Pharmaceutical Considerations behind the Development and Evaluation of Mucoadhesive Tablets

 

Rashmi Verma, Yamini Dewangan, Lokeshwari Sahu, Barkha Dongre, Khushboo Mishra, Trilok Patel, Sakhram Nishad, Ashish Damle, Ghanshyam Sahu, K. DeviRao, MithleshPatle MuktaAgrawal, D. K. Tripathi, Ajazuddin, Amit Alexander*

Rungta College of Pharmaceutical Sciences and Research, Kohka-Kurud Road, Bhilai, Chhattisgarh, India, 490024

 

ABSTRACT:

The current article has been focused on the Mucoadhesive drug delivery system may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome. Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. Application of dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. The Mucoadhesive ability of a dosage form is dependent upon a variety of factors, including the nature of the mucosal tissue and the physicochemical properties of the polymeric formulation. This review article aims to provide an overview of the various aspects of mucoadhesion, Mucoadhesive materials, factors affecting mucoadhesion, evaluating methods, and finally various Mucoadhesive drug delivery systems (buccal, nasal, ocular, gastro, vaginal, and rectal) based on literatures were reported so far. In this review article, the various aspects of pharmaceutical microemulsion were compiled together and the target audiences are specifically the M. Pharm and B. Pharm students so that their knowledge towards the subject concern can be enhanced and also at the same time can be motivated towards the publication.

 

 

 

INTRODUCTION:

Oral delivery has so far been the most common and preferred route of adminis­tration for most of the therapeutic agents. The popularity of the oral route has been attributed to the patient acceptance, ease of administration, accurate dosing, cost effective manufacturing method, least ste­rility constraints, and flexible design of dosage forms and generally improved shelf-life of the product.^[1]

 

Mucoadhesive substances could also be used as therapeutic agents in their own right, to coat and protect and soothe the injured tis­sues (gastric ulcers or lesions of the oral mucosa) or as lubricants (in the oral cavity, eye and vagina).Drug delivery is the most desirable and preferred method of administering therapeuticsagent for their systemic effect. In addition the oral medication is generally considered as the first avenue investigated in the discovery and development of new drug entities and pharmaceutical formulation, mainly because of patient acceptance, convenience in administration and cost effective manufacturing process. The treatment of illness has been accomplished by administrating drug to the human body via. various pharmaceutical dosage forms like tablet, capsule, microspheres. To achieve and maintain the therapeutics range extensive effort have recently been focused on targeting a drug or drug delivery system in a particular region of the body for extended period of time, not only for local targeting of drug but for better control of systemic drug delivery. To achieve and maintain the drug concentration in the body within the therapeutics range required for medication, it is necessary to take this type of drug delivery system several times a day this yield undesirable “seesaw drug level in body. A number of advancement has been made recently in the development of new technique for drug delivery, the technique capable of regulating the rate of drug delivery system. Clarithromycin is a macrolide antibiotic, It prevents bacteria from growing by interfering with their protein synthesis. In this review article, the various aspects of pharmaceutical microemulsion were compiled together and the target audiences are specifically the M. Pharm and B. Pharm students so that their knowledge towards the subject concern can be enhanced and also at the same time can be motivated towards the publication.

 

ADVANTAGE                                                                             

·         Prolongs the residence time of the dosage form at the site of absorption, hence increases the bioavail­ability.

·         Excellent accessibility, rapid onset of action possible.

·         Rapid absorption because of enormous blood sup­ply and good perfusion rates

·         Increased safety margin of high potency drugs due to better control of plasma levels.

·         Maximum utilization of drug enabling reduction in total amount of drug administered.

·         An alternative to oral route, whereby the drug is pro­tected from degradation in the acidic environment of the GIT.

·         Better patient compliance.

·         Moreover, rapid cellular recovery and healing of the local site.

·         Reduced dosing frequency.

·         Shorter treatment period

 

DISADVANTAGES

·         Drugs, which irritate the oral mucosa, have a bitter or unpleasant taste, odour, cannot be administered by this route.

·         Drugs, which are unstable at buccal pH, cannot be administered by this route.

·         Only drugs with small dose requirements can be administered.

·         Eating and drinking may become restricted.

·         In case of vaginal drug delivery, the drug has to be stable in the acidic vaginal pH.

·         The vaginal formulation may interfere with sexual intercourse.

·         The vaginal formulation may leak and cause messi­ness.

·         The vaginal formulation may be contraindicated in case of pregnancy.

·         In case of ocular formulations, the formulation may cause uneasiness and blurring.

·         It may get dislodged.^[2]

 

MECHANISM OF MUCOADHESIVE TABLET

Mucoadhesion is a complex process involv­ing wetting, adsorption and interpenetra­tion of polymer chains. Mucoadhesion is established in the following stages:

·         Contact stage: Intimate physical con­tact between a bioadhesive/Mucoadhesive material and a membrane (wetting or swell­ing phenomenon).

·         Consolidation stage: Penetration of the bioadhesive/Mucoadhesive into underlying the tissue or into the surface of the mucous membrane (interpenetration).^[3]

 

Mucoadhesion and bioadhesion

Mucoadhesion may be defined as a state in which two components, of which one is of biological source, are joined together for prolonged periods of time by the aid of interfacial forces. ‘Bioadhesion’ broadly includes adhesive interactions with any biological or biologically derived substance, whereas ‘Mucoadhesion’ is used when the bond is formed with a mucosal surface, while the term cytoadhesive means adhesion to cells. Muco­adhesive drug delivery systems arealso a sub- type of gastro- retentive drug delivery systems. In the formu­lation of oral controlled-release dosage forms, signifi­cant benefits may follow from the use of Mucoadhesive polymers providing brief adhesion between the drug delivery system and the mucous or epithelial cell surface of the alimentary canal.^[4]

 

The term bioadhesion can be defined as the statein which two materials, at least one biologic in Nature, are held together for an extended period of time by interfacial forces (Good, 1983). Inbiological systems, bioadhesion can be classified into3 types:

• Type 1, adhesion between two biological phases, for example, platelet aggregation and wound     

healing.

• Type 2, adhesion of a biological phase to an artificial substrate, for example, cell adhesion to

culture dishes and bio-film formation on prosthetic devices and inserts.

• Type 3, adhesion of an artificial material to a biological substrate, for example, adhesion of synthetic hydro gels to soft tissues (Henriksenet al., 1996) and adhesion of sealants to dentalenamel. For drug delivery purposes, the term bioadhesion implies attachment of a drug carrier system to a specified biological location. The biological surface can be epithelial tissue or the mucus coat on the surface of a tissue. If adhesive attachment is to a mucus coat, the phenomenonis referred to as mucoadhesion. Leung and Robinson (Leung and Robinson, 1988) described mucoadhesion as the interaction between a mucin surface and a synthetic or natural polymer. Mucoadhesion should not be confused with bioadhesion; in bioadhesion, the polymer in attached to the biological membrane and if the substrate is mucus membrane the term mucoadhesion is used. Mucoadhesive/ bioadhesive drug delivery system can be applied to the following systems:

·         Buccal delivery system

·         Oral delivery system

·         Vaginal delivery system

·         Rectal delivery system

·         Nasal delivery system

·         Ocular delivery system

 

Functions of mucous layer              

·         Mucous layer is protective because of its hydropho­bicity.

·         It influences the bioavailability of drugs as it acts as a barrier in tissue absorption of drugs and other sub­strates.

·         It strongly bonds with the epithelial cell surface as a continuous gel layer.

·         It plays a major role in the lubrication of the mucosal membrane and maintenance of its moisture.

 

 

SITES FOR MUCOADHESIVE DRUG DELIVERY SYSTEM

The common sites for mucoadhesive drug delivery sys­tems include oral cavity, eye conjunctiva, vagina, nasal cavity and gastrointestinal tract.

·         The buccal cavity has a very limited surface area of around 50 cm² but the accessibility of the site makes it a preferred location for delivering therapeutic agents. Deliv­ery through this site avoids hepatic first-pass metabolism in addition to the local treatment of the oral infections. The sublingual mucosa is relatively more permeable than the buccal mucosa; hence formulations for sublingual delivery are formulated to release the active agent immedi­ately. The mucoadhesive formulation is of importance for the delivery of active agents to the buccal mucosa where the active agent has to be released in a controlled manner. Hence, the buccal cavity is more suitable for mucoadhe­sive drug delivery.

·         Nasal cavity also offers a potential site for the designing of formulations using mucoadhesive polymers. The nasal mucosa has a surface area of about 150-200 cm² but the residence time of a particulate matter in the nasal mucosa varies between 15 and 30 min. This short time is due to the increased activity of the mucociliary layer due to stimulation by foreign particles.

·         Ophthalmic mucoadhesive drug delivery is also of great interest. Due to the continuous formation of tears and blinking of eye lids there is a rapid removal of the active medicament from the ocular cavity, which results in the poor bioavailability of the active agents which can be reduced by delivering the drugs using ocular inserts or patches.

·         The vaginal and the rectal lumen have also been explored for the delivery of the active agents both sys­temically and locally. The active agents meant for the sys­temic delivery by this route of administration by passes the hepatic first-pass metabolism. Quite often the delivery systems suffer from migration within the vaginal/rectal lumen which might affect the delivery of the active agent to the specific location. This can be overcome by applying the principles of mucoadhesion.

·         Gastrointestinal tract is also a potential site which has been explored since long for the development of mucoadhesive based formulations. The manipulation of the transit time of the delivery systems in a particular area of the gastrointestinal system by using mucoadhesive polymers has evinced a great interest among researchers around the world.^[5][6]

 

 

THEORIES OF MUCOADHESION

Many theories have been hypothesized for explaining mucoadhesion, although the chemical and physical basis of mucoadhesion is not yet clearly understood. There are six classical theories which have resulted from stud­ies on the performance of several materials and poly­mer- polymer adhesion. The contact angle and time of contact plays a significant role in mucoadhesion. Fig. 1 depicts the various theories of mucoadhesion.

 

 

Figure 1: Theories of Mucoadhesion.[adopted from Arshad Bashir Khan et al. Review on Mucoadhesive Drug Delivery System: Novel Approaches in Modern Era(Oct–Dec, 2014) Vol 4 | Issue 4:131-132]

 

Wetting theory

The ability of a bioadhesive or mucous to spread and develop intimate contact with its corresponding sub­strate is a major factor in bond formation. The affinity between the liquid systems and the mucus membrane can be determined by measuring the contact angle. As a general rule, lower the contact angle, greater is the affin­ity. The contact angle should be equal or close to zero to provide adequate spreadability. Fig-2 is a schematic diagram showing influence of contact angle between the formulation and mucous membrane. The spreadability coefficient, SAB, can be calculated from the difference between the surface energies.

 

γB and γA and the interfacial energy γAB, as indicated in equation:

SAB = γB - γA - γAB

 

Greater the individual surface energy of mucus and device in relation to the interfacial energy, greater is the adhesion work, WA.

WA= γA + γB – γAB

 

Diffusion theory

The phenomenon of the interpenetration and entangle­ment of the bioadhesive polymer chains and mucous polymer chains is explained by the diffusion theory. The bond strength increases with the enhancement in the degree of the penetration. Diffusion coefficient, flex­ibility and nature of mucoadhesive chains, mobility and contact time of polymer chains are the factors on which the degree of penetration depends. The depth of interpenetration required to produce a firm bioadhesive bond lies in the range 0.2–0.5 μm. This interpenetration depth of polymer and mucin chains can be found out by the following equation

 

The interpenetration depth, l = (tD_b) ½

Where t is the contact time and Db is the diffusion coef­ficient of the mucoadhesive material in the mucus

 

Figure 2: A schematic diagram showing the influence of contact angle between device and mucous membrane on bioadhesion. [adopted from Alexander amit et al. Review on theories and factor affecting Mucoadhesive Drug Delivery System: International Journal of Research in Ayurveda and Pharmacy, 2(4):1155-1161.]

 

The adhesion strength for a polymer is reached when the depth of penetration is approximately equivalent to the polymer chain size. In order for diffusion to occur, it is important that the components involved have good mutual solubility, that is, both the bioadhesive and the mucus have similar chemical structures.^[7]

 

Fracture theory

The most widely used theory in studies on the mechani­cal measurement of mucoadhesion, is the fracture the­ory. It analyses the force needed to separate two surfaces after adhesionis established.

 

This theory helps in the determina­tion of fracture strength (σ) following the separation of two surfaces via its relationship to the Young’s modulus of elasticity (E), the fracture energy (ε) and the critical crack length (L) through the following equation. Fig 4 shows regions of mucoadhesive bond rupture.

 

Mechanical theory

Mechanical theory proposes that the adhesion is due to the filling of the irregularities on a rough surface by a mucoadhesive liquid. The roughness enhances the inter­facial area available to interactions thereby aiding dis­sipation of energy.

 

Electronic theory

The electronic theory depends on the assumption that the bioadhesive material and the target biological mate­rial have different electronic surface characteristics. Based on this, when two surfaces come in contact with each other, electron transfer occurs in an attempt to balance the Fermi levels, resulting in the formation of a double layer of electrical charge at the interface of the bioadhesive and the biologic surface . The bioadhe­sive force is believed to be present due to the attractive forces across this double layer.

 

Adsorption theory

This theory states that the bioadhesive bond formed between an adhesive substrate and the tissue is due to the weak Vander Waals forces and hydrogen bond formation. It is one of the most widely accepted the­ories of bioadhesion. Table 1 indicates types of bond formed.^[8]

 

FACTORS AFFECTING MUCOADHESION POLYMER RELATED FACTORS

Molecular weight

The interpenetration of polymer molecules into the mucus layer is variable, for low molecular weight poly­mers penetration is more than high molecular weight polymers because entanglements are favored in high molecular weight polymers. Fig 4 below show Regions where the mucoadhesive bond rupture.

 

Figure 4:  Regions where the mucoadhesive bond rupture can occur..[adopted from Arshad Bashir Khanetal.Review on Mucoadhesive Drug Delivery System: Novel Approaches in Modern Era (Oct–Dec, 2014) Vol 4 | Issue 4:133-136]

 

Table 1: Mucoadhesive/ mucosa interactions

Types of chemical bonds	Process of bonding
Ionic bonds	Two oppositely charged ions attract each other via electrostatic interaction to form a strong bond (e.g. in a salt crystal)
Covalent bonds	Electrons are shared in pairs between the bonded atoms in order to fill the orbitals in both. These are strong bonds
Hydrogen bonds	Hydrogen atom covalently bonds to electronegative atom such as oxygen, fluorine or nitrogen, carries a slight positive charge and is therefore attracted to other electronegative atoms. The hydrogen can therefore be thought of as being shared and the bond formed is generally weaker than ionic and covalent bond
Van der Waals bonds	These are some of the weakest forms of interaction that arise from dipole-dipole and dipole-induced dipole attractions in polar molecules, and dispersion forces with non polar substances
Hydrophobic bonds	Indirect bonds that occur when non polar groups are present in an aqueous solution.

 

Concentration of polymer

There is an optimum concentration for a mucoadhesive polymer to produce maximum bioadhesion. In highly concentrated system, beyond the optimum level, the adhesive strength drops significantly because the coiled molecules become separated from the medium so the chain available for interpenetration become limited.

 

Flexibility of polymer chains

For an effective bioadhesion, the polymer chain should effectively diffuse into the mucus layer. For achieving such diffusion, the polymer chain should have sufficient flexibility which depends on the viscosity and diffusion coefficient. Higher flexibility of polymer causes greater diffusion into mucus network.

 

Spatial confirmation

Bioadhesive force is also dependent on the conforma­tion of polymers, i.e., helical or linear. The helical con­formation of polymers may shield many active groups, primarily responsible for adhesion, thus reducing the mucoadhesive strength of the polymer.

 

Swelling or hydration

Proper hydration to mucoadhesive polymer is essen­tial to create macromolecular mesh of sufficient pore size and also induces mobility, which are necessary for enhancing the interpenetration.

                    

Hydrogen bonding capacity

Hydrogen bonding is another important factor for mucoadhesion of a polymer. For mucoadhesion to occur, desired polymers must have functional groups that are able to form hydrogen bonds. Ability to form hydrogen bonds is due to the presence of (COOH, OH etc.).

 

Cross linking density

The cross linking density indicates the number of aver­age molecular weight of the cross linked polymer, which determines the average pore size. When the cross link­ing density is higher, then the pore size becomes small, so that diffusion of water into the polymer network occurs at a lower rate, thus there is only an insufficient swelling of polymer resulting in decreased penetration of polymer into the mucin.

 

Charge

The bioadhesive property of ionic polymer is always higher than that of non-ionic polymer. In neutral or slightly alkaline medium, the cationic polymer shows superior mucoadhesive property. It has been proven that, cationic high molecular weight polymer such as Chitosan possess good bioadhesive property.^[9]

 

ENVIRONMENT RELATED FACTORS

pH of polymer-substrate interface

pH influences the charge on the surface of both mucus and polymers. Mucus will have a different charge den­sity depending on pH, because of difference in dissocia­tion of functional groups on carbohydrate moiety and amino acids of the polypeptide backbone, which may affect adhesion.

 

Applied strength

While placing a buccal mucoadhesive drug delivery sys­tem, sufficient strength should be applied in order to provide a good bioadhesive property. Even though there is no attractive forces between polymer and mucus, then application of high pressure for sufficient long time make the polymer become bioadhesive with mucus.

 

Initial contact time

Contact time between the bioadhesive and mucus layer determines the extent of swelling and interpenetration of the bioadhesive polymer chains. Moreover, bio­adhesive strength increases as the initial contact time increases.

 

 

Moistening

Moistening is required to allow the mucoadhesive poly­mer to spread over the surface and create a macromolec­ular network of sufficient size for the interpenetration of polymer and mucin molecules to increase the mobil­ity of polymer chains. However, there is a critical level of hydration for mucoadhesive polymers characterized by optimum swelling and bioadhesion.

 

Presence of metal ions.

Interaction with charged groups of polymer and/or mucous can decrease the number of interaction sites and the tightness of mucoadhesive bonding.

 

PHYSIOLOGICAL FACTORS

Mucin turnover

High mucin turnover is not beneficial for the mucoadhesive property because of following reasons:

·         The high mucin turn over limits the residence time of bioadhesive polymer as it detaches from the mucin layer, even though it has a good bioadhesive property.

·         High mucin turn over may produce soluble mucin molecule, thus molecule interact with the polymer, before they interact with mucin layer.

Hence there will not be sufficient mucoadhesion.

 

Disease state.

The physicochemical property of mucus may alter dur­ing some disease state, such as common cold, gastric ulcers, ulcerative colitis, bacterial and fungal infections etc. Thus alteration in the physiological state may affect the bioadhesive property.

 

Rate of renewal of mucosal cells

Rate of renewal of mucosal cells varies extensively from different types of mucosa. It limits the persistence of bioadhesive systems on mucosal surfaces.

 

Concomitant diseases

Concomitant diseases can alter the physicochemical properties of mucous or its quantity (for example, hypo and hyper secretion of gastric juice), increases in body temperature, ulcer disease, colitis, tissue fibrosis, allergic rhinitis, bacterial or fungal infection and inflammation.

 

Tissue movement

Tissue movement occurs on consumption of liquid and food, speaking, peristalsis in the GIT and it affects the mucoadhesive system especially in case of gastro reten­tive dosage form.^[10][11]

 

MUCOADHESIVE POLYMERS

Mucoadhesive polymers are water-soluble and water insoluble polymers, which are swellable networks, joined by cross-linking agents. These polymers possess optimal polarity to make sure that they permit sufficient wetting by the mucus and optimal fluidity that permits the mutual adsorption and interpenetration of polymer and mucus to take place.

 

There are two broad classes of mucoadhesive polymers hydrophilic polymer and hydrogels. In the large classes of hydrophilic polymers those containing carboxylic group exhibit the best mucoadhesive properties, poly vinyl pyrrolidone (PVP), Methyl cellulose (MC), Sodium carboxymethylcellulose (SCMC) Hydroxypropyl cellu­lose (HPC) and other cellulose derivative. Hydrogels are the class of polymeric biomaterial that exhibit the basic characteristics of hydrogel to swell by absorbing water interacting by means of adhesion with the mucus that covers epithelia i.e.

Anionic group- Carbopol, Polyacrylates and their cross linked modifications

Cationic group- Chitosan and its derivatives

Neutral group- Eudragit- NE30D etc. ^[12][13]

 

CHARACTERISTICS OF AN IDEAL MUCOADHESIVE POLYMER

·         The polymer and its degradation products should be nontoxic and should be non absorbable from the GI tract.

·         It should be nonirritant to the mucus membrane.

·         It should preferably form a strong non covalent bond with the mucin–epithelial cell surfaces.

·         It should adhere quickly to most tissue and should possess some site specificity.

·         It should allow easy incorporation of the drug and should offer no hindrance to its release.

·         The polymers must not decompose on storage or during the shelf life of the dosage form.^[14][15]

·         The cost of polymer should not be high so that the prepared dosage form remains competitive.

·         Biocompatible and biodegradable polymers.

                              

EVALUATION OF MUCOADHESIVE TABLETS

·         Weight uniformity – Ten tablets were taken and weighed individually. Average weight was calculated and standard deviation was computed.

·         Hardness –Hardness or crushing strength of tablet was measured using Pfizer hardness tester. It is expressed in Kg/cm².

·         Thickness–Thickness of tablet was measured using Vernier calipers. Three tablets were selected at random from each batch. It is expressed in mm.

·         Friability – Percentage friability of the tablet was determined by using Rouch friabilator.

·         Swelling studies –The degree of swelling of mucoadhesive polymer is an important factor affecting adhesive. For conducting study, three tablets were weighed individually (W1) and immersed in a petri dishes containing simulated saliva fluid (pH 6.75) for predetermined times (0.25, 0.5, 1, 2, 4, 8 h). After immersion tablets were wiped off by the excess surface water by the use of filter paper and weighed (W2). The percent swelling index was calculated by using the following formula and results were summarized in table 5.

 

% Swelling Index = [W2‐ W1] / W2 x 100

 

Where, W1 is the initial weight of the tablet, W2 is the weight of the tablet after the particular swelling time interval.^[25][26]

 

Surface PH

The surface pH of the tablets was determined in order to investigate the possibility of any side effects, on the oral cavity. As acidic or alkaline pH is found to cause irritation to the buccal mucosa, hence an attempt has been made to keep surface pH close to the neutral pH. Three tablets were allowed to swell for four h in distilled water and pH was found out by placing the electrode of pH meter just in contact with the surface of the tablets. Average of three readings was computed.

 

Drug content uniformity

Randomly ten tablets from each batch were weighed accurately and powdered; the equivalent weight of100 mg of clotrimazole was taken and made the volume up to 100ml with methanol in 100 ml volumetric flask and kept aside with constant shaking for 24 h to extract the total drug present in the tablet. Then the solution was filtered and the volume was made with methanol and analyzed for drug content at λmax of 262 nm. Averages of triplicate readings were taken.^[16]

 

EVALUATION PARAMETER OF INVITRO AND INVIVO STUDY TESTS

In vitro/ex vivo tests

In vivo methods

·          Methods determining tensile strength ·          Methods determining shear stress ·          Adhesion weight method ·          Fluorescent probe method ·          Flow channel method ·          Mechanical spectroscopic method ·          Falling liquid film method ·          Colloidal gold staining method ·          Viscometer method ·          Thumb method ·          Adhesion number ·          Electrical conductance ·          Swelling properties ·          In vitrodrug release studies ·          Mucoretentability studies

·          Use of radioisotopes ·          Use of gamma scintigraphy ·          Use of pharmacoscintigraphy ·          Use of electron paramagnetic resonance (EPR

 

 

In vitro/ex vivo tests

Methods determining tensile strength

In tensile and shear experiments, the stress is uniformly distributed over the adhesive joint, whereas in the peel strength stress is focused at the edge of the joint. Thus tensile and shear measure the mechanical properties of the system, whereas peel strength measures the peeling force. Texture profile analyzer is a commercial instrument which is used to measure the force required to remove bioadhesive films from excised tissue in vitro.

                    

Methods determining shear stress

The measurement of the shear stress gives a direct cor­relation to the adhesion strength. In a simple shear stress measurement based method two smooth, polished flexi glass boxes are selected; one block is fixed with adhe­sive Araldite® on a glass plate, which is fixed on leveled table. The level is adjusted with the spirit level. To the upper block, a thread is tied and the thread is passed down through a pulley, the length of the thread from the pulley to the pan was 12 cm.

 

Colloidal gold staining method

Colloidal gold staining technique is proposed for the study of bioadhesion. The technique employs red col­loidal gold particles, which are adsorbed on mucin mol­ecules to form mucin–gold conjugates, which upon interaction with bioadhesives hydrogels develops a red color on the surface.

 

Viscometric method

A simple viscometric method is used to quantify mucin– polymer bioadhesive bond strength. Viscosities of 15% w/v porcine gastric mucin dispersion in 0.1M HCl (pH 1) or 0.1M acetate buffer (pH 5.5) is measured with a Brook­field viscometer in the absence or presence of selected neutral, anionic, and cationic polymers. Viscosity compo­nents and the forces of bioadhesion are calculated.

 

Thumb method

This is a very simple test used for the qualitative deter­mination of peel adhesive strength of the polymer and is useful tool in the development of buccal adhesive delivery systems. The adhesiveness is measured by the difficulty of pulling the thumb from the adhesive as a function of the pressure and the contact time.

 

Stability Studies

The success of an effective formulation can be evaluated only through stability studies. The purpose of stability testing is to obtain a stable product which assures its safety and efficacy up to the end of shelf life at defined storage conditions and peak profile. ICH guidelines can be followed in this regard.^[17]

Measurement of the Residence Time/In Vivo Techniques

Measurements of the residence time of mucoadhesive at the application site provide quantitative information on their mucoadhesive properties. The GI transit times of many mucoadhesive preparations have been exam­ined using radioisotopes and the fluorescent labeling Techniques.

 

GI Transit using Radio-Opaque Tablets

It is a simple procedure involving the use of radio-opaque markers, e.g. barium sulfate, encapsulated in mucoadhesive tablets to determine the effects of muco­adhesive polymers on GI transit time. Feces collection (using an automated feces collection machine) and X-ray inspection provide a non-invasive method of monitor­ing total GI residence time without affecting normal GI motility. Mucoadhesives labeled with Cr-51, Tc- 99m, In-113m, or I-123 have been used to study the transit of the tablets in the GI tract.

 

Gamma Scintigraphy Technique

Distribution and retention time of the mucoadhe­sive tablets can be studied using the gamma scintigra­phy technique. A study has reported the intensity anddistribution of radioactivity in the genital tract after administration of technetium-labeled HYAFF tablets. Dimensions of the stomach part of the sheep can be outlined and imaged using labeled gellan gum, and the data collected are subsequently used to compare the distribution of radio labeled HYAFF formulations.^[18][24]

                                                         

RECENT APPLICATIONS IN AN ORAL MUCOADHESIVE DRUG DELIVERY SYSTEM

Oral mucoadhesive drug delivery has widespread applications for many drugs which on oral administration result in poor bioavailability and are rapidly degraded by the oral mucoadhesive drug delivery provides advantages of high accessibility and low enzymatic activity. Earlier the hydrophilic polymers like SCMC, HPC and polycarbophilwere used for the treatment of periodontal diseases, but now the trend is shifting towards the effective utilization of these systems to the delivery of peptides, proteins and polysaccharides (Park K and  Robinson J R, 1984).The buccal cavity has additional advantages of high patient compliance. Orabase, a first generation mucoadhesive paste has been used as barrier system for mouth ulcers. Semisolids offer more ease in administration, but tablets have also been formulated. Tablets include matrix devices or multilayered systems containing amucoadhesive agent. The tablet is kept under the upper lip to avoid clearance mechanism of the salivary gland. Buccostem, an adhesive antiemetic tablet containing prochloroperazine is usually administered in this manner (Patel V M et al., 2007 and Peppas N A and Buri P A,1985). Buccal mucoadhesive dosage forms may be classified into three types,        

• A single layer device with multidirectional drug release.

• A dosage form with impermeable backing layer which is superimposed on top of a drug loaded bioadhesive layer, creating a double layered device and preventing loss from the top surface of the dosage form into the oral cavity.

• Unidirectional release device, the drug is released only from the side adjacent to the buccal mucosa.^[19][20][21]

 

CURRENTLY USED FORMULATIONS

Representative drugs with transmucosal dosage former with type of release and manufacturer are shown in table. Many novel formulations have been advanced to various stages of development and approval and have met with varying manufacturing and marketing successes.(Aluret al., 1999)Lozenges, troches and tablets for systemic delivery across the oral mucosa are currently commercially available for drugs including nitroglycerin and fentanyl. Solid formulations such as tablets and lozenges dissolve into the salivautilizing the whole surface area of the oral cavity for absorption. Drawbacks of tablets and lozenges include variation due to differences in saliva productionand sucking intensity, accidental swallowing and short exposure time, usually no greater than 30min. Mucoadhesive tablet formulations are better. In this respect as they adhere to the mucosa increasing exposure time. One example of this is a mucoadhesive tablet under development shown to deliver therapeutic doses of flurbiprofen to the saliva for 12 h. This mucoadhesive tablet allowed patients to eat and speak without Discomfort and caused no irritation, bad taste or pain. When compared to delivery of the same drug via lozenges such as Bioactive or orally in Froben the daily dosage requirement was reduced as the drug release was sustained within the oral cavity. Striant is a commercially available mucoadhesive tablet for testosterone replacement therapy.^[22][23][24]

 

CONCLUSION:

The phenomenon of mucoadhesion can be used as a model for the controlled drug delivery approaches for a number of drug candidates. The various advantages of the oral mucoadhesive drug delivery systems like prolongation of the residence time of the drug which in turn increases the absorption of the drug are important factors in the oral bioavailability of many drugs. The introduction of a large num­ber of new drug molecules from drug discovery, muco­adhesive drug delivery will play an even more important role in delivering these molecules. Improvements in mucoadhesive based oral delivery and, in particular, the development of novel, highly-effective and mucosa compatible polymers, are creating new commercial and clinical opportunities. With this compilation we assure that the content of the article would be useful tool to understand in depth knowledge of the subject.

 

ACKNOWLEDGMENT

Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors are also grateful to the e-library of Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India, 490001 for providing UGC-INFLIBNET facility. The authors acknowledge Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015 and 1115/CCOST/MRP/2015; Dated: September 4, 2015

 

REFERENCES

1.   Verma S, Kaul M, Rawat A, Saini S. An overview on buccal drug delivery system. Int J Pharm Sci. 2011; 2(6): 1303-21.

2.   Rao MBM, Shyam PSS, Shelke N. Preparation and characterization of solid self microemulsifying drug delivery system by adsorbent technique to improve dissolution profile of poorly aqueous soluble drug ramipril. Int J Pharm and Pharm Sci. 2(6): 2011; 85-90.

3.   Khairnar GA, Sayyad FJ. Development of buccal drug delivery system based on mucoadhesive polymers. Int J Pharm Tech. 2(1):2010; 719- 35.

4.   *Corresponding Author:- Dhruba Sankar Goswami., Lecturer in Pharmaceutics, S.D. College of Pharmacy, Barnala

5.   Gupta A, Garg S, Khar RK. Measurement of bioadhesive strengthof mucoadhesive buccal tablets: Design of an in vitro assembly.Indian Drugs30: 1992; 152-55

6.   Verma P, Thakur AS, Deshmukh K, Jha AK, Verma S. Routes of drug administration. Int         

7.   J Pharm Stud Res, 1(1), 2010, 54-59.

8.   Asane GS, Mucoadhesive Gastro intestinal drug delivery system , Pharmasist.net , 5:2007

9.   Ahuja A, Khar R K and Ali J “Mucoadhesive Drug Delivery Systems”,  Drug Dev Ind Pharm., Vol. 23, pp. 1997, 489-515.

10. Allur H H, Johnston T P and Mitra A K, in Swarbrick J and Boylan J C (Eds.),   Encyclopedia of Pharmaceutical Technology, Vol. 20, No. 3, pp. 1990: 193-218,Marcel Dekker, New York.

11. Higuchi T, Connors KA. Phase-solubility techniques, In: Reilly CN, ed. Advances in Analytical and Chemistry Instrumentation, Wiley-Interscience Publication, New York, USA, 4, 1965, 117-212.

12. Chowdary K P R and Srinivas L, Mucoadhesive Drug Delivery Systems: A Review  of  Current Status”, Indian Drugs, Vol. 37, No. 9, 2000 . 400-406.

13. Jian-Hwa Guo, Carbopol Polymers For Pharmaceutical Drug Delivery Applications. Excipient Updates, Drug Delivery Technology

14. Patel V M, Prajapati B G and Patel M M, “Formulation, Evaluation And Comparision of Bilayered And Multilayered Mucoadhesive Buccal Devices of  Propranolol Hydrochloride”, AAPS PharmSciTech. , Vol. 8, 2007 22-28.

15. Richard WK, Robert G, Eric D, Pierre B and Peppas NA. Mechanism of solute release from porous hydrophilic polymers. Int J Pharm 1983; 15:25-35.

16. Brain RM. Regulatory expects of stability testing in Europe.  Drug Dev Ind Pharm 25(7):1999; 831-56.

17. Wolfgang G. Extension of international conference on harmonization tripartite guideline for stability testing of  drug substances and products to countries of climate zones III and IV. Drug Dev Ind Pharm 24(4):1998; 313-25.

18. Cirri M, Mura AM, Gines JM, Moyano JR, Gonzalez‐ Rodriguez ML. Characterization of  Ibuproxam binary ternar dispersions with hydrophyllic carriers. Drug Dev Ind Pharm30(1): 2004; 65-74.

19. Longxiao L, Suyan Z. Preparation and characterization of  inclusion complexes of prazosin  hydrochloride with β‐ cyclodextrin and Hydroxypropyl β‐cyclodextrin. J Pharm and Biomed Analysis 40: 2006; 122‐27.

20. Drs. Bhaskara Jasti, Xioling Li, Gary Cleary, Recent advances in mucoadhesive drug delivery system, Bussiness briefing, Pharmatech, (2003), 53-58.

21. R. Khanna, S. P. Agrawal and Alka Ahuja. “Mucoadhesive Buccal drug delivery a potential alternative to conventional therapy.” Indian Journal of pharmaceutical Sciences, Vol 60(1):1998, 1-11.

22. Toress D., Cunna, M., Alonso M.J. “Preparation and In Vivo Evaluation of Mucoadhesive  Microparticles Containing Amoxycillin-Resin Complexes for Drug Delivery  To The Gastric Mucosa.” European Journal of Pharmaceutics and Biopharmaceutics  Vol  51, 2001, 199-205. 

23. Anil K. Shingla, Manish Chawla and Amarjit Singh.; “Potential application of carbomer in  Oral Mucoadhesive controlled drug delivery system: A review”; Drug Development and Industrial Pharmacy, Vol. 26(9) 2000, , 913- 914.

24. R.B. Satoskar, S.D. Bhandarkar, Pharmacology and Phamacotherapeutics, , Popular Prakashan, (18th Edn) (2003) 410.

25. Deepak Tivari, Robert Sause and Parshotam L. Madan,; “Evaluation of polyoxyethylene  homopolymers for Buccal bioadhesive drug delivery device formulation”; AAP Pharmscitech, Vol.1(3) article 13:1999,.

26. Kazuhiro Morimoto, Jian Wang, Yasuhiko Tabata, Dianzhou Bi, Evaluation of gastric mucoadhesive properties of aminated gelatin microspheres, Journal of Controlled Release  73, (2001), 223–231.

 

 

 

 

 

Accepted on 28.04.2017           © RJPT All right reserved