Transmucosal Drug Delivery- an Overview

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Send Orders for Reprints to [email protected] 26 Drug Delivery Letters, 2014, 4, 26-37 Transmucosal Drug Delivery- An Overview

Pooja Abhang*, Munira Momin, Mayur Inamdar and 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: Bioadhesive polymer, drug delivery, mucoadhesion, transmucosal.

INTRODUCTION NEED OF TRANSMUCOSAL DRUG DELIVERY Transmucosal delivery of therapeutic agents is a popular There is a need for transmucosal drug delivery for Con- method because mucous membranes are relatively perme- trolled release, for targeted and localized drug delivery, for able, allowing for rapid uptake of a drug into the systemic bypass first pass metabolism, for avoidance of drug degrada- circulation and avoiding the first pass metabolism. This effi- tion, for prolonged effect, for high drug flux through the ab- cient uptake offers several benefits over other methods of sorbing tissue, and for reduction in fluctuation of steady state delivery and allows drugs to circumvent some of the body’s plasma level. natural defense mechanisms. Transmucosal products can be designed to be administered via the nasal route by using An ideal dosage form is one which attains the desired sprays, pumps and gels, via the oral/buccal route using mu- therapeutic concentration of drug in plasma and maintains a coadhesive, quick dissolve tablets and solid lozenge formula- constant for the entire duration of treatment. This is possi- tions and via vaginal or urethral routes using suppositories ble through administration of a conventional dosage form [1]. in a particular dose and at a particular frequency. In most cases, the dosing intervals are much shorter than the half In the development of these drug delivery systems, mu- life of the drug resulting in a number of limitations associ- coadhesion of the device is a key element. The term ‘muco- ated with such a conventional dosage form which is as adhesive’ is commonly used for materials that bind to the follows: mucin layer of a biological membrane. Mucoadhesive polymers have been utilized in many different dosage forms in Poor patient compliance; increased chances of missing efforts to achieve systemic delivery of drugs through the the dose of a drug with a short half-life for which frequent different mucosae. These dosage forms include tablets, administration is necessary; a typical peak plasma concentra- patches, tapes, films, semisolids and powders. To serve as tion time profile which makes attainment of a steady state mucoadhesive polymers, the polymers should possess some condition difficult; unavoidable fluctuation in the drug con- general physiochemical features such as predominantly ani- centration that may lead to under medication or over medica- onic hydrophilicity with numerous hydrogen bond-forming tion as the steady state concentration values fall or rise be- groups, suitable surface property for wetting mucus/mucosal yond the therapeutic range; fluctuating drug levels that may tissue surfaces and sufficient flexibility to penetrate the mu- lead to precipitation of adverse effects especially of a drug cus network or tissue crevices [2, 3]. with a small therapeutic index whenever overmedication occurs [4].

*Address correspondence to this author at the Oriental College of Phar- macy, Secctor-2, Sanpada, Navi Mumbai-400705, Maharastra, India; Tel: +91-8108146662; E-mail: [email protected]

ADVANTAGES OF TRANSMUCOSAL DRUG DE- safety margin of high potency drugs due to better con- LIVERY trol of plasma levels, maximum utilization of the drug enabling a reduction in the total amount of drug admin- Advantages of Transmucosal Drug Delivery are Stated as istered, improved patient convenience and compliance Follows: due to less frequent drug administration, reduction in • A prolonged residence time at the site of drug action or fluctuation of steady state levels and therefore better absorption. control of disease conditions and a reduced intensity of local or systemic side effects. • Localization of drug action of the delivery system at a given target site 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 gas- LIMITATIONS OF TRANSMUCOSAL DRUG DELIV- trointestinal route), ERY • Permits localization of the drug to the oral cavity for a Drugs, which irritate the oral mucosa, have a bitter or prolonged period of time unpleasant taste and odour and cannot be administered by • Can be administered to unconscious patients, except this route. Drugs which are unstable at buccal pH cannot be gastrointestinal administered by this route. Only drugs with small dose re- quirements can be administered. Drugs may be swallowed • Offers an excellent route for the systemic delivery of with saliva and lose the advantages of the buccal route. Only drugs with high first pass metabolism, thereby offering a those drugs which are absorbed by passive diffusion can be greater bioavailability, administered by this route. Eating and drinking may become • Facilitation in achieving a significant reduction in dose restricted, however swallowing of the formulation by the thereby reducing dose related side effects, patient may be possible. Over hydration may lead to the formation of a slippery surface and the structural integrity of the • Causing drugs which are unstable in the acidic environ- formulation may get disrupted by the swelling and hydration ment to be destroyed by the enzymatic or alkaline envi- of the bioadhesive polymers [6]. ronment of the intestine to be administered by this route. Eg. Buccal, sublingual and vaginal. Drugs which show MECHANISM OF MUCOADHESION poor bioavailability via the oral route can be administered conveniently The concept of mucoadhesion is one that has the potential to improve the highly variable residence times experi- • Offers a passive system of drug absorption and does not enced by drugs and dosage forms at various sites in the gas- require any activation, trointestinal tract, and consequently, to reduce variability and • The presence of saliva ensures a relatively large amount improve efficacy. Intimate contact with the mucosa should of water for drug dissolution unlike in the case of rectal enhance absorption. The mechanisms responsible in the for- and transdermal routes mation of bioadhesive bonds are not fully known, however most research has described bioadhesive bond formation as a Rapid systemic absorption • three step process: [7, 8]. Provides an alternative for the administration of various • Step 1: Wetting and swelling of the polymer. hormones, narcotic analgesic, steroids, enzymes, cardio- vascular agents, etc Step 2: Interpenetration between the polymer chains and the mucosal membrane. • The buccal mucosa is highly perfused with blood vessels and offers a greater permeability than the skin, with less Step 3: Formation of Chemical bonds between the entangled dosing frequency, shorter treatment period, increased chains.

Fig. (1). Wetting and swelling of polymer. 28 Drug Delivery Letters, 2014, Vol. 4, No. 1 Abhang et al.

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 Fig. (3). Entanglement of Polymer and Mucus by Chemical bonds. surface tension and forces that exist at the site of adsorption or contact. Swelling of polymers occurs because the compo- TRANSMUCOSAL ROUTES OF DRUG DELIVERY nents within the polymers have an affinity for water. Drugs for systemic medication are administered tradi- Step 2 tionally and routinely by oral and parenteral routes. Although generally convenient, both routes have a number of disad- The surface of mucosal membranes is composed of high vantages, especially for the delivery of peptides and proteins- molecular weight polymers known as glycoprotein’s. In a class of drugs that has been rapidly emerging over the last this step, interdiffusion and interpenetration take place be- few decades. Oral administration results in the exposure of tween the chains of mucoadhesive polymers and the mu- the drug to the harsh environment of the gastrointestinal tract cous gel network creating a great area of contact. The and thus to potential chemical and enzymatic degradation strength of these bonds depends on the degree of penetra- [9]. After gastrointestinal absorption the drug has to pass the tion between the two polymer groups. In order to form liver, where, dependent on the nature of the drug, extensive strong adhesive bonds, one polymer group must be soluble first pass metabolism can take place with subsequent rapid in the other and both polymer types must be of a similar clearance from the blood stream. Low permeability across chemical structure. 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 (Fig. 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 be- low 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. At this site, first-pass metabolism is avoided, and the non-keratinized epithelium is relatively permeable to drugs. Step 3 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 In this step entanglement and formation of weak chemi- suitable areas for the development of bioadhesive devices cal bonds as well as secondary bonds between the polymer that adhere to the buccal mucosa and remain in place for a chains of mucin molecule take place. The types of bonding considerable period of time [13-15]. The inner lining of oral formed between the chains include primary bonds such as cavity known as oral mucosa is one of the most sensitive covalent bonds and weaker secondary interactions such as parts of the body and is particularly vulnerable to chemo- van der Waals Interactions and hydrogen bonds. Both pri- therapy and radiation. Oral mucositis is probably the most mary and secondary bonds are exploited in the manufacture common, debilitating complication of cancer treatments. It of bioadhesive formulations in which strong adhesions be- can lead to several problems, including pain, nutritional tween polymers are formed. problems as a result of inability to eat, and increased risk of ® infection due to open sores in the mucosa. OTFC (ACTIQ , Transmucosal Drug Delivery- An Overview Drug Delivery Letters, 2014, Vol. 4, No. 1 29

TRANSMUCOSAL PATHWAYS HEPATO- GASTRO- INTESTINAL

BIOTRANSFORMATION Ocular route Mucosal Oral route Naso lachrymal drainage system layer GIT absorption Transmucosal

penetration portal circulation Nose

First pass Nasal route Nasal mucosa Liver pulmonary respiratory Second pass General route mucosa circulation

rectal rectal (PK)

route mucosa Target Distribution vaginal vaginal tissues

route mucosa

buccal, gingival & sublingual

oral mucosa Pharmacodynamic responses

Fig. (4). Various potential mucosal pathways for systemic delivery of therapeutic agents.

Cephalon, Inc., Salt Lake City, UT, USA) is a buccal formu- absorbed compounds, therapeutic concentrations in the blood lation composed of a sweetened fentanyl lozenge on a stick, circulation are reached within a few minutes. This is desir- which dissolves as the patient sweeps the lozenge over the able for indications requiring a fast onset of action (e.g., inner portion of their cheek. It is approved in the US and status epilepticus, acute pain). Further, nasally absorbed Europe (the EU brand name is also ACTIQ) as treatment for compounds circumvent the first-pass elimination in the liver. BTP (Breakthrough pain) in adults with cancer pain who are Therefore, nasal drug delivery is an attractive alternative to receiving and are tolerant of opioid analgesics for underlying i.v. or i.m. injections. For drugs extensively metabolized in chronic cancer pain [16]. the gastrointestinal tract or in the liver, such as proteins, peptides, and steroid hormones (estradiol, progesterone, and Vagina testosterone), nasal administration is a convenient alternative [18, 19]. The vagina is a highly suitable site for a bioadhesive. The bioadhesion increases the retention time (up to 72 h) and a The mucosal grafting method represents an adaptation of smaller amount of the active ingredient can be used, reduc- a surgical technique which is currently in widespread use in ing any adverse effects. As a progressive hydration approach the field of endoscopic skull base surgery and is, in fact, con- to bioadhesive delivery, the product absorbs moisture, be- sidered the gold standard in reconstruction of skull base de- comes a gel and releases medication in a time-controlled fects. In order to test the feasibility of direct transmucosal manner. Equipment has been designed to measure the bioad- CNS drug delivery, an appropriate animal model had to be hesion characteristics of polymers and formulations in a developed and validated. While the described murine extrac- simulated vaginal environment [17]. ranial model does not replicate the intranasal milieu, it pre- cisely recapitulates the skull base morphology following Nasal Cavity surgical mucosal graft reconstruction. The discreet lack of rhodamine-dextran uptake in the negative control condition Transmucosal nasal drug delivery has been suggested as confirmed that the BCSFB was present and intact in the mur- an alternative route for drugs with poor systemic bioavail- ine arachnoid. Additionally it was critical to validate the inability after oral administration. For efficiently transmucosal tegrity of each mucosal graft following rhodamine-dextran 30 Drug Delivery Letters, 2014, Vol. 4, No. 1 Abhang et al. exposure to ensure that the observed absorption could not be in poly(vinyl alcohol) (PVA) hydrogel were designed for the attributed to a disruption of the epithelium secondary to poor therapeutic treatment of hypertension by transrectal delivery healing or surgical trauma. The described Evans blue testing [30, 31]. confirmed that all of the observed rhodamine-dextran absorption resulted from transport through an intact mucosal Pulmonary Drug Delivery graft [20, 21]. Pulmonary drug delivery has traditionally been used for the systemic administration of drugs such as anesthetic gases Eye and nicotine (tobacco smoke). The lungs offer a number of One major problem for drug administration to the eye is advantages which render them also a suitable organ for sys- rapid loss of the drug and or vehicle as a result of tear flow, temic drug delivery: a large surface area of about 150 m2 and so it is a target for prolonging the residence time by and an extremely well vascularized, thin epithelium. Thus, bioadhesion [22]. various drugs including peptides and proteins (e.g. insulin, human growth hormone, luteinizing hormone releasing hor- Gastrointestinal Tract mone analogue, glucagon, calcitonin) have efficiently been delivered via the lungs [32]. The gastrointestinal tract has been the subject of intense study for the use of bioadhesive formulations to improve TRANSMUCOSAL POLYMER drug bioavailability. The disadvantage is that the polymeric bioadhesive formulations bind the intestinal mucus, which is Over the years, transmucosal polymers were shown to be constantly turning over and are transported down the gut by able to adhere to various other mucosal membranes. The peristalsis. Another problem is that with conventional formu- capability to adhere to the mucus gel layer, which covers lations such as tablets, the active ingredient may diffuse rela- epithelial tissues, makes such polymers very useful excipi- tively rapidly away from the bioadhesive [23, 24]. ents in drug delivery. Polymers that adhere to the mucin- epithelial surface can be divided into three broad categories: Oesophagagus 1). Polymers that become sticky when placed in water and Tablets or capsules lodging in the oesophagus lead to owe their mucoadhesion to stickiness. delayed absorption and therefore delayed onset of action, as 2). Polymers that adhere through nonspecific, noncovalent the oesophageal epithelial layer is impermeable to most interactions those are primarily electrostatic in nature drugs. In addition, adhesion at such a site may cause prob- (although hydrogen and hydrophobic bonding may be lems if localization of the drug or dosage form leads to irrita- significant). tion of the mucosa. Development of a DDS that adheres to the oesophagus has implications in both the protection of the 3). Polymers that bind to specific receptor sites on the cell epithelial surface from damage caused by reflux and as a surface. vehicle to deliver drugs for local action within the oesopha- These polymers could be either natural such as gelatin, gus. Bioadhesive dosage forms that adhere to the oesophag- sodium alginate, and guar gum or synthetic and semi syn- eal mucosa and prolong contact have been investigated to thetic such as hydroxypropylmethyl cellulose (HPMC), Car- improve the efficacy of locally acting agents [25]. bopol 934 and Sodium carboxymethyl cellulose (Sodium CMC). Also different blends of two or more adhesive poly- Rectal Drug Delivery mers may be used as mucoadhesive systems [33-35]. The lower digestive tract is less harmful to administered Characteristics of the ideal mucoadhesive polymer to be drugs than the stomach and the small intestine due to the used in a drug delivery system: lower enzymatic activity and neutral pH. Also the rectal route of drug administration is safe and convenient. The cir- 1). The polymer and its degradation products should be cumvention of the hepatic first pass metabolism by rectal nontoxic and nonabsorbable from the gastrointestinal administration is only partial and depends on the positioning tract. and / or spreading of the drug formulation. Recent studies 2). It should be nonirritant to the mucous membrane. have evaluated thermo gelling dosage forms, gels, osmotic 3). It should preferably form a strong noncovalent bond mini pumps, and hard gelatin capsules as rectal drug delivery systems. Strategies to improve the rectal bioavailability of with the mucin-epithelial cell surfaces. peptide and protein drugs include the use of absorption en- 4). It should adhere quickly to soft tissue and should posses hancers, the use of protease inhibitors and structural modifi- some site specificity. cations of peptide and protein drugs [26, 27]. 5). It should allow some easy incorporation of the drug and Transmucosal and particularly buccal, sublingual or offer no hindrance to its release. transrectal administration of phosphodiesterase inhibitors to 6). The polymer must not decompose on storage or during treat erectile dysfunction accordingly represents an important the shelf life of the dosage form. advance in the treatment of impotence and other erectile disorders [28, 29]. Direct transrectal delivery of therapeutic 7). The cost of the polymer should not be high, so that the genes utilizing adenoviral vectors for advanced prostate can- prepared dosage form remains competitive. cer may offer effective treatment at the molecular level. 8). The polymer should not interfere in drug analysis. Preparations of beta-blockers, propranolol-HCl and atenolol, Transmucosal Drug Delivery- An Overview Drug Delivery Letters, 2014, Vol. 4, No. 1 31

Table 1. Examples of different of bioadhesive polymers: lose undergo a phase change from a liquid to a semisolid. [36, 37]. This change enhances or improves the viscosity, resulting in the sustained or controlled release of drugs [42].

Cationic Polymers Chitosan (Hydrogel polymers) Sprays Polyacrylic acid (Hydrophilic soluble polymer) An aerosol spray is one of the suitable alternatives to the Carbopol 934P, 971P, 980 (Hydrogel polymers) solid dosage forms and can deliver the drug into the salivary fluid or onto the mucosal surface and thus is readily avail- Anionic polymers Polycarbophil (Hydrogel polymers) able for the absorption. As the spray delivers the dose in fine Poly(methacrylic acid) particulates or droplets, the lag time for the drug to be available for the site of the absorption is reduced. Sodium alginate

Methocel (HPMC) K100M, K15M, K4M In Situ-gel

Hydroxyethylcelullose (HEC) The timely gelation and retention of in situ-gelling for- Non-ionic mulations could be fundamental in improving the efficacy of polymers Hydroxypropylcelullose (HPC) drugs. The phase changes polymers are used to form ther- Polyoxyethylene (POE) moreversible gels when incorporated into aqueous solutions, these polymers exhibit sol-gel transition in response to body Ion exchange Cholestyramine (Duolite AP-143) temperature, pH and specific ions, therefore allowing advan- resins tageous topical applications. Miscellaneous Sucralfate, Gliadin Microemulsion

Microemulsion based formulations that offer rapid dis- APPROACHES OF TRANSMUCOSAL DRUG DELIV- persion and enhanced drug absorption profiles can be ex- ERY [38, 39] ploited for the development of novel vaginal delivery sys- Tablets tems. GM-144, a novel lipophilic gel-microemulsion, was investigated as a vehicle for lipophilic drugs used in reducing Tablets have been the most commonly investigated dos- the risk of heterosexual transmission of STDs. age form for drug delivery. Tablets are small, flat, and an oval shaped dosage form. Unlike conventional tablets, Liposome transmucosal tablets allow for drinking and speaking without major discomfort. They soften, adhere to the mucosa and are Liposome’s are well established as a novel drug delivery retained in position until dissolution and/or release is com- system, able to effectively deliver entrapped drugs for an plete. Monolithic and two-layered matrix tablets have been extended period of time at the site of action. designed for buccal drug delivery [40]. Vaginal Ring Patches The vaginal ring technology offers an innovative plat- Patches eg the buccal patch are described as laminates form for a convenient delivery of hormonal agents. The which comprise of an impermeable backing layer, a drug- vaginal ring is a torous shaped device made of a silicone containing reservoir layer which releases the drug in a con- elastomer which contains drug released by diffusion through trolled manner, and a bioadhesive surface for mucosal at- the elastomer. Ring design, solubility of drug in the elas- tachment. Two methods, namely, solvent casting method and tomer and the molecular weight of the drug are important direct milling are used to prepare adhesive patches [41]. factors that regulate the release pattern of the drug. The vaginal ring technology has the capacity to deliver a rela- Films tively constant dose of drug intravaginally over an extended period of time in a single application, to treat conditions such Films are preferable over mucoadhesive discs and tablets as depression, eating disorders, migraine headaches, pain, in terms of patient comfort and flexibility they ensure more pre-menstrual dysphoric disorders (PMDD) and obsessive accurate drug dosing and a longer residence time compared to gels and ointments. Films also reduce pain by protecting compulsive disorders. the wound surface and hence increase the treatment effec- tiveness. Drops Liquid preparations are mainly based on aqueous formu- Gels and Ointments lations and contain excipients for osmolarity and pH adjust- These are semisolid dosage forms having the advantage ment as well as preservatives in case of multi-dose contain- of easy dispersion throughout the oral mucosa. The problem ers. Their humidifying effect is convenient and useful, since of poor retention of gels at the application site has been many allergic and chronic diseases are often connected with overcome by using bioadhesive formulations. Certain bioad- crust and drying of mucus membranes. hesive polymers for example, sodium carboxymethylcellu- 32 Drug Delivery Letters, 2014, Vol. 4, No. 1 Abhang et al.

Powders and Microparticles ness of the polymer is lost before the bioadhesive polymer has a chance to interact with the mucus layer. Particulate dosage forms are usually prepared by simply mixing of the drug substance and the excipients, by spray- METHODS OF EVALUATION drying or freeze drying of drug and excipients / preformed microparticles together or by direct production of drug Mucoadhesive polymers and drug delivery systems can loaded nano- and microparticles. 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 dehydra- tion of the local mucosal surface. The ocular inserts, ocular Methods based on Measurement of Tensile Strength films, wafers, and rods are solid devices which are placed in the cornea, cul-de-sac. These have advantages over liquid In these methods the force required to break the adhesive bond between a model membrane and the test polymer is formulations of a longer retention time, accurate dosing, in- measured. creased stability and shelf life.

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 glau- Fig. (5). Automatic surface tensiometer. coma. Complexes were prepared with varying degrees of drug loading, such that the same PAA chain would have free Tensinometer -COOH groups for mucoadhesion along with ionic complexes of LB x H+ with COO- groups. This instrument consists of two jaws from flat glasses. The upper glass was fixed and the lower glass had been Capsules mounted on a screw-elevating surface. The upper fixed glass was attached to a sensitive digital balance. The adhesive tab- Capsules, usually gelatin capsules, containing a suspen- lets were placed on the surface of lower glass and were ele- sion or liquid, include bioadhesive polymers such polycar- vated until they contacted the surface of the upper glass. The bophil or carbopol. Gelatin interacts with bioadhesive poly- lower glass was then lowered until the tablet clearly was mer during or following dissolution, and thus bioadhesive-

Fig. (6). Modified balance method.

Transmucosal Drug Delivery- An Overview Drug Delivery Letters, 2014, Vol. 4, No. 1 33 pulled free from the upper glass. The maximum tensile force Adhesion Weight Method was calculated and recorded. A system where suspension of an exchange resin parti- Modified balance method: A modified double beam cles flowed over the inner mucosal surface of a section of physical balance was used as the Bioadhesion test apparatus. guinea pig intestine and the weight of adherent particles was The mucus membrane was tied with the mucosal side up- determined. ward using a thread over a Teflon block. The balance beam was raised by removing the fixed weight kept on the right Fluorescent Probe Method side of the pan. This lowered the Teflon cylinder along with the tablet over the mucosa. The excess weight on right hand In this method the membrane lipid bilayered and mem- side gave the Bioadhesive strength of the tablet in grams. brane proteins were labeled with pyrene and fluorescein iso- thiocyanate, respectively. The cells were mixed with the mu- Microbalance Method coadhesive agents and changes in fluorescence spectra were monitored. This gave a direct indication of polymer binding The microforce balance technique is used to measure the and its influence on polymer adhesion. specific adhesion force of microparticles. This involves the use of a microtensiometer and a microforce balance, yielding Flow Channel Method both contact angle and surface tension. The mucous membrane is placed in a small mobile chamber with both pH and A particle of Bioadhesive polymer was placed on the physiological temperature controlled. A unique microsphere mucin gel, and its static and dynamic behaviour was moni- is attached by a thread to the stationary microbalance. The tored at frequent intervals using a camera, thereby calculat- chamber with the mucous membrane is raised until it comes ing its adhesive property into contact with the microsphere and, after contact time, is lowered back to the initial position. 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 com- paring 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

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 Fig. (8). Diagram of shear stress method. 34 Drug Delivery Letters, 2014, Vol. 4, No. 1 Abhang et al. are stabilized by the adsorbed mucin molecule by forming Texture Analyzer mucin–gold conjugates. Bioadhesive hydrogels develop a red The rupture tensile strength is evaluated by using the colour on the Surface on interaction with mucin–gold conju- equipment known as a texture analyzer or a universal testing gates [47]. machine. In addition to rupture tensile strength, the texture Viscometer Method analyzer can evaluate the texture of the formulations and assess other mechanical properties of the system. In this test, A simple viscometric method was used by Hassan and the force required to remove the formulation from a model Gallo to quantify mucin–polymer bioadhesive bond strength. membrane is measured, which can be a disc composed of It was measured by a Brookefield viscometer in the absence mucin, a piece of animal mucous membrane, generally por- or presence of selected neutral, anionic, and cationic poly- cine nasal mucus or intestinal mucus from rats. mers [48]. Thumb Method The adhesiveness is qualitatively measured by the diffi- culty 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 ex- pressed 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 Fig. (11). Bioadhesion test using the texture analyzer [49]. artificial saliva was studied by using a modified rotational viscometer capable of measuring electrical conductance. In Vitro Drug Release Studies Everted SAC Technique Mucoretentability Studies A segment of intestinal tissue is removed from the rat, A 1-cm by 1-cm piece of porcine buccal mucosa was tied everted, and one of its ends sutured and filled with saline. onto a glass slide (3-inch by 1-inch) using thread. A tablet The sacs are introduced into tubes containing the system was stuck onto the wet, rinsed, tissue specimen, by applying under analysis at known concentrations, stirred, incubated light force with a fingertip for 30 seconds. The prepared slide and then removed. The percent adhesion rate of the release was hung onto one of the groves of a USP tablet disintegrat- system onto the sac is determined by subtracting the residual ing test apparatus [50, 51]. mass from the initial mass. 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 Fig. (10). Diagrammatic Representation of Everted Gut Sac Tech- in vivo performance of the dosage forms. nique. 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 Transmucosal Drug Delivery- An Overview Drug Delivery Letters, 2014, Vol. 4, No. 1 35

Fig. (12). Modified disintegration apparatus for determining in-vitro residence time.

digestive tract, with reasonably low exposure of subjects to Magnetic Resonance Imaging and Fluorescence Detection radiation. Location of microspheres on oral administration, extent of transit through the GIT, distribution and retention Magnetic resonance imaging (MRI) is a noninvasive time of the mucoadhesive microspheres in GIT can be stud- technique that is widely available for in vivo visualization ied using the gamma scintigraphy technique. and localization of solid oral dosage forms in the rat gastrointestinal tract. Compared to other imaging modalities MRI Use of Pharmacoscintigraphy allows the representation of anatomical structures with different contrasts and high spatial resolution [53]. A tool to examine drug delivery to eye Gamma- scintigraphy 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

X-Ray Studies To study the bioadhesive character and mean residence time of the natural polymer in the stomach, a barium sul- phate 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 Fig. (13). Diagrammatic representation of biacore. small intestine is removed and washed with physiological saline. The microsphere suspension is filled into lengths of Quantitative GIT Distribution Fluorescence Microscopy small intestine (about 15 cm in length) and sealed. These tubes are incubated in saline at 37°C for 60 min. The micro- Fluorescence microscopy was performed to determine the sphere suspension is then removed and the number of micro- extent of distribution and penetration of microsphere formu- spheres present in the suspension before and after the adhe- lations. The excised tissue sections of GIT were blotted with sion study is counted using a Coulter Counter method. The tissue paper. The results of quantitative GI distribution study percentage of microspheres adhered to the tissue is calcu- also showed significant higher retention of mucoadhesive lated from the difference of the counts microspheres in the upper GI tract. 36 Drug Delivery Letters, 2014, Vol. 4, No. 1 Abhang et al.

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Received: July 27, 2013 Revised: August 24, 2013 Accepted: August 28, 2013