Diabetess mellitus was recognized every bit early as 1500 B.C. by Egyptian Physicians, who described it as a disease associated with “ the transition of much piss ” . The term “ diabetes ” ( the Hellenic for Siphon ) was coined by the Grecian Physician Aretaeus the Cappadocian around A.D.2. In 1674 a doctor named Willis coined the term “ Diabetes Mellitus ” ( from the Grecian word for Honey ) .1, 2
Diabetess mellitus is a complex syndrome that affects multiple organ systems. It is now clear that diabetes is a heterogenous group of upsets that are elicited secondary to assorted familial sensitivities and precipitating factors.3
Diabetess mellitus is a chronic disease that is characterized by upsets in saccharide, protein and lipid metamorphosis. Its cardinal perturbation appears to affect an abnormalcy either in the secernment of or effects produced by insulin although other factors besides may be involved.4 Diabetes mellitus is a metabolic upset in which saccharide metamorphosis is reduced while that of proteins and lipoids is increased.5
The external secernment of the pancreas is digestive in map and the enteric secernments play a major function in the ordinance of metamorphosis. The endocrines which regulate the degree of blood sugar are chiefly 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: besides called type I ) .
Non-insulin-dependent diabetes mellitus ( NIDDM: besides called type II ) .
Gestational diabetes mellitus.
Maturity onset diabetes of young person ( MODY: glucokinase cistron mutants ) .
Mutants of the insulin receptor ( including leprechaunism ) .
Insulin cistron mutants.
Tropical diabetes ( chronic pancreatitis associated with nutritionary or toxic factors ) .
Diabetess secondary to pancreatic disease or surgery.
Diabetess associated with familial syndromes, e.g. , Prader-Willi syndrome.
Diabetess secondary to endocrinopathies.
Categorization OF ANTIDIABETIC DRUGS: 7
These drugs lower blood glucose degrees. The main drawback of insulin is it must be given by injection. The early sulfa drugs tested in 1940 ‘s produced hypoglycaemia as side consequence.
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 powerful.
First Generation Analogs Second-Generation Analogs
Tolbutamide ( Orinase ) Glipizide ( Glyburide )
Chlorpropamide ( Diabenese ) Glipizide ( Glucotrol )
Acetohexamide ( Dymelor ) Gliclazide ( Diamicron )
Tolazamide ( Tolinase )
Other Hypoglycemic Agents:
PHARMACOTHERAPY OF DIABETIES MELLITUS:
Glipizide is a 2nd coevals Sulfonylurea compound used as an unwritten hypoglycemic or antidiabetic agent.8 Therapy with Glipizide is normally initiated with 2.5mg given one time day-to-day. The maximal recommended daily dose is 20mg.9
Glipizide is 200 times more powerful than Orinase in arousing pancreatic secernment of insulin. It differs from other unwritten hypoglycemic drugs where in tolerance to this action seemingly does non occur.9 It besides upregulates insulin receptors in the fringe, which seems to be the primary action. It has a particular position in the intervention of non-insulin-dependent diabetes mellitus because it is effectual in many instances which are immune to all other unwritten hypoglycaemic drugs. It differs from other unwritten hypoglycaemic drugs i.e. more effectual during eating than during fasting.
Approximately 50 % of Glipizide is metabolized to its inactive metabolites in liver. With a position to short-circuit the hepatic first base on balls consequence and thereby bettering bioavailability of drug an effort to develop a buccal mucoadhesive dose signifier 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 deleterious, external and internal stimulation. The inflammatory stimulations can be classified into four classs. They are physical stimulations, chemical stimulations, morbific stimulation and immunological stimulations.
Chronic inflammatory conditions lead to the development of diseases including degenerative arthritis, arthritic arthritis, and other anti-inflammatory disease of the articulations. Anti-inflammatory drugs offer diagnostic alleviation in the inflammatory diseases when the underlying cause of redness is unidentified. The anti-inflammatory drugs can sort into two classs.
Corticosteroids: Which produce a dramatic decrease in the stiffness and associated with inflammatory joint diseases. However, there are several disadvantages associated with long term usage of corticoids for the intervention of chronic inflammatory diseases of the joint.
Nonsteroidal anti-inflammatory: Which act by suppressing the catalytic activity of the enzyme Cox ( COX ) . This enzyme is responsible for catalysing an of import intermediate measure in the synthesis of arachidonic acid to prostaglandins ( PG ) and thromboxanes ( TX ) which are go-betweens of inflammation.9
Prostaglandins are synthesized by oxygenation and ring closing of arachidonic acid, controlled by a rate restricting cyclo-oxygenase ( COX ) which occurs as two isoenzymes: COX-1 and COX-2. The merchandises of this reaction are unstable intermediates known as cyclic endoperoxides specific enzymes which differ from cell to cell, convert these intermediates to assorted prostaglandins. The merchandises of the COX tract, hence, differ among assorted tissues, reflecting the diverse nature of their actions and the single demands of each cell types.
Mechanism of action of Nonsteroidal anti-inflammatory:
The non-steroidal anti-inflammatory drugs ( NSAIDs ) portion a common manner of action, by suppression of COX-1 and/or COX-2. Different NSAIDs have different comparative effects on the two isozymes. Inhibition of COX reduces the coevals of prostaglandins but does non impact the production of leukotrienes. Indeed, leukotrienes production can increase as a consequence of recreation of arachidonic acid into the lipoxygenase tract.
Figure No. 1: Nonsteroidal anti-inflammatory and Cyclooxygenase ( COX ) 1 and 2 Isozymes
Many “ conventional ” NSAIDs inhibit COX-1 and COX-2 selective COX-2 inhibiting NSAIDs may demo the advantage of a lower GI side-effect profile. However COX-2 is widely distributed and may be constitutively expressed in some countries.
E.g. Kidney – Inhibition with long-run intervention may impact nephritic function.10
Selective COX-1 Inhibition:
Selective COX-1 suppression reduces platelet collection. Aspirin ( Acetyl salicylic acid ) is 150 times more effectual of suppressing COX-1 than COX-2. This is unwanted in patients with coagulating upsets but good in some disease province.
COX-1 suppression predisposes to damage to the stomachic mucous membrane. Doses of aspirin sufficient to hold anti-inflammatory effects by suppression of COX-2, hence, cause stomachic harm because the doses required to suppress many COX-2 mediated inflammatory procedures must hold important repressive effects on COX-1.
Selective COX-2 Inhibition:
The analgetic actions of NSAIDs appear to ensue from suppression of COX-2.
NSAIDs that inhibit COX-2 selectively ( Celecoxib, Rofecoxib, Valdecoxib, Meloxicam ) appear to hold utile anti-inflammatory actions and have fewer GI damaging actions ( COX-1 dependant gastroprotection ) when compared with “ conventional NSAIDs ” .
Highly selective COX-2 inhibitors have small consequence on thrombocyte TXA2 ( COX-1 dependant ) and hence do non impact collection. These drugs may be better tolerated by patients with coagulating upsets.
In mice that have been breed to genetically deficient in COX-2, there is significantly higher incidence of nephritic harm compared with normal animals.10
Categorization of COX-Inhibitors:9
The COX inhibitors can be classified on the footing of type of adhering into the undermentioned four classs.
The drugs doing irreversible suppression of both COX-1 and COX-2. E.g. Aspirin
The drugs doing reversible and competitory suppression of both COX-1 and COX-2. E.g. Ibuprofen
The drugs doing slow, clip dependent suppression of COX-1 and COX-2.
E.g. Flurbiprofen, Indomethacin.
The drugs doing extremely selective suppression of COX-2. E.g. Rofecoxib, Celecoxib, Valdecoxib.
Unwanted effects of selective COX-1 inhibitors:10
Most unwanted effects arise from the non-selective suppression of prostaglandin synthesis throughout the organic structure. They are normally dose dependent..
Gastric annoyance, stomachic ulceration, indigestion are thought to happen chiefly as a consequence of suppression of mucosal production of PGE2 and PGI2.
Inhibition of prostaglandin coevals reduces mucosal blood flow, which likely enhances cytotoxicity by bring forthing tissue hypoxia and local free group.
Rectal disposal can ensue in local annoyance and hemorrhage.
Aspirin produces tinnitus in toxic doses ; overdose of acetylsalicylic acid may take to risky consequence.
Indomethacin causes CNS unwanted effects such as giddiness, sleepiness and confusion, peculiarly in the aged.
Skin reaction can happen, particularly with Fenbufen.
Phenylbutazone can bring forth bone marrow aplasia ; its usage is now restricted to patients with ancylosing spondylitis, for which it is peculiarly effectual.
Paracetamol causes hepatic harm and nephritic failure in overdose.
Indications of NSAIDs:10, 11.
NSAIDs are indicated for followerss: –
Treatment of musculoskeletal upsets such as degenerative arthritis, arthritic arthritis and primary dysmenorrhoea.
As an antipyretic in feverish status.
For modest decrease of catamenial blood loss in hypermenorrhea ( inordinate blood loss at menses ) .
Prevention of vascular occlusion by suppression of thrombocyte collection ( particularly low dose acetylsalicylic acid ) .
Decrease in colonic polyps and malignant neoplastic disease ( COX-1 and COX-2 inhibitors ) .
Recent surveies suggest NSAIDs may cut down the patterned advance 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 happen with specific suppression of the inducible isoform of the COX enzyme while giving comparable efficaciousness.
First coevals COX-2 selective inhibitors like Celecoxib launched in 1999 and was foremost marketed merchandise 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 intervention of Osteoarthritis ( OA ) in grownups. Clinical tests demonstrated greater efficaciousness in patients with OA with valdecoxib 5mg and 10 milligrams bid than with placebo.12
Adolescents enduring from dysmenorrhea with a anterior history of peptic ulcer or history of NS-NSAIDs ( Non-selective NSAIDs ) GI inauspicious effects or who require high doses of NS-NSAIDs during catamenial period, every bit good as striplings with curdling lacks, may profit from the usage of specific COX-2 inhibitors.
In vitro surveies have shown that the selective COX-2 inhibitors have potent tocolytic consequence. In vivo surveies have found the specific COX-2 inhibitors Rofecoxib, ( Vioxx ) and Valdecoxib ( Bextra ) effectual in the intervention of primary dysmenorrhea in adult females more than 18 years.13
Need and Aims of the survey
demand of the survey
Over the twelvemonth controlled drug bringing engineering has a broad progresss. Due to its high potency a bioadhesive system topographic point a major function in commanding drug release. Mucoadhesive system prolong the abode clip of the dose signifier at the site of application or soaking up and ease an curative public presentation of the drug. Recent involvement has been expressed in the bringing of drug via mucous secretion membrane by the usage of adhesive stuffs on which surveies are been intensively undertaken.58
Glipizide is an unwritten antidiabetic drug, belonging to the sulphonylurea group. Soon the drug is marketed in conventional dose signifier of tablet in usual strength of 2.5 to 20 milligrams. When the drug is administered by this path, approximately 50 % of drug is metabolized in the liver to the several inactive metabolites. Hence there is demand of the alternate path disposal to avoid first base on balls hepatic metabolism.7 More over the combination of anti-diabetic drugs with NSAIDS are non available in market.
Physicochemical belongingss of this drug like little dosage, lipophilicity, stableness at buccal pH, odourlessness, flavorlessness, low molecular weight etc. makes it an ideal campaigner for disposal by buccal path.
To get the better of the built-in drawbacks associated with conventional dose signifier of Glipizide, an effort is being made to plan and measure an alternate drug bringing system in signifier of buccal mucoadhesive advantages.
Enhancement of curative index.
Optimized concentration of drug in systemic circulation.
MUCOADHESIVE DRUG DELIVERY SYSTEM: 14
The term bioadhesion refers to either adhesion between two biological stuffs or adhesion between some biological stuff ( including cells, cellular secernments, mucous secretion, extracellular matrix etc. ) and an unreal substrate ( metals, ceramics, polymers etc. ) . In footings of pharmaceutical industry, bioadhesion by and large refers to adhesion between a polymer based bringing system and soft tissue in presence of H2O.
Pharmaceutical facets of mucoadhesion have been the topic of great involvement during recent old ages because it provides the possibility of avoiding either devastation by GI contents or hepatic first-pass inactivation of drug.
The construct of mucosal adhesives or mucoadhesives was introduced into the controlled drug bringing country in the early 1980 ‘s. Mucoadhesives are man-made or natural polymers which interact with the mucous secretion bed covering the mucosal epithelial surface and mucin molecules dwelling a major portion of mucous secretion. The construct of mucoadhesive has alerted many research workers for the possibility that ; these polymers can be used to get the better of physiological barriers in long-run drug bringing. They render the intervention more efficient and safe, non merely for topical upsets but besides for systemic jobs.
MUCOADHESIVE BUCCAL DRUG DELIVERY SYSTEM: 11, 12, 13
Drug bringing via the membranes of the unwritten pit can be subdivided as follows:
Sublingual bringing, which is the disposal via the sub-lingual mucous membrane to the systemic circulation.
Buccal bringing, which is disposal of drug via the buccal mucous membrane to the systemic circulation ; and
Local bringing, which is used for the intervention of conditions of the unwritten pit, chiefly aphthous ulcers, fungous conditions and periodontic diseases by application of the bioadhesive system either to the roof of the mouth, the gum or the cheek.
These unwritten mucosal sites differ greatly from one another, in footings of anatomy, permeableness to an applied drug and their ability to retain a bringing system for coveted length of clip.
The combination of several facets that makes buccal site an attractive path for drug bringing are:
The unwritten mucous membrane is easy accessible, so dosage signifiers can be easy administered and even removed from the site of application.
Since patients are good adopted to unwritten disposal of drugs in general, patient credence and conformity is expected to be good.
Harmonizing to its natural map the unwritten mucous membrane is routinely exposed to a battalion of different external compounds and hence, is supposed to be instead robust and less prone to irreversible annoyance or harm by a dose signifier, its drug excipients or additives.
Its ability to retrieve after local intervention is pronounced and therefore allows a broad scope of preparation to be used. E.g. , bioadhesive unctions and spots.
Local bringing of drugs to the unwritten pit has a figure of applications viz. , intervention of odontalgia, periodontic disease, dental cavities, bacterial and fungous infections and aphthous stomatitis.
Conventional preparations for local unwritten bringing are chiefly lozenges, cough drops, oral cavity pigments, oral cavity washes, unwritten gels, pastes and suspensions.
ADVANTAGES OF MUCOADHESIVE BUCCAL DRUG DELIVERY SYSTEM:
Drug disposal via the unwritten mucous membrane offers several advantages.15, 16
Ease of disposal.
Termination of therapy is easy.
Flexibility in physical province, form, size and surface.
Maximized soaking up rate due to adumbrate contact with the absorbing membrane and reduced diffusion barriers.
Licenses localisation of the drug to the unwritten pit for a drawn-out period of clip.
Can be administered to unconscious patients.
Offers an first-class path for the systemic bringing of drugs with high first base on balls metamorphosis, thereby offering a greater bioavailability and decrease in dose.
A important decrease in dosage can be achieved, thereby cut downing dose dependent side effects.
It allows for the local alteration of tissue permeableness, suppression of peptidase activity or decrease in immunogenic response. Therefore, selective usage of curative agents like peptides, proteins and ionized species can be achieved.
Drugs which are unstable in the acidic environment of the tummy or are destroyed by the enzymatic or alkalic environment of the bowels can be administered by this path.
Drugs which show hapless bioavailability via the unwritten path can be administered handily.
It offers a inactive system for drug soaking up and does non necessitate any activation.
The unwritten mucous membrane lacks outstanding mucous secretion releasing goblet cells and hence there is no job of diffusion limited mucous secretion construct up beneath the applied dose signifier.
The presence of saliva ensures comparatively big sum of H2O for drug disintegration unlike in instance of rectal and transdermic paths.
It satisfies several characteristics of the controlled release systems.
It can be made unidirectional to guarantee merely buccal soaking up.
The buccal mucous membrane is extremely perfused with blood vass and offers greater permeableness than tegument.
Bioadhesion prolongs the abode clip at the site of drug soaking up, and therefore improves bioavailability and reduces dosing interval.
Rapid oncoming of action.
LIMITATIONS OF BUCCAL DRUG ADMINISTRATION:
Drug disposal via this path has certain restrictions.
Drugs which irritate the mucous membrane or have a bitter or unpleasant gustatory sensation or an objectionable smell can non be administered by this path.
Drugs which are unstable at buccal pH can non be administered by this path.
Merely drugs with a little dose demand can be administered.
Merely those drugs which are absorbed by inactive diffusion can be administered by this path.
Eating and imbibing may go restricted.
There is an of all time present possibility of the patient get downing the dose signifier.
Over hydration may take to formation of slippery surface and structural unity of the preparation may acquire disrupted by this puffiness and hydration of the bioadhesive polymers.
Anatomy of Oral Mucosa
As the stratum horny layer may be a possible barrier to mucosal incursions, drugs are traditionally placed at the non-keratinized sites like the buccal and sublingual parts.
In the grownup homo, the mucous membrane run alonging the unwritten pit covers an country of about 200cm2. The thickness of human unwritten mucous membrane varies harmonizing to its site. For illustration, epithelial thickness of buccal mucous membrane ( non-keratinized ) is about 500mm. Palatal epithelial tissue 270mm which includes a ceratin bed thickness of 32mm and gingival epithelial tissue about 250mm. In general, non-keratinized tissue is well thicker than keratinized tissue, nevertheless the floor of the oral cavity ( non-keratinized ) is really thin ( about 100mm ) .
A ] The Mucus Layer:
Mucus is a translucent and viscid secernment which forms a thin, uninterrupted gel cover disciple to the mucosal epithelial surface. The average thickness of this bed varies from approximately 50 to 450 millimeters in worlds, it is secreted by the goblet cells, run alonging the epithelial tissue or by particular exocrine secretory organs with mucous secretion cells acini.
The exact composing of the mucous secretion bed varies well, depending on the species, the anatomical location and the pathophysiological province. However, it has the undermentioned general composing:
1. Water – 95 %
2. Glycoproteins and lipoids – 0.5 to 5 %
3. Mineral salts – 1 %
4. Free proteins – 0.5 % to 1 %
B ] Functions of Mucus Layer:
The primary maps of the mucous secretion bed are: –
Protective: ensuing peculiarly from its hydrophobicity.
Barrier: the function of the mucous secretion bed as a barrier in tissue soaking up of drugs and other substrates is good known as it influences the bioavailability of drugs.
Adhesion: mucous secretion has strong cohesional belongingss and steadfastly binds to the cell surface as a uninterrupted gel bed.
Lubrication: an of import function of the mucous secretion bed is to maintain the mucosal membrane moist. Continuous secernment of mucous secretion from the goblet cell is necessary to counterbalance for the remotion of the mucous secretion bed due to digestion, bacterial debasement and solubilization of mucin molecules.
At physiological pH, the mucous secretion web may transport a important negative charge because of the presence of sialic acid and sulphate residues and this high charge denseness due to negative charge contributes significantly to bioadhesion.
C ] The Salivary Secretion:
Besides the mucous secretion, the mucosal bed of the unwritten pit is kept moist by the spit secreted chiefly by three braces of salivary secretory organs viz. the submaxillary, the parotid and the sublingual secretory organs. The pH of salivary secernment ranges from approximately 6.2 to 7.4 with an norm of 6.6. About 1.5 liters of spit is secreted per twenty-four hours.
There is a considerable fluctuation in the single spit flow rates. It ranges from 0.21 to 1.18 ml/min. with a mean of 0.65 ml/min under the resting status 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 province in which two stuffs, at least one of which being of a iological nature, are held together for an drawn-out period of clip by interfacial forces.
If adhesive fond regard is to a mucous secretion the phenomenon is referred to as mucoadhesion. The first measure is an intimate contact between a bioadhesive and a membrane, in the 2nd measure, bioadhesive with those of the mucous secretion takes topographic point.
Several theories have been proposed to explicate the cardinal mechanisms of adhesion. In a peculiar system, one or more theories can every bit good explicate or lend to the formation of bioadhesive bonds.
THEORIES OF BIOADHESION / MUCOADHESION: 17
Several theories have been proposed to explicate the cardinal mechanisms of adhesion. The surface features, composing of the mucoadhesive stuff every bit good as the substrate and the associated applied force to convey the attachment of substrate in contact are of import parametric quantities to be considered in measuring mucoadhesion. The bonding occurs chiefly through both physical and chemical interactions.
Covalent bonding, such as that occurs with cyanoacrylates, is besides possible for mucoadhesion, but is non yet common in pharmaceutical systems. Electrostatic interactions and H bonding look to be of import as a consequence of the big figure of charged and hydrophilic species e.g. , hydroxylic ( -OH ) , carboxylic ( -COOH ) , sulphate ( -SO3H ) , and amino ( -NH2 ) groups. Proposed theories of mucoadhesion include wetting, diffusion, electronic, soaking up and break.
Electronic Theory: The electronic theory of adhesion was suggested by Derjaguin et Al. ( 1969 ) . Harmonizing to this theory negatron transportation occurs on contact of an adhesive polymer and the mucous secretion glycoproteins web due to differences in differences in electronic construction, negatron transportation occurs on contact of an adhesive polymer & A ; the mucas glycoprotein web, which consequences in formation of an electrical dual bed at the interface. Adhesion occurs due to attractive forces across the dual bed. Such a system behaves correspondent to a capacitance, which is charged when two different surfaces come in contact, and discharged when they are separated.
Weting: This theory best describes the adhesion of liquid or paste to a biological surface. The work of adhesion can be expressed in footings of surface and interfacial tenseness ( g ) being defined as the energy per cm2 released when an interface is formed. Harmonizing to Dupre ‘s equation the work of adhesion is given by: 18
Wa = tabun + sarin – chitchat — — – ( 1 )
Where the inferior A and B refer to the biological membrane and the bioadhesive preparation severally. The work of coherence is given by:
Wc = 2gA or 2gB — — — ( 2 )
For a mucoadhesive stuff B spreading on a biological substrate A the spreading coefficient is given by:
SB/A = gA – ( gB – chitchat ) — — – ( 3 )
SB/A should be negative for a mucoadhesive stuff 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 writers observed an addition in bioadhesive strength as the contact angle increased. Hence surface feature of the bioadhesive stuff appear to be an of import parametric quantity to be considered.
The wetting theory of bioadhesion
Diffusion: Voyutski ( 1963 ) appears to be the first to discourse diffusion, as a theory for adhesion. Harmonizing to this, the polymer ironss and the mucous secretion co-mingle to a sufficient deepness to make a semi-permanent adhesive bond. Extra penetration as to the mechanism of interpenetration has late been provided by Pager et Al. ( 1981 ) . The mucoadhesive stuff and glycoprotein of the biological membrane are brought in close contact. The polymer ironss penetrate the mucous secretion, the exact deepness to which it penetrates to accomplish sufficient mucoadhesion depends on the diffusion coefficient, clip of contact, and other experimental variables. The diffusion coefficient depends on molecular weight and decreases quickly as the cross-linking denseness additions shown by Peppas et Al. ( 1985 ) . Flexibility of the bioadhesive polymer and mucous secretion glycoprotein molecule plays an of import function in bioadhesion, due to the demand for co-mingling of ironss to increase the country of contact. Park and Robinson ( 1985 ) , have shown that partial mucolysis additions mucoadhesiveness, due to enhanced flexibleness of the mucin molecules. Gluteraldehyde intervention to increase cross-linking of the mucous secretion glycoprotein decreases mucoadhesion. This behaviour is in understanding with the interpenetration theory.
In drumhead, the molecular weight, concatenation flexibleness, expanded nature of both the mucoadhesive and substrate every bit good as similarity in chemical construction are required for good mucoadhesion.
Fracture theory: This theory attempts to associate the trouble of separation of two surfaces after adhesion. Fracture theory equivalent to adhesive strength is given by:
G = ( E I/L ) 1/2 — — – ( 5 )
Where E is Young ‘s modulus of snap, I is the break energy and L is critical cleft length when two surfaces are separated. The work of break of an elastomer web Gc is given by:
Gc = K ( Mc ) A? — — – ( 6 )
K is a changeless dependant on denseness of the polymer, effectual mass, length and flexibleness of a individual mucin concatenation bonds and dissociation energy. Gc of an elastometric web additions with molecular weight Mc of the web stands.
Absorption theory: Harmonizing to this theory, after an initial contact between two surfaces, the stuff adheres because of surface forces moving between the atoms in the two surfaces. Two type of chemical bonds ensuing from these forces can be distinguished.
Primary chemical bonds of covalent nature which are unwanted in bioadhesion because their high strength may ensue in lasting bonds.
Secondary chemical bonds holding many different forces of attractive force, including electrostatic forces, vander waals forces H 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 besides by the nature of the environing media ( Gandhi R.B. et al. , 1988 ) .
Polymer related factors:
Molecular weight: Numerous surveies have indicated that there is a certain molecular weight at which bioadhesion is at a upper limit. The interpenetration of polymer molecule is favourable for low molecular weight polymers whereas expansions are favoured for high molecular weight polymers. Harmonizing to Gurny et Al. ( 1984 ) it seems that the bioadhesive force additions with the molecular weight of the bioadhesive polymer, upto 100,000 and beyond this degree there is non much consequence. To let concatenation interpenetration, the polymer molecule must hold an equal length.
Flexibility of Polymer ironss: . As H2O soluble polymers become cross-linked, the mobility of the single polymer concatenation lessenings. As the cross-linking denseness additions, the effectual length of the concatenation which can perforate into the mucous secretion bed decreases even further and mucoadhesive strength is reduced.
Spatial conformation: Besides molecular weight or concatenation length, spacial conformation of a molecule is besides of import. The coiling verification of dextran may screen many adhesively active groups chiefly responsible for adhesion, unlike PEG polymers which have a additive verification. 19
2. Environment Related Factors:
pH: pH was besides found to hold a important consequence on mucoadhesion as observed in surveies of polyacrylic polymers cross-linked with -COOH groups. pH influences the charge on the surface of both mucous secretion and the polymers. Mucus will hold a different charge denseness, depending on pH, because of differences in dissociation of functional groups on the saccharide mediety and aminic acids of the polypeptide anchor. Romanson et Al. ( 1985 ) , observed that pH of the medium is critical for the grade of hydration of lightly cross-linked polyacrylic acid polymers. Maximal adhesion was observed at pH 5 and 6 and lower limit at pH 7. This behaviour was attributed to differences in charge denseness at different pH ‘s. Hence, the charge denseness of both mucin and the polymer are influenced by pH, which in bend affects mucoadhesion.
Applied Strength: To put a solid bioadhesive system, it is necessary to use a defined strength. The adhesion strength additions with the applied strength or with the continuance of its application, upto an optimum. If high force per unit area is applied for a sufficiently long period of clip, polymers become mucoadhesive even though they do non hold attractive interactions with mucin.
Initial contact clip: The initial contact clip between mucoadhesives and the mucous secretion bed determines the extent of swelling and the interpenetrations of polymer ironss. Along with the initial force per unit area, the initial contact clip can dramatically consequence the public presentation of a system. The mucoadhesive strength additions as the initial contact clip additions.
Degree of hydration: Depending on the grade of hydration adhesion belongingss will be different. It is maximal at a certain grade of hydration. When the grade of hydration is high, adhesion is lost likely due to formation of slippery, non-adhesive mucilage in an environment of big sum of H2O at or near the interface.
METHODS USED TO STUDY BIOADHESION: 17
Several trial methods have been reported for analyzing bioadhesion. These trials are necessary non merely to test a big figure of campaigner mucoadhesives, but besides to analyze their mechanisms. These trials are besides of import during the design and development of a bioadhesive controlled release system as they guarantee compatibility, physical and mechanical stableness, surface analysis and bioadhesive bond strength.
The trial methods can loosely be classified into two major classs: –
In Vitro/ex-vivo method:
Most in-vitro methods are based on the measuring of either tensile or shear emphasis. Bioadhesiveness determined by measuring of emphasis tends to be subjective since there is no standard trial method established for bioadhesion.
Method based on measuring of tensile strength.
Eg ; Modified balance or tensile examiners.
Methods based on measuring of shear strength.
Eg: Wilhelmy home base method.
Other in vitro methods.
A figure of other methods including electrical conductance and thumb trial method, adhesion weight method, fluorescent investigation method, flow channel method, falling liquid movie method, colloidal gold staining method, viscometeric method, mechanical spectroscopic method have been used for the finding of bioadhesion. 20
Recently, two setups have been described for the in situ rating of bioadhesion belongingss of buccal tablet.
2 ) In Vivo method:
In vivo techniques for mensurating the bioadhesive strength are comparatively few. Some of the reported methods are based on the measurings of the abode clip of bioadhesive at the application site ( Kamath and Park, 1994 ) . The GI theodolite times of many bioadhesives have been examined utilizing radioisotopes.
PERMEABILITY OF THE ORAL MUCOSAE: 14, 15
The permeableness features of the unwritten mucous membranes have been reviewed by a figure of writers.
The permeableness barrier of the unwritten mucous membrane is thought to shack with the superficial bed ( about the outer most one-fourth ) of the epithelial tissue. Permeation surveies have been performed utilizing a figure 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 cellar membrane is the functional pervasion barrier of the unwritten mucous membrane or that it presents at least a grade of resistants to permeants.
The lamina propria is non by and large thought to show the barrier to pervasion. Its construction is insufficiently heavy to except even comparatively big molecules, and its hydrous matrix should ease the transition of hydrophilic penetrants.
Membrane surfacing granules:
The most plausible account at nowadays for the beginning of the permeableness barrier of unwritten epithelial tissue involves the alleged “ membrane-coating granules ” ( MCG ) , which are spherical or egg-shaped cell organs. 100-300nm in diameter, and are found in the intermediate cell beds of many stratified epithelial tissues and they have been widely explored in both keratinized and non-keratinized epithelia21 and cuticle. MCG are involved in the thickener of the plasma membrane.
Since the MCG are thought to be involved in the development of the intracellular matrix, it follows that intervention with the MCG themselves or with their released contents may act upon the permeableness of the mucous membrane and of the paracellular path in peculiar. This scheme was adopted by Squier and others who attempted to increase mucosal permeableness by the usage of glycoprotein or glycolipid-specific enzymes. However, the range for such schemes is likely to stay limited without a sensible apprehension of the function of MCG in non-keratinized epithelial permeableness ; since these cell organs lack any characteristic staining reactions or microscopic features its degree of understanding remains elusive.
Nature of permeant:
Most published surveies of unwritten mucosal permeableness have focused on comparatively little Numberss of permeating molecules, and few have attempted to consistently measure the comparative part of factors such as molecular size, lipid solubility and ionisation on permeableness. From the systematic surveies that have been reported, nevertheless, it appears that the ability of a molecule to pervade through the mucous membrane can be related to molecular size, lipid solubility and ionisation.
For hydrophilic substances, the rate of soaking up is a map of the molecular size. Small molecules ( & lt ; 75-100 Da. ) appear to traverse the mucous membrane quickly, but permeableness falls away quickly as molecular size additions. Since permeableness has been observed to diminish aggressively as molar volume is increased beyond 80ml/mol, research workers have proposed – two distinguishable polar paths. This relationship between size and permeableness has non been demonstrated for lipotropic substances, although common sense suggests that such a relationship must be.
For any series of unioniozable compounds, their comparative permeablenesss are maps of their oil-water divider co-efficients with the more lipid-soluble compounds holding higher permeablenesss.
The grade of ionisation of a permeant is a map of both its pka and the pH at the mucosal surface. For many weak acids and weak bases, merely the nonionized signifier possesses appreciable lipid solubility. The soaking up of many compounds has been shown to be maximum at the pH at which they are largely nonionized, chasing off as the grade of ionisation additions. Other surveies, nevertheless, have failed to demo this form.
In common with drug conveyance across other epithelial tissue, there are a figure of possible pervasion tracts across the unwritten mucous membrane. The classical differentiation is between transcellular and paracellular pervasion, mentioning to passage across the single cells of the epithelial tissue and transition between these cells, severally. For transcellular pervasion, the permeant must be capable of go throughing through pores in the cell membranes or spreading through the lipid bi-layers of these membranes. Passage through membrane pore would likely be limited to little molecules, while diffusion across cell membranes would necessitate appreciable aqueous and lipid solubilities. Paracelluler pervasion requires the epithelial tissue to hold a sufficiently unfastened matrix and requires the permeant to hold an appreciable diffusivity in the intercellular surroundings. It seems likely that big and/or extremely polar permeants may be unable to go through through the epithelial cell membranes and might, hence, follow the paracellular path.
An alternate categorization is into polar and non-polar paths, the former affecting transition of water-soluble substances through aqueous channels in the mucous membrane and the latter affecting breakdown of the drug into the lipid bilayer of the plasma membrane or into the lipoid of the intercellular matrix and diffusion through these lipid elements.
About all surveies have shown that, for most permeants transition across the unwritten mucous membrane appears to be a first-order simple diffusion procedure. It has besides been suggested, nevertheless that the unwritten mucous membrane contain active or carrier-mediated systems for little molecules such as monosaccharoses and aminic acids. However, these procedures have non been to the full characterized in footings of location, conveyance capacity or specificity.
The dynamicss of unwritten mucosal soaking up have been studied by a figure of workers. Some probes have shown a slow oncoming of visual aspect of permeant in the systemic circulation and a depot-like behavior of the unwritten mucous membrane which have been attributed to some signifier of adhering within the mucous membrane. To day of the month, nevertheless, this country has non been consistently investigated and remains for the most portion ill understood.
Possible paths for drug conveyance across the unwritten mucous membrane: 16
The cellular construction of the unwritten mucous membrane suggests that there are two permeableness barriers. The intercellular infinites and cytol are basically hydrophilic in character and go a conveyance barrier for lipotropic compounds chiefly because the solubility of lipotropic compound in this environment is low. In contrast, the cell membrane is lipotropic and the incursion of a hydrophilic compound into the cell membrane is low due to a low divider coefficient. Therefore, closely compacted cell membranes become obstructions that hydrophilic compounds have to travel about.
The coexistence of the hydrophilic and lipotropic parts in the unwritten mucous membrane suggests that there are two paths for drug conveyance, i.e. , the paracellular and the transcellular paths ( Diag.3 ) .
PERMEATION ENHANCEMENT: 14, 15
While the sublingual mucous membrane is sufficiently permeable to let the curative bringing of a figure of little drug molecules, low mucosal permeableness is perceived to be a important obstruction to buccal bringing.
Permeation foils are substances added to a pharmaceutical preparation in order to increase the membrane pervasion rate or soaking up rate of a co-administered drug.
Attention is therefore focused on some of the schemes that have been proposed for heightening the permeableness of the unwritten mucous membrane. A considerable figure of agents have been proposed as incursion foils. The agents used have largely been little hydrophilic molecules. E.g. , dimethyl sulphoxide, dimethyl formamide, ethyl alcohol, propene ethanediol, and the 2-pyrrolidones, long-chain amphiphathic molecules ( decylmethyl sulphoxide, azone, Na lauryl sulfate, oleic acid and the gall salts ) , and non-toxic wetting agents ( polysorbates ) . Although some are effectual, either entirely or in combination, their manners of action are non to the full understood.
A related issue is the usage of enzyme inhibitors to cut down the enzymatic debasement of the drug within the mucous membrane. Hirai et Al. showed improved rhinal soaking up of insulin utilizing the gall salts.
Plan OF the survey
Preformulation surveies for Drug – Excipients Compatibility.
Preparation of standard curve for Glipizide and Valdecoxib.
Preparation of assorted buccal tablets utilizing Carbopol 940, Sodium carboxy methyl cellulose and Polyvinyl pyrrolidone as polymers in different concentrations.
Evaluation of buccal tablets by following parametric quantities: –
General visual aspect
Weight fluctuation trial
Contented uniformity trial
Tablet decomposition trial
Measurement of surface pH.
Water soaking up survey.
Measurement of bioadhesion strength
In-vitro diffusion surveies.
The consequences are presented in tabular arraies and diagrammatically by utilizing assorted equations regulating release dynamicss.