membranes.

These aims require a detailed understanding of:

The limitations and problems of the oral cavity as a site for systemic drug delivery.

The role of saliva in the distribution and clearance of drug in the oral cavity;

The mechanisms, pathways and barriers to drug permeation;

d) A mechanistic insight into how permeation enhancers increase membrane permeability (Rathbone et al., 1993).

We refer specifically to the use of the term buccal being interchangeable with the term oral, for example, the buccal cavity and oral cavity. Therefore for the sake of clarity some common terms will be defined and the terms that should become redundant identified. Oral cavity - that area of the mouth delineated by the lips, cheeks, hard palate, soft palate and floor of mouth, oral cavity mucosa - the membrane that line the oral cavity which include the sublingual, buccal mucosa, the gums (gingivae), the palatal mucosa and the labial mucosa; buccal membrane - the membrane inside the mouth that lines the cheek; sublingual administration - systemic administration of drugs via the membranes that line the floor of the mouth and ventral surface of the tongue; buccal administration - systemic and local administration via or to the buccal membrane.

Oral mucosal drug delivery system:

A delivery system designed to systemically or locally delivery drugs via or to the oral cavity membranes.

Buccal drug delivery system

A delivery system designed to deliver drugs systemically or locally via or to the buccal mucosa (Michael J. Rathbone

et al., 1993).

Sublingual mucosa as a site for drug delivery:

The sublingual mucosa is relatively permeable, giving rapid absorption and acceptable bioavailabilities of many drugs, and is convenient, accessible and generally well accepted. (Harris et al., 1992). The Sublingual route is by far the most widely studied of these routes. Sublingual dosage forms are of two different forms, those composed of rapidly disintegrating tablets, and those consisting of soft gelatin capsules filled with liquid drug; such systems create a very high drug concentration in the Sublingual region before they are systemically absorbed across the mucosa. Local delivery to tissues of the oral cavity has a number of applications, including the treatment of tooth aches, periodontal disease, bacterial and fungal infections, apthous and dental stomatitis, and in facililitating tooth movement with prostaglandins. The Sublingual region lacks expanse of smooth muscle or immobile mucosa and is constantly washed by a considerable amount of saliva making it difficult for device placement. Because of the high permeability and the rich blood supply, the sublingual route is capable of producing a rapid onset of action making it appropriate for drugs with short delivery period requirements with infrequent dosing regimen. (Amir H. Shojaei

et al., 1998).

ALTERNATIVE ROUTES

The gastrointestinal tract is the major route of drug entry to the systemic circulation. However, for some drugs this route presents problems. The gastrointestinal tract is a hostile environment; it contains enzymes, a varying range of pH conditions and varies in its composition, e.g., food. In addition the membranes of the gastrointestinal tract contain enzymes, while the blood that drains the gastrointestinal tract goes directly into liver. Thus drugs which are susceptible to acid hydrolysis, extensive metabolism are readily degraded in the liver may exhibit poor bioavailability when administered through this route. In an attempt, to circumvent these problems alternative routes of drug administration are sought. Parenteral, mucosal and transdermal routes circumvent hepatic first-pass metabolism and offer alternative routes for the systemic delivery of drugs.

Systemic delivery of drugs through mucosal membranes presents a possible solution to the problems of hepatic and gastrointestinal metabolism associated with oral delivery and the health risks associated with the parenteral route.

The major limitations of mucosal drug delivery are

(a) The low permeability of (most) mucosal membranes and relatively small surface area available for absorption resulting in low flux through the tissues and

(b) Poor retention of the drug and /or delivery system at the site of absorption resulting in short contact times. These problems may, however, be overcome by rational drug delivery system design as transdermal drug delivery attests.

Originally the skin was considered to be impermeable to drugs, however, following extensive research and development together with the introduction of new concepts, strategies, approaches and technologies, it was recognized that this barriers could be overcome and the skin became an alternative site for drug delivery.

The rectal route suffers from variable patient acceptance and depending upon the site of absorption the drug may be subjected to hepatic first-pass metabolism. Buccal and sublingual mucosa are not associated with many of these disadvantages. As a result the oral cavity may be a viable site for the systemic delivery of pharmacologic compounds.

1.1 ADVANTAGES OF TRANSMUCOSAL ROUTE:

I) Oral mucosa has a rich blood supply

II) Drugs are absorbed from the oral cavity through the oral mucosa, and transported through the deep lingual or facial vein, internal jugular vein, and braciocephalic vein into the systemic circulation.

III) Avoidance of first pass effect, presystemic elimination within the GIT, and, depending on the particular drug, a better enzymatic flora for drug absorption.

iv) The mucosal lining of the oral cavity is generally more permeable to drugs than the skin, but in contrast has a much smaller surface area available for absorption.

v) However, the area of the buccal membrane is sufficiently large to allow a delivery system to be placed at different sites on the same region of the oral cavity on different occasions which may be advantageous if the drug, delivery systems or other excipients reversibly damage or irritate the mucosa.

vi) There is good accessibility to the membranes that line the oral cavity which makes application painless and without discomfort, precise dosage form localization possible and facilities ease of removal without significant associated pain and discomfort.

vii) Patients could conceivably control the period of administration or terminate delivery in cases of emergencies.

viii) The oral mucosal route has in the past exhibited better patient compliance than either the vaginal or rectal route of drug administration thus it would be anticipated that novel buccal or sublingual dosage forms would be well accepted by patients.

ix) There are some therapeutic reasons why the oral cavity may be a useful route for drug delivery, for example, for those patients nil-by-mouth, if either nausea or vomiting is a problem, if the patient is unconscious, in patients with an upper gastrointestinal tract disease or surgery which effects oral drug absorption, or in patient group which have difficulty swallowing peroral medications, e.g., the very young and the elderly.

x) Sterile techniques are not required during manufacture or administration, the oral cavity contains teeth upon which drug delivery systems can be physically attached using dental adhesives.

xi) The oral mucosa is low in enzyme activity and enzymatic degradation is relatively slow, hence from the point of drug inactivation, considered the oral mucosal route would be preferred to the nasal or rectal routes.

1.2 LIMITATIONS

1.2.1 The oral cavity

1) The available surface area for absorption in the oral cavity is relatively small (total surface area of oral cavity membranes

 170cm2).

2) The oral cavity is a complex environment for drug delivery as there are many interdependent and independent factors which reduce the absorbable concentration at the site of absorption.

3) The tongue is highly innervated area and any delivery system administered to the oral cavity is likely to be explored by this organ which may affect release rates or retention times.

4) Involuntary swallowing of saliva results in a major part of the dissolved or suspended released drug being removed from the site of absorption.

5) Only the drugs with small dose can be administered though.

6) Some of the factors not been mentioned above is been shown in figure 1.

Figure 1: Problems associated with the oral cavity as a site for systemic delivery of drug

1.2.2 Drugs:

Drug characteristics may limit the use of the oral cavity as a site for drug delivery. Taste, irritancy, allergenicity and adverse properties such as discolouration or erosion of the teeth may limit the drug candidate list for this route. In addition the drug should not adversely affect the natural microbial flora-the oral cavity has a complex micro flora whose composition and variability is essential for its health and appearance.

Either drug (or excipients) may act as irritants, cause allergic reactions or be keratinolytic. There is therefore the need for careful evaluation of the potential for mucosal irritation with new delivery systems and their components. They found that the noninvasive system was capable of assessing the contact irritation of drugs under varying formulation conditions. It is important during preformulation studies that all additives should be critically evaluated for their irritancy, allergenic response and effect on the natural microbial flora. The problems of taste, discoloration of teeth and erosion of teeth may be overcome using unidirectional delivery systems; however, the potential for lateral diffusion during penetration followed by back partitioning of the drug into the oral cavity may mean that this problem is not overcome in all cases. In such circumstances, however, the concentration of drug in the oral cavity will be reduced.

1.3 STRUCTURE OF THE HUMAN ORAL MUCOSA:

The composition of oral mucosa, whereas outermost layer was stratified squamous epithelium (Figure 2). Below squamous epithelium basement membrane is held over, lamina propria followed by the sub mucosa as the innermost layer. The epithelium is similar to stratified squamous epithelia found in 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 (Gandhi et al., 1988). The epithelium of the buccal mucosa is about 40-50 cell layers thick, while that of the sublingual epithelium contains some what fewer. The epithelial cells increase in size and become flatter as they travel from the basal layers to the superficial layers. The oral mucosal thickness varies depending on the site: the buccal mucosa measures at 500-800µm, while the mucosal thickness of the hard and soft palates, the floor of the mouth, the ventral tongue and the gingiva measure at about 100-200µm. The mucosae of the gingivae and hard plate are keratinized and the mucosa of the soft palate, the sublingual and the buccal regions, are not keratinized (Harris et al., 1992). The non-keratinized epithelia are more permeable to water than the keratinized epithelia (Squier et al., 1991).

Figure 2: Structure Of Mucosa

1.3.1 Physiological Importance of Mucins and Saliva

The mucosal tissues are further covered with mucus, which is negatively charged, and contains large glycoproteins termed mucins. These are thought to contribute significantly to the viscoelastic nature of saliva, and maintain a pH of 5.8-7.4

(Wu et al., 1994). Mucin consists of a protein core, rich in

O-glycosylated serine and threonine, containing many helix-breaking proline residues. The salivary glands secreting mucus also synthesize saliva, which offers protection to the soft tissues from chemical and mechanical abrasions. The average thickness of the salivary film in the mouth varies between 0.07 and 0.10 mm. Sustained adhesion of the dosage form (tablet, patch) to the mucosa is an important first step to successful buccal delivery. The mucus plays an important role during this mucoadhesive process by buccal drug delivery systems. The interaction between the mucus and mucoadhesive polymers generally used in most dosage forms can be explained by theories summarized in Table 1. The mean total surface area of the mouth has been calculated to be 214.7+12.9 cm2 (Collins and Dawes., 1987). The teeth, keratinized epithelium, and nonkeratinized epithelium occupy about 20%, 50%, and 30% of this surface area, respectively. Drug delivery through the oral mucosa can be achieved via different pathways: sublingual (floor of the mouth), buccal (lining of the cheeks), and gingival (gums). The sublingual mucosa is the most permeable followed by the buccal and then the palatal. This is due to the presence of neutral lipids such as ceramides and acylceramides in the keratinized epithelia present on the palatal region, which are impermeable to water. The nonkeratinized epithelia contain water-permeable ceramides and cholesterol sulfate. A comparison of the various mucosae is provided in Table 2. The thickness of the buccal epithelium varies from 10 to about 50 cell layers in different regions because of serrations in connective tissue. In fact, the thickness of buccal mucosa has been observed to be 580 µm, the hard palate 310 µm, the epidermis 120 µm, and the floor of mouth mucosa 190 µm Table 3.

Table 1: Postulated mechanism for polymer-mucosal

adhesive properties

S.No

Theory of adhesion

Mechanism of adhesion

1

Adsorption

Secondary chemical bond such as vanderwaals forces, hydrophobic interactions, electro static attractions, and hydrogen bonds between mucus and polymer [ Kaelble 1977].

2

Diffusion

Entanglements of the polymer chains into mucus network [Voyutskii 1963].

3

Electronic

Attractive forces across electrical double layer formed due to electron transfer across polymer and mucus [ Deryaguin 1997].

4

Wetting

Analysis the ability of a paste to spread over a biological surface and calculates the interfacial tension between the two [Helfand et al.,1972]. The tension is considered proportional to X1/2, where X is the Flory polymer interaction parameter. Low values of this parameter correspond to structural similarities between polymers and an increased miscibility

5

Fracture

Relates the force necessary to separate two surfaces to the adhesive bond strength and is often used to calculate fracture strength of adhesive bonds (Chickering et al.,1999).

Table 2: Based on various tissue properties composition of oral mucosae at suitable region (De vries et al.,1991).

S.No

Region

Permeability

Blood flow

Residence time

1

Buccal

+

++

+

2

Sublingual

++

_ _

_ _

3

Gingival

_ _

+

+

4

Palatal

_ _

_ _

++

NOTE: ++ Means very suitable; - - Means least suitable.

Table 3: Thickness of epithelium in different

regions of oral mucosa

S.No

Region

Average epithelial thickness(µm)

1

Skin (mammary region)

100-120

2

Hard palate

250

3

Attached gingival

200

4

Buccal mucosa

500-600

5

Floor of mouth

100-200

1.3.2 Vascular system of the oral mucosa

The blood flows in the various regions of the oral mucosa have been studied in the rhesus monkey (Squire et al., 1985) and is represented as

Table 4: Blood flow in the various regions of the oral mucosa

S.No

Tissue

Blood flow ml/min/100 cm2

1

Buccal

2.40

2

Sublingual

3.14

3

Floor of mouth

0.97

4

Ventral tongue

1.17

5

Fraenulum

1.00

6

Gingival(+)

1.47

7

Palatal(-)

0.89

(+) average value of maxillary and mandibular attached gingival mucosa.

(-) average value of the anterior and posterior hard palatal mucosa.

The mucosa membranes of the buccal cavity have a highly vascular nature, and drugs diffusing across the membranes have easy access to the systemic circulation via the internal jugular vein. The blood supply to the mouth is delivered principally via the external carotid artery. The maxillary artery is the major branch, and the major branches are the lingual and facial arteries. The lingual artery and its branch, the sublingual artery, supply the tongue, the floor of the mouth, and the gingiva and the facial artery supplies blood to the lips and soft palate. The maxillary artery supplies the main cheek, hard palate, and the maxillary and mandibular gingiva. The internal jugular vein eventually receives almost all the blood derived from the mouth and pharynx.

1.3.3 Characteristics of mucus

The composition of oral mucus varies widely depending on animal species, anatomical location and state of tissue whether it is in a normal or pathological state. Native mucin, in addition to mucus, also contains water, electrolytes, sloughed epithelial cells, enzymes, bacteria, bacterial by products and other debris. The glycoprotein fraction of the mucus imparts a viscous gel like characteristics to mucus due to its water retention capacity.

Mucus is a glycoprotein, which is chemically built with a large peptide backbone, pendent oligosaccharide side chains whose terminal end is either sialic or sulfonic acid or L-fructose. The oligosaccharide side chains are covalently linked to the hydroxyl, amino acids, serine and threonine, and also with the polypeptide backbone. About 25% of the polypeptide back bone is without sugars, the so called 'naked' protein region, which is especially prone to enzymatic cleavage. The remaining 75% of the back bone is heavily glycosylated. The end sialic groups in the mucin molecule contain a pKa value of 2.6 so that the mucin molecule should be viewed as a polyelectrolyte under neutral or acid condition. At physiological pH the mucin network may carry a significant negative charge because of the presence of sialic acid and sulfate, residues and this high charge density plays an important role in mucoadhesion. ( Rajesh B. Gandhi et al., 1994).

Figure 3: Schematic structure of mucin (Pigman,1977).

1.4 PERMEABILITY OF THE ORAL MUCOSA

The oral mucosa in general has leaky epithelia, held in between that of the epidermis and intestinal mucosa. It has estimated that the permeability through buccal mucosa was 4-4000 times greater than that of the skin (Galey et al., 1976). As indicative by the wide range in this reported value, there are considerable differences in permeability between different regions of the oral cavity because of the diverse structures and functions of the different oral mucosae. In general, the permeabilities of the oral mucosae decrease in the order of sublingual greater than buccal, and buccal greater than palatal (Harris et al.,1992). This rank order was based on the relative thickness and degree of keratinization of these tissues, whereas with the sublingual mucosa it was relatively thin and non-keratinized, the buccal thicker and non-keratinized, and the palatal intermediate in thickness but keratinized (Gandhi et al., 1994).

The buccal mucosa, however, lacks the intercellular lamellar bilayer structure found in the stratum corneum, and hence is more permeable. An additional factor contributing to the enhanced permeability is the rich blood supply in the oral cavity. The lamina propia, an irregular dense connective tissue, supports the oral epithelium. Though the epithelium is a vascular, the lamina propia is endowed with the presence of small capillaries. These vessels drain absorbed drugs along with the blood into three major veins-lingual, facial, and retromandibular, which open directly into the internal jugular vein, thus avoiding first-pass metabolism

(Canady et al., 1993). Numerous studies have been conducted comparing the blood supply of the oral cavity to the skin in animals. A thicker epithelium has been associated with a higher blood flow probably due to the greater metabolic demands of such epithelia. Gingiva and anterior and posterior dorsum of tongue have significantly higher blood flows than all other regions; skin has a lower flow than the majority of oral regions; and palate has the lowest of all regions (Johnson, G.K., et al. 1987). In fact, the mean blood flow to the buccal mucosa in the rhesus monkey was observed to be 20.3 ml=min=100 g tissue as compared to 9.4 ml=min=100 g in the skin (Squier, C.A., and D. Nanny. 1985).

1.4.1 Barriers to permeation

The main resistance to drug permeation is caused by the variant patterns of differentiation exhibited by the keratinized and non keratinized epithelia. As mucosal cells leave the basal layer, they differentiate and become flattened. Accumulation of lipids and proteins also occurs. This further culminates in a portion of the lipid that concentrates into small organelles called membrane-coating granules (MCGs). In addition, the cornified cells also synthesize and retain a number of proteins such as profillagrin and involucrin, which contribute to the formation of a thick cell envelope. The MCGs then migrate further and fuse with the intercellular spaces to release into the lipid lamellae. The lamellae then fuse from end to end to form broad lipid sheets in the extracellular matrix, forming the main barrier to permeation in the keratinized regions in the oral cavity. These lamellae were first observed in porcine buccal mucosa (Wertz et al. ,1996), and have been recently identified in human buccal mucosa (Garza et al., 1998). Though the nonkeratinized epithelia also contain a small portion of these lamellae, the random placement of these lamellae in the noncornified tissue in comparison with the organized structure in the cornified tissue makes the former more permeable. Also, the nonkeratinized mucosa does not contain the acylceramides, but also contains small amounts of ceramides, glucosylceramides, and cholesterol sulfate. The lack of organized lipid lamellae and the presence of other lipids instead of acylceramides make the nonkeratinized mucosa more water permeable as compared to the keratinized mucosa.

1.4.2 Physicochemical properties and routes of permeation

Small molecules can be transported across buccal mucosa by two routes: 1) the transcellular (Intracellular) route and 2) the paracellular (intercellular) route.Molecules can use either of these two routes or a combination, and the mucosal membrane and physicochemical properties of the molecule determine the final route of permeation. Hydrophilic molecules passes through the aqueous pores adjacent to the polar head groups of the lipids held over in the membrane or through the hydrophilic intercellular cytoplasm. At the same time, lipophilic drug molecules are likely to use the transcellular route and passes through the lipophilic cell membrane, where as the permeation will depend on the partition coefficient. They can also pass through the lipophilic lipid lamellae present between the cells. The intercellular route is a complex route and presents a lesser area for the drug to permeate, but has been found to be a predominant route for absorption of many drugs.

Figure 4: Routes of transepithelial penetration: Transcellular route versus paracellular route ( Wertz and Squier, 1991).

1.5 FACTORS AFFECTING SYSTEMIC ORAL MUCOSAL DRUG DELIVERY

1.5.1 Membrane factors

The permeability of the oral mucosa is not enormous compared to other mucosal membranes (Rojanasakul et al., 1992) and represents a major difficulty in the successful development of the oral cavity (as a site) for systemic delivery of drug.

1.5.1.1 Factors affecting thickness and surface area

Regional variation exist within the oral cavity, and both keratinized and non keratinized tissues of varying thickness and composition are found in the oral cavity (Michael J. Rathbone

et al., 1993). The mean total surface area [±SD] of the mouth has been calculated to be 214.7± 12.9 cm2. The teeth, keratinized epithelium, and nonkeratinized epithelium occupy about 20%, 50% and 30% of this surface area, respectively. The Connective tissue papillae, which will penetrate into the epithelia, give the basement membrane an enormous surface area compared to that of the epithelium.

1.5.2 Absorption

Basic principle of drug absorption occurs by passive diffusion of the nonionised species (Beckett et al., 1967) , a process governed primarily by a concentration gradient, through the intercellular spaces of the epithelium.

Passive diffusion is the most common route of permeation through the oral mucosa, and uses Fick's first law of diffusion given by the general equation

The amount of drug absorbed A is given by

Where, C is the free drug concentration on the delivery medium, P is the permeability coefficient Kp is the partition coefficient of the drug between the delivery medium and the oral mucosa, h is the thickness of the oral mucosa , D is the diffusion coefficient of the drug in the oral mucosa, , S is the surface area of the delivery or the absorption site on the mucosa , and t is the duration of time the drug stays in contact with the mucosa.

The thickness of the tissue, diffusion coefficient, and the partition coefficient are properties of the mucosa and cannot be altered. Designing appropriate formulations that need the necessary conditions can vary the surface area for delivery of the drug, time of contact, and the free drug concentration. The partitioning of the drug through the membrane will depend on its ratio of hydrophilicity and lipophilicity [HLB Value].

1.5.2.1 Factors affecting absorption

Besides the biochemical characteristics of the buccal and sublingual membranes, which are responsible for the barrier function and permeability, various factors of the drug molecule influence the extent of permeation through the membrane.

The lipid solubility, degree of ionization, Pka of the drug, PH of the drug solution, presence of saliva and the membrane characteristics , molecular weight and size of the drug , various physicochemical properties of the formulation, and the presence or absence of permeation enhancers, all affect the absorption and the permeation of drugs through the oral mucosa.

1.5.2.1.1 Degree of ionization , PH and lipid solubility

The permeability of unionizable drug compound is a function of their lipid solubility, determined by their oil-water partition coefficient (Squier et al., 1985). Demonstrated the dependence of water permeability in the lipid contents of keratinized and non-keratinized epithelia. The lipids present however contribute to this effect more in the keratinized epithelia (more total lipid content, non polar lipids, ceramides) than in the non keratinized epithelia where permeability seems to be related to the amount of glycosylceramides present.

The absorption of drug through a membrane depends upon its lipophilicity , which in turn depends on its degree of ionization and partition coefficient. The higher the unionized fraction of a drug, the greater is its lipid solubility. The degree of ionization in turn depends on the pH of the mucosal surface may be different from that of buccal and sublingual surfaces throughout the length of the permeation pathway ( Harris et al., 1992) . Thus the drug in its unionized form may be well absorbed from the surface of the membrane, but the pH in the deeper layers of the membrane may change the ionization and thus the absorption. Also, the extent of ionization of a drug reflects the partitioning into the membrane, but may not reflect the permeation through the lipid layers of the mucosa.

1.5.2.1.2 Molecular size and weight:

The permeability of a molecule through the mucosa is also related to its molecular size and weight, especially for hydrophilic substances. Molecules that are smaller in size appear to traverse the mucosa rapidly. The smaller hydrophilic molecules are thought to pass through the membrane pores, and larger molecules pass extra cellularly. Increases in molar volume to greater than 80mL/mol produced a sharp decrease in permeability ( Siegel et al., 1981).

Due to the advantages offered by the buccal and the sublingual route, delivery of various proteins and peptides through this route has been investigated. It is difficult for the peptide molecules with high molecular weights to make passage through the mucosal membrane. Also, peptides are usually hydrophilic in nature. Thus they would be traversing the membrane by the paracellular route, between cells through the aqueous regions next to the intercellular lipids. In addition, peptides often have charges associated with their molecules, and thus their absorption would depend on the amount of charge associated with the peptides, pH of the formulation and the membrane , and their isoelectric point.

In addition the absorptive membranes thickness, blood supply, blood/lymph drainage, cell renewal and enzyme content will all contribute to reducing the rate and amount of drug entering the systemic circulation [Michael J.Rathbone et al., 1993].

1.5.2.1.3 Permeability coefficient

To compare the permeation of various drugs, a standard equation calculating the permeability coefficient can be used. One form of this equation is

Where, A is the surface area for permeation, p is the permeability coefficient (cm/s), vdis the volume of donar compartment, and t is the time. This equation assumes that the concentration gradient of the drug passing through the membrane remains constant with time, as long as the percentage of drug absorbed is small. (ElkaTouitou and Brain W. Barry, 2007).

1.5.3 Environmental factors

1.5.3.1 Saliva

All the tissues in the oral cavity were protected by Saliva as the protective fluid and its necessity for oral health generally only becomes significant when either the amount of saliva is reduced. These changes, particularly a reduction in the amount of saliva produced, occur in many systemic diseases, Eg; diabetes, and as a consequence of the treatments of disease, Eg; radiation therapy or drugs (Srrebny et al., 1986). Its reduction or change in quality may result in a rapid increase in dental caries, in acute and chronic inflammation of the soft tissues and in extreme discomfort during eating or prolonged talking. Such changes may also affect successful drug delivery via this route and thus it may inappropriate to consider what changes occur in saliva in disease conditions and as a consequence of the treatments.

1.5.3.2 Salivary glands:

Saliva is produced in three pairs of major glands (parotid, submandibular and sublingual) each situated outside of the oral cavity and in minor salivary glands situated in the tissues lining most of the oral cavity.

1.5.3.2.1 Major salivary glands

Parotid glands are situated anterior to the ear and in the retromolar fossa. Submandibular glands lie mostly behind and below the free border of the mylohyoid muscle with a small extension above it. Sublingual glands lie between the mylohyoid muscle and the floor of the mouth. The saliva and these major glands reaches the mouth via Bartholin's ducts which open with or adjacent to the submandibular ducts. The main excretory drugs (stenson's ducts) open into the mouth in the lining of the cheek or buccal mucosa adjacent to the upper first and second molar teeth. Wharton's ducts open into the floor of the mouth on either side of the lingual fraenum. The position of entry of the ducts into the oral cavity is a consideration on the placement of delivery systems. Placement of delivery system over a duct may be inappropriate on physiological/health grounds while placement adjacent to a duct may result in excessive wash out of drugs or rapid dissolution/erosion of the delivery system. The entry of the both submandibular and sublingual drugs is one reason why it is difficult to retain drugs and delivery systems, and build or maintain high concentrations of drugs, in the sublingual region.

Each salivary gland is made up of acinar units and ducts. The acinar units produce most of the components of the saliva. The major cells which make up the acinaruntis are mucous cells, serous cells and the cells of the straited ducts and intercalated ducts (Tandler 1978). The stimulation of saliva production is under parasympathetic and sympathetic control. Parasympathetic stimulation produces a seviour watery saliva, while sympathetic stimulation produces a much thicker saliva which is higher in organic content and lower in volume. (Baun 1987).

The total average volume of saliva produced daily in an adult is around 750ml (Mandel et al.,1976). This is made up of 60% from submandibular glands, 30% from the parotids, less than 5% from the sublingual glands and between 5% and 7% from the minor salivary glands. However, it must be remembered that the rates reported will have been influenced by the , type of stimulus used, the time of day , the length of time the glands had been stimulated, the age and sex of the individuals and by their state of health.

Flow rates for individuals major glands have also been determined and reported (Mandal and wotman, 1976) the flow rate of unstimulated parotid saliva to be 0.04ml/min/gland and the submandibular salivary flow rate to be 0.05ml/min/gland. With stimulation such as by chewing paraffin wax, applying citric acid to the tongue or by giving systemic pilocarpine or other cholinergic agents, the flow rates of each gland will increase to an average of 0.6ml/min/gland. The production of saliva has also been shown to follow a circardian rhythm , to be affected by hormonal levels, salivary gland disease , some pharmacologic agents and to some extent by changes in plasma concentration of electrolytes and other plasma constituents ( Shannon et al.,1974).

1.5.3.2.2 Minor salivary glands

Saliva is also produced in the minor salivary glands (also called accessory and intrinsic glands). These are found beneath the epithelium throughout the mouth except for the anterior part of the hard palate and the alveolar ridges supporting the teeth. Most of the mucous present in the oral cavity is derived from the minor salivary glands; however minor glands do not produce the same composition of the saliva (Table 5).

Table 5: Type of saliva produced by various glands

S.No

Glands

Production

1

Glands on buccal mucosa

Mixed saliva

2

Labile glands of lips

Mucous saliva

3

Glossopalatine glands in isthmus of glossopalative fold/sometimes on the soft palate

Mucous saliva

4

Palatine glands found in the posterolateral areas of the hard palate/ the submosa of hard palate/uvula

Mucous saliva

5

Anterior lingual glands of Blandin and Nuhn

Mucous saliva

6

Posterior lingual glands associated with the ventral surface of tongue

Mucous saliva

7

Lingual glands which open on to the

Dorsal surface of the tongue

Mixed saliva

The flow rate of individual minor salivary glands is difficult to determine. The saliva produced in the minor salivary glands may play an important role in drug delivery as this is the saliva which may be most directly in contact with the drug or delivery system. If drugs are delivered from a patch with an outer surface impermeable to saliva the low buffering capacity of the saliva from these glands may permit easy modification of the local microenvironment by appropriate delivery system excipients.

From the point of view of drug absorption from adhesive patches the minor salivary glands and their contents are probably of the most significant. A retensive oro- mucosal drug delivery system is likely to be located over these minor salivary glands. Whether these ducts will become blocked or infected during the administration of these systems has yet to be reported. However, their low flow rates would almost certainly not resulted in the formation of a mucous layer forming between the membrane surface and the delivery system. It has been reported that the flow of saliva from minor salivary glands is continuous thus it does not appear possible to choose a time of day when the salivary flow may be lower from the point of view of application. It may be significant to distinguish which saliva (mucous or serous) best aids/ hinders the adhesion of patches since this may also determine the most appropriate site for application.

Thus far we have considered the mucous film as a asset to aid retention of the delivery system. A additional consideration is that the mucous film of saliva produced on the tissues may prevent to some degree absorption of materials from the mouth therefore acts as a barrier to drug absorption.

1.6 MOVEMENT OF ORAL TISSUES

Here we considered the effect of swallowing, talking and eating on the movement of tissues in the oral cavity. If oro- mucosal drug delivery systems are to remain in place for a period of time some idea over the movement of the tissues at the site of attachment, and on their movement over other tissues and of the movement of other tissues against the delivery systems would be required. The least movement of any of the tissues in the oral cavity has been observed during sleeping and this period may be the most suitable period for drug administration, if dislodgement of delivery system proves to be a problem; however, swallowing and mouth movement do continue while sleeping. If delivery needs to be continued for prolonged periods, some research would need to be performed on the role of the tongue during oral mucosal drug delivery which, at various stages of mastication and swallowing, and may compress against the palate, induce suction pressures and wipe across tissues and delivery systems. It necessary to prove and determine the exact movement of the tongue during mastication and talking and to measure which pressures are exerted on the various regions of the oral cavity during these activities. Such information may dictate site selection and help optimize retention of the delivery system at a specific site.

1.7 IN VITRO AND IN VIVO STUDY METHODS

1.7.1 Animal models

Due to the limited tissue area in the human buccal cavity has encouraged the use of animal models that may imitate human oral mucosal absorption. Each and every animal

model have their advantages and disadvantages. Rats, hamsters, dogs, rabbits, guinea

pigs, and rhesus monkeys have all been used in buccal studies (Ritschel et al., 1985). Almost all animals have a completely keratinized epithelium. The hamster cheek pouch has a large surface area but is not flushed with the saliva. The oral mucosa of the monkey, has been widely used but the high cost of procurement as well as difficult to handle are disadvantages when it comes to select these animals. Human mucosa is similar to rabbit mucosa since it has regions of nonkeratinized tissue. However, the small surface area and difficulty in accessing the required tissue make it unusable. The animal of primary choice remains the pig because of comparable permeability to human buccal mucosa and a large surface area enabling reduced changeability in the data (Song et al., 2004).

The methods used for measuring the amount of drug absorbed have to be designed in such

a way as to account for local delivery of the drug to the mucosa as well as systemic delivery through the mucosa into the circulation. A selection of in vivo and in vitro techniques has been developed and tested over the years.

1.7.2 In vivo studies

Both human and animal models have been used for in vivo testing of oro- mucosal drug delivery. The animal model which reflects with the structure and properties of the human mucosa has been selected. An important in vivo technique has implemented using human test volunteers, the ''buccal absorption test'' was developed and established by (Beckett and Triggs, 1967). They adjusted solutions of several basic drugs to various pH values with buffer, and placed the solution in the subject's mouth. The basic drug solution of varying pH was circulated about 300-400 times by the movement of the cheeks and tongue for a contact time of 5 min. The solution was then expelled, and the volunteer's mouth was rinsed with 10 ml distilled water for 10 s. The rinsed distilled water was collected, and combined with the earlier expelled solution, and the fraction of the drug remaining in this solution was measured by gas-liquid chromatography. Finally observed that the absorption of drug from the oral cavity dependent on pH.

These methods have been used to examine different types of dosage forms (composite films, patches, and bioadhesive tablets) and their mucosal drug absorption and have been used to evaluate both buccal and sublingual absorptions across the respective mucosa (Aungst et al., 1988).

Yamahara et al., 1990 developed and used glass perfusion cell for the measurement of drug absorption through mucosal membranes of anesthetized male beagle dogs. The cell enclosed a biocompatible bioadhesive polymer O-ring that adhered the cell to the oral mucosal membrane. This type of cell can be used to measure buccal and sublingual absorption as well as perfusion through the surface of the tongue

1.7.3 In vitro studies

The in vivo studies does not provide information regarding the varying permeabilities of different regions in the oral cavity, and also information on the actual systemic absorption of the drugs. Also, the continuous flow of saliva affects the pH of the applied solution as well as the overall volume. So, several methods have been used as tools in in vitro assessing of such drawbacks, mainly Disk method, Perfusion cell method were used as tools.

These methods have been proved to be important tools in the study of transmucosal absorption, Since they can make easy studies of drug permeation under controlled experimental conditions.

Oral mucosal tissue can be surgically removed from the oral cavity of the selected animal and the connective tissue held over on it is removed by applying heat at 60oc or chemically by using various enzymes or EDTA, ( De Vries et al., 1991, Garren and Repta, 1989) if not removed it may acts as a permeation barrier. Tissues are stored in buffer solution (usually in kreb's). Storage step is the important in preserving the integrity and viability of the tissue. The separated tissue is placed in between donar and receptor compartment of side by side diffusion cell. The donor contains the drug solution, whereas the receptor usually contains a buffer solution to emulate the body fluids. The chambers can be stirred continuously to ensure even distribution of the drug and are maintained at a desired temperature. The epithelial side of the tissue faces the donor chamber, allowing the drug to pass from the donor chamber through the tissue into the receptor chamber from where samples can be withdrawn at specific time intervals and replaced with fresh receptor solution.

Different kinds of diffusion cell apparatus have been used in such in vitro experiments. Some of these are small volume diffusion cells (Grass and Sweetana, 1988), Using chambers (Artusi et al., 2003) and Franz diffusion cells (Senel et al., 1998).

The in vitro methods, though relatively simple have various disadvantages:

(a) The conditions of tissue separation, preparation, and storage may affect the viability, integrity, and therefore their barrier function. Tests assessing the ATP levels have been used to analyze the viability and integrity of tissue. A method for ATP extraction using perchloric acid and subsequent analysis of ATP in nanomoles per gram of tissue has been described by (Dowty et al., 1992).

(b) Human oral mucosa is relatively expensive and available in limited amounts. Therefore, animal mucosae which have to be chosen carefully in order to resemble the human mucosa as closely as possible are used.

(c) A specific complication occurs in cases of sublingual mucosa. Various ducts from the submandibular and the sublingual salivary glands open into the mucosal surface, and thus a sufficiently large piece of mucosa that is not perforated by these ducts is difficult to obtain (Harris and Robinson, 1992). Also, the presence of enzymes in the tissue indicates that there is a high probability of the drugs being metabolized during transport across the mucosa and therefore appropriate metabolism studies and drug-stabilizing efforts should be undertaken, these Studies were performed and measured the extent of metabolism of TRH in rabbit buccal mucosa in vitro and reported by (Dowty et al., 1992).

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