Pharmaceutical Chemistry Journal

Vol. 43, No. 4, 2009

MUCOADHESIVE DRUG DELIVERY SYSTEMS (REVIEW) E. A. Kharenko,1 N. I. Larionova,1 and N. B. Demina1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 4, pp. 21 – 29, April, 2009. Original article submitted October 2, 2007.

This review addresses contemporary mucoadhesive drug delivery systems. The use of hydrophilic polymers increases the retention time of the delivery system on mucosal tissues, leading to the gradual release of the active ingredient and better tolerance by the patient. The mucoadhesive interaction is explained in relation to the structural characteristics of mucosal tissues and the properties of the polymers. A separate section addresses the advantages and disadvantages of various mucoadhesive drug delivery systems (tablets, films, gels, microcapsules, and nanocarriers) and developed and commercially available medicinal formulations based on mucoadhesive polymers. Key words: Mucin, mucoadhesive polymer for pharmaceutical use.

and applied studies are currently under way, pointing to the potential of this approach for biopharmaceuticals.

Among the various approaches to modifying drug delivery systems (DDS) aiming to increase bioavailability, mucoadhesion (the ability of a object to remain attached to mucous membranes) occupies a special position. As gates to the entry of nutrients, antigens, and medicinal formulations (MF) into the body, mucosal tissues mediate the assimilation of substances needed by the body and protection against foreign substances. The moist surface and constant movement of mucosal tissues prevent the strong and long-lasting attachment of traditional MF. Thus, overcoming the protective and barrier functions of the mucosa is the basis of solving the problems of reductions in bioavailability. Adhesion of mucoadhesive MF (MAMF) to mucous membranes leads to increases in the concentrations of medicinal substances (MS) at the application site, allowing reductions in the total dose of MS given both systemically [1-8] and on local application [1, 9 – 13]. The development of mucoadhesive drug delivery systems clearly requires an understanding of the principles and mechanisms of interactions between MF and mucosal tissue components in the conditions obtaining in the body. And, although this approach was first formulated only in the 1980s with the appearance of a report from Park and Robinson [14], mucoadhesion as a means of influencing the duration of contact of MF with mucous membranes immediately became a subject of interest to technologists. As a result, both basic

1 2

Structure and function of mucous membranes Mucous membranes (the mucosa) have moist surfaces lining the walls of the organs of the gastrointestinal tract and respiratory passages, the inner part of the eyes, as well as the nasal and oral cavities and the genital organs [1, 6, 7, 15 – 17]. Thus, the mucosa represent a tissue with an enormous area - the small intestine alone, with its numerous finger-like projections of the intestinal wall and epithelial cell plasma membrane microvilli, has a surface area of 300 m2, which is more than 100 times greater than the area of the skin [18]. The structure of the mucous membrane of the mouth is shown in Fig. 1. The mucous gelatinous layer (1) covers the epithelium (2), beneath which lies the connective-tissue lamina propria (3), which has an abundant supply of blood and lymph vessels; beneath this is a thin layer of smooth-muscle tissue (4). The thickness of the mucus layer varies in different mucosal tissue surfaces from 50 to 500 mm in the stomach and to less than 1 mm in the oral cavity [5 – 7, 19]. The epithelium may consist of a single layer (stomach, small and large intestine, bronchi) or multiple layers (esophagus, vagina). The upper layer contains goblet cells, which secrete mucus components directly onto the epithelial surface. Specialized glands producing components of the mucous layer may also be located beneath the epithelium [1, 6,

I. M. Sechenov Moscow Medical Academy, Moscow, Russia; e-mail: [email protected]. M. V. Lomonosov Moscow State University, Moscow. Russia.

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201 Non-glycosylated regions

1 Oligosaccharides 2 Protein core

a 3

4

Fig. 1. Structure of the mucosa of the oral cavity: 1) mucus layer; 2) epithelium; 3) connective tissue (lamina propria); 4) smooth muscle layer [1].

7, 19]. The moist surface of the tissue results from the mucus – a viscous, gelatinous secretion whose composition includes glycoproteins, lipids, inorganic salts, and up to 95% water [1, 6, 20]. Mucus may be secreted either constantly or intermittently. The volume of secretion changes under the influence of external and internal factors [1, 5, 6, 19, 20]. Glycoproteins (mucins) are the most important components of mucus and are responsible for its gelatinous structure, cohesion, and antiadhesive properties [17]. Despite the various body sites at which mucus is secreted, glycoproteins usually have similar structure (Fig. 2) and are highly glycosylated protein molecules with molecular weights reaching 5 ´ 105 [21]. In space, glycoproteins form a branched three-dimensional network with large numbers of loops (Fig. 2b ) [5 – 7, 20]. The polypeptide chain consists of 800 – 4500 amino acid residues and is characterized by two types of area - strongly glycosylated areas (Fig. 2a, shown by thick lines in Fig. 2b ) and areas lacking carbohydrate side chains (shown by thin lines in Fig. 2b ). Glycosylation increases the resistance of the molecules to proteolytic hydrolysis [7, 20, 21]. The terminal domains of the glycoprotein (C- and N-) are areas containing more than 10% cysteine. These parts of the domains are responsible for the formation of large mucin oligomers due to the formation of disulfide bonds [5]. The greater part of the protein carcass consists of a repeating sequence of serine, threonine, and proline residues [5, 6, 17]. Oligosaccharide sequences are attached to 63% of the protein core, at every third residue within the glycosylated areas, with the result that there are more than 200 carbohydrate chains per glycoprotein molecule [16]. Each carbohydrate side chain contains from two to 20 sugar residues. Thus, the carbohydrate areas can account for more than 80% of the molecular weight of the molecule [7]. As the polysaccharide side chains usually terminate with either fucose or sialic acid (N-acetylneuraminic acid, pKa = 2.6),

Highly glycosylated regions b

Fig. 2. Structure of glycoprotein (diagram): a) structure of branched section; b) formation of network structure [20].

the glycoproteins are negatively charged at physiological pH values [16]. Human mucins are divided into “anchored” mucins, i.e., those bound to the membrane, and secreted mucins. Secreted mucins can also be subdivided into gel-forming or soluble on the basis of their ability to form associates. Membrane-bound mucins contain short tails pointing towards the cytoplasm, which are hydrophobic and anchored in the depth of the membrane domain, holding the molecule in the apical surface of the cell, and an extracellular domain generally containing a repeating glycosylated sequence. The length of the glycosylated region has been shown to reach 200 – 500 mm from the cell surface, depending on the number of repeat sequences present [16]. The main functions of the mucus are to protect and lubricate the supporting epithelial layer [6, 16, 17]. In the gastrointestinal tract, the mucus facilitates the movement of food boluses along the digestive canal and protects the epithelium from harmful influences due to intrinsic peristaltic movements and proteolytic enzymes [5]. The components of the mucus secreted onto the surface of the eye by goblet cells adhere tightly to the glycocalyx of corneal-conjunctival epithelial cells, protecting the epithelium from damage and facilitating the movement of the eyelids [16]. Mucoadherent polymers Studies in the middle of the last century showed that addition of various polymers to DDS, such as gums, increased the duration of attachment of the MF to the mucous surface and increased the efficacy of antibiotic treatment [22]. The development of the mucoadhesion theory and improvements in practical methods were accompanied by investigation of many polymers used in pharmaceuticals and new materials and their mixtures for the presence of mucoadhesive properties. The classification of mucoadhesive polymers and examples are presented in Table 1.

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TABLE 1. Classification of Mucoadhesive Polymers [6] Property used for classification

Source

Solubility in water

Source

Natural and modified natural polymers Synthetic

Agarose, chitosan, gelatin, hyaluronic acid, carrageenan, pectin, sodium alginate

Water-soluble

Cellulose derivatives CMC, thiolated CMC, Na CMC, hydroxyethylcellulose, HPC, HPMC, methylcellulose, methylhydroxyethylcellulose Polymers based on poly(meth)acrylic acid Carbopol, polycarbophil, polyacrylic acid, polyacrylates, copolymer of acrylic acid and PEG, copolymer of methylvinyl ether and methacrylic acid, poly-2-hydroxyethylmethacrylate, copolymer of acrylic acid and ethylhexylacrylate, polymethacrylate, polyalkylcyanoacrylates: polyisobutylcyanoacrylate, polyisohexylcyanoacrylate Others Poly-N-2-hydroxypropylmethacrylamide, polyhydroxyethylene, PVA, PVP, thiolated polymers Ethylcellulose, polycarbophil Aminodextran, dimethylaminoethyldextran, chitosan, quaternized chitosan

Water-insoluble Charge

Examples

Cationic Anionic Uncharged

Possible mecha- Covalent nism of formaHydrogen bonds tion of Electrostatic interactions bioadhesive bonds

Cellulose derivatives CMC, thiolated CMC, Na CMC, hydroxyethylcellulose, HPC, HPMC, methylcellulose, methylhydroxyethylcellulose Polymers based on poly(meth)acrylic acid Carbopol, polycarbophil, polyacrylic acid, polyacrylates, copolymer of acrylic acid and PEG, copolymer of methylvinyl ether and methacrylic acid, poly-2-hydroxyethylmethacrylate, copolymer of acrylic acid and ethylhexylacrylate, polymethacrylate, polyalkylcyanoacrylates: polyisobutylcyanoacrylate, polyisohexylcyanoacrylate Others Poly-N-2-hydroxypropylmethacrylamide, polyhydroxyethylene, PVA, PVP, thiolated polymers

Chitosan-EDTA, PAC, carbopol, polycarbophil, pectin, sodium alginate, Na CMC, CMC Hydroxyethylated starch, HPC, PEG, PVA, PVP Cyanoacrylate Acrylates, carbopol, polycarbophil, PVA Chitosan

Notes. CMC = carboxymethylcellulose; HPMC = hydroxypropylmethylcellulose; PEG = polyethylene glycol; PVA = polyvinyl alcohol; PVP = polyvinylpyrrolidone; HEC = hydroxyethylcellulose; HPC = hydroxypropylcellulose; PAA = polyacrylic acid; EDTA = ethylenediaminetetraacetate.

A mucoadhesive polymer (MAP) must be characterized by certain physicochemical properties, including hydrophilicity, large numbers of groups able to form hydrogen bonds, sufficient chain mobility to allow diffusion through both mucus and epithelial tissue [1, 16, 17, 20, 21, 23, 24]. The ability to absorb water from the mucosal surface in the dry state leads to a strong initial interaction [25]. Wetting of MAP leads to the formation of a viscous fluid, which increases the duration of adhesion to the mucous surface and promotes the formation of further adhesive interactions, including [1, 5, 17, 20, 25]: - mechanical and physical interactions, such as tangling of the flexible polymer and mucin chains,

- hydrogen bonds, - hydrophobic interactions, - van der Waals interactions, - electrostatic interactions, - covalent bonding, - recognition of specific ligands (lectins-sugars, etc.). Studies have focused on the development of mucoadhesive systems forming contacts with surfaces by van der Waals interactions and hydrogen bonds. Although these forces are weak, quite strong adhesion can be achieved by formation of large numbers of interaction sites [1]. Polymers with high molecular weight and high polar group contents (such as COOH and OH) may therefore be character-

Mucoadhesive Drug Delivery Systems

ized by stronger mucoadhesion with a minimum of toxic effects [1]. Anionic polyelectrolytes such as cellulose derivatives and acrylates [21] have promise. Chitosan is presently the only MAP containing positively charged groups with a demonstrated lack of toxic actions [26 – 28], and the possibility that this could be used in ophthalmology has been studied [29, 30]. Mucoadhesives with specific actions Many MAP are characterized by a lack of specificity. For oral use of DDS, if absorption of the active ingredients has to take place in a specific part of the GIT, lack of specificity has the result that the polymer adheres to the first site available on its route or becomes covered with mucin in the soluble/suspended state and passes through the GIT without making contact with the mucosal surface [5]. A variety of biological molecules display specific mucoadhesion, recognizing target structures on cell surfaces or in the depth of the mucosa. The directed access of MF to epithelial M cells in Peyer’s patches in the intestine, which have marked pinocytic function, has been discussed in [5]. Examples of molecules with specific mucoadhesion are lectins, vitamin B12, antibodies, fibrin, and bacterial invasin [6]. Insertion of such molecules into liquid and solid mucoadhesive DDS (MADDS) produces further advantages in terms of specificity and direction of action, with efficacies severalfold greater than those of currently existing oral drug delivery systems [31]. Mechanisms of mucoadhesion Mucoadhesion arises between different types of mucous membranes and drug delivery systems, which may be solid, viscous, or liquid; there is no universal theory combining all the observed types of mucoadhesion interaction (Fig. 3). Some theories (the electronic [32], adsorptive [33], diffusion [17], and wetting [34] theories) have been proposed to explain the mechanisms of interactions between polymers and glycoproteins, though each provides only a partial explanation [6, 7, 10, 17, 25]. The first point to address is formation of the close contact between the mucoadhesive polymer and the biological tissue, which is mediated by the suitably moist surface of the mucosa and swelling of the adhesive [25]. This is followed by diffusion of the polymer chain (which must have sufficient flexibility) into gaps, loops, and pores in the glycoprotein network (diffusion theory) [17]. Mechanical tangling is followed by the formation of weak primary bonds, mostly covalent (adsorption theory) [7, 17]. The surface roughness of the mucosa promotes attachment of the DDS [5, 7]. The viscosity of the DDS and the ability of the polymer to become wet and to swell become important for surfaces with quite smooth relief (wetting theory) [7]. The electronic theory links the developing interaction with the transfer of an electron between the polymer and mucin

203 a

Moistened olymer layer

b

Microgranule

Microgranule

Mucosal gel

Mucosal gel

c

d

Tablet

Gel

Fig. 3. Variants of the interaction of DDS and the mucosal surface [25]: a) a dry or partially moistened DDS comes into contact with the underlying mucosal surface (for example, aerosol microgranules used in the nasal cavity); b) a completely moistened DDS comes into contact with the underlying mucosal surface (for example, microgranule suspensions in the GIT); c) a dry or partially moistened DDS comes into contact with thin/discontinuous layers of mucosal tissue (for example, tablets in contact with the buccal mucosal surface); d) a completely moistened DDS comes into contact with thin/discontinuous layers of mucosal tissue (for example, gels used in gynecology).

layers, which in physiological conditions carry opposite charges [1]. Mucin contains a significant number of groups able to form hydrogen bonds: the hydroxyl groups of the carbohydrate side chains, the amino groups of the protein carcass, and the carboxyl and sulfo groups of the terminal parts of the side chains. There therefore appear to be grounds for the suggestion that hydrogen bond formation plays the key role in mucoadhesion. Given the structure of mucin and its spatial conformation, it is unlikely that the groups of the protein carcass play an important role in interactions with polymers [21]. As most of the molecule is covered with carbohydrate chains forming a bristled structure, the amino acid sequence is screened and is not accessible to form interactions with diffusing polymer chains. The carboxyl and sulfo groups of the terminal parts of the side chains, which are turned outward to the surface of the molecule, may therefore play the main role in forming hydrogen bonds with polymers [21]. On the basis of knowledge of the nature of mucoadhesive interactions, and factors affecting the strength of links between polymers and the mucosa (Table 2), substances can be combined in DDS to obtained medicines with specified properties, for example, with modified MS release [7, 21, 23, 25]. It must also be noted that a strong mucoadhesive may remain at the application site for very short periods of time because of loss of binding properties in the presence of excess moisture. MAP are therefore added to a polymer matrix or the

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TABLE 2. Factors Affecting Mucoadhesion Factor

Characteristics, examples

Molecular weight Molecular weight Properties of the mucoadhesive polymer Low-molecular-weight polymers penetrate the mucus layer better [17]. High molecular weight promotes physical entangling [1]. The optimum molecular weight is between 104 and 4 ´ 106 Dal. Polymers with higher molecular weights will not moisten quickly to expose free groups for interaction with the substrate, while polymers with low molecular weights will form loose gels or will dissolve quickly [6]. For linear polymers, the mucoadhesion strength increases with increases in molecular weight, for example, mucoadhesive properties in a series of polyethylene glycols increased in the order: 2 ´ 104 < 2 ´ 105 < 4 ´ 105. At the same time, dextran with very high molecular weight, ~2 ´ 107, shows mucoadhesion similar to that of PEG with molecular weight 2 ´ 105. This may result from the molecular conformation [41]. Polymer chain flexibility Required for diffusion of chains and their entanglement with mucin [17]. For polymers with high levels of linkage, the mobilities of the individual polymer chains decrease, leading to decreases in mucoadhesion strength [21]. Ability to form hydrogen bonds Presence of functional groups able to form hydrogen bonds (COOH, OH, etc.) [21]. Concentration Affects the availability for penetration of long polymer chains into the mucus layer; important mainly for liquid and viscous DDS [7]. Extent of swelling of polymer or Swelling of the polymer allows mechanical entangling because of the exposure of polymer chains and subsequent DDS formation of hydrogen bonds and/or electrostatic interactions between the polymer and components of the mucosa [17, 25]. Environmental factors pH Changes in pH lead to differences in the extent of dissociation of functional groups in carbohydrate sequences or polypeptide amino acid sequences, as well as in the polymer [17, 41]. Pressure applied to the system for Affects the depth of diffusion of chains [6]. Cannot be controlled for systems used in the GIT [8]. attachment Duration of initial contact Determines the extent of swelling and diffusion of polymer chains [6]. Cannot be controlled for systems used in the GIT [8]. 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 and to increase the mobility of polymer chains [25]. However, there is a critical level of hydration for mucoadhesive polymers characterized by optimum swelling and bioadhesion [6]. Presence of metal ions Interaction with charged groups of polymers and/or mucus can decrease the number of interaction sites and the tightness of mucoadhesive bonding [7]. Physiological factors Rate of renewal of mucosal cells Varies extensively for different types of mucosa. Limits the persistence of bioadhesive systems on mucosal surfaces [25]. Concomitant diseases Can alter the physicochemical properties of mucus or its quantity (for example, hypo- and hypersecretion of gastric juice). Increases in body temperature, ulcer disease, colitis, tissue fibrosis, allergic rhinitis, bacterial or fungal infection, and inflammation [6, 7, 40]. Tissue movement On consumption of liquid and food, speaking, peristalsis in the GIT [1, 6].

surface of the DDS is modified [21]. Both approaches were first proposed by Peppas, who suggested the diffusion theory of mucoadhesion [17]. In particular, the interaction of modified PEG on the surfaces of medicine carriers and mucous membranes was considered [35]. Factors affecting mucoadhesion Mucoadhesion is a property for whose appearance both the bioadhesive polymer and the medium in which it is placed are important [6, 8, 17]. The characteristics of the mucoadhesive and the mucosa, as well as other factors which can influence the strength and duration of the mucoadhesive interaction, are summarized in Table 2.

Approaches to the use of MAMF The use of mucoadhesive polymers led to progress in the technology of buccal drug delivery systems. In this case, retention of the DDS is complicated by constant saliva production (0.5 – 2 liters/day) and tissue mobility. The retention time of the agent in the oral cavity is usually short, at less than 5 – 10 min [1, 6]. Nonetheless, the anatomical structure of the mucosa, its relatively high permeability as compared with skin, and the arrival of substances in the systemic circulation without a hepatic first-pass effect, and also the accessibility, the possibility of locating the application site and removing the agent quickly if side effects occur, are among the clear advantages of using drug delivery systems in the oral cavity as compared with other delivery approaches [1, 6].

Mucoadhesive Drug Delivery Systems

The surface area of the buccal mucosa (the inner surface of the cheek and part of the gums) is relatively small and in humans is less than 50 cm2 [6], though in contrast to the sublingual part of the oral cavity, the buccal area is used for the systemic treatment of chronic diseases and not when a rapid response is required from the patient. The gradual delivery of MS into the systemic circulation and prolongation of the action of the agent can be achieved because of the lower permeability and mobility of the buccal mucosa as compared with the sublingual and by using specially selected MADDS compositions providing tight attachment [1]. A further direction in the development of MAMF is represented by intranasal DDS [3, 7, 15, 36 – 39]. The epithelium of the mucosa of the nasal cavity overlies a large network of blood vessels, which provides for effective absorption of MS. Here, as in the case of the mucosa of the oral cavity, the blood flow passes directly into the systemic circulation. However, the intranasal route for administration also has a series of limitations, particularly mucociliary clearance - a vital physiological mechanism for cleaning the respiratory passages [40]. Foreign particles and pathogenic microorganisms are trapped and held by the layer of mucus, after which the oscillatory movements of cilia located on the surfaces of ciliary cells discharge them into the GIT, where they are neutralized [7]. The ciliary epithelium of the nasal cavity increases the effective surface area for MS absorption by a large factor - up to 150 cm2 [41]. The bioavailability of an MAMF used in the nasal cavity can therefore in some cases be comparable with the bioavailabilities of injected MF [7, 15]. The oral route of use, remaining the most preferred of all routes from the point of view of patient tolerance, also has some limitations [5]. For example, oral administration of proteins, peptides, and nucleotides is ineffective, because they lack stability in the aggressive media of the GIT and because of the low permeability of mucosa for high-molecular-weight substances. Mucoadhesive polymers can not only slow the movement of DDS along the GIT, but can also inhibit the actions of proteolytic enzymes, thus increasing the bioavailability of low-stability MS [4]. The use of mucoadhesive polymers in DDS for intranasal and oral use is interesting in relation to WHO mucosal immunization programs [42, 43]. Until recently, the main purpose of immunization was to induce a systemic immune response using intramuscular or subcutaneous injections. However, most pathogens enter the human body via mucous membranes: orally, intranasally, or via the genital tract [7, 44]. In this context, mucosal vaccines have a number of important advantages, including the development of a local immune response, simple use, and a reduction in the incidence of side effects [7, 45]. In addition, the use of mucosal vaccines does not impose the need for highly qualified medical personnel [46]. Thus, mucosal vaccines (including polyvalent vaccines) are an attractive direction for biotechnology. Intranasal vaccines against influenza [47], diphtheria [48], tetanus [28], and other infections have been developed

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and introduced. Addition of mucoadhesive polymers to vaccines can, firstly, increase affinity for mucous membranes and, secondly, increase the stability of the preparation, as most vaccines in current use contain either proteins or DNA and are very unstable [39]. The local use of MS in ophthalmology is the basis for the treatment of a variety of eye diseases [16]. The bioavailability of MS on instillation with eye drops is very low because of the effective intrinsic protection system of the eye. The anatomical structure of the cornea prevents rapid absorption, and blinking, and baseline and reflex lacrimation have the result that foreign substances, including medicines, are rapidly washed away from the surface of the eye, preventing penetration into the eye and exerting actions on the surface of the cornea [8, 16, 49, 50]. As a result, frequent instillation of eye drops is required to achieve adequate MS concentrations in the tear fluid. However, regular application of concentrated solutions can have harmful influences both on the mucosa and on the surface of the eyeball [16, 49]. Addition of mucoadhesive polymers interacting both with components of the mucosal tissues lining the eyelids and glycoproteins covering the cornea increases the persistence time of the MF on the eye surface and treatment efficacy [16]. The main types of mucoadhesive DDS: advantages and disadvantages The variety of target organs ensures a large selection of DDS for use on mucous membranes and means of modernizing them. Solid MADDS. Mucoadhesive tablets are mostly developed for use in the oral cavity but also have potential for use in gynecology [6, 19]. Tablets attaching to the buccal mucosa have been commercially successful, as exemplified by testosterone preparations (Striant®, Columbia Laboratories Inc, USA) and nitroglycerin (Nitrogard®, Forest Pharmaceuticals Inc., USA and Suscard®, Forest Pharmaceuticals UK Ltd., UK), as well as prochlorperazine (an agent used outside of Russia to relieve the symptoms of nausea and vomiting) in Buccastem® (Reckitt Benckiser, UK) buccal tablets. With the aim of conferring mucoadhesive properties on drug delivery systems, tablets are supplemented with: carbomers (Striat® [51]), natural gums and resins (Buccastem® [23]), hydroxypropylmethylcellulose (HPMC) (Suscard® [23]), as well as combinations of polymers such as Carbopol, Polycarbophil, HPMC, and Na-carboxymethylcellulose (CMC) in buccal tablets containing diltiazem and metoclopramide [52]. In the case of tablets, like other non-wetting solid MADDS, mucoadhesion arises as a result of dehydration of an area of the mucosa [10, 25]. Commercially available tablets are characterized by slow dissolution and maintenance of a therapeutic concentration of the MS in patient’s blood for prolonged periods: from 1 – 2 (Buccastem®) to 8 or more hours (Striant®).

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Despite the demonstrated efficacy of the local application of mucoadhesive buccal tablets, for example, in the treatment of candidiasis of the oral cavity [13], the main restriction to their wide use arises from their size and shape, as there is the need for the DDS to make close contact with the mucosal surface [10]. Polymer mucoadhesive films (PMAF) have been developed for use in oral medicine and ophthalmology [9, 12, 53 – 55]. Unlike tablets, polymer films are sufficiently flexible to take up the shape of the underlying surface; they also have a number of advantages over creams and ointments, as they can maintain a precise dose of the MS at the application site [1, 6]. Ocular films, solid formulations applied behind the eyelid or to the cul de sac, appeared about 50 years ago. Gelatin films containing atropine were first described in the British Pharmacopeia in 1948 [56]. Ocular films have a series of advantages over the liquid DDS traditionally used in ophthalmology at that time, namely, the prolonged retention time and the long elimination halflife, the precision of dosage, and increased stability. However, the ophthalmological delivery system Ocusert® (Ocusert®), Alza [57]), approved for use in 1974 and subsequently included in the US Pharmacopeia, was found to have a number of disadvantages in use, including movement across the surface of the eye with resulting irritation, visual blurring, etc. [58]. Thus, despite its positive qualities, the Ocusert® system has not received wide use in the treatment of eye diseases. The use of mucoadhesive polymers (cellulose derivatives, PEG, acrylates, etc. [16]) in ocular films produced additional advantages, as DDS are prevented from moving freely across the surface of the eye, such that irritation and washing from the surface are minimized [10, 59]. Recent studies have demonstrated that ocular films containing thiolated polyacrylic acid, a polymer with good mucoadhesive properties, represent a promising example of solid DDS for ophthalmology [16]. Films used in oral medicine generally have more complex structures and are reminiscent of a “two layer cake:” the mucoadhesive layer makes contact with the mucosa, while the coated surface faces the inside of the oral cavity, which minimizes the release and swallowing of the MS. The polymer base (the mucoadhesive or an additional intermediate layer) modifies the release of the MS [1]. Polymer films have been developed for local application of antimicrobial, antiviral, and analgesic agents: metronidazole [9], acyclovir [55], and lidocaine [12], as well as agents decreasing the symptoms of inflammation, such as triamcinolone acetonide [53] and aprotinin [60]. Two-layer films consisting of mucoadhesive and protective layers and containing oxytocin [61], testosterone [62], and the Russian agent Trinitrolong [63], are examples of buccal mucoadhesive films with systemic actions. In vivo studies of films containing calcitonin (in rabbits) demonstrated that therapeutic doses of calcitonin (a peptide hormone agent) can be delivered via the buccal route [2].

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Mucoadhesive micro- and nanocarriers. Enormous interest in microcapsules and microgranules results from their set of unique properties. Thus, despite restrictions to the content of the packaged MS, which is the main disadvantage of most methods of microencapsulation, mucoadhesive microand nanocarriers produce an enormous area of contact, as compared with other solid MADDS, for the effective absorption of the MS into the bloodstream, giving high bioavailability [41]. Prolonged release of MS, in some cases accompanied by targeted actions [5], provide additional advantages for effective medicinal therapy. Mucoadhesive properties promote the formation of close contact with the mucosal surface, while their small size allows easy penetration into sites with difficult access, uptake, gripping, and holding on uneven mucosal structures (for example, between intestinal villi). In the case of application to the eye surface, micro- and nanocarriers did not produce the sensation of a foreign body or visual blurring [16]. Mucoadhesive microand nanocapsules, as well as microgranules, have been discussed in detail in reviews [5, 8]. Micro- and nanocarriers have been produced using biocompatible polymers (derivatives of cellulose and starch, polyethylene glycol and its copolymers, polyvinyl alcohol, polyvinyl acetate, and hyaluronic acid esters) and biodegradable polymers (polylactates, polyglycolides, poly(lactide-co-glycolides), polycaprolactones, and polyalkylcyanoacrylates), as well as mixtures of polymers and polyelectrolyte complexes [8]. Methods for preparing microcapsules and microgranules have been described in [8, 64, 65]. Many studies have been performed in relation to the use of mucoadhesive micro- and nanocarriers, including investigations of the intranasal administration of desmopressin [37] and insulin [38], the local application of acyclovir in ophthalmology [11], and the oral administration of vincamine [5] and cyclosporin [29]. Studies reported in [66] demonstrated that the increase in the efficacy of antibacterial therapy of gastric ulcers with suspensions of microgranules based on ethylcellulose and carbopol 934 with amoxycillin was due to factors including their mucoadhesive properties. Use of nanocarriers allowed peptides such as calcitonin to be given orally [67]. Intranasal mucoadhesive microspheres based on chitosan, hyaluronic acid, and other polymers swell on making contact with the mucosa, forming gels, increasing the persistence time of the DDS in the nasal cavity and the bioavailability of medicines [15, 36, 38, 47, 48]. Most contemporary studies on the production and investigation of mucoadhesive micro- and nanocarriers are performed in scientific centers and their commercialization is restricted by the complexity of scaling up production from the laboratory to the industrial level. Soft DDS. The advantages of gels as drug delivery systems include the formation of close contact with the mucosal surface and rapid release of the medicinal substance at the application site [10]. The main disadvantage is the inability to control the dose of MS given. Gels therefore have limited application for MS with narrow therapeutic indexes and for

Mucoadhesive Drug Delivery Systems

sites which are difficult to access [10], but are suitable DDS for ophthalmology, oral medicine, and gynecology [6, 16, 19]. Addition of mucoadhesive polymers, generally carbomers, to gels increases efficacy because of the increased persistence time on mucous membranes and the long duration of action [6, 10, 19]. Examples of such mucoadhesive gels are: in ophthalmology - NyoGel® (timolol, Novartis, Switzerland, containing a carbomer and polyvinyl alcohol) and Pilogel® (pilocarpine hydrochloride, Alcon Laboratories, Switzerland, containing carbopol 940); in oral medicine - the gel Corsodyl Dental (chlorhexidine gluconate, containing HPMC, GlaxoSmithKline, UK); in gynecology - Crinone® (Crinone®, Serono, Switzerland), a progesterone formulation, and Zidoval™, 3M, USA), a vaginal gel containing metronidazole; in both cases, the mucoadhesive components are carbomers [23]. Zilactin® gel (Zilactin®, Zila Pharmaceuticals, USA) forms a mucoadhesive gel on use, and this reliably attaches at the application site. It is used for the symptomatic treatment of herpes on the lips and contains benzocaine and lidocaine [10]. Liquid DDS. Liquids supplemented with MAP can be used both as the basis for the subsequent addition of MS and independently - to protect mucosal tissue from harmful influences [10]. Thus, artificial tears used in the treatment of dry eye syndrome, such as Viscotears® (Novartis, Switzerland) consists of a solution of carbomers, which attach to the eye surface and protect the cornea [68]. Xerostomia - increased mouth dryness due to impairments to the secretory functions of the salivary glands - is treated with artificial saliva, which spreads over the mucosal surface and attaches to it, performing a protective function [69]. These solutions contain sodium carboxymethylcellulose as the mucoadhesive polymer (for example, Luborant®, Antigen [10], and Saliveze®, Wyvern, UK [69]). Mucoadhesive liquids are used for the protection of the esophageal mucosa. For example, the sodium alginate present in Gaviscon (Gaviscon Liquid®, Reckitt Benckiser Healthcare, UK) can attach to the surface of the esophageal mucosa for 1 h after use and provides protection in gastric reflux, when regurgitation of acidic contents from the stomach into the esophagus leads to epithelial damage [10]. However, it has been suggested that liquids with mucoadhesive components can also be used as the basis for subsequent administration of MS, for example, in the treatment of local diseases of esophagus, motor dysfunction, fungal infections, and esophageal tumors [10]. Liquids forming gels at the site of application contain polymers characterized by phase transitions and the formation of viscoelastic gels in response to a variety of factors, including temperature, ionic strength, and pH [16]. These properties have been seen with poloxamers, pectin, carbopol, hyaluronic acid, and several other polymers [41]. Solutions of carbomers become more viscous when the pH increases [10]. Smart Hydrogel™ (GelMed, USA) contains Pluronic and polyacrylic acid and forms a gel on heating to body tem-

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perature; it has been suggested that this would be of value for the transmucosal delivery of MS [70]. Gel-forming DDS are presently used in ophthalmology, for example, a formulation based on gellan gum - Timoptol LA® (timolol maleate, Merck, Sharpe, and Dohme, UK) [10]. MADDS with phase transitions are suitable for intranasal use [7]. West Pharmaceuticals have developed a system based on pectin, which is used as a nasal spray; on contacting the mucosa in the nasal cavity, pectin undergoes a transition to form a mucoadhesive gel [71]. The decades since the publication of the first studies on mucoadhesion have seen the accumulation of data on the anatomical structure and biochemistry of mucous membranes, which can be used for modeling the delivery of MS to specific body sites. At the same time, there is no consensus between scientists in relation to the mechanisms of the interaction between materials and components of mucosal tissue. Many studies have addressed the development of MAMF and studies of the efficacy of their use, though here too there remain significant gaps, as there is as yet no generally accepted method for assessing mucoadhesive properties. All these points indicate that the potential of this method is far from exhausted and we can only highlight the rapid development of this field. Mucoadhesion can clearly play a fundamental role as non-parenteral DDS for protein formulations, as well as vaccines able to attach to mucous membranes to stimulate local immunity. Mucoadhesive micro- and nanocarriers in this context are of particular interest to scientists, as they simultaneously resolve the main problems - increasing the stability and bioavailability of MS. REFERENCES 1. R. Birudaraj, R. Mahalingam, X. Li, and B. R. Jasti, Crit. Rev. Ther. Drug Carrier Syst., 3(22), 295 – 330 (2005). 2. Z. Cui and R. J. Mumper, Pharm. Res., 19(12), 1901 – 1906 (2002). 3. E. Gavini, G. Rassu, M. Cossu, and P. Giunchedi, J. Pharm. Phamacol., 57(3), 287 – 294 (2005). 4. H. E. Junginger, J. A. Hoogstraate, and J. C. Verhoef, J. Contr. Rel., 62(1 – 2), 149 – 159 (1999). 5. G. Ponchel and J.-M. Irache, Adv. Drug. Del. Rev., 34(2 – 3), 191 – 219 (1998). 6. N. Salamat-Miller, M. Chittchang, and T. P. Johnston, Adv. Drug. Del. Rev., 57(11), 1666 – 1691 (2005). 7. M. I. Ugwoke, R. U. Agu, N. Verbeke, and R. Kinget, Adv. Drug. Del. Rev., 57(11), 1640 – 1665 (2005). 8. J. K. Vasir, K. Tambwekar, and S. Garg, Int. J. Pharm., 255(1 – 2), 13 – 32 (2003). 9. A. Ahuja, J. Ali, and S. Rahman, Pharmazie, 61(1), 25–29 (2006). 10. H. Batchelor, The Drug Delivery Companies Report: Autumn / Winter 2004, 16 – 19, (2004). 11. I. Genta, B. Conti, P. Perugini, et al., J. Pharm. Pharmacol., 49(8), 737 – 742 (1997). 12. H. Okamoto, H. Taguchi, K. Iida, and K. Danjo, J. Contr. Rel., 77(3), 253 – 260 (2001). 13. J. Van Roey, M. Haxaire, M. Kamya, et al., J. Acquir. Immune Defic. Syndr., 35(2), 144 – 150 (2004).

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