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Diabetes mellitus was recognized as early as 1500 B.C. by Egyptian Physicians, who described it as a disease associated with "the passage of much urine". The term "diabetes" (the Greek for Siphon) was coined by the Greek Physician Aretaeus the Cappadocian around A.D.2. In 1674 a physician named Willis coined the term "Diabetes Mellitus" (from the Greek word for Honey).1, 2
Diabetes mellitus is a complex syndrome that affects multiple organ systems. It is now clear that diabetes is a heterogeneous group of disorders that are elicited secondary to various genetic predispositions and precipitating factors.3
Diabetes mellitus is a chronic disease that is characterized by disorders in carbohydrate, protein and lipid metabolism. Its central disturbance appears to involve an abnormality either in the secretion of or effects produced by insulin although other factors also may be involved.4 Diabetes mellitus is a metabolic disorder in which carbohydrate metabolism is reduced while that of proteins and lipids is increased.5
The external secretion of the pancreas is digestive in function and the intestinal secretions play a major role in the regulation of metabolism. The hormones which regulate the level of blood sugar are mainly two; glucagon from the alpha-cells and insulin from the beta-cells of the islets of langerhans.6
DIFFERENT FORMS OF DIABETES MELLITUS: 7
Insulin-dependent diabetes mellitus (IDDM: also called type I).
Non-insulin-dependent diabetes mellitus (NIDDM: also called type II).
Gestational diabetes mellitus.
Maturity onset diabetes of youth (MODY: glucokinase gene mutations).
Mutations of the insulin receptor (including leprechaunism).
Insulin gene mutations.
Tropical diabetes (chronic pancreatitis associated with nutritional or toxic factors).
Diabetes secondary to pancreatic disease or surgery.
Diabetes associated with genetic syndromes, e.g., Prader-Willi syndrome.
Diabetes secondary to endocrinopathies.
CLASSIFICATION OF ANTIDIABETIC DRUGS: 7
These drugs lower blood glucose levels. The chief drawback of insulin is it must be given by injection. The early sulfonamides tested in 1940's produced hypoglycemia as side effect.
Taking this lead, the first clinically acceptable sulfonylurea; Tolbutamide was introduced in 1957. In the 1970's many so called Second Generation sulfonylureas have been developed which are 10-100 times more potent.
First Generation Analogs Second-Generation Analogs
Tolbutamide (Orinase) Glipizide (Glyburide)
Chlorpropamide (Diabenese) Glipizide (Glucotrol)
Acetohexamide (Dymelor) Gliclazide (Diamicron)
Other Hypoglycemic Agents:
PHARMACOTHERAPY OF DIABETIES MELLITUS:
Glipizide is a second generation Sulfonylurea compound used as an oral hypoglycemic or antidiabetic agent.8 Therapy with Glipizide is usually initiated with 2.5mg given once daily. The maximal recommended daily dose is 20mg.9
Glipizide is 200 times more potent than tolbutamide in evoking pancreatic secretion of insulin. It differs from other oral hypoglycemic drugs where in tolerance to this action apparently does not occur.9 It also upregulates insulin receptors in the periphery, which seems to be the primary action. It has a special status in the treatment of non-insulin-dependent diabetes mellitus because it is effective in many cases which are resistant to all other oral hypoglycemic drugs. It differs from other oral hypoglycemic drugs ie more effective during eating than during fasting.
About 50% of Glipizide is metabolized to its inactive metabolites in liver. With a view to bypass the hepatic first pass effect and thereby improving bioavailability of drug an attempt to develop a buccal mucoadhesive dosage form for Glipizide has been made in the study.10
INtroduction to Non-Steroidal Anti-inflammatory Drugs (NSAIDs):
Inflammation is defined as a directed tissue response to noxious and injurious, external and internal stimuli. The inflammatory stimuli can be classified into four categories. They are physical stimuli, chemical stimuli, infective stimuli and immunological stimuli.
Chronic inflammatory conditions lead to the development of diseases including osteoarthritis, rheumatoid arthritis, and other anti-inflammatory disease of the joints. Anti-inflammatory drugs offer symptomatic relief in the inflammatory diseases when the underlying cause of inflammation is unidentified. The anti-inflammatory drugs can classified into two categories.
Corticosteroids: Which produce a dramatic reduction in the stiffness and associated with inflammatory joint diseases. However, there are several disadvantages associated with long term use of corticosteroids for the treatment of chronic inflammatory diseases of the joint.
NSAIDs: Which act by inhibiting the catalytic activity of the enzyme cyclooxygenase (COX). This enzyme is responsible for catalyzing an important intermediate step in the synthesis of arachidonic acid to prostaglandins (PG) and thromboxanes (TX) which are mediators of inflammation.9
Prostaglandins are synthesized by oxygenation and ring closure of arachidonic acid, controlled by a rate limiting cyclo-oxygenase (COX) which occurs as two isoenzymes: COX-1 and COX-2. The products of this reaction are unstable intermediates known as cyclic endoperoxides specific enzymes which differ from cell to cell, convert these intermediates to various prostaglandins. The products of the COX pathway, therefore, differ among various tissues, reflecting the diverse nature of their actions and the individual requirements of each cell types.
Mechanism of action of NSAIDs:
The non-steroidal anti-inflammatory drugs (NSAIDs) share a common mode of action, by inhibition of COX-1 and/or COX-2. Different NSAIDs have different relative effects on the two isozymes. Inhibition of COX reduces the generation of prostaglandins but does not affect the production of leukotrienes. Indeed, leukotrienes production can increase as a result of diversion of arachidonic acid into the lipoxygenase pathway.
Figure No. 1: NSAIDs and Cyclooxygenase (COX) 1 and 2 Isozymes
Many "conventional" NSAIDs inhibit COX-1 and COX-2 selective COX-2 inhibiting NSAIDs may show the advantage of a lower gastrointestinal side-effect profile. However COX-2 is widely distributed and may be constitutively expressed in some areas.
E.g. Kidney - Inhibition with long-term treatment may affect renal function.10
Selective COX-1 Inhibition:
Selective COX-1 inhibition reduces platelet aggregation. Aspirin (Acetyl salicylic acid) is 150 times more effective of inhibiting COX-1 than COX-2. This is undesirable in patients with clotting disorders but beneficial in some disease state.
COX-1 inhibition predisposes to damage to the gastric mucosa. Doses of aspirin sufficient to have anti-inflammatory effects by inhibition of COX-2, therefore, cause gastric damage because the doses required to inhibit many COX-2 mediated inflammatory processes must have significant inhibitory effects on COX-1.
Selective COX-2 Inhibition:
The analgesic actions of NSAIDs appear to result from inhibition of COX-2.
NSAIDs that inhibit COX-2 selectively (Celecoxib, Rofecoxib, Valdecoxib, Meloxicam) appear to have useful anti-inflammatory actions and have fewer gastrointestinal damaging actions (COX-1 dependent gastroprotection) when compared with "conventional NSAIDs".
Highly selective COX-2 inhibitors have little effect on platelet TXA2 (COX-1 dependent) and therefore do not affect aggregation. These drugs may be better tolerated by patients with clotting disorders.
In mice that have been breed to genetically deficient in COX-2, there is significantly higher incidence of renal damage compared with normal animals.10
Classification of COX-Inhibitors:9
The COX inhibitors can be classified on the basis of type of binding into the following four categories.
The drugs causing irreversible inhibition of both COX-1 and COX-2. E.g. Aspirin
The drugs causing reversible and competitive inhibition of both COX-1 and COX-2. E.g. Ibuprofen
The drugs causing slow, time dependent inhibition of COX-1 and COX-2.
E.g. Flurbiprofen, Indomethacin.
The drugs causing highly selective inhibition of COX-2. E.g. Rofecoxib, Celecoxib, Valdecoxib.
Unwanted effects of selective COX-1 inhibitors:10
Most unwanted effects arise from the non-selective inhibition of prostaglandin synthesis throughout the body. They are usually dose dependent..
Gastric irritation, gastric ulceration, dyspepsia are thought to occur principally as a result of inhibition of mucosal production of PGE2 and PGI2.
Inhibition of prostaglandin generation reduces mucosal blood flow, which probably enhances cytotoxicity by producing tissue hypoxia and local free radical.
Rectal administration can result in local irritation and bleeding.
Aspirin produces tinnitus in toxic doses; overdose of aspirin may lead to hazardous effect.
Indomethacin causes CNS unwanted effects such as dizziness, drowsiness and confusion, particularly in the elderly.
Skin reaction can occur, especially with Fenbufen.
Phenylbutazone can produce bone marrow aplasia; its use is now restricted to patients with ankylosing spondylitis, for which it is particularly effective.
Paracetamol causes hepatic damage and renal failure in overdose.
Indications of NSAIDs:10, 11.
NSAIDs are indicated for followings:-
Treatment of musculoskeletal disorders such as osteoarthritis, rheumatoid arthritis and primary dysmenorrhoea.
As an antipyretic in febrile condition.
For modest reduction of menstrual blood loss in menorrhagia (excessive blood loss at menstruation).
Prevention of vascular occlusion by inhibition of platelet aggregation (especially low dose aspirin).
Reduction in colonic polyps and cancer (COX-1 and COX-2 inhibitors).
Recent studies suggest NSAIDs may reduce the progression of Alzheimer's disease.10
Selective COX-2 inhibitors were developed on the promise that, compared with non-selective NSAIDs, significantly fewer serious GI adverse effects would occur with specific inhibition of the inducible isoform of the COX enzyme while yielding comparable efficacy.
First generation COX-2 selective inhibitors like Celecoxib launched in 1999 and was first marketed product to be approved by US-FDA (US-Food and Drug Administration).
Second-generation COX-2 selective inhibitors rofecoxib and valdecoxib were approved by US-FDA in 2001, for the treatment of Osteoarthritis (OA) in adults. Clinical trials demonstrated greater efficacy in patients with OA with valdecoxib 5mg and 10 mg bid than with placebo.12
Adolescents suffering from dysmenorrhea with a prior history of peptic ulcer or history of NS-NSAIDs (Non-selective NSAIDs) gastrointestinal adverse effects or who require high doses of NS-NSAIDs during menstrual period, as well as adolescents with coagulation deficiencies, may benefit from the use of specific COX-2 inhibitors.
In vitro studies have shown that the selective COX-2 inhibitors have potent tocolytic effect. In vivo studies have found the specific COX-2 inhibitors Rofecoxib, (Vioxx) and Valdecoxib (Bextra) effective in the treatment of primary dysmenorrhea in women more than 18 years.13
Need and Objectives of the study
need of the study
Over the year controlled drug delivery technology has a wide advances. Due to its high potential a bioadhesive system place a major role in controlling drug release. Mucoadhesive system prolong the residence time of the dosage form at the site of application or absorption and facilitate an therapeutic performance of the drug. Recent interest has been expressed in the delivery of drug via mucus membrane by the use of adhesive materials on which studies are been intensively undertaken.58
Glipizide is an oral antidiabetic drug, belonging to the sulphonylurea group. Presently the drug is marketed in conventional dosage form of tablet in usual strength of 2.5 to 20 mg. When the drug is administered by this route, about 50% of drug is metabolized in the liver to the several inactive metabolites. Hence there is need of the alternative route administration to avoid first pass hepatic metabolism.7 More over the combination of anti-diabetic drugs with NSAIDS are not available in market.
Physicochemical properties of this drug like small dose, lipophilicity, stability at buccal pH, odourlessness, tastelessness, low molecular weight etc. makes it an ideal candidate for administration by buccal route.
To overcome the inherent drawbacks associated with conventional dosage form of Glipizide, an attempt is being made to design and evaluate an alternative drug delivery system in form of buccal mucoadhesive advantages.
Enhancement of therapeutic index.
Optimized concentration of drug in systemic circulation.
MUCOADHESIVE DRUG DELIVERY SYSTEM: 14
The term bioadhesion refers to either adhesion between two biological materials or adhesion between some biological material (including cells, cellular secretions, mucus, extracellular matrix etc.) and an artificial substrate (metals, ceramics, polymers etc.). In terms of pharmaceutical industry, bioadhesion generally refers to adhesion between a polymer based delivery system and soft tissue in presence of water.
Pharmaceutical aspects of mucoadhesion have been the subject of great interest during recent years because it provides the possibility of avoiding either destruction by gastrointestinal contents or hepatic first-pass inactivation of drug.
The concept of mucosal adhesives or mucoadhesives was introduced into the controlled drug delivery area in the early 1980's. Mucoadhesives are synthetic or natural polymers which interact with the mucus layer covering the mucosal epithelial surface and mucin molecules consisting a major part of mucus. The concept of mucoadhesive has alerted many investigators for the possibility that; these polymers can be used to overcome physiological barriers in long-term drug delivery. They render the treatment more efficient and safe, not only for topical disorders but also for systemic problems.
MUCOADHESIVE BUCCAL DRUG DELIVERY SYSTEM: 11, 12, 13
Drug delivery via the membranes of the oral cavity can be subdivided as follows :
Sublingual delivery, which is the administration via the sub-lingual mucosa to the systemic circulation.
Buccal delivery, which is administration of drug via the buccal mucosa to the systemic circulation; and
Local delivery, which is used for the treatment of conditions of the oral cavity, principally aphthous ulcers, fungal conditions and periodontal diseases by application of the bioadhesive system either to the palate, the gingiva or the cheek.
These oral mucosal sites differ greatly from one another, in terms of anatomy, permeability to an applied drug and their ability to retain a delivery system for desired length of time.
The combination of several aspects that makes buccal site an attractive route for drug delivery are:
The oral mucosa is easily accessible, so dosage forms can be easily administered and even removed from the site of application.
Since patients are well adopted to oral administration of drugs in general, patient acceptance and compliance is expected to be good.
According to its natural function the oral mucosa is routinely exposed to a multitude of different external compounds and therefore, is supposed to be rather robust and less prone to irreversible irritation or damage by a dosage form, its drug excipients or additives.
Its ability to recover after local treatment is pronounced and hence allows a wide range of formulation to be used. E.g., bioadhesive ointments and patches.
Local delivery of drugs to the oral cavity has a number of applications viz., treatment of toothache, periodontal disease, dental caries, bacterial and fungal infections and aphthous stomatitis.
Conventional formulations for local oral delivery are principally lozenges, troches, mouth paints, mouth washes, oral gels, pastes and suspensions.
ADVANTAGES OF MUCOADHESIVE BUCCAL DRUG DELIVERY SYSTEM:
Drug administration via the oral mucosa offers several advantages.15, 16
Ease of administration.
Termination of therapy is easy.
Flexibility in physical state, shape, size and surface.
Maximized absorption rate due to intimate contact with the absorbing membrane and decreased diffusion barriers.
Permits localization of the drug to the oral cavity for a prolonged period of time.
Can be administered to unconscious patients.
Offers an excellent route for the systemic delivery of drugs with high first pass metabolism, thereby offering a greater bioavailability and reduction in dosage.
A significant reduction in dose can be achieved, thereby reducing dose dependent side effects.
It allows for the local modification of tissue permeability, inhibition of protease activity or reduction in immunogenic response. Thus, selective use of therapeutic agents like peptides, proteins and ionised species can be achieved.
Drugs which are unstable in the acidic environment of the stomach or are destroyed by the enzymatic or alkaline environment of the intestines can be administered by this route.
Drugs which show poor bioavailability via the oral route can be administered conveniently.
It offers a passive system for drug absorption and does not require any activation.
The oral mucosa lacks prominent mucus secreting goblet cells and therefore there is no problem of diffusion limited mucus build up beneath the applied dosage form.
The presence of saliva ensures relatively large amount of water for drug dissolution unlike in case of rectal and transdermal routes.
It satisfies several features of the controlled release systems.
It can be made unidirectional to ensure only buccal absorption.
The buccal mucosa is highly perfused with blood vessels and offers greater permeability than skin.
Bioadhesion prolongs the residence time at the site of drug absorption, and thus improves bioavailability and reduces dosing interval.
Rapid onset of action.
LIMITATIONS OF BUCCAL DRUG ADMINISTRATION:
Drug administration via this route has certain limitations.
Drugs which irritate the mucosa or have a bitter or unpleasant taste or an obnoxious odour cannot be administered by this route.
Drugs which are unstable at buccal pH cannot be administered by this route.
Only drugs with a small dose requirement can be administered.
Only those drugs which are absorbed by passive diffusion can be administered by this route.
Eating and drinking may become restricted.
There is an ever present possibility of the patient swallowing the dosage form.
Over hydration may lead to formation of slippery surface and structural integrity of the formulation may get disrupted by this swelling and hydration of the bioadhesive polymers.
Anatomy of Oral Mucosa
As the stratum corneum may be a potential barrier to mucosal penetrations, drugs are traditionally placed at the non-keratinized sites like the buccal and sublingual regions.
In the adult human, the mucosa lining the oral cavity covers an area of approximately 200cm2. The thickness of human oral mucosa varies according to its site. For example, epithelial thickness of buccal mucosa (non-keratinized) is approximately 500mm. Palatal epithelium 270mm which includes a keratin layer thickness of 32mm and gingival epithelium approximately 250mm. In general, non-keratinized tissue is considerably thicker than keratinized tissue, however the floor of the mouth (non-keratinized) is very thin (approximately 100mm).
A] The Mucus Layer :
Mucus is a translucent and viscid secretion which forms a thin, continuous gel blanket adherent to the mucosal epithelial surface. The mean thickness of this layer varies from about 50 to 450 mm in humans, it is secreted by the goblet cells, lining the epithelia or by special exocrine glands with mucus cells acini.
The exact composition of the mucus layer varies substantially, depending on the species, the anatomical location and the pathophysiological state. However, it has the following general composition :
1. Water - 95%
2. Glycoproteins and lipids - 0.5 to 5%
3. Mineral salts - 1%
4. Free proteins - 0.5% to 1%
B] Functions of Mucus Layer :
The primary functions of the mucus layer are :-
Protective : resulting particularly from its hydrophobicity.
Barrier : the role of the mucus layer as a barrier in tissue absorption of drugs and other substrates is well known as it influences the bioavailability of drugs.
Adhesion : mucus has strong cohesional properties and firmly binds to the cell surface as a continuous gel layer.
Lubrication : an important role of the mucus layer is to keep the mucosal membrane moist. Continuous secretion of mucus from the goblet cell is necessary to compensate for the removal of the mucus layer due to digestion, bacterial degradation and solubilization of mucin molecules.
At physiological pH, the mucus network may carry a significant negative charge because of the presence of sialic acid and sulfate residues and this high charge density due to negative charge contributes significantly to bioadhesion.
C] The Salivary Secretion :
Besides the mucus, the mucosal layer of the oral cavity is kept moist by the saliva secreted mainly by three pairs of salivary glands namely the submaxillary, the parotid and the sublingual glands. The pH of salivary secretion ranges from about 6.2 to 7.4 with an average of 6.6. About 1.5 litres of saliva is secreted per day.
There is a considerable variation in the individual saliva flow rates. It ranges from 0.21 to 1.18 ml/min. with a mean of 0.65 ml/min under the resting condition and 0.56 to 2.70 ml/min with a mean of 1.63 ml/min under exogenously stimulated conditions.
Good (1976), defined bioadhesion as the state in which two materials, at least one of which being of a iological nature, are held together for an extended period of time by interfacial forces.
If adhesive attachment is to a mucus the phenomenon is referred to as mucoadhesion. The first step is an intimate contact between a bioadhesive and a membrane, in the second step, bioadhesive with those of the mucus takes place.
Several theories have been proposed to explain the fundamental mechanisms of adhesion. In a particular system, one or more theories can equally well explain or contribute to the formation of bioadhesive bonds.
THEORIES OF BIOADHESION / MUCOADHESION : 17
Several theories have been proposed to explain the fundamental mechanisms of adhesion. The surface characteristics, composition of the mucoadhesive material as well as the substrate and the associated applied force to bring the adherence of substrate in contact are important parameters to be considered in assessing mucoadhesion. The bonding occurs chiefly through both physical and chemical interactions.
Covalent bonding, such as that occurs with cyanoacrylates, is also possible for mucoadhesion, but is not yet common in pharmaceutical systems. Electrostatic interactions and hydrogen bonding appear to be important as a result of the large number of charged and hydrophilic species e.g., hydroxylic (-OH), carboxylic (-COOH), sulfate (-SO3H), and amino (-NH2) groups. Proposed theories of mucoadhesion include wetting, diffusion, electronic, absorption and fracture.
Electronic Theory : The electronic theory of adhesion was suggested by Derjaguin et al. (1969). According to this theory electron transfer occurs on contact of an adhesive polymer and the mucus glycoproteins network due to differences in differences in electronic structure, electron transfer occurs on contact of an adhesive polymer & the mucas glycoprotein network, which results in formation of an electrical double layer at the interface. Adhesion occurs due to attractive forces across the double layer. Such a system behaves analogous to a capacitor, which is charged when two different surfaces come in contact, and discharged when they are separated.
Wetting : This theory best describes the adhesion of liquid or paste to a biological surface. The work of adhesion can be expressed in terms of surface and interfacial tension (g) being defined as the energy per cm2 released when an interface is formed. According to Dupre's equation the work of adhesion is given by : 18
Wa = gA + gB - gAB ----- (1)
Where the subscript A and B refer to the biological membrane and the bioadhesive formulation respectively. The work of cohesion is given by :
Wc = 2gA or 2gB ------ (2)
For a mucoadhesive material B spreading on a biological substrate A the spreading coefficient is given by :
SB/A = gA - (gB - gAB) ----- (3)
SB/A should be negative for a mucoadhesive material to adhere to a biological membrane. For a mucoadhesive liquid B adhering to a biological membrane A the contact angle is given by:
Cos q = (gA - gAB/gB) ----- (4)
In a homologous series of cellulosic polymers the authors observed an increase in bioadhesive strength as the contact angle increased. Hence surface characteristic of the bioadhesive material appear to be an important parameter to be considered.
The wetting theory of bioadhesion
Diffusion : Voyutski (1963) appears to be the first to discuss diffusion, as a theory for adhesion. According to this, the polymer chains and the mucus co-mingle to a sufficient depth to create a semi-permanent adhesive bond. Additional insight as to the mechanism of interpenetration has recently been provided by Pager et al. (1981). The mucoadhesive material and glycoprotein of the biological membrane are brought in close contact. The polymer chains penetrate the mucus, the exact depth to which it penetrates to achieve sufficient mucoadhesion depends on the diffusion coefficient, time of contact, and other experimental variables. The diffusion coefficient depends on molecular weight and decreases rapidly as the cross-linking density increases shown by Peppas et al. (1985). Flexibility of the bioadhesive polymer and mucus glycoprotein molecule plays an important role in bioadhesion, due to the need for co-mingling of chains to increase the area of contact. Park and Robinson (1985), have shown that partial mucolysis increases mucoadhesiveness, due to enhanced flexibility of the mucin molecules. Gluteraldehyde treatment to increase cross-linking of the mucus glycoprotein decreases mucoadhesion. This behavior is in agreement with the interpenetration theory.
In summary, the molecular weight, chain flexibility, expanded nature of both the mucoadhesive and substrate as well as similarity in chemical structure are required for good mucoadhesion.
Fracture theory : This theory attempts to relate the difficulty of separation of two surfaces after adhesion. Fracture theory equivalent to adhesive strength is given by:
G = (E Î/L)1/2 ----- (5)
Where E is Young's modulus of elasticity, Î is the fracture energy and L is critical crack length when two surfaces are separated. The work of fracture of an elastomer network Gc is given by :
Gc = K ( Mc)½ ----- (6)
K is a constant dependent on density of the polymer, effective mass, length and flexibility of a single mucin chain bonds and dissociation energy. Gc of an elastometric network increases with molecular weight Mc of the network stands.
Absorption theory : According to this theory, after an initial contact between two surfaces, the material adheres because of surface forces acting between the atoms in the two surfaces. Two type of chemical bonds resulting from these forces can be distinguished.
Primary chemical bonds of covalent nature which are undesirable in bioadhesion because their high strength may result in permanent bonds.
Secondary chemical bonds having many different forces of attraction, including electrostatic forces, vander waals forces hydrogen and hydrophobic bonds.
FACTORS AFFECTING BIOADHESION : 17, 18
The bioadhesive power of a polymer or of a series of polymers is affected by the nature of the polymer and also by the nature of the surrounding media (Gandhi R.B. et al., 1988).
Polymer related factors :
Molecular weight: Numerous studies have indicated that there is a certain molecular weight at which bioadhesion is at a maximum. The interpenetration of polymer molecule is favorable for low molecular weight polymers whereas enlargements are favoured for high molecular weight polymers. According to Gurny et al. (1984) it seems that the bioadhesive force increases with the molecular weight of the bioadhesive polymer, upto 100,000 and beyond this level there is not much effect. To allow chain interpenetration, the polymer molecule must have an adequate length.
Flexibility of Polymer chains:. As water soluble polymers become cross-linked, the mobility of the individual polymer chain decreases. As the cross-linking density increases, the effective length of the chain which can penetrate into the mucus layer decreases even further and mucoadhesive strength is reduced.
Spatial conformation: Besides molecular weight or chain length, spatial conformation of a molecule is also important. The helical confirmation of dextran may shield many adhesively active groups primarily responsible for adhesion, unlike PEG polymers which have a linear confirmation. 19
2. Environment Related Factors :
pH : pH was also found to have a significant effect on mucoadhesion as observed in studies of polyacrylic polymers cross-linked with -COOH groups. pH influences the charge on the surface of both mucus and the polymers. Mucus will have a different charge density, depending on pH, because of differences in dissociation of functional groups on the carbohydrate moiety and amino acids of the polypeptide backbone. Romanson et al. (1985), observed that pH of the medium is critical for the degree of hydration of lightly cross-linked polyacrylic acid polymers. Maximum adhesion was observed at pH 5 and 6 and minimum at pH 7. This behavior was attributed to differences in charge density at different pH's. Hence, the charge density of both mucin and the polymer are influenced by pH, which in turn affects mucoadhesion.
Applied Strength: To place a solid bioadhesive system, it is necessary to apply a defined strength. The adhesion strength increases with the applied strength or with the duration of its application, upto an optimum. If high pressure is applied for a sufficiently long period of time, polymers become mucoadhesive even though they do not have attractive interactions with mucin.
Initial contact time: The initial contact time between mucoadhesives and the mucus layer determines the extent of swelling and the interpenetrations of polymer chains. Along with the initial pressure, the initial contact time can dramatically effect the performance of a system. The mucoadhesive strength increases as the initial contact time increases.
Degree of hydration: Depending on the degree of hydration adhesion properties will be different. It is maximum at a certain degree of hydration. When the degree of hydration is high, adhesiveness is lost probably due to formation of slippery, non-adhesive mucilage in an environment of large amount of water at or near the interface.
METHODS USED TO STUDY BIOADHESION: 17
Several test methods have been reported for studying bioadhesion. These tests are necessary not only to screen a large number of candidate mucoadhesives, but also to study their mechanisms. These tests are also important during the design and development of a bioadhesive controlled release system as they ensure compatibility, physical and mechanical stability, surface analysis and bioadhesive bond strength.
The test methods can broadly be classified into two major categories :-
In Vitro/ex-vivo method :
Most in-vitro methods are based on the measurement of either tensile or shear stress. Bioadhesiveness determined by measurement of stress tends to be subjective since there is no standard test method established for bioadhesion.
Method based on measurement of tensile strength.
Eg; Modified balance or tensile testers.
Methods based on measurement of shear strength.
Eg : Wilhelmy plate method.
Other in vitro methods.
A number of other methods including electrical conductance and thumb test method, adhesion weight method, fluorescent probe method, flow channel method, falling liquid film method, colloidal gold staining method, viscometeric method, mechanical spectroscopic method have been used for the determination of bioadhesion. 20
Recently, two apparatus have been described for the in situ evaluation of bioadhesion properties of buccal tablet.
2) In Vivo method :
In vivo techniques for measuring the bioadhesive strength are relatively few. Some of the reported methods are based on the measurements of the residence time of bioadhesive at the application site (Kamath and Park, 1994). The GI transit times of many bioadhesives have been examined using radioisotopes.
PERMEABILITY OF THE ORAL MUCOSAE: 14, 15
The permeability characteristics of the oral mucosae have been reviewed by a number of authors.
The permeability barrier of the oral mucosae is thought to reside with the superficial layer (approximately the outer most quarter) of the epithelium. Permeation studies have been performed using a number of tracers such as horseradish peroxidase (an enzyme of 40,000 and 5-6mm in size) and lathanum nitrate (an electron-dense marker, 2nm in size).
Some workers have suggested that the basement membrane is the functional permeation barrier of the oral mucosae or that it presents at least a degree of resistants to permeants.
The lamina propria is not generally thought to present the barrier to permeation. Its structure is insufficiently dense to exclude even relatively large molecules, and its hydrated matrix should facilitate the passage of hydrophilic penetrants.
Membrane coating granules:
The most plausible explanation at present for the origin of the permeability barrier of oral epithelia involves the so-called "membrane-coating granules" (MCG), which are spherical or oval organelles. 100-300nm in diameter, and are found in the intermediate cell layers of many stratified epithelia and they have been widely explored in both keratinized and non-keratinized epithelia21 and epidermis. MCG are involved in the thickening of the plasma membrane.
Since the MCG are thought to be involved in the development of the intracellular matrix, it follows that interference with the MCG themselves or with their released contents may influence the permeability of the mucosa and of the paracellular route in particular. This strategy was adopted by Squier and others who attempted to increase mucosal permeability by the use of glycoprotein or glycolipid-specific enzymes. However, the scope for such strategies is likely to remain limited without a reasonable understanding of the role of MCG in non-keratinized epithelial permeability; since these organelles lack any characteristic staining reactions or microscopic features its level of understanding remains elusive.
Nature of permeant:
Most published studies of oral mucosal permeability have focused on relatively small numbers of permeant molecules, and few have attempted to systematically evaluate the relative contribution of factors such as molecular size, lipid solubility and ionization on permeability. From the systematic studies that have been reported, however, it appears that the ability of a molecule to permeate through the mucosa can be related to molecular size, lipid solubility and ionization.
For hydrophilic substances, the rate of absorption is a function of the molecular size. Small molecules (<75-100 Da.) appear to cross the mucosa rapidly, but permeability falls off rapidly as molecular size increases. Since permeability has been observed to decrease sharply as molar volume is increased beyond 80ml/mol, investigators have proposed - two distinct polar routes. This relationship between size and permeability has not been demonstrated for lipophilic substances, although common sense suggests that such a relationship must exist.
For any series of unioniozable compounds, their relative permeabilities are functions of their oil-water partition co-efficients with the more lipid-soluble compounds having higher permeabilities.
The degree of ionization of a permeant is a function of both its pka and the pH at the mucosal surface. For many weak acids and weak bases, only the unionized form possesses appreciable lipid solubility. The absorption of many compounds has been shown to be maximal at the pH at which they are mostly unionized, tailing off as the degree of ionization increases. Other studies, however, have failed to show this pattern.
In common with drug transport across other epithelia, there are a number of possible permeation pathways across the oral mucosae. The classical distinction is between transcellular and paracellular permeation, referring to passage across the individual cells of the epithelium and passage between these cells, respectively. For transcellular permeation, the permeant must be capable of passing through pores in the cell membranes or diffusing through the lipid bi-layers of these membranes. Passage through membrane pore would probably be limited to small molecules, while diffusion across cell membranes would require appreciable aqueous and lipid solubilities. Paracelluler permeation requires the epithelium to have a sufficiently open matrix and requires the permeant to have an appreciable diffusivity in the intercellular milieu. It seems likely that large and/or highly polar permeants may be unable to pass through the epithelial cell membranes and might, therefore, follow the paracellular route.
An alternative classification is into polar and non-polar routes, the former involving passage of water-soluble substances through aqueous channels in the mucosa and the latter involving partitioning of the drug into the lipid bilayer of the plasma membrane or into the lipid of the intercellular matrix and diffusion through these lipid elements.
Almost all studies have shown that, for most permeants passage across the oral mucosae appears to be a first-order simple diffusion process. It has also been suggested, however that the oral mucosae contain active or carrier-mediated systems for small molecules such as monosaccharides and amino acids. However, these processes have not been fully characterized in terms of location, transport capacity or specificity.
The kinetics of oral mucosal absorption have been studied by a number of workers. Some investigations have shown a slow onset of appearance of permeant in the systemic circulation and a depot-like behaviour of the oral mucosae which have been attributed to some form of binding within the mucosae. To date, however, this area has not been systematically investigated and remains for the most part poorly understood.
Possible routes for drug transport across the oral mucosa: 16
The cellular structure of the oral mucosa suggests that there are two permeability barriers. The intercellular spaces and cytoplasm are essentially hydrophilic in character and become a transport barrier for lipophilic compounds mainly because the solubility of lipophilic compound in this environment is low. In contrast, the cell membrane is lipophilic and the penetration of a hydrophilic compound into the cell membrane is low due to a low partition coefficient. Thus, closely compacted cell membranes become obstacles that hydrophilic compounds have to move around.
The coexistence of the hydrophilic and lipophilic regions in the oral mucosa suggests that there are two routes for drug transport, i.e., the paracellular and the transcellular routes (Diag.3).
PERMEATION ENHANCEMENT: 14, 15
While the sublingual mucosa is sufficiently permeable to allow the therapeutic delivery of a number of small drug molecules, low mucosal permeability is perceived to be a significant obstacle to buccal delivery.
Permeation enhancers are substances added to a pharmaceutical formulation in order to increase the membrane permeation rate or absorption rate of a co-administered drug.
Attention is thus focused on some of the strategies that have been proposed for enhancing the permeability of the oral mucosae. A considerable number of agents have been proposed as penetration enhancers. The agents used have mostly been small hydrophilic molecules. E.g., dimethyl sulphoxide, dimethyl formamide, ethanol, propylene glycol, and the 2-pyrrolidones, long-chain amphiphathic molecules (decylmethyl sulphoxide, azone, sodium lauryl sulphate, oleic acid and the bile salts), and non-toxic surfactants (polysorbates). Although some are effective, either alone or in combination, their modes of action are not fully understood.
A related issue is the use of enzyme inhibitors to reduce the enzymatic degradation of the drug within the mucosa. Hirai et al. showed improved nasal absorption of insulin using the bile salts.
Plan OF the study
Preformulation studies for Drug - Excipients Compatibility.
Preparation of standard curve for Glipizide and Valdecoxib.
Preparation of various buccal tablets using Carbopol 940, Sodium carboxy methyl cellulose and Polyvinyl pyrrolidone as polymers in different concentrations.
Evaluation of buccal tablets by following parameters:-
Weight variation test
Content uniformity test
Tablet disintegration test
Measurement of surface pH.
Water absorption study.
Measurement of bioadhesion strength
In-vitro diffusion studies.
The results are presented in tables and graphically by using various equations governing release kinetics.