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Transmucosal Drug Delivery- An Overview Pooja Abhang*, Munira Momin, Mayur Inamdar, Swapan Kar Oriental College of Pharmacy, Secctor-2, Sanpada, Navi Mumbai-400705, Maharastra, India Abstract: During the past 20 years, advances in drug formulations and innovative routes of administration have been made. The understanding of drug transport across tissues has increased. The administration of drug by transmucosal routes offers the advantage of being a relatively painless administration and has the potential for greater flexibility in a variety of clinical situations. The transmucosal route includes oral, nasal, vaginal, and urethral and presents a challenge in the field of novel drug delivery technology. The oral transmucosal delivery, especially the buccal and sublingual routes have been explored successfully for a number of drugs in the last few decades with novel approaches emerging continuously. The transmucosal membranes are relatively permeable, have a rich blood flow and hence allow the rapid uptake of a drug into systemic circulation to avoid first pass metabolism. This route of drug delivery offers a number of benefits over other drug delivery approaches and allows drugs to circumvent some of the body’s natural defense mechanisms like first pass metabolism, harsh stomach environment etc. Several approaches have been used like drug delivery through the nasal route by using sprays, pumps and gels while the mucoadhesive, quick dissolve tablets and solid lozenge formulations are for the oral mucosal route. Also, vaginal or urethral routes can be explored using mucoadhesive suppositories, in-situ gel and foam etc. The purpose of this review is to compile the basic approach studies by different research groups in the last few years.
Keywords: Transmucosal, Bioadhesive polymer, Drug delivery, Mucoadhesion. INTRODUCTION
NEED OF TRANSMUCOSAL DRUG DELIVERY
Transmucosal delivery of therapeutic agents is a popular method because mucous membranes are relatively permeable, allowing for rapid uptake of a drug into the systemic circulation and avoiding the first pass metabolism. This efficient uptake offers several benefits over other methods of delivery and allows drugs to circumvent some of the body’s natural defense mechanisms. Transmucosal products can be designed to be administered via the nasal route by using sprays, pumps and gels, via the oral/buccal route using mucoadhesive, quick dissolve tablets and solid lozenge formulations and via vaginal or urethral routes using suppositories [1].
There is a need for transmucosal drug delivery for Controlled release, for targeted and localized drug delivery, for bypass first pass metabolism, for avoidance of drug degradation, for prolonged effect, for high drug flux through the absorbing tissue, and for reduction in fluctuation of steady state plasma level.
In the development of these drug delivery systems, mucoadhesion of the device is a key element. The term ‘mucoadhesive’ is commonly used for materials that bind to the mucin layer of a biological membrane. Mucoadhesive polymers have been utilized in many different dosage forms in efforts to achieve systemic delivery of drugs through the different mucosae. These dosage forms include tablets, patches, tapes, films, semisolids and powders. To serve as mucoadhesive polymers, the polymers should possess some general physiochemical features such as predominantly anionic hydrophilicity with numerous hydrogen bond-forming groups, suitable surface property for wetting mucus/mucosal tissue surfaces and sufficient flexibility to penetrate the mucus network or tissue crevices [2,3].
An ideal dosage form is one which attains the desired therapeutic concentration of drug in plasma and maintains a constant for the entire duration of treatment. This is possible through administration of a conventional dosage form in a particular dose and at a particular frequency. In most cases, the dosing intervals are much shorter than the half life of the drug resulting in a number of limitations associated with such a conventional dosage form which is as follows: Poor patient compliance; increased chances of missing the dose of a drug with a short half-life for which frequent administration is necessary; a typical peak plasma concentration time profile which makes attainment of a steady state condition difficult; unavoidable fluctuation in the drug concentration that may lead to under medication or over medication as the steady state concentration values fall or rise beyond the therapeutic range; fluctuating drug levels that may lead to precipitation of adverse effects especially of a drug with a small therapeutic index whenever overmedication occurs [4].
*Address correspondence to this author at the Oriental College of Pharmacy, Secctor-2, Sanpada, Navi Mumbai-400705, Maharastra, India; Tel: +91-8108146662; E-mail:
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ADVANTAGES OF TRANSMUCOSAL DRUG DELIVERY Advantages of Transmucosal Drug Delivery are Stated as Follows: •
A prolonged residence time at the site of drug action or absorption.
•
Localization of drug action of the delivery system at a given target site
Abhang et al.
safety margin of high potency drugs due to better control of plasma levels, maximum utilization of the drug enabling a reduction in the total amount of drug administered, improved patient convenience and compliance due to less frequent drug administration, reduction in fluctuation of steady state levels and therefore better control of disease conditions and a reduced intensity of local or systemic side effects. Despite the several advantages associated with oral controlled drug delivery systems, there are many limitations [5].
•
Ease of administration
•
Convenient termination of therapy (except through gastrointestinal route),
LIMITATIONS OF TRANSMUCOSAL DRUG DELIVERY
•
Permits localization of the drug to the oral cavity for a prolonged period of time
•
Can be administered to unconscious patients, except gastrointestinal
•
Offers an excellent route for the systemic delivery of drugs with high first pass metabolism, thereby offering a greater bioavailability,
•
Facilitation in achieving a significant reduction in dose thereby reducing dose related side effects,
•
Causing drugs which are unstable in the acidic environment to be destroyed by the enzymatic or alkaline environment of the intestine to be administered by this route. Eg. Buccal, sublingual and vaginal. Drugs which show poor bioavailability via the oral route can be administered conveniently
Drugs, which irritate the oral mucosa, have a bitter or unpleasant taste and odour and 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. Drugs may be swallowed with saliva and lose the advantages of the buccal route. Only those drugs which are absorbed by passive diffusion can be administered by this route. Eating and drinking may become restricted, however swallowing of the formulation by the patient may be possible. Over hydration may lead to the formation of a slippery surface and the structural integrity of the formulation may get disrupted by the swelling and hydration of the bioadhesive polymers [6].
•
Offers a passive system of drug absorption and does not require any activation,
•
The presence of saliva ensures a relatively large amount of water for drug dissolution unlike in the case of rectal and transdermal routes
•
Rapid systemic absorption
•
Provides an alternative for the administration of various hormones, narcotic analgesic, steroids, enzymes, cardiovascular agents, etc
•
The buccal mucosa is highly perfused with blood vessels and offers a greater permeability than the skin, with less dosing frequency, shorter treatment period, increased
Fig. (1). Wetting and swelling of polymer.
MECHANISM OF MUCOADHESION The concept of mucoadhesion is one that has the potential to improve the highly variable residence times experienced by drugs and dosage forms at various sites in the gastrointestinal tract, and consequently, to reduce variability and improve efficacy. Intimate contact with the mucosa should enhance absorption. The mechanisms responsible in the formation of bioadhesive bonds are not fully known, however most research has described bioadhesive bond formation as a three step process: [7,8]. Step 1: Wetting and swelling of the polymer Step 2: Interpenetration between the polymer chains and the mucosal membrane. Step 3: Formation of Chemical bonds between the entangled chains.
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Step 1 The wetting and swelling step occurs when the polymer spreads over the surface of the biological substrate or mucosal membrane in order to develop an intimate contact with the substrate. This can be readily achieved for example by placing a bioadhesive formulation such as a tablet or paste within the oral cavity or vagina. Bioadhesives are able to adhere to or bond with biological tissues by the help of the surface tension and forces that exist at the site of adsorption or contact. Swelling of polymers occurs because the components within the polymers have an affinity for water. Step 2 The surface of mucosal membranes is composed of high molecular weight polymers known as glycoprotein’s. In this step, interdiffusion and interpenetration take place between the chains of mucoadhesive polymers and the mucous gel network creating a great area of contact. The strength of these bonds depends on the degree of penetration between the two polymer groups. In order to form strong adhesive bonds, one polymer group must be soluble in the other and both polymer types must be of a similar chemical structure.
Fig. (3). Entanglement of Polymer and Mucus by Chemical bonds.
TRANSMUCOSAL ROUTES OF DRUG DELIVERY Drugs for systemic medication are administered traditionally and routinely by oral and parenteral routes. Although generally convenient, both routes have a number of disadvantages, especially for the delivery of peptides and proteinsa class of drugs that has been rapidly emerging over the last few decades. Oral administration results in the exposure of the drug to the harsh environment of the gastrointestinal tract and thus to potential chemical and enzymatic degradation [9]. After gastrointestinal absorption the drug has to pass the liver, where, dependent on the nature of the drug, extensive first pass metabolism can take place with subsequent rapid clearance from the blood stream. Low permeability across the gastrointestinal mucosa is also often encountered for macromolecular drugs. Parenteral administration avoids drug degradation in the gastrointestinal tract and hepatic first pass clearance but due to pain or discomfort during injection, patient compliance is poor, particularly if multiple daily injections are required e.g. in the insulin therapy. Also injection related side effects like tissue necrosis and thrombophlebitis lead to low patient acceptability. In addition, administration by injection requires a trained personnel which adds to the relatively high costs of Parenteral medication [10]. Several mucosal routes have been investigated over the last decades as alternatives to oral and parenteral drug administration, including nasal, buccal, rectal, ocular, pulmonary, and vaginal mucosa. (figure. 4) Their advantages are easy accessibility and circumvention of the hepatic first pass metabolism. Mucosal bioavailability can vary between almost 100% for low molecular weight hydrophobic drugs and below 1% for polar macromolecules depending on the nature of the delivered drug. In the following, a short overview over the different alternative mucosal drug delivery routes is given [11,12]. Buccal Cavity
Fig. (2). Interdiffusion and Interpenetration of Polymer and Mucus.
Step 3 In this step entanglement and formation of weak chemical bonds as well as secondary bonds between the polymer chains of mucin molecule take place. The types of bonding formed between the chains include primary bonds such as covalent bonds and weaker secondary interactions such as van der Waals Interactions and hydrogen bonds. Both primary and secondary bonds are exploited in the manufacture of bioadhesive formulations in which strong adhesions between polymers are formed.
At this site, first-pass metabolism is avoided, and the non-keratinized epithelium is relatively permeable to drugs. Due to flow of saliva and swallowing, materials in the buccal cavity have a short residence time and so it is one of the most suitable areas for the development of bioadhesive devices that adhere to the buccal mucosa and remain in place for a considerable period of time [13-15]. The inner lining of oral cavity known as oral mucosa is one of the most sensitive parts of the body and is particularly vulnerable to chemotherapy and radiation. Oral mucositis is probably the most common, debilitating complication of cancer treatments. It can lead to several problems, including pain, nutritional problems as a result of inability to eat, and increased risk of infection due to open sores in the mucosa. OTFC (ACTIQ® ,
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Fig. (4). Various potential mucosal pathways for systemic delivery of therapeutic agents.
Cephalon, Inc., Salt Lake City, UT, USA) is a buccal formulation composed of a sweetened fentanyl lozenge on a stick, which dissolves as the patient sweeps the lozenge over the inner portion of their cheek. It is approved in the US and Europe (the EU brand name is also ACTIQ) as treatment for BTP (Breakthrough pain) in adults with cancer pain who are receiving and are tolerant of opioid analgesics for underlying chronic cancer pain [16]. Vagina The vagina is a highly suitable site for a bioadhesive. The bioadhesion increases the retention time (up to 72 h) and a smaller amount of the active ingredient can be used, reducing any adverse effects. As a progressive hydration approach to bioadhesive delivery, the product absorbs moisture, becomes a gel and releases medication in a time-controlled manner. Equipment has been designed to measure the bioadhesion characteristics of polymers and formulations in a simulated vaginal environment [17]. Nasal Cavity Transmucosal nasal drug delivery has been suggested as an alternative route for drugs with poor systemic bioavailability after oral administration. For efficiently transmucosal
absorbed compounds, therapeutic concentrations in the blood circulation are reached within a few minutes. This is desirable for indications requiring a fast onset of action (e.g., status epilepticus, acute pain). Further, nasally absorbed compounds circumvent the first-pass elimination in the liver. Therefore, nasal drug delivery is an attractive alternative to i.v. or i.m. injections. For drugs extensively metabolized in the gastrointestinal tract or in the liver, such as proteins, peptides, and steroid hormones (estradiol, progesterone, and testosterone), nasal administration is a convenient alternative [18,19]. The mucosal grafting method represents an adaptation of a surgical technique which is currently in widespread use in the field of endoscopic skull base surgery and is, in fact, considered the gold standard in reconstruction of skull base defects. In order to test the feasibility of direct transmucosal CNS drug delivery, an appropriate animal model had to be developed and validated. While the described murine extracranial model does not replicate the intranasal milieu, it precisely recapitulates the skull base morphology following surgical mucosal graft reconstruction. The discreet lack of rhodamine-dextran uptake in the negative control condition confirmed that the BCSFB was present and intact in the murine arachnoid. Additionally it was critical to validate the integrity of each mucosal graft following rhodamine-dextran
Transmucosal Drug Delivery- An Overview
exposure to ensure that the observed absorption could not be attributed to a disruption of the epithelium secondary to poor healing or surgical trauma. The described Evans blue testing confirmed that all of the observed rhodamine-dextran absorption resulted from transport through an intact mucosal graft [20,21]. Eye One major problem for drug administration to the eye is rapid loss of the drug and or vehicle as a result of tear flow, and so it is a target for prolonging the residence time by bioadhesion [22]. Gastrointestinal Tract The gastrointestinal tract has been the subject of intense study for the use of bioadhesive formulations to improve drug bioavailability. The disadvantage is that the polymeric bioadhesive formulations bind the intestinal mucus, which is constantly turning over and are transported down the gut by peristalsis. Another problem is that with conventional formulations such as tablets, the active ingredient may diffuse relatively rapidly away from the bioadhesive [23,24]. Oesophagagus Tablets or capsules lodging in the oesophagus lead to delayed absorption and therefore delayed onset of action, as the oesophageal epithelial layer is impermeable to most drugs. In addition, adhesion at such a site may cause problems if localization of the drug or dosage form leads to irritation of the mucosa. Development of a DDS that adheres to the oesophagus has implications in both the protection of the epithelial surface from damage caused by reflux and as a vehicle to deliver drugs for local action within the oesophagus. Bioadhesive dosage forms that adhere to the oesophageal mucosa and prolong contact have been investigated to improve the efficacy of locally acting agents [25]. Rectal Drug Delivery The lower digestive tract is less harmful to administered drugs than the stomach and the small intestine due to the lower enzymatic activity and neutral pH. Also the rectal route of drug administration is safe and convenient. The circumvention of the hepatic first pass metabolism by rectal administration is only partial and depends on the positioning and / or spreading of the drug formulation. Recent studies have evaluated thermo gelling dosage forms, gels, osmotic mini pumps, and hard gelatin capsules as rectal drug delivery systems. Strategies to improve the rectal bioavailability of peptide and protein drugs include the use of absorption enhancers, the use of protease inhibitors and structural modifications of peptide and protein drugs [26,27]. Transmucosal and particularly buccal, sublingual or transrectal administration of phosphodiesterase inhibitors to treat erectile dysfunction accordingly represents an important advance in the treatment of impotence and other erectile disorders [28,29]. Direct transrectal delivery of therapeutic genes utilizing adenoviral vectors for advanced prostate cancer may offer effective treatment at the molecular level. Preparations of beta-blockers, propranolol-HCl and atenolol,
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in poly(vinyl alcohol) (PVA) hydrogel were designed for the therapeutic treatment of hypertension by transrectal delivery [30,31]. Pulmonary Drug Delivery Pulmonary drug delivery has traditionally been used for the systemic administration of drugs such as anesthetic gases and nicotine (tobacco smoke). The lungs offer a number of advantages which render them also a suitable organ for systemic drug delivery: a large surface area of about 150 m2 and an extremely well vascularized, thin epithelium. Thus, various drugs including peptides and proteins (e.g. insulin, human growth hormone, luteinizing hormone releasing hormone analogue, glucagon, calcitonin) have efficiently been delivered via the lungs [32]. TRANSMUCOSAL POLYMER Over the years, transmucosal polymers were shown to be able to adhere to various other mucosal membranes. The capability to adhere to the mucus gel layer, which covers epithelial tissues, makes such polymers very useful excipients in drug delivery. Polymers that adhere to the mucinepithelial surface can be divided into three broad categories: 1). Polymers that become sticky when placed in water and owe their mucoadhesion to stickiness. 2). Polymers that adhere through nonspecific, noncovalent interactions those are primarily electrostatic in nature (although hydrogen and hydrophobic bonding may be significant). 3). Polymers that bind to specific receptor sites on the cell surface. These polymers could be either natural such as gelatin, sodium alginate, and guar gum or synthetic and semi synthetic such as hydroxypropylmethyl cellulose (HPMC), Carbopol 934 and Sodium carboxymethyl cellulose (Sodium CMC). Also different blends of two or more adhesive polymers may be used as mucoadhesive systems [33-35]. Characteristics of the ideal mucoadhesive polymer to be used in a drug delivery system: 1). The polymer and its degradation products should be nontoxic and nonabsorbable from the gastrointestinal tract. 2). It should be nonirritant to the mucous membrane. 3). It should preferably form a strong noncovalent bond with the mucin-epithelial cell surfaces. 4). It should adhere quickly to soft tissue and should posses some site specificity. 5). It should allow some easy incorporation of the drug and offer no hindrance to its release. 6). The polymer must not decompose on storage or during the shelf life of the dosage form. 7). The cost of the polymer should not be high, so that the prepared dosage form remains competitive. 8). The polymer should not interfere in drug analysis.
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Table 1.
Examples of Different of Bioadhesive Polymers: [36,37].
Cationic Polymers
lose undergo a phase change from a liquid to a semisolid. This change enhances or improves the viscosity, resulting in the sustained or controlled release of drugs [42].
Chitosan (Hydrogel polymers)
Sprays
Polyacrylic acid (Hydrophilic soluble polymer)
An aerosol spray is one of the suitable alternatives to the solid dosage forms and can deliver the drug into the salivary fluid or onto the mucosal surface and thus is readily available for the absorption. As the spray delivers the dose in fine particulates or droplets, the lag time for the drug to be available for the site of the absorption is reduced.
Carbopol 934P, 971P, 980 (Hydrogel polymers) Anionic polymers
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Polycarbophil (Hydrogel polymers) Poly(methacrylic acid) Sodium alginate Methocel (HPMC) K100M, K15M, K4M
Non-ionic polymers
Hydroxyethylcelullose (HEC) Hydroxypropylcelullose (HPC) Polyoxyethylene (POE)
Ion exchange resins
Cholestyramine (Duolite AP-143)
Miscellaneous
Sucralfate, Gliadin
APPROACHES OF TRANSMUCOSAL DRUG DELIVERY [38,39] Tablets Tablets have been the most commonly investigated dosage form for drug delivery. Tablets are small, flat, and an oval shaped dosage form. Unlike conventional tablets, transmucosal tablets allow for drinking and speaking without major discomfort. They soften, adhere to the mucosa and are retained in position until dissolution and/or release is complete. Monolithic and two-layered matrix tablets have been designed for buccal drug delivery [40].
In Situ-gel The timely gelation and retention of in situ-gelling formulations could be fundamental in improving the efficacy of drugs. The phase changes polymers are used to form thermoreversible gels when incorporated into aqueous solutions, these polymers exhibit sol-gel transition in response to body temperature, pH and specific ions, therefore allowing advantageous topical applications. Microemulsion Microemulsion based formulations that offer rapid dispersion and enhanced drug absorption profiles can be exploited for the development of novel vaginal delivery systems. GM-144, a novel lipophilic gel-microemulsion, was investigated as a vehicle for lipophilic drugs used in reducing the risk of heterosexual transmission of STDs. Liposome Liposome’s are well established as a novel drug delivery system, able to effectively deliver entrapped drugs for an extended period of time at the site of action. Vaginal Ring
Patches Patches eg the buccal patch are described as laminates which comprise of an impermeable backing layer, a drugcontaining reservoir layer which releases the drug in a controlled manner, and a bioadhesive surface for mucosal attachment. Two methods, namely, solvent casting method and direct milling are used to prepare adhesive patches [41]. Films Films are preferable over mucoadhesive discs and tablets in terms of patient comfort and flexibility they ensure more accurate drug dosing and a longer residence time compared to gels and ointments. Films also reduce pain by protecting the wound surface and hence increase the treatment effectiveness. Gels and Ointments These are semisolid dosage forms having the advantage of easy dispersion throughout the oral mucosa. The problem of poor retention of gels at the application site has been overcome by using bioadhesive formulations. Certain bioadhesive polymers for example, sodium carboxymethylcellu-
The vaginal ring technology offers an innovative platform for a convenient delivery of hormonal agents. The vaginal ring is a torous shaped device made of a silicone elastomer which contains drug released by diffusion through the elastomer. Ring design, solubility of drug in the elastomer and the molecular weight of the drug are important factors that regulate the release pattern of the drug. The vaginal ring technology has the capacity to deliver a relatively constant dose of drug intravaginally over an extended period of time in a single application, to treat conditions such as depression, eating disorders, migraine headaches, pain, pre-menstrual dysphoric disorders (PMDD) and obsessive compulsive disorders. Drops Liquid preparations are mainly based on aqueous formulations and contain excipients for osmolarity and pH adjustment as well as preservatives in case of multi-dose containers. Their humidifying effect is convenient and useful, since many allergic and chronic diseases are often connected with crust and drying of mucus membranes.
Transmucosal Drug Delivery- An Overview
Powders and Microparticles Particulate dosage forms are usually prepared by simply mixing of the drug substance and the excipients, by spraydrying or freeze drying of drug and excipients / preformed microparticles together or by direct production of drug loaded nano- and microparticles.
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has a chance to interact with the mucus layer. METHODS OF EVALUATION Mucoadhesive polymers and drug delivery systems can be evaluated by testing their adhesion strength by both in vitro and in vivo tests [44-46].
Ophthalmic Inserts/Films
In Vitro Tests/ Ex Vivo
The dry formulation is achieved by adhesion via dehydration of the local mucosal surface. The ocular inserts, ocular films, wafers, and rods are solid devices which are placed in the cornea, cul-de-sac. These have advantages over liquid formulations of a longer retention time, accurate dosing, increased stability and shelf life.
Methods based on Measurement of Tensile Strength In these methods the force required to break the adhesive bond between a model membrane and the test polymer is measured.
Microspheres and Nanoparticles These colloidal particles have the advantage of being applied in a liquid form just like eye drop solutions. Thus they avoid the discomfort that is combined with the application of viscous or sticky preparations such as ointments. Their advantage is the targeting of the drug to the site of action, leading to a decrease in the dose required and a decrease in side effects. [43] Ion Exchange Resins A new mucoadhesive drug delivery formulation based on an ionic complex of partially neutralized PAA and a highly potent beta blocker drug, for use in the treatment of glaucoma. Complexes were prepared with varying degrees of drug loading, such that the same PAA chain would have free -COOH groups for mucoadhesion along with ionic complexes of LB x H+ with COO- groups. Capsules Capsules, usually gelatin capsules, containing a suspension or liquid, include bioadhesive polymers such polycarbophil or carbopol. Gelatin interacts with bioadhesive polymer during or following dissolution, and thus bioadhesiveness of the polymer is lost before the bioadhesive polymer
Fig. (6). Modified balance method.
Fig. (5). Automatic surface tensiometer.
Tensinometer This instrument consists of two jaws from flat glasses. The upper glass was fixed and the lower glass had been mounted on a screw-elevating surface. The upper fixed glass was attached to a sensitive digital balance. the adhesive tablets were placed on the surface of lower glass and were elevated until they contacted the surface of the upper glass. The lower glass was then lowered until the tablet clearly was pulled free from the upper glass. The maximum tensile force was calculated and recorded.
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Modified balance method: A modified double beam physical balance was used as the Bioadhesion test apparatus. The mucus membrane was tied with the mucosal side upward using a thread over a Teflon block. The balance beam was raised by removing the fixed weight kept on the right side of the pan. This lowered the Teflon cylinder along with the tablet over the mucosa. the excess weight on right hand side gave the Bioadhesive strength of the tablet in grams. Microbalance Method The microforce balance technique is used to measure the specific adhesion force of microparticles. This involves the use of a microtensiometer and a microforce balance, yielding both contact angle and surface tension. The mucous membrane is placed in a small mobile chamber with both pH and physiological temperature controlled. A unique microsphere is attached by a thread to the stationary microbalance. The chamber with the mucous membrane is raised until it comes into contact with the microsphere and, after contact time, is lowered back to the initial position.
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Adhesion Weight Method A system where suspension of an exchange resin particles flowed over the inner mucosal surface of a section of guinea pig intestine and the weight of adherent particles was determined. Fluorescent Probe Method In this method the membrane lipid bilayered and membrane proteins were labeled with pyrene and fluorescein isothiocyanate, respectively. The cells were mixed with the mucoadhesive agents and changes in fluorescence spectra were monitored. This gave a direct indication of polymer binding and its influence on polymer adhesion. Flow Channel Method A particle of Bioadhesive polymer was placed on the mucin gel, and its static and dynamic behaviour was monitored at frequent intervals using a camera, thereby calculating its adhesive property Mechanical Spectroscopic Method Mechanical spectroscopy was used to investigate the interaction between glycoprotein gel and polyacrylic acid, and the effect of pH and polymer chain length on this. Falling Liquid Film Method The adhesion of particles to this surface is measured by passing the particle suspension over the surface and by comparing the fraction of particles adhered to the tissue. The quantification can be done by the aid of coultercurrent method. It is a quantitative, in-situ technique.
Fig. (7). Diagram of microbalance method.
Methods Determining Shear Stress The shear stress technique measures the force that causes a mucoadhesive to slide with respect to the mucous layer in a direction parallel to their plane of contact.
Fig. (9). Diagrammatic representation of falling liquid film method.
Colloidal Gold Staining Method Fig. (8). Diagram of shear stress method.
The interaction between mucin and adhesive particles is monitored by the appearance of a red color on the surface. This technique employs red colloidal gold particles, which
Transmucosal Drug Delivery- An Overview
are stabilized by the adsorbed mucin molecule by forming mucin–gold conjugates. Bioadhesive hydrogels develop a red colour on the Surface on interaction with mucin–gold conjugates [47]. Viscometer Method A simple viscometric method was used by Hassan and Gallo to quantify mucin–polymer bioadhesive bond strength. It was measured by a Brookefield viscometer in the absence or presence of selected neutral, anionic, and cationic polymers [48].
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Texture Analyzer The rupture tensile strength is evaluated by using the equipment known as a texture analyzer or a universal testing machine. In addition to rupture tensile strength, the texture analyzer can evaluate the texture of the formulations and assess other mechanical properties of the system. In this test, the force required to remove the formulation from a model membrane is measured, which can be a disc composed of mucin, a piece of animal mucous membrane, generally porcine nasal mucus or intestinal mucus from rats.
Thumb Method The adhesiveness is qualitatively measured by the difficulty of pulling the thumb from the adhesive as a function of the pressure and the contact time. It provides useful information on peel strength of the polymer. Adhesion Number It is the ratio of the number of particles attached to the substrate to the total number of applied particles. It is expressed as a percentage. Electrical Conductance This method is used to test the semisolid mucoadhesive ointments. The adhesion of Orabase, carbopol, eudispert, guar gum and methylcellulose to artificial membranes in artificial saliva was studied by using a modified rotational viscometer capable of measuring electrical conductance.
Fig. (11). Bioadhesion test using the texture analyzer [49].
Everted sac Technique
Mucoretentability Studies
A segment of intestinal tissue is removed from the rat, everted, and one of its ends sutured and filled with saline. The sacs are introduced into tubes containing the system under analysis at known concentrations, stirred, incubated and then removed. The percent adhesion rate of the release system onto the sac is determined by subtracting the residual mass from the initial mass.
A 1-cm by 1-cm piece of porcine buccal mucosa was tied onto a glass slide (3-inch by 1-inch) using thread. A tablet was stuck onto the wet, rinsed, tissue specimen, by applying light force with a fingertip for 30 seconds. The prepared slide was hung onto one of the groves of a USP tablet disintegrating test apparatus [50, 51].
In Vitro Drug Release Studies
In Vivo Methods [52] Use of Radioisotopes It is a simple procedure involving the use of radio-opaque markers, e.g. barium sulfate, encapsulated in bioadhesive to determine the effects of bioadhesive polymers on GI transit time. Faeces collection (using an automated faeces collection machine) and X-ray inspection provide a non-invasive method of monitoring total GI residence time without affecting normal GI motility. Use of Gamma Scintigraphy This technique gives information of oral dosage forms across the different regions of the GI tract, the time and site of disintegration of dosage forms, the site of drug absorption, the effect of food, disease, and size of the dosage form on the in vivo performance of the dosage forms. Fig. (10). Diagrammatic Representation of Everted Gut Sac Technique.
The greatest advantage of gamma scintigraphy over radiological studies is that it allows visualization over time of the entire course of transit of a formulation through the di-
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Fig. (12). Modified disintegration apparatus for determining in- vitro residence time.
gestive tract, with reasonably low exposure of subjects to radiation. Location of microspheres on oral administration, extent of transit through the GIT, distribution and retention time of the mucoadhesive microspheres in GIT can be studied using the gamma scintigraphy technique. Use of Pharmacoscintigraphy A tool to examine drug delivery to eye Gammascintigraphy provides information on the deposition, dispersion and movement of the formulation. The combination of such studies with the assay of drug levels in blood or urine specimens, pharmacoscintigraphy, provides information concerning the sites of drug release and absorption
Magnetic Resonance Imaging and Fluorescence Detection Magnetic resonance imaging (MRI) is a noninvasive technique that is widely available for in vivo visualization and localization of solid oral dosage forms in the rat gastrointestinal tract. Compared to other imaging modalities MRI allows the representation of anatomical structures with different contrasts and high spatial resolution [53].
X-Ray Studies To study the bioadhesive character and mean residence time of the natural polymer in the stomach, a barium sulphate loaded tablet is used. Two healthy rabbits weighing 2.5 kg are selected and administered orally with the tablet. X-ray photograph is taken at different time intervals. Rat Gut Loop Studies of Mucoadhesion Male Wistar rats, with a mean weight about 300 g, are anesthetized and killed with an overdose of barbiturate. The small intestine is removed and washed with physiological saline. The microsphere suspension is filled into lengths of small intestine (about 15 cm in length) and sealed. These tubes are incubated in saline at 37°C for 60 min. The microsphere suspension is then removed and the number of microspheres present in the suspension before and after the adhesion study is counted using a Coulter Counter method. The percentage of microspheres adhered to the tissue is calculated from the difference of the counts
Fig. (13). Diagrammatic representation of biacore.
Quantitative GIT distribution fluorescence Microscopy Fluorescence microscopy was performed to determine the extent of distribution and penetration of microsphere formulations. The excised tissue sections of GIT were blotted with tissue paper. The results of quantitative GI distribution study also showed significant higher retention of mucoadhesive microspheres in the upper GI tract.
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In vivo as well as in vitro Technique
[14]
BIACORE Surface Plasmon Resonance (SPR)
[15]
Mucoadhesion studies have been reported by using BIACORE integrated chip (IC) systems. The method involves immobilization of the polymer (powder) on to the surface of the IC with the subsequent passage of the mucin solution over the same. This results in the interaction of the mucin with that of the polymer surface. The polymer-mucin interaction is measured by an optical phenomenon called Surface Plasmon Resonance (SPR), which measures the change in the refractive index when mucin binds on the polymer surface [54]. CONCLUSION The transmucosal route can address the limitations by traditional oral route and parenteral route. The close contact of the formulation with the biological membrane enhances the transportation possibilities of the drug. Larger molecules can be given with permeation enhancers. This review compiles the exploration of different transmucosal barriers for drug delivery, nasal, buccal, rectal, ocular, pulmonary, and vaginal mucosa. The author believes that transmucosal membrane can further be studied in detail for safe delivery of protein and peptide drug molecules using different formulations approaches.
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CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest.
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Received: July 27, 2013
Revised: August 24, 2013
Accepted: August 28, 2013
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