Bioadhesive‐Based Dosage Forms: The Next Generation

MINI-REVIEW Bioadhesive-Based Dosage Forms: The Next Generation JIN WHAN LEE, JAE HAN PARK, JOSEPH R. ROBINSON School of Pharmacy, University of Wisconsin, 425 N. Charter Street, Madison, Wisconsin 53706

Received 2 December 1999; revised 25 February 2000; accepted 15 March 2000

Prolonged contact time of a drug with a body tissue, through the use of a bioadhesive polymer, can significantly improve the performance of many drugs. These improvements range from better treatment of local pathologies to improved drug bioavailability and controlled release to enhanced patient compliance. There are abundant examples in the literature over the past 15 years of these improvements using first generation or “off-the-shelf” bioadhesive polymers. The present mini-review will remind us of the success achieved with these first-generation polymers and focus on proposals for the next-generation polymers and attendant benefits likely to occur with these improved polymeric systems. © 2000 Wiley-Liss, Inc. and the American Pharmaceutical As-

ABSTRACT:

sociation J Pharm Sci 89: 850–866, 2000

INTRODUCTION Since the early 1980s, there has been renewed interest in the use of bioadhesive polymers to prolong contact time in the various mucosal routes of drug administration. The ability to maintain a delivery system at a particular location for an extended period of time has great appeal for both local disease treatment as well as systemic drug bioavailability. Normal contact time for mucosal routes of drug delivery ranges from a few minutes for the front of the eye to ∼3 h for the small intestine, with intermediate times for the other routes, thereby resulting in a significant barrier to drug delivery. A strong catalyst in the use of bioadhesive polymers was the pioneering work of Nagai,1 in the late 1970s through early 1980s, who showed that

Correspondence to: J.R. Robinson (Telephone: 608-2627968; fax: 608-262-4054; e-mail: jrrobinson@pharmacy. wisc.edu) Journal of Pharmaceutical Sciences, Vol. 89, 850–866 (2000) © 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association

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aphthae (canker sore) could be better treated locally with an antiinflammatory steroid if a bioadhesive polymer was used. In addition, he showed that cervical cancer could be treated locally, and nasal delivery of a peptide had much better bioavailability when used with a bioadhesive.2 The term bioadhesion,3 defined as attachment of a synthetic or natural macromolecule to mucus and/or an epithelial surface, has been used to describe the phenomenon and to identify the field of inquiry. Early pioneering work2,4–6 on bioadhesive-based drug delivery used nonspecific, “offthe-shelf” polymers that would be considered safe by regulatory agencies. However, these polymers lacked targeting ability and typically did not possess ideal physicochemical properties for controlled drug delivery. As an alternative to nonspecific adhesion, there were reports of targeting bioadhesives to a specific mucus site using carriers such as poly(N-2-hydroxypropyl methacrylamide)(PHPMAm),7 lectins,8 and fimbrial proteins.9 In spite of the considerable success with current bioadhesive-based dosage forms, there is need of second-generation bioadhesive polymers

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to address several areas of need. Thus, the next generation polymers must: • show bioadhesive properties in both the dry and liquid state; • be able to accommodate both oil- and watersoluble drugs for purpose of controlled drug delivery; • demonstrate local enzyme inhibition and/ or penetration enhancement properties; • show specificity for attachment to an area or cellular site; • show specificity for attachment and stimulate endocytosis; • show specificity for attachment and stimulate release of intracellular cytokines; • possess a wide margin of safety both locally and systemically. Given the relative size limitation of dosage forms, it is preferable that all or most of the characteristics just listed be contained within the same polymer system; that is, the polymers are multifunctional. The present review will examine progress in the field of bioadhesion in terms of understanding how bioadhesive polymers work in drug delivery as well as the growing application of these specialized polymers to drug delivery in every route of drug administration. Finally, we offer our opinion on the nature of the next generation of bioadhesives.

TYPES AND PROPERTIES OF CURRENT BIOADHESIVE POLYMERS Many types of forces can be used to anchor a polymer to a mucus and/or a tissue surface as shown in Table 1. Covalent forces are suitable provided the polymeric material is not toxic to the tissue. More likely polymer candidates will be those that are capable of either weak polar or electrostatic interactions. Undoubtedly, the ultimate force for

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any polymeric material attached to a tissue will be a combination of forces including hydrophilic and hydrophobic. It is also clear that strong interactions between chemical groups on the polymer and the mucus/tissue are needed to keep the dosage form in contact with the tissue for an extended period of time. Many bioadhesives are made of either synthetic or natural polymers. Most of the current synthetic bioadhesive polymers are either polyacrylic acid or cellulose derivatives. Examples of polyacrylic acid-based polymers are carbopol, polycarbophil, polyacrylic acid (PAAc), polyacrylate, poly(methylvinylether-co-methacrylic) acid, poly(2-hydroxyethyl methacrylate), poly(methacrylate), poly(alkylcyanoacrylate), poly(isohexylcyanoacrylate), and poly(isobutylcyanoacrylate). Cellulosics include carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, and methylhydroxyethyl cellulose. In addition, (semi)natural bioadhesive polymers include chitosan and various gums such as guar, xanthan, gellan, carrageenan, pectin, and alginate. Finally, PHPMAm, poly(vinylpyrrolidone), and poly(vinylalcohol) can be included as synthetic bioadhesive polymers. In a more functional type of classification, bioadhesive polymers can be grouped into (1) watersoluble, which are typically linear or random (e.g., PAAc) and (2) water-insoluble, which are commonly a swellable network formed by covalent or ionic bonds via a crosslinking agent (e.g., polycarbophil). In the case of water-soluble polymers, the duration of residence time on tissue surfaces is based on dissolution rate of the polymer. In contrast, cross-linked polymers, given their lack of solubility in common solvents, have a residence time based on the rate of mucus/tissue turnover. Structural units of some commonly used bioadhesive polymers are shown in Figure 1. In addition, some properties and characteristics of bioadhesive polymers are described in Table 2.10–13 Choice of a particular polymer type, and perhaps specific polymer, will depend on a number of formulation issues as well as patent status.

Table 1. Potential Bioadhesive Forces Type of Force Covalent Hydrogen bond Electrostatic interaction

Example Cyanoacrylate Carbopol, polycarbophil, acrylates Chitosan

MECHANISM OF ATTACHMENT OF POLYMERS TO MUCUS/TISSUE SURFACES Mechanisms of Bioadhesion A complete understanding of how and why certain macromolecules attach to a mucosal tissue JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 7, JULY 2000

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Figure 1. Structures of some common bioadhesive polymers (I: polyacrylic acid derivatives; II: chitosans; III: cellulose derivatives).

surface is not yet available but certain elements of the process are clear.14,15 • The bioadhesive must spread over the substrate to initiate intimate contact and to increase the surface area of contact. • Chains of the adhesive can interdiffuse into the mucus substrate to create a greater area of contact. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 7, JULY 2000

• Forces of attraction and repulsion develop and, for successful bioadhesives, the attractive forces dominates. Each of these steps can be facilitated by the nature of the dosage form and how it is applied. Thus, an increase in applied pressure will contribute to intimate contact by causing viscoelastic deformation at the interface. Moreover, a par-

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Table 2. Some Bioadhesive Polymers and Their Properties Propertiesa

Bioadhesives Polycarbophil (polyacrylic acid crosslinked with divinyl glycol)

Characteristics

● synthesized by lightly cross● Mw 2.2 × 105 linking of divinyl glycol ● ␩ 2000–22,500 cps (1% aq. soln.) ● swellable depending on pH, but ● ␬ 15–35 mL/g in acidic media insoluble in water (pH 1–3) 100 mL/g in neutral ● entangle the polymer with mucus and basic media on the surface of the tissue ● ␾ viscous colloid in cold water ● hydrogen bonding between the nonionized carboxylic acid and mucin

Carbopol/carbomer ● Mw 1 × 106–4 × 106 (carboxy polymethylene) ● ␩ 29,400–39,400 cps at 25 °C with 0.5% aq. soln. ● ␳ 5 g/cm3 in bulk ● pH 2.5–3.0 ● ␾ water, alcohol, glycerin

Reference 10

● synthesized by cross-linker of allyl sucrose or allyl pentaerythritol ● excellent thickening, emulsifying, suspending, gelling agent ● common component in bioadhesive dosage forms

11

● sodium salt of a polycarboxymethyl ether of cellulose ● emulsifying, gelling, binding agent ● good bioadhesive strength

12

Sodium carboxymethyl cellulose (cellulose carboxymethyl ether sodium salt)

● ● ● ● ●

Hydroxypropylcellulose (cellulose 2hydroxypropyl ether)

● Mw 6 × 104–1 × 106 ● ␩ 4000–6500 cps with 2.0% aq. soln. ● ␳ 0.5 g/cm3 in bulk ● pH 5.0–8.0 ● ␾ soluble in water below 38 °C, ethanol

● partially substituted polyhydroxypropylether of cellulose ● granulating and film coating agent for tablet ● thickening agent, emulsion stabilizer, suspending agent in oral and topical liquid soln. or suspension formulation

13

Hydroxypropylmethyl cellulose (cellulose 2hydroxypropylmethyl ether)

● Mw 8.6 × 104 ● ␩ 15–4000 cps (2% aq. soln.) ● ␾ cold water

● mixed alkyl hydroxyalkyl cellulosic ether ● suspending, viscosity-increasing and film-forming agent ● tablet binder and adhesive ointment ingredient

11

Hydroxyethylcellulose

● ␳ 0.6 g/mL ● pH 6–8.5

● used as suspending or viscosityincreasing agent ● binder, film former, thickener

11

Alginate

● pH 7.2 ● ␩ 20–400 cps (1% aq. soln.) ● ␾ water

● stabilizer in emulsion, suspending agent, tablet disintegrant, tablet binder

12

Mw 9 × 104–7 × 105 ␩ 1200 cps with 1.0% soln. ␳ 0.75 g/cm3 in bulk pH 6.5–8.5 ␾ water

a ␩: Viscosity; ␳: density; Mw: molecular weight; pH measured at 1.0% aqueous solution (aq. soln.); ␬: absorption measured at water; ␾: soluble solvent.

tially hydrated polymer will be drawn to the substrate surface by attracting water from the surface. A more complete and comprehensive bioadhe-

sion theory that predicts adhesions based on the chemical or physical nature of a particular polymer is not yet available. However, there are four classic theories of bioadhesion. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 7, JULY 2000

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Electronic Theory16 The adhesive polymer and mucus typically have different electronic characteristics. When these two surfaces come in contact, a double layer of electrical charge forms at the interface, and then adhesion develops due to the attractive force from electron transfer across the electrical double layer.

Adsorption Theory17,18 In the adsorption theory, a bioadhesive polymer adheres to mucus because of secondary surface forces such as van der Waals forces, hydrogen bonds, or hydrophobic interactions.19 For a bioadhesive polymer with a carboxyl group, hydrogen bonding is considered to be the dominant force at the interface. On the other hand, hydrophobic interactions can explain the fact that a bioadhesive may bind to a hydrophobic substrate more tightly than to a hydrophilic surface.

ing a tensile test measure of adhesiveness (i.e., detachment strength between the bioadhesive and substrate). Although a precise understanding of structural features and bioadhesion is at present absent, it is possible to make some generalizations. 1. Nonionic polymers appear to be inferior to charged type polymers. This is probably an erroneous conclusion because it is likely to be the number of hydrogen bonding groups rather than fixed charge that is important. 2. Polymer blends, such as polycarbophil and daichitosan can combine attributes of different polymers to give a superior bioadhesive. 3. There can be considerable differences in detachment force within a group of polymers depending on molecular weight and purity. The adhesiveness of a bioadhesive polymer is de-

20

Wetting Theory

Primarily applicable to liquid bioadhesive systems, the wetting theory emphasizes the intimate contact between the adhesive and mucus. Thus, a wetted surface is controlled by structural similarity, degree of cross-linking of the adhesive polymer, or use of a surfactant.

Table 3. Detachment Strength of Various Bioadhesive Polymers26

Type Cationic

Diffusion Theory21–23 The essence of this theory is that chains of the adhesive and the substrate interpenetrate one another to a sufficient depth to create a semipermanent adhesive bond. The penetration rate depends on the diffusion coefficients of both interacting polymers, and the diffusion coefficient is known to depend on molecular weight and crosslinking density. In addition, segment mobility, flexibility of the bioadhesive polymer, mucus glycoprotein, and the expanded nature of both networks are important parameters that need to be considered. These general theories are not particularly useful in establishing a mechanistic base to modern bioadhesives but they do identify variables that are important to the bioadhesive process. Additional comments on mechanism of attachment will be given later. Factors Influencing Bioadhesive Properties Table 3 provides some comparative data on bioadhesive strengths for a variety of chemicals usJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 7, JULY 2000

Nonionic

Anionic

Bioadhesive polymer Chitosan (Wella ‘low viscosity’) Chitosan (Wella ‘high viscosity’) Chitosan (Dr. Knapczyk) Daichitosan Daichitosan Sea Cure 240 Sea Cure 210+ Chitosan (Sigma) Polycarbophil/ Daichitosan VH blend DEAE-dextran Aminodextran Scleroglucan HE-starch HPC CMC (low viscosity) CMC (medium viscosity) CMC (high viscosity) Pectin Xanthan gum Polycarbophil

Force of detachment (mN/cm2)

SD

3.9

(1.2)

6.7

(0.7)

5.7

(1.1)

8.0 9.5 4.1 9.5 6.6 11.9

(5.7) (2.4) (2.9) (2.5) (3.0) (2.5)

0 0 2.8 0.6 0 1.8 0.3 1.3 0 0 17.6

(2.8) (0.8) (1.1) (0.3) (1.0)

(3.6)

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termined by its intrinsic polymeric properties and the environment in which it is placed and is influenced by many factors.24,25

Bioadhesive Polymer-Related Factors Molecular Weight. The optimum molecular weight for maximum bioadhesion depends on the type of bioadhesive polymer at issue. It is generally understood that the threshold required for successful bioadhesion is at least 100,000 molecular weight. For example, polyethylene glycol (PEG), with a molecular weight of 20,000, has little adhesive character, whereas PEG with 200,000 molecular weight has improved, and a PEG with 400,000 has superior adhesive properties. The fact that bioadhesiveness improves with increasing molecular weight for linear polymers implies two things: (1) interpenetration is more critical for lower molecular weight polymers to be a good bioadhesive, and (2) entanglement is important for higher molecular weight polymers. Adhesiveness of a nonlinear structure, by comparison, follows a quite different trend. The adhesive strength of dextran, with a very high molecular weight of 19,500,000, is similar to that of PEG, with a molecular weight of 200,000. The reason for this similarity may be that the helical conformation of dextran may shield many of the adhesive groups, which are primarily responsible for adhesion, unlike the conformation of PEG.25 Concentration.28 There is an optimum concentration of a bioadhesive polymer to produce maximum bioadhesion.25 In highly concentrated systems, beyond the optimum level, however, the adhesive strength drops significantly because the coiled molecules become separated from the medium so that the chains available for interpenetration become limited. Chain Flexibility.29,30 Chain flexibility is critical for interpenetration and entanglement. As watersoluble polymers become crosslinked, mobility of individual polymer chains decrease and thus the effective length of the chain that can penetrate into the mucus layer decreases, which reduces bioadhesive strength.

Environment-Related Factors pH.4,10,31 pH can influence the formal charge on the surface of mucus as well as certain ionizable bioadhesive polymers. Mucus will have a different

charge density depending on pH due to differences in dissociation of functional groups on the carbohydrate moiety and the amino acids of the polypeptide backbone. Some studies10,31 have shown that the pH of the medium is important for the degree of hydration of cross-linked polyacrylic acid, showing consistently increased hydration from pH 4 through pH 7, and then a decrease as alkalinity and ionic strength increases. For example, polycarbophil does not show a strong bioadhesive property above pH 5 because uncharged, rather than ionized, carboxyl groups react with mucin molecules, presumably through numerous hydrogen bonds. However, at higher pH, the chains are fully extended due to electrostatic repulsion of the carboxylate anions. Initial Contact Time.32 Contact time between the bioadhesive and mucus layer determines the extent of swelling and interpenetration of the bioadhesive polymer chains. Moreover, bioadhesive strength increases as the initial contact time increases. Swelling.27,33 Swelling characteristics are related to the bioadhesive itself and its environment. Swelling depends on the polymer concentration, ionic strength, as well as the presence of water. During the dynamic process of bioadhesion, maximum bioadhesion in vitro occurs with an optimum water content. Overhydration results in the formation of a wet slippery mucilage without adhesion. The results of water transfer studies on dry and gel dosage forms are described in Table 4. Physiological Variables (e.g., Mucin Properties, Turnover, and Disease States).35 In many routes of administration, surface mucus is encountered by the bioadhesive before it reaches the tissue.

Table 4. Water Uptake by Dry and Gel Dosage Forms over 1 Min (n ⳱ 3)34

Sample Carbopol 934 (C934) Polycarbophil (Carbopol EX55) Gelatin Hydroxypropylcellulose (Mw 1 × 106) Carbopol 934 25% Gel

Weight gain (mg/cm2)

(SD)

2.28 1.53 0.75

(0.34) (0.16) (0.08)

0.68 4.50

(0.08) (0.59)

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The extent of interaction between the polymer and the mucus depends on mucus viscosity, degree of entanglement, and water content. How long the bioadhesive remains at the site depends on whether the polymer is soluble or insoluble in water and the associated turnover rate of mucin. Estimates of mucin turnover vary widely, depending on location and method of measurement. Values ranging from a few hours to a day have been reported. However, residence time of bioadhesives that are thought to attach to mucin are typically longer than the reported mucin turnover, suggesting that the presence of a bioadhesive polymer on mucin may alter the turnover of this biopolymer. A tentative goal of a bioadhesive, whether it sticks to mucin or to an epithelial surface is to remain in place long enough for once daily dosing. It is not known what influence certain disease states have on bioadhesive retention, and this is an area requiring additional investigations. Test Methods Used to Study Bioadhesion To date, most of the available information on bioadhesives has come from in vitro experimentation. In vivo techniques represent the ultimate test for bioadhesives that appear promising from initial screening using in vitro techniques.

In Vitro Methods In vitro tests were initially designed to screen potential bioadhesives with a view to in vivo testing, if successful. Presently, more emphasis is being placed on elucidating the precise mechanisms of bioadhesion because an evaluation of bioadhesive properties is fundamental to the development of new bioadhesives. The most commonly employed in vitro techniques are adhesive strength,26 perfusion wash technique,36 and rheological test.37

In Vivo Methods The three main in vivo techniques to monitor bioadhesion include gamma scintigraphy,38 isolated loop techniques,35,39 and transit studies with radiolabeled or fluorescent coupled dosage forms.10,40 In summary, some of the polymeric structural characteristics necessary for bioadhesion can be summarized as follows: (1) strong hydrogen bonding groups, (2) strong anionic or cationic charges, (3) high molecular weight, (4) chain flexibility, and (5) surface energy properties favoring spreading onto mucus.5 The latter three features appear JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 7, JULY 2000

to be important in light of more recent work on mechanism of bioadhesion.41,42 For example, Mathiowitz et al.43 showed that with the bioerodible and bioadhesive chitosan, bioadhesion lacking chain flexibility could be a result of surface energy effects and/or hydrogen bonding between mucin and carboxyl groups of the bioadhesive. Chain flexibility and interpenetration of polymer and mucin chains should not be considered as sole prerequisites for bioadhesion. Lehr et al.41 reported on attempts to measure and match the surface energy parameters of the substrate mucosa and adhesive in relevant physiological fluids. They reported that the mismatch in surface polarities between substrate and adhesive, calculated from contact angle date, followed the measured adhesive performance. Subsequently Lehr et al.42 introduced a single term, the combined spreading coefficient, which combines the polymer spreading coefficient and Griffith fracture energy, to predict measured mucoadhesive performance under various experimental conditions. Correct predictions were obtained, and it was therefore concluded that the formation of a mucoadhesive bond is controlled primarily by surface energy effects and spreading processes. Esposito et al.44 reported that by calculation of surface energy of the materials at issue, both mucoadhesion and biocompatibility could be predicted. Another attempt to predict bioadhesive performance was reported by Mathiowitz et al.43 In this work, a microbalance was modified to behave as a microtensiometer and via software determined such features as a compressive deformation, peak compressive load, compressive work, yield point, etc.. Of the 11 parameters studied, the authors reported that fracture strength, deformation to failure, and tensile work give direct predictions of bioadhesive potential.

CELL RESPONSIVE BIOADHESIVES Earlier work by Florence45 had established oral translocation of nanoparticles through normal intestinal cells. Subsequent work by Mathiowitz46 continued this work and showed significant uptake of small particles with bioadhesive particles. More recent work by Florence47 has established that latex nanoparticles coupled to tomato lectin significantly enhanced oral uptake of these particles. In addition, they48 have coupled a bacterial outer membrane protein, from an organism ca-

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pable of penetrating epithelia, to latex nanoparticles and observed substantial uptake into cultured cells. Witschi and Mrsny49 reported that certain bioadhesives, in contact with nasal epithelia, can be biocompatible with the tissue because they induce release of cytokines. This type of cell communication opens up considerable possibilities for future use.

MULTIFUNCTIONAL POLYMERS Modern pharmaceutical formulations may require a number of additives to carry out the complex activities of a good drug delivery system. Thus, it may be necessary to solubilize a sparingly soluble drug, enhance the permeability of the drug across a biological membrane, have the dosage form adhere to a particular site, etc. Each of these functions is over and above the normal roles of formulation additives. Clearly, addition of a separate agent for each of these functions would generate a very large dosage form, and therefore it has become necessary to generate polymeric material with multiple functions. PAAc derivatives have been identified as inhibitors of certain proteolytic enzymes. It was reported50–52 that polycarbophil and other carbomers inhibited the formation of N-␣-benzoyl arginine ethylester by trypsin, probably because of complexation of calcium ion as an essential cofactor for proteolytic activity. Trypsin inhibition by these bioadhesives was prominent at neutral pH, but cellulose and chitosan as control agents did not show such an effect. For penetration enhancement, it was shown that the interaction between various types of bioadhesive polymers and epithelial cells has a direct influence on permeability of the tissue. In this way the transport of large and hydrophilic molecules across an epithelial barrier can be enhanced.53 This enhancement is presumably due to the fact54 that the epithelial mucosa is dehydrated in the presence of dry dextran–starch microspheres, leading to a reversible shrinkage of the cells, which ultimately leads to a physical separation of the intercellular junctions. In contrast, bioadhesive polymers that were applied as an aqueous gel or solution55–57 had a different biological effect on epithelial cells than that exerted by the hydrated polymers. Both mechanisms of penetration enhancement await further clarification.

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Lastly, phase change polymers show continuous or discontinuous changes in properties in response to external stimuli such as pH, temperature, specific ions, or other chemicals. Thus, certain bioadhesive polymers that undergo a phase change (i.e., from a liquid to a semisolid) have also been studied because the accompanying viscosity change results in sustained and controlled release of drug.58 Separating the contribution of phase change and/or bioadhesion to prolonged residence time has not yet been accomplished. These approaches are conceptually easy, but considerably more complex to commercialize. Poloxamer 407,59 sodium carboxymethylcellulose,60 carbopol,61 hyaluronic acid,62 or xanthan gum63 has each been reported to be a phase-change polymer.

TARGETED BIOADHESIVE POLYMERS Lectins Rapid mucus turnover and coating of bioadhesive dosage forms by soluble mucin at the site of administration have been problematic. To overcome these barriers and simultaneously provide targeting capability, new approaches not based on classic bioadhesive polymers, but on lectin–sugar interactions have been suggested.8 The name lectin (Latin: legere ⳱ to select) originally described plant extracts capable of agglutinating red blood cells and was found in plants, vertebrates, bacteria, or invertebrates.64 Lectins are defined as proteins or glycoproteins of a nonimmunoglobulin nature capable of specific recognition and of reversible binding to carbohydrate moieties of complex glycoconjugates, without altering the covalent structure of any of the recognized glycosyl ligands.65 Based on their specificity, the following five carbohydrate groups can be distinguished: N-acetylgalactosamine (11.36% of w/w of carbohydrate chain), Nacetylglucosamine (31.82%), galactose (32.95%), fructose (21.95%), and sialic acid (2.27%). Thus, these carbohydrates with mucus glycoproteins form the chief components of the mucus gel layer either at the surface of the epithelial cells or in the mucus layer.66 Plant lectins, likewise, can be classified into four classes based on the different configuration of their 3- and 4-hydroxyl groups, as shown in Figure 2. Among these configurations, group III has been most intensively investigated. Wheat germ agglutinin, potatoes, tomatoes, stinging nettle, and leguminosae are in the diverse group JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 7, JULY 2000

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an efficient means to enhance adhesion of particulate drug carriers or hydrogels to epithelial surfaces. Poly-N-2-Hydroxypropyl methacrylamide Figure 2. Classification of lectins according to the configuration of C-3 or C-4 OH group at the pyranose ring of specifically binding sugars.71

of N-acetylglucosamine-binding lectins that belong to group III. These lectins are dimeric glycoproteins, composed of two different subunits, A and B, linked by a disulfide bridge, where chain A functions primarily for toxicity and chain B is responsible for adhesion and cell entry. A 60–90 kDa membrane glycoprotein was reported to interact with tomato lectin in the stomach. Phaseolus vulgaris lectin was found to bind to the noncrypt regions of villi in the proximal region of rat small intestine but not to the brush border region of the ileal villi.69 Furthermore, it was reported that M-cells, which constitute an interesting target for lectin– nanoparticle conjugates because of their high pinocytotic and endocytotic activity, are possible sites for lectin attachment.70 Later, cytoadhesion theory, in contrast to nonspecific bioadhesion, was proposed by Lehr et al. for this class of bioadhesives.71 The ability to specifically bind to membrane-bound sugar moieties located on the cell surface of epithelial cells and to resist digestion within the gastrointestinal (GI) tract has continued the interest of pharmaceutical scientists even though the exact physiological role of lectins is unknown. Therefore, lectins continue to be considered as potential bioadhesives and drugtargeting agents.72 Fimbrial Proteins “Bacteria are able to adhere to epithelial surfaces of the GI tract with the aid of fimbriae.”73 Fimbriae are long, lectin-like proteins found on the surface of many bacterial strains. The presence of fimbriae has been found to be correlated with pathogenicity; for example, adherence of Escherichiacoli to the brush border of the epithelial cell mediated by K99-fimbriae is a prerequisite for the subsequent production and uptake of the E. coli enterotoxin. Therefore, drug-delivery systems based on bacterial adhesion factors could be JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 7, JULY 2000

Water-soluble and bioadhesive PHPMAm polymeric drug carriers for targeting to the colon have been studied by Kopecek et al.74 It is understood that a number of recognition systems for terminal sugars on carbohydrate chains of glycoproteins operate in living organisms. Consequently, PHPMAm has been synthesized with pendant carbohydrate groups to exploit the natural recognition systems for delivery of drugs into cells with specificity for these carbohydrate moieties.

BIOADHESIVE DOSAGE FORM APPLICATION Gastrointestinal There is no doubt that the oral route is the most favored and probably most complex route of drug delivery. Critical barriers,75–77 such as mucus covering the GI epithelia, high turnover rate of mucus, variable range of pH, transit time with broad spectrum, absorption barrier, degradation during absorption, hepatic first-pass metabolism, rapid luminal enzymatic degradation, longer time to achieve therapeutic blood levels, and inter- and intrasubject variability, are all possible issues with the oral route. The idea of bioadhesives began with the clear need to localize a drug at a certain site in the GI tract. Therefore, a primary objective11 of using bioadhesive systems orally would be achieved by obtaining a substantial increase in residence time of the drug for local drug effect and to permit once-daily dosing. Robinson et al.4 studied the bioadhesive properties of a broad spectrum of polymers. His group78 also reported that albumin beads containing chlorthiazide mixed with polycarbophil offered sustained release for 8 h after being administered orally in the form of capsules to rats. Although these materials have shown good bioadhesion in vitro and in vivo in the rat, results in humans were disappointing79 because of two problems; one is that the bioadhesive formulation must attach to the surface of the mucus layer, which is itself a continuously eroding surface, without adhering to and becoming coated with soluble luminal mucus, the other is that the de-

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livery system must withstand motility of the GI tract, which is highly efficient at transiting ingested materials and preventing adhesions such as this from forming. A number of bioadhesive based dosage forms including sustained-release tablets, semisolid forms, powders, and micro- and/or nanoparticles in the GI tract have been widely studied. Nonetheless, successful systems which will be retained in the GI tract of humans for a desirable time have not yet been developed.80,81 As an alternative, lectin systems, 47,71,82 PHPMAm systems, and bioadhesive–inhibitor conjugate systems52,83,84 have been studied for specific bioadhesion as described in an earlier section as to why and the relevant mechanism. Several dosage forms for oral use have been reported: • Tablets: Multilayered tablet allows a variety of geometrical arrangement. Such systems that consist of acrylic polymers or cellulose provide immediate and high adhesion strength at a certain site for a prolonged period of time.85 • Micro- and/or Nanoparticles: Despite the limited loading capacity of drug, bioadhesive micro- and/or nanoparticles have been widely investigated for three major features: (1)immobilization of particles on the mucosal surface by adhesion after modification of surface properties via bioadhesive polymers, (2) very large specific surface between the dosage form and the oral mucosa, and (3)sustained release of entrapped drug, leading to higher absorption.36 • Capsules: Capsules, usually gelatin capsules containing a suspension or liquid, include bioadhesive polymers such as polycarbophil or carbopol. Gelatin interacts with the bioadhesive polymer during or following dissolution, and thus bioadhesiveness of the polymer is lost before the bioadhesive polymer has a chance to interact with the mucus layer.86 Oral cavity The small total surface area of ∼50 cm2, the relatively low permeability of buccal tissues, and a typically short residence time of <5–10 min are considered as significant disadvantages to using the oral cavity for drug delivery. In spite of these barriers, the buccal and sublingual routes are

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considered attractive for drug delivery for a variety of reasons. First, these routes avoid first-pass metabolism. Second, these regions consist of a nonkeratinized epithelium, resulting in a somewhat more permeable tissue than the skin. Third, these regions are very suitable for a bioadhesive system because of a smooth and relatively immobile surface and accessibility. Therefore, drugs with a short biological halflife, requiring a sustained-release effect, and exhibiting poor permeability, sensitivity to enzymatic degradation, or poor solubility may be good candidates to deliver via the oral cavity. Relevant bioadhesive dosage forms for the oral cavity include gels, patches, tablets, and ointments:87–91 • Gels: Using gel-forming polymers such as PAAc derivatives allows sustained release and improved bioavailability compared with solutions. Nagai et al.92 formulated a highly viscous gel containing carbopol and hydroxypropyl cellulose for ointment dosage forms that were maintained on the tissue for up to 8 h. • Patches: To overcome the drawback of tablets, flexible patches for use in the mouth have been developed. Erodible and nonerodible adhesive films have been used as bioadhesive patches. These adhesive patches for oral mucosal delivery can be used to design uni- or bidirectional systems for buccal tissue absorption. Robinson et al.93 showed that a three-layer buccal patch, composed of an impermeable backing membrane, a ratelimiting middle membrane, and a basement membrane containing polycarbophil, can remain in place for up to 15 h in humans regardless of eating or drinking. • Tablets: Adhesive tablets provide a platform for the drug to remain on the tongue, or other oral cavity tissue, for at least 30 min, leading to higher local drug levels than that from existing ointment dosage forms. Ahuja et al.94 showed that tablets of triamcinolone acetonide, prepared using mixed bioadhesive polymers such as carbopol-934P and sodium carboxymethyl cellulose along with excipients like mannitol and PEG-6000, eroded completely after providing 79.08 % of drug release for 8 h in vitro, and reported no adverse local effects. • Ointments: Bioadhesive ointments have not been reported on as extensively as tablets or patches.1 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 7, JULY 2000

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Ocular There are two major surface tissues of the eye, the conjunctiva and cornea, that interface with the outside world. The conjunctiva is a thin tissue that extends from the edge of the eyelid and across the globe of the eye to the cornea. The cornea is the window of the eye and is the transparent tissue in the center of the globe surface. Mucin is secreted by conjunctival goblet cells but there are no goblet cells on the cornea. On this basis, a bioadhesive polymer will firmly attach to conjunctival mucus but only loosely, if at all, to corneal mucus.95,96 Turnover rate of the mucin is ∼15–20 h, whereas normal tear turnover time is ∼16 %/min in humans except during sleeping or anesthesia. Obviously, attaching a polymer to mucin will considerably slow removal of ocular drug delivery systems from the front of the eye. Ophthalmic dosage forms can be improved by increasing the time the active ingredients remain in contact with eye tissues. There are several bioadhesive dosage forms that have been developed to this end; liquid systems, in situ gelling systems, dispersed systems, and solid systems:98–104 • Liquid systems: Mostly solutions or suspensions include bioadhesive polymers as described earlier.105 • In situ gelling systems: Administered in liquid form, these products gel or solidify in the conjunctival folds. This phase change transition can be affected by a change in pH, temperature, ionic strength, or specific ions.106,107 • Dispersed systems: Because of their low viscosity, these colloidal systems using nanoparticles can be used as eye drops with the advantage of a drug reservoir. In fact, encapsulation of drugs in these systems is related to an increase of drug concentration in ocular tissues.108,109 • Solid systems: Ocular inserts are defined as solid or semisolid sterile preparations. With an optimum size and shape, these can be designed to be placed in the conjunctional pocket to deliver drugs for topical or systemic effects. The inserts based on bioadhesive polymers form a homogeneous viscous solution, providing higher drug levels in ocular tissues.103 Nasal Histologically, the nasal mucosa provides a potentially good route for systemic drug delivery. With JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 7, JULY 2000

a surface area of 150 cm2, a highly dense vascular network, and a relatively permeable membrane structure, the nasal route has good absorption potential. Drawbacks are potential local toxicity/irritation, relatively lower permeability for large macromolecules, rapid mucociliary clearance of ∼4–6 mm/min, presence of proteolytic enzymes causing drug degradation in the nasal cavity, limited formulation for changing drug delivery profiles, and the influence of pathological conditions (i.e., colds or allergies).110,111 One of the most important features of the nasal route is that it avoids first-pass hepatic metabolism, thereby reducing metabolism. Bioadhesive application of liquids, semisolids, or solid formulations to the nose has been explored with respect to deposition and retention. In addition, it was reported that combinations of bioadhesive polymers with permeation enhancers would further improve nasal bioavailability:115 • Dry powders: These are less frequently used in the nasal route. Compared with simple solutions, the administration of bioadhesive powders could result in prolonged contact with the nasal mucosa. The use of dry powder formulations, containing bioadhesive polymers for nasal administration of peptides and proteins was first investigated by Nagai et al.112 Water-insoluble cellulose derivatives were mixed with insulin and instilled in dry form in the nose. The product swelled and established a gel form with prolonged residence time in the nasal cavity. • Microspheres: Bioadhesive microspheres are another way of prolonging the residence time in the nasal cavity. Illum et al.113 reported that small volumes of liquid and powder particles have almost the same clearance rate. The addition of bioadhesive excipients such as chitosan results in a decreased clearance rate. • Solutions: For a nasal solution, ionic interactions between the bioadhesives and mucus layer can be used for sustained drug delivery. For example, chitosan has bioadhesive properties most likely mediated by ionic interaction between the positively charged amino groups in chitosan and the negatively charged sialic acid residues in mucus, permitting delivery of insulin for 30 min.

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Vaginal The vagina is a fibrovascular tube connecting the uterus to the exterior of the body. In adults, the length of the vagina varies from 6 to 10 cm, with the posterior wall a ∼1.5–2.0 cm longer than the anterior wall. The vaginal epithelium is a stratified squamous epithelium resting on a lamina propria. The surface area of the vagina is increased by numerous folds in the epithelium and by microridges covering the epithelium cell surface.120 A surface film of moisture consisting primarily of cervical mucus and of fluid exuded from the rich, vascular lamina propria covers the vaginal wall.121 Volume, viscosity, and pH of the cervical mucus vary with age, and hormonal state of the patient that can influence the vaginal drug absorption. The permeability of the vaginal epithelium may vary during estrus or menstrual cycle.11 In general, traditional vaginal dosage forms include solutions, suspensions, gels, microparticles, suppositories, creams, foams, and tablets,121–124 and all have a relatively short contact time. A bioadhesive system for cervical/vaginal drug delivery was used to deliver an anticancer agent in the form of tablets containing hydroxypropyl cellulose and carbopol 934. Studies in vivo showed that, after 5 days of treatment, with a total of 150 mg of bleomycin, in some cases the cancerous lesion had changed to a rough surface due to necrosis and the normal mucosa was unaffected.2 Robinson et al.121 reported on a system treatment, using a gel containing the bioadhesive polycarbophil that remained on vaginal tissue for 3–4 days and hence served as a platform for delivery of drug such as progesterone. In addition, the polymer appears to be an effective delivery system for the spermicidal–antiviral agent nonoxynol-9.

NEXT GENERATION Current use of bioadhesive polymers to increase contact time for a wide variety of drugs and routes of administration has shown dramatic improvement in both specific therapies and the more general patient compliance. Almost all of the commercially useful bioadhesive polymers had other uses and were “drafted” into their use as bioadhesives. The general properties of these polymers for purpose of sustained release of chemicals are marginal in being able to accommodate a wide

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range of physicochemical drug properties. Moreover, when specialty function of these polymers, ranging from tissue permeability enhancement to cell communication, is added on to the basic bioadhesive function, it is clear that multifunctional specialty polymers will be needed. Thus, advanced polymer technology required for comprehensive bioadhesiveness is being worked on as evidenced by the range of hydrophobically modified polymers, star polymers, interpenetrating polymer network, and, more recently, hybrid hydrogel.125–132 In addition, the cellular mechanism of solute transport is sufficiently well understood as to the absorption of various drugs, so that there is now the possibility of targeting drugs to outside or inside the cell of a particular locatin by use of ligand–receptor interactions.71,81,133 Unfortunately it is not yet possible to design a bioadhesive based on specific structural features of a polymer. The more sophisticated screening techniques allow polymer ranking as to bioadhesion, but much more work is needed mechanistically so that specific structure–activity relationships can be predicted.

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