Chapter- 1

1. Introduction
By, Vikram Viswajit Mishra, M.Pharma Jeypore College of Pharmacy E-mail id Vikram2only@gmail.com

The effect of new formulations can be enhanced by the development of newer release systems. The main controlled drug delivery systems currently available include matrices, pellets, floating systems, liposomes, microemulsions, liquid crystals, solid dispersions, nanosuspensions, transdermal systems, cyclodextrin inclusion complexes, osmotic pumps and bioadhesive systems. The potential use for mucoadhesive systems as drug carriers lies in its prolongation of the residence time at the absorption site, allowing intensified contact with the epithelial barrier. When adhesion is restricted to the mucosal membrane it is called as mucoadhesion. Mucous membrane is the main administration site for bioadhesive systems. Mucous membranes of human organism are relatively permeable and allow fast drug absorption. They are characterized by an epithelial layer whose surface is covered by mucus. This approach to confer bioadhesion properties has been widely applied in the development of a number of drug delivery systems. [1-2] The Mucosal Buccal Delivery has brought about a great change in the pharmaceutical arena. It produces a sustained release of drug over a prolonged time, thereby reducing frequent dosing. The area is well suited for a retentive device and appears to be acceptable to the patient. With the right dosage form design and formulation, the permeability and the local environment of the mucosa can be controlled and manipulated in order to accommodate drug permeation. Buccal drug delivery is a promising area for continued research with the aim of systemic delivery of orally inefficient drugs as well as a feasible and attractive alternative for non-invasive delivery of potent peptide and protein drug molecules.[3- 4]

1.1 Diabetes Diabetes is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).
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Diabetes is a condition in which the quantity of glucose in the blood is raised called hyperglycemia. This happens when there is low or no insulin production or improper use of insulin.

Types of Diabetes There are two major types of diabetes. They are as follows: 1. Type 1 DM: It results from the body's failure to produce insulin, and presently requires the person to inject insulin. (Also referred to as insulin-dependent diabetes mellitus (IDDM) or "juvenile" diabetes). Type 1 diabetes can occur in an older individual due to destruction of the pancreas by alcohol, disease, or removal by surgery. 2. Type 2 DM: It results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. (Formerly referred to as noninsulin-dependent diabetes mellitus (NIDDM) or "adult-onset" diabetes).

Epidemiology Globally, as of 2010, an estimated 285 million people had diabetes, with type 2 making up about 90% of the cases. Its incidence is increasing rapidly, and by 2030, this number is estimated to almost double. Diabetes mellitus occurs throughout the world, but is more common (especially type 2) in the more developed countries. The greatest increase in prevalence is, however, expected to occur in Asia and Africa, where most patients will probably be found by 2030. The increase in incidence in developing countries follows the trend of urbanization and lifestyle changes, perhaps most importantly a "Western-style" diet. This has suggested an environmental (i.e., dietary) effect, but there is little understanding of the mechanism(s) at present, though there is much speculation, some of it most compellingly presented. India has more diabetics than any other country in the world, according to the International Diabetes Foundation, although more recent data suggest that China has even more. The disease affects more than 50 million Indians - 7.1% of the nation's adults - and kills about 1 million Indians a year. The average age on onset is 42.5 years. The high

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incidence is attributed to a combination of genetic susceptibility plus adoption of a highcalorie, low-activity lifestyle by India's growing middle class. [6-7]

Pathology of Diabetes Diabetes (Hyperglycemia), which is defined as fasting plasma glucose above 126 mg/dl & oral glucose tolerance test (OGTT) above 200 mg/dl Pre-Diabetes is defined as impaired fasting glucose (IFG) of 100-125 mg/dl & impaired glucose tolerance (IGT) of 140-199 mg/dl Acute Complications of Uncontrolled Diabetes (all directly caused by hyperglycemia) --Polyuria due to excess fluid intake and glucose-induced osmotic diuresis --Weight loss due to calories lost as glucosuria, leaving a negative calorie balance --Poor wound healing, gingivitis, blurred vision Chronic Complications of Uncontrolled Diabetes Chronic complications may be due to mitochondrial superoxide overproduction in response to hyperglycemia. Macro vascular Atherosclerosis: diabetics have a high incidence of coronary, cerebral, and peripheral artery diseases. Caused by dyslipidemias including elevated LDL and triglycerides, low HDL, and reduced fibrinolysis activity. Management includes foot care. Micro vascular Diseases of Diabetes 1. Diabetic Retinopathy has many manifestations, including micro aneurysms, micro

hemorrhages, proliferative vessel changes, and vitreous bleeds (cause blindness). Diabetic retinopathy is caused by basement membrane deterioration and ischemia. 2. Nephropathy progresses from micro albuminuria to proteinuria to uremia to ESRD.

Nephropathy is caused by hyper filtration, increased glomerular pressure, and BM thickening. End stage Complications of Uncontrolled Diabetes

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1. Diabetic Ketoacidosis results from complete lack of insulin and reliance on fatty acids for energy. There is unrestrained lipolysis and ketone synthesis, causing acidosis and ketonemia. Patients will show Kussmaul respiration. This is a medical emergency. 2. Non-Ketotic Hyperosmolarity is an extreme hyperglycemia without acidosis. It is caused by insufficient insulin resulting in poor glucose uptake and increased hepatic glucose The extreme

output. There is just enough insulin to suppress ketone synthesis. hyperglycemia leads to osmotic diuresis and vascular collapse

Fig 1.1Pathology of Diabetes Mellitus

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Sign and symptoms

In both types of diabetes, signs and symptoms are more likely to be similar as the blood sugar is high, either due to less or no production of insulin, or insulin resistance. In any case, if there is inadequate glucose in the cells, it is identifiable through certain signs and symptoms. These symptoms are quickly relieved once the Diabetes is treated and also reduce the chances of developing serious health problems .

DiabetesType1:

In type 1, the pancreas stop producing insulin due to autoimmune response or possibly viral attack on pancreas. In absence of insulin, body cells dont get the required glucose for producing ATP (Adenosin Triphosphate) units which results into primary symptom in the form of nausea and vomiting. In later stage, which leads to ketoacidosis, the body starts breaking down the muscle tissue and fat for producing energy hence, causing fast weight loss. Dehydration is also usually observed due to electrolyte disturbance. In advanced stages, coma and death is witnessed .

Diabetes Type 2:

Increased fatigue: Due to inefficiency of the cell to metabolize glucose, reserve fat of body is metabolized to gain energy. When fat is broken down in the body, it uses more energy as compared to glucose, hence body goes in negative calorie effect, which results in fatigue.

Polydipsia: As the concentration of glucose increases in the blood, brain receives signal for diluting it and, in its counteraction we feel thirsty.

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Polyuria: Increase in urine production is due to excess glucose present in body. Body gets rid of the extra sugar in the blood by excreting it through urine. This leads to dehydration because along with the sugar, a large amount of water is excreted out of the body.

Polyphagia : The hormone insulin is also responsible for stimulating hunger. In order to cope up with high sugar levels in blood, body produces insulin which leads to increased hunger.

Blurry vision: Hyperosmolar hyperglycemia nonketotic syndrome is the condition when body fluid is pulled out of tissues including lenses of the eye, which affects its ability to focus, resulting blurry vision.

Poor wound healing : High blood sugar resists the flourishing of WBC, (white blood cell) which are responsible for body immune system. When these cells do not function accordingly, wound healing is not at good pace. Secondly, long standing diabetes leads to thickening of blood vessels which affect proper circulation of blood in different body parts.[8]

Treatment
The major goal in treating diabetes is to minimize any elevation of blood sugar (glucose) without causing abnormally low levels of blood sugar. Type 1 diabetes is treated with insulin, exercise, and a diabetic diet. Type 2 diabetes is treated first with weight reduction, a diabetic diet, and exercise. When these measures fail to control the elevated blood sugars, oral medications are used. If oral medications are still insufficient, treatment with insulin is considered. Adherence to a diabetic diet is an important aspect of controlling elevated blood sugar in patients with diabetes.Weight reduction and exercise increase the body's sensitivity to insulin, thus helping to control blood sugar elevations. Testosterone replacement therapy may improve glucose tolerance and insulin sensitivity in diabetic hypogonadal men. The mechanisms by which testosterone decreases insulin resistance is under study. Moreover testosterone may have a protective effect on pancreatic beta cells, which is possibly exerted by androgen-receptor-mediated mechanisms and influence of inflammatory cytokines. Recently it has been suggested that a type of gastric bypass surgery may normalize blood glucose levels in 80-100% of severely obese patients with diabetes.. This approach may become a treatment for some people with type 2 diabetes, but has not yet been studied in prospective clinical trials.[94] This surgery may have the
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additional benefit of reducing the death rate from all causes by up to 40% in severely obese people.[95] A small number of normal to moderately obese patients with type 2 diabetes have successfully undergone similar operations. MODY is another classification of diabetes and it can be treated by early lifesyle management and medical management. it has to be treated in the early stage, so as to provide a good health.[9]

1.2 Mucoadhesive Buccal Drug Delivery

Buccal drug delivery is a promising area for continued research and attractive alternative for non-invasive delivery of potent peptide and protein drug molecules. Buccal administration of drugs provides a convenient route of administration for both systemic and local drug actions. The need for safe and effective buccal permeation absorption enhancers is a crucial component for a prospective future in the area of buccal drug delivery. Buccal nitroglycerin, can use for acute therapy for an animal attack as well as for chronic prophylaxis Novel liquid aerosol formulation of insulin Development of suitable delivery devices, permeation enhancement, and Buccal delivery of drugs that undergo a first-pass effect, such as cardiovascular drugs, analgesics, and peptides Research yield some successes Promote further research; more companies Rest depend on delivery technology. [10]

Buccal Route of Drug Absorption

There are two permeation pathways for passive drug transport across the oral mucosa: paracellular and transcellular routes. Permeants can use these two routes simultaneously, but one route is usually preferred over the other depending on the physicochemical properties of the diffusant. Since the intercellular spaces and cytoplasm are hydrophilic in character, lipophilic compounds would have low solubility in this environment. The cell membrane, however, is rather lipophilic in nature and hydrophilic solutes will have difficulty permeating through the cell membrane due to a low partition coefficient. Therefore, the intercellular spaces pose as the major barrier to permeation of lipophilic compounds and the cell membrane acts as the major transport barrier for hydrophilic compounds. Since the oral epithelium is stratified, solute permeation may involve a combination of these two routes. The route that predominates, however, is generally the one that provides the least amount of hindrance to passage.
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Buccal mucosa as a site for Drug Delivery

There are three different categories of drug delivery within the oral cavity (i.e., Sublingual, buccal, and local drug delivery). Selecting one over another is mainly based on anatomical and permeability differences that exist among the various oral mucosal sites. The sublingual mucosa is relatively permeable, giving rapid absorption and acceptable bioavailability of many drugs, and is convenient, accessible, and generally well accepted .The sublingual route is by far the most widely studied of these routes. Sublingual dosage forms are of two different designs, 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 toothaches, periodontal disease, bacterial and fungal infections, and dental stomatitis, and in facilitating tooth movement with prostaglandins. First difference being in the permeability characteristics of the region, where the buccal mucosa is less permeable and is thus not able to give a rapid onset of absorption (i.e., more suitable for a sustained release formulation). Second being that, the buccal mucosa has an expanse of smooth muscle and relatively immobile mucosa which makes it a more desirable region for retentive systems used for oral transmucosal drug delivery. Thus the buccal mucosa is more fitted for sustained delivery applications, delivery of less permeable molecules, and perhaps peptide drugs.

1.3 Advantages of Mucosal Buccal Drug Delivery

1. Bypass of the gastrointestinal tract and hepatic portal system, increasing the bioavailability of orally administered drugs that otherwise undergo hepatic first-pass metabolism. In addition the drug is protected from degradation due to pH and digestive enzymes of the middle gastrointestinal tract 2. Improved patient compliance due to the elimination of associated pain with injections; administration of drugs in unconscious or incapacitated patients; convenience of administration as compared to injections or oral medications. 3. Sustained drug delivery.
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4. A relatively rapid onset of action can be achieved relative to the oral route, and the formulation can be removed if therapy is required to be discontinued. 5. Increased ease of drug administration. 6. Though less permeable than the sublingual area, the buccal mucosa is well vascularized, and drugs can be rapidly absorbed into the venous system underneath the oral mucosa. 7. In comparison to TDDS, mucosal surfaces do not have a stratum corneum. Thus, the major barrier layer to transdermal drug delivery is not a factor in transmucosal routes of administration. Hence transmucosal systems exhibit a faster initiation and decline of delivery than do transdermal patches. 8. Transmucosal delivery occurs is less variable between patients, resulting in lower intersubject variability as compared to transdermal patches. [11-14]

1.4 Limitations of Mucosal Buccal Drug Delivery

1. For local action the rapid elimination of drugs due to the flushing action of saliva or the ingestion of foods stuffs may lead to the requirement for frequent dosing. Depending on whether local or systemic action is required the challenges faced while delivering drug via buccal drug delivery can be enumerated as follows. 2. The non-uniform distribution of drugs within saliva on release from a solid or semisolid delivery system could mean that some areas of the oral cavity may not receive effective levels. 3. For both local and systemic action, patient acceptability in terms of taste, irritancy and mouth feel is an issue. [11-14]

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1.5 Overview of the Oral Mucosa

Structure The oral mucosa is composed of outermost layer of stratified epithelium.Below lies a basement membrane, a lamina prairie 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 epithelium18. 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.It 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 m, while the mucosal thickness of the hard and soft palates, the floor of the mouth, the ventral tongue, and the gingival measure at about 100-200 m.[15]

Fig 1.2. Section of buccal mucosal layer

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Permeability
The oral mucosa in general is a somewhat leaky epithelial intermediate between that of the epidermis and intestinal mucosa. It is estimated that the permeability of the buccal mucosa is 4-4000 times greater than that of the skin . 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 greaterthan buccal, and buccal greater than palatal. This rank order is based on the relative thickness and degree of keratinization of these tissues, with the sublingual mucosa being relatively thin and non-keratinized, the buccal thicker and non-keratinized, and the palatal intermediate in thickness but keratinized. The MCGs of keratinized epithelium are composed of lamellar lipid stacks, whereas the non-keratinized epithelium contains MCGs that are non-lamellar. The MCG lipids of keratinized epithelia include sphingomyelin, glucosylceramides, ceramides, and other nonpolar lipids, however for non-keratinized epithelia, the major MCG lipid components are cholesterol esters, cholesterol, and glycosphingolipids Aside from the MCGs, the basement membrane may present some resistance to permeation as well,however the outer epithelium is still considered to be the rate limiting step to mucosal penetration. The structure of the basement membrane is not dense enough to exclude even relatively large molecules. [16]

Environment
The cells of the oral epithelia are surrounded by an intercellular ground substance, mucus, the principle components of which are complexes made up of proteins and carbohydrates. These complexes may be free of association or some maybe attached to certain regions on the cell surfaces. This matrix may actually play a role in cell-cell adhesion, as well as acting as a lubricant, allowing cells to move relative to one another. Along the same lines, the mucus is also believed to play a role in bio adhesion of mucoadhesive drug delivery systems. In stratified squamous epithelia found elsewhere in the body, mucus is synthesized by specialized mucus secreting cells like the goblet cells, however in the oral mucosa, mucus is secreted by the major and minor salivary glands as part of saliva . Up to 70% of the total
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mucin found in saliva is contributed by the minor salivary glands . At physiological pH the mucus network carries a negative charge (due to the sialic acid and sulfate residues) which may play a role inmucoadhesion. At this pH mucus can form a strongly cohesive gel structure that will bind to the epithelial cell surface as a gelatinous layer.

1.6 Mechanism of Mucoadhesion

The mechanism of adhesion of certain macromolecules to the surface of a mucous tissue is not well understood yet. The mucoadhesive must spread over the substrate to initiate close contact and increase surface contact, promoting the diffusion of its chains within the mucus. Attraction and repulsion forces arise and, for a mucoadhesive to be successful, the attraction forces must dominate. Each step can be facilitated by the nature of the dosage form and how it is administered. For example, a partially hydrated polymer can be adsorbed by the substrate because of the attraction by the surface water. Thus, the mechanism of mucoadhesion is generally divided in two steps, the contact stage and the consolidation stage (Figure1.3). The first stage is characterized by Mucoadhesive drug delivery systems 3 the contact between the mucoadhesive and the mucous membrane, with spreading and swelling of the formulation, initiating its deep contact with the mucus layer .In some cases, such as for ocular or vaginal formulations, the delivery system is mechanically attached over the membrane. In other cases, the deposition is promoted by the aerodynamics of the organ to which the system is administered, such as for the nasal route. On the other hand, in the gastrointestinal tract direct formulation attachment over the mucous membrane is not feasible. Peristaltic motions can contribute to this contact, but there is little evidence in the literature showing appropriate adhesion. Additionally, an undesirable adhesion in the esophagus can occur. In these cases, mucoadhesion can be explained by peristalsis, the motion of organic fluids in the organ cavity, or by Brownian motion. If the particle approaches the mucous surface, it will come into contact with repulsive forces (osmotic pressure, electrostatic repulsion, etc.) and attractive forces (van der Waals forces and electrostatic attraction). Therefore, the particle must overcome this repulsive barrier. In the consolidation step (Figure 1.3), the mucoadhesive materials are activated by the presence of moisture. Moisture plasticizes the system, allowing the mucoadhesive molecules to break free and to link up by weak van der Waals and hydrogen bonds. Essentially, there are two theories explaining the consolidation step: the diffusion theory and the dehydration theory. According to diffusion theory, the mucoadhesive molecules and the glycoproteins of the mucus mutually interact by means of

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interpenetration of their chains and the building of secondary bonds .For this to take place the mucoadhesive device has features favoring both chemical and mechanical interactions. For example, molecules with hydrogen bonds building groups (OH, COOH), with an anionic surface charge, high molecular weight, flexible chains and surface-active properties, which induct its spread throughout the mucus layer, can present mucoadhesive properties. [17]

Fig 1.3 The two steps of mucoadhesive process

1.7 Mucoadhesive Theories

There are six classical theories adapted from studies on the performance of several materials and polymer-polymer adhesion which explain the phenomenon Electronic theory Electronic theory is based on the fact that both mucoadhesive and biological materials possess opposing electrical charges. Thus, when both materials come into contact, they transfer electrons leading to the building of a double electronic layer at the interface, where the attractive forces within this electronic double layer determines the mucoadhesive strength. Adsorption theory According to the adsorption theory, the mucoadhesive device adheres to the mucus by secondary chemical interactions, such as in van der Waals and hydrogen bonds, electrostatic
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attraction or hydrophobic interactions For example, hydrogen bonds are the prevalent interfacial forces in polymers containing carboxyl groups .Such forces have been considered the most important in the adhesive interaction phenomenon because, although they are individually weak, a great number of interactions can result in an intense global adhesion Wetting theory The wetting theory applies to liquid systems which present affinity to the surface in order to spread over it. This affinity can be found by using measuring techniques such as the contact angle. The general rule states that the lower the contact angle then the greater the affinity (Figure 1.3). The contact angle should be equal or close to zero to provide adequate spread ability

Fig. 1.4 .Schematic diagram showing influence of contact angle between device and mucous membrane Fracture theory This is perhaps the most-used theory in studies on the mechanical measurement of mucoadhesion. It analyses the force required to separate two surfaces after adhesion is established

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Mechanical theory Mechanical theory considers adhesion to be due to the filling of the irregularities on a rough surface by a mucoadhesive liquid. Moreover, such roughness increases the interfacial area available to interactions thereby aiding dissipating energy and can be considered the most important phenomenon of the process. It is unlikely that the mucoadhesion process is the same for all cases and therefore it cannot be described by single theory. The mechanisms governing mucoadhesion are also determined by the intrinsic properties of the formulation and by the environment in which it is applied. Intrinsic factors of the polymer are related to its molecular weight, concentration and chain flexibility. For linear polymers, mucoadhesion increases with molecular weight, but the same relationship does not hold for nonlinear polymers. [18]

1. 8 Factors Affecting Drug Delivery via Buccal Route

The rate of absorption of hydrophilic compounds is a function of the molecular size. Smaller molecules (75-100 Da) generally exhibit rapid transport across the mucosa, with permeability decreasing as molecular size increases. For hydrophilic macromolecules such as peptides, absorption enhancers have been used to successfully alter the permeability of the buccal epithelium, causing this route to be more suitable for the delivery of larger molecules

1. 9 Methods to Increase Drug Delivery via Buccal Route

(1) Absorption enhancers: Absorption enhancers have demonstrated their effectiveness in delivering high molecular weight compounds, such as peptides, that generally exhibit low buccal absorption rates.[19]

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Table 1.1: List of Permeation Enhancers

Sr. no

Permeation Enhancers

Sr. no

Permeation Enhancers

1 2 3 4 5 6 7 8

2,3-Lauryl ether Aprotinin Azone Benzalkonium chloride Cetylpyridinium chloride Cetyltrimethyl ammonium bromide Cyclodextrin Dextran sulfate

9 10 11 12 13 14 15 16

Phosphatidylcholine Polyoxyethylene Polysorbate 80 Polyoxyethylene Phosphatidylcholine Sodium EDTA Sodium glycoholate Sodium glycodeoxycholate

(2) Prodrugs: Hussein et al delivered opioid agonists and antagonists in bitterness prodrug forms and found that the drug exhibited low bioavailability as prodrug. Nalbuphine and naloxone bitter drugs when administered to dogs via the buccal mucosa, the caused excess salivation and swallowing. As a result, the drug exhibited low bioavailability. [20] (3) pH : Shojaei et al evaluated permeability of acyclovir at pH ranges of 3.3 to 8.8, and in the presence of the absorption enhancer, sodium glycocholate. The in vitro permeability of acyclovir was found to be pH dependent with an increase in flux and permeability coefficient at both pH extremes (pH 3.3 and 8.8), as compared to the mid-range values (pH 4.1, 5.8, and 7.0).

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(4) Patch design: Several in vitro studies have been conducted regarding on the type and amount of backing materials and the drug release profile and it showed that both are interrelated. Also, the drug release pattern was different between single-layered and multi-layered patches. 1.4 Classifications of buccal bioadhesive dosage forms 1. Buccal Bioadhesive Tablets. 2. Buccal Bioadhesive semisolids 3. Buccal Bioadhesive patch and films 4. Buccal Bioadhesive Powders

1. Buccal bioadhesive tablets Buccal bioadhesive tablets are dry dosage forms that are to be moistened prior to placing in contact with buccal mucosa. Double and multilayered tablets are already formulated using bioadhesive polymers and excipients. The two buccal bioadhesive tablets commercially available buccoadhcsive tablets in UK are "Bucastem" and Suscard buccaP'. 2. Buccal bioadhesivc semisolid dosage forms Buccal bioadhesive semisolid dosage forms consists of finally powdered natural or synthetic polymer dispersed in a polyethylene or in aqueous solution, Example: Arabase.21 3. Buccal bioadhesive patches and films Buccal bioadhesive patches consists of two ply laminates or multilayered thin film round or oval as consisting of basically of bioadhesive polymeric layer and impermeable backing layer to provide unidirectional flow of drug across buccal mucosa. Buccal bioadhesive films arc formulated by incorporating the drug in alcohol solution of bioadhesive polymer.

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4.Buccal bioadhesive powder dosage forms Buccal bioadhesive powder dosage forms are a mixture of Bioadhesive polymers and the drug and are sprayed onto the buccal mucosa the reduction in diastolic B.P after the administration of buccal tablet and buccal film of Nifedipine.

1.10 Basic Components of Buccal Bioadhesive Drug Delivery

The basic components of buccal bioadhesive drug delivery system are 1. Drug substance 2. Bioadhesive polymers 3. Backing membrane 4. Penetration enhancers 5. Adhesives

1. Drug substance: Before formulating buccoadhcsive drug delivery systems, one has to decide whether the intended, action is for rapid release/prolonged release and for local/systemic effect The drug should have following characteristics.[21] 1. The conventional single dose of the drug should be small. The drugs having biological half-life between 2-8 hours are good candidates for controlled drug delivery. 2. Tmax of the drug shows wider-fluctuations or higher values when given orally.30 3. The drug absorption should be passive when given orally. 2. Bioadhesive polymers: The first step in the development of buccoadhcsive dosage forms is the selection and characterization of appropriate bioadhesive polymers in the formulation." Bioadhesive polymers play a major role in buccoadhcsive drug delivery systems of drugs. Polymers arc also used in matrix devices in which the drug is embedded in the polymer matrix, which controls the duration of release of drugs

An ideal polymer for buccoadhcsive drug delivery systems should have following Characteristics:

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It should be inert and compatible with the environment The polymer and its degradation products should be non-toxic absorbable from the Mucous layer. It should adhere quickly to moist tissue surface and should possess some site specificity. The polymer must not decompose on storage or during the shelf life of the dosage form. The polymer should be easily available in the market and economical. 3. Backing membrane: Backing membrane plays a major role in the attachment of bioadhesive devices to the mucus membrane. The materials used as backing membrane should be inert, and impermeable to the drug and penetration enhancer. The commonly used materials in backing membrane include carbopol, magnesium separate, HPMC, HPC, CMC, polycarbophil etc. 4. Penetration enhancers: Penetration enhancers arc used in buccoadhcsive formulations to improve the release of the drug. They aid in the systemic delivery of the drug by allowing the drug to penetrate more readily into the viable tissues. 5. Bioadhesion: Bioadhesive are the substances that are capable of interacting with the biological material and being retained on them or holding them together for extended period of time.Bioadhesive can be used to apply to any mucous or no mucous membranes and it also increases intimacy and duration of contact of the drug with the absorbing membrane. The commonly used bioadhesive are sodium alginate, carbomers, polycarbophil, HPMC, HPC, gelatin etc.

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1.11 LIST OF DRUGS DELIVERED VIA BUCCAL ROUTE.

Table 1.2: List of drugs delivered via buccal route Sr.No 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Active Ingredients Acitretin Acyclovir Arecoline Buprenorpine Carbamazepine Cetyl Pyridium Chloride Chitosan Chlorpheniramine Maleate Cyanocobalamine Danazol Denbufylline Diclofenac Sodium Diltiazem Hydrochloride Ergotamine Tartrate Fluride Metronidazole Melatonin Metoprolol Morphine Sulphate Nalbuphine Nicotine Nifedipine Omeprazole Oxytocin Pindolol

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26

Propolis

1.12 Mucoadhesive Buccal Tablet

Mucoadhesive Buccal tablets comprising hydrogels can adhere to the buccal mucosa. They are similar to conventional tablets and are prepared by wet granulation, dry granulation, or direct compression processes. Drug is released upon the hydration and adhesion of the device. Buccal tablets should be fabricated and optimized for swelling behavior and drug release to ensure a prolonged period of bioadhesion and sustained or controlled release. Generally, the tablets are formulated with flat punches with dimensions less than 10 mm in diameter and 2 mm thick to aid in establishing intimate contact with buccal mucosa and reduce their interference with normal activities. In addition to mucoadhesive components, most of the tablets contained water-soluble excipients such as high-molecular-weight polyethylene glycols and mannitol. [22-24]

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