Hydrogels for buccal drug delivery: properties relevant for muco-adhesion

M. E. de Vries* and H. E. Bodd6 Center for Biopharmaceutical Sciences, Division of Pharmaceutical Technology, Gorlaeus Laboratories, P . 0 . Box 9502, 2300 RA Leyden, The Netherlands
H. J. Busscher Laboratory for Materia Technica, Dental School, State University of Groningen, Groningen, The Netherlands H. E. Junginger Center for Biopharmaceutical Sciences, Division of Pharmaceutical Technology, Gorlaeus Laboratories, P.O. Box 9502, 2300 RA Leyden, The Netherlands In order to develop a muco-adhesive hydrogel for buccal drug delivery it is necessary to understand fully the properties determining adhesiveness a s well a s mechanisms involved. In this study we measured glass transition temperatures, water contact angles and the peel- and shear detachment forces from porcine oral mucosa, of acrylic acid and butyl acrylate copolymers. The contact angle maximizes at 50% butyl acrylate content. The glass transition temperature decreases from 0% to 100% butyl acrylate. There seems to exist a certain combination of contact angle and glass transition temperature which is related to adhesiveness. This strongly suggests that, in order to obtain a muco-adhesive hydrogel, at least two properties have to be optimized: (1) the polarity of the polymer surface and (2) the molecular mobility of the polymer groups.

INTRODUCTION

In order to develop a new drug delivery system for metabolically unstable drugs, investigations are being conducted on the buccal route of drug delivery, i.e., the transport route through the oral mucosa into the systemic circulation. Advantages of the buccal drug delivery route over, e.g., the peroral one are the avoidance of both inactivation of drugs by gastrointestinal enzymes, and of hepatic first pass effects, i.e., inactivation of drugs during the first liver passage. Furthermore the buccal route possesses high patient compliance and, given an appropriate adhesive dosage form (i-e., a drug delivery system which adheres to the oral mucosa), the buccal route offers an excellent opportunity for controlled drug delivery. A disadvantage

*To whom correspondence should be addressed.

Journal of Biomedical Materials Research, Vol. 22, 1023-1032 (1988) 01988 John Wiley & Sons, Inc. CCC 0021-9304/88/111023-10$04.00

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of buccal delivery may be the obvious limits imposed on the dimensions of a buccal patch and hence the limited dosage. Therefore buccal delivery will be especially suitable for highly potent drugs, e.g., peptides. One example of a buccal delivery system consists of an adhesive polymer layer, a reservoir polymeric layer, and an impermeable backing. Such a multilaminated system will need to be removed after therapy. Therefore the adhesiveness must be sufficient to prevent detachment, but on the other hand should not be so strong as to damage the mucosa upon removal. Such a film should not cause any irritation and be small and flexible enough to "follow" the movements of the cheek. Hydrogels are suitable candidates for this purpose because of their high flexibility and biocompatibility.'r2 Flexibility, since it reflects molecular mobility, also plays an important role in the process of adhesion itself. Adhesion can be understood as a process that is determined by adsorption of an adherent onto a substrate and, in several cases as for example, in muco-adhesion, by subsequent interpenetration of adherent and substrate into each other.' These phenomena require liquid-like (viscous) properties. Furthermore, the integrity of the adhesive bond can only be upheld in sofar as the adhesive provides mechanical strength and creep resistance.4 This requires that the adhesive also possesses solid-like (elastic) properties. Hydrogels in fact have viscoelastic properties" and thus are suitable as basic materials for muco-adhesive systems. Interpenetration of the hydrogel into the oral mucosa is only possible when the mobility of polymer molecules is high enough. This mobility can be considered to determine the kinetic part of the adhesion process. The thermodynamic aspect of the process deals with adsorption which may be determined by the surface polarity of the hydrogel. This polarity determines whether links can be formed across the hydrogel-mucosa interface; the molecular mobility of the hydrogel determines the actual extent and speed of bonding. Furthermore, it has been shown that adhesive peel strength is mainly governed by rheological energy dissipation in the adhesive. Hence, the molecular mobility also determines the bond strength, in that it determines the extensibility of the adhesive. Glass transition temperatures (T,) can be considered as a measure of molecular mobility inside a hydrogel film. As a measure of surface polarity of the hydrogel, water contact angles ( 0 ) can be taken. Copolymers can be made of acrylic acid, which is polar and has a T, of 86"C, and butyl acrylate, which is apolar and has a T , of -50C. By using different amounts of these monomers, with or without a crosslinker, we are able to vary the T, and surface polarity of the resulting copolymers. Our aim was to investigate the adhesiveness of these hydrogels and see whether a relationship among T,,contact angle, and adhesiveness exists. The crosslinker was introduced to investigate the effect of larger cohesive strength within the hydrogel. Adhesiveness can be measured by performing peel- and shear force measurements on hydrogels bonded to porcine oral mucosa, which can be considered as a satisfactory model of the human oral muc0sa.l

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Copolymer hydrogels were made of acrylic acid (Fluka AG, Buchs) (abbreviated AA) and butyl acrylate (Fluka)(BuAA) in various molar ratios. Polymerization took place in an ethanolic solution at 70C during 22 h. Azo-bis-isobutylonitrile (Polyscience, Warrington) was used as an initiator for the radical polymerization process and ethylene glycol dimethacrylate (Fluka)(EDMA) as a crosslinker (XL), its concentration varying from 0% to 1% of the molar monomer content. Syntheses were carried out in triplicate. After cooling down, the copolymer/ethanol mixtures were cast onto backing material. Upon drying for 48 h at 70"C, strips of 10 X 1.5 cm were cut from these specimens. These strips were used for peel- and shear force measurements. The residual ethanol content upon drying systematically varied from 10.2% to 0.2% w/w going from 90% AA to 60% AA noncrosslinked polymers and it was 5.6% 2.8% w/w in the crosslinked ones. Samples for glass transition temperature and water contact angle measurements were dried a t 100Cfor 48 h in ZJUCUO. The residual ethanol content upon drying systematically varied from 9.9% to 4.4% for the non-crosslinked polymers and from 13.7%to 6.2% for the crosslinked ones (depending on the AA content). Samples with 1% XL were also dried over 72 and 96 h to investigate the influence of drying time on residual ethanol content as well as on T,. On prolonged drying beyond 48 h, sample weights hardly changed. Therefore the residual amounts of ethanol were supposed to be bound and the samples considered to be suitable for measuring. Measurements were carried out in a Mettler TA3000 DSC. Water contact angles were measured at 34C under saturated water vapor upon equilibration of the samples for 30 min, with the help of a computerized a n a l y ~ e rUpon placing a 5 p drop of water of atomic absorption .~ 1 quality on the polymer surface, according to the sessile drop method, the advancing contact angle could be measured instantaneously. All T, and contact angle measurements were carried out in duplicate. The adhesive force was measured in two ways: first an Instron 1122 Test Unit was used for the determination of the peel force on porcine oral mucosa at room temperature (Fig. 1). Upon attaching the hydrogel strip by hand

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Figure 1. Schematic drawing of the peel force test, the adherent being a piece of porcine oral mucosa.

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without using extra force on top of the porcine tissue, it was allowed to set for 15 min before peel force was measured, the angle of peel remaining 90" by moving the sample forward. Shear force measurements were done as follows: a porcine epithelial flap, 5 -f- 1 mm thick, was attached with pins to a vertically placed piece of inelastic material, with the mucosa facing outward. A hydrogel strip was then layed on top of the mucosa surface by applying a 200g force during 1 min, the contact surface area being 1.5 x 4 cm, allowing part of the strip to stick out freely at the bottom end. Pressures much smaller than 200g/6 cm2 lead to insufficient bonding, and much higher pressures seemed to prevent swelling of the hydrogel and thus interpenetration of adherent and substrate. Subsequently, upon attaching a 50-g weight to the bottom end of the test strip, the time needed for the test strip to come off the substrate (the "shear time"), was measured (Fig. 2). The test was performed at 34C and 100% relative humidity. The porcine oral mucosa was obtained from freshly slaughtered pigs and used within 24 h without prior freezing.

shear force

Figure 2. Schematic drawing of the shear time test.

RESULTS

Contact angle and glass transition temperature measurements

In Figure 3 the water contact angles, measured after 1 min, are plotted versus the BuAA mole fraction. A maximum contact angle appears at 50% BuAA for the crosslinked as well as for the non-crosslinked polymers; there is a minimum at 90% BuAA and again a rise in 8 for higher BuAA contents going up to 100%. The crosslinked hydrogels show higher contact angles than their non-crosslinked counterparts, the increase with BuAA fraction being larger with increasing crosslinker content. The accuracy within these measurements is 2 1.5". The glass transition temperature is plotted versus

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Figure 3. Water contact angles, measured 1 minute after a 5 pl drop of Atomic Absorption Quality water was put on the polymer surface.
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Figure 4. Glass transition temperatures measured upon drying the polymer samples for 48 h at 100C and vacuum.

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the BuAA mole fraction in Figure 4. Going from 0% to 100% BuAA there is a pronounced decline. This tendency holds for the crosslinked samples, as well as for the non-crosslinked ones. The crosslinked polymers show higher glass transition temperatures than their non-crosslinked counterparts, the increase again being larger with increasing crosslinker content. Only at very high AA content (90%-100%) this relationship does not seem to exist. However, when these samples are dried more extensively, their T,'s increase accordingly, so that the expected tendency becomes indeed visible (Compare Figs. 4 and 5). In most measurements the deviations of T g were less than 2C. T g measurements among the three synthesized samples were ?3"C.

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Figure 5. Influencc of drying at 100C in w c u o . for an extended period of time, on glass transition temperatures of AA-BuAA copolymers with 1 Mol% XL.

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Peel and shear force measurements

Peel forces are plotted as a function of the BuAA fraction in Figure 6. The adhesiveness of both the crosslinked and non-crosslinked hydrogels tends to decrease with BuAA content increasing from 20% onward (below 20% BuAA no data available), regardless the XL content. The shear force (see Fig. 7) tends to peak around 20% BuAA, then gradually decreases with increasing BuAA content.

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Figure 6 . Peel forces measured at room temperature (20C) a n d normal humidity.

DISCUSSION

Since AA is polar and BuAA is much more apolar one could have expected the contact angle to rise with increasing BuAA fractions. This accounts only for the left-hand part of the curve in Figure 3 and for the 0.9 to 1 BuAA fractions. It is interesting to note, that the contact angle peaks around 40-50% BuAA content (Fig. 3), just about where the glass transition temperature passes through the experimental temperature (Fig. 4). In other words: above 50% BuAA the system becomes rubbery at experimental temperature and the surface properties tend to be strongly influenced by the now much greater molecular mobility. Hence, the contact angle decline with BuAA fractions going from 50% to 90% can be explained by the greater mobility of the polymer molecules at the hydrogel surface; the hydrophilic groups can easily turn outward, thus enlarging the polarity of the surface and decreasing the contact angle. The fact that the contact angle rises again from 90% to 100% BuAA can be explained because there are no or only very few polar groups present. The larger molecular mobility (i.e., flexibility of the hydrogel) at higher BuAA contents is reflected in the glass transition temperature. Because 10070 AA has a much higher glass transition temperature than 100% BuAA it is obvious that intermediate copolymers show intermediate glass transition tempera tures.

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Shear time f r o m p o r c i n e oral mucosa 13LC 100% R H I

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Figure 7. Shear times from porcine oral mucosa, measured at 34C and 100% RH .

Introduction of a crosslinker should result theoretically in a higher Tg. In practice this tendency can indeed be seen but the differences between 0.5% and 1%XL are not as large as expected. This can be explained as follows: the high AA content samples are the most polar ones and bind ethanol very strongly. Drying for only 48 h is not enough to evaporate all ethanol, so these samples are not completely dry when measured and therefore show a relatively low T,. Drying of these (low BuAA) samples over a longer period of time causes a gradual loss of the residual ethanol and an increase in Tguntil at about 72 h, a minimum is reached, as can be seen from Figure 5. The higher the crosslinker content, the stronger ethanol seems to be bound. As could be expected, the influence of XL on the contact angles is more pronounced: EDMA is hydrophobic and therefore decreases the polarity of the hydrogel surface. A polymer film should have a certain molecular mobility to be able to adhere. This implies that the Tgmay not be too high because the polymer has to be in the rubbery state at body temperature rather than in the glass state. The fact that a number of polymers with high T g (0% to 20% BuAA) show good adhesive properties is probably due to the fact that under the circumstances of the shear force measurements (34C and 100% RH) glass transition temperatures are lower, which in turn can be explained by the uptake of water into the polymer. However, a low T, is not the only prerequisite for

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adhesiveness. The data clearly indicate that there has to be a certain optimal number of polar groups to allow for adhesion thermodynamically. This result is partly in agreement with the results of Robinson who claims that 100% AA polymers do adhere the best.8 The applied procedures for shear- and peel force measurements not only probe molecular mobility and surface structure but also the internal strength of the polymer film. It should be stressed here that the bond strength is greatly influenced by the rheological properties of the adhesive. Hydrogels with low Tg are less coherent at test temperature and are pulled apart easily. Therefore the resulting shear time is less than would be expected from surface adhesion alone. The crosslinked samples show a relatively longer shear time because of their larger internal cohesion.
CONCLUSIONS

In developing muco-adhesive hydrogel films for buccal drug delivery a number of considerations should be made. First, the choice of basic components will have to meet requirements dealing with both surface polarity and molecular mobility of the polymer. In the polyacrylate systems studied, these considerations lead to an optimal range of AA/BuAA ratios. It should be kept in mind that most of the data were obtained from thoroughly dried systems. It can be expected that the presence of water may have an influence on these results. This will be dealt with in a following publication. Furthermore, the internal cohesion is an important factor, which can be controlled by varying the degree of crosslinking. The combination of glass transition temperature measurements, contact angle measurements, and adhesive force tests offers a solid basis for assessing the abovementioned properties and their interdependence.
We thank Fasson (Turnhout, Belgium) for letting us use their Instron Test Unit and the department of Materia Technica (State University, Groningen) where a computerized analyzer for contact angle measurements was put at our disposal.

References
1. W.E. Roorda, H.E. BoddC, A.G. de Boer, J.A. Bouwstra, and H.E. Junginger, Synthetic hydrogels as drug delivery systems, Pharm. Weekbl.; Sc. Ed., 8, 165-189 (1986). 2. H. P. Merkle, R. Anders, J. Sandow, and W. Schurr, Drug delivery o f peptides: the buccal route, in Deliz7ery Systems for Peptide Drugs, E. Tomlinson and S. S. Davis (Eds.), Plenum Press, New York, 1986, pp. 159-175. 3. N. A. Peppas and P. A. Buri, Surface, interfacial and molecular aspects of polymer bioadhesion on soft tissues, I. Contr. Rel., 2, 257-275 (1985). 4. E. H. Andrews, T. A. Khan, J. K. Rieke, and J. F. Rudd, Adhesion to skin 1 1 Glass transition temperatures of surgical adhesives with added 1. sebum, Clin. Mat., 1 205-213 (1986). ,

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5. W.E. Roorda, J . A . Bouwstra, M.A. de Vries, and H.E. Junginger, Thermal analysis of pHEMA gels, Biornaterials, accepted. 6. P. Collins, J. Laffoon, and C. A. Squier, Comparative structure of porcine oral epithelium, 1. Dent. Res., 60, 933 (abstract) (1981). 7. H. J. Busscher, Surface free energies and the adhesion of oral bacteria, Thesis, Groningen, 1985, pp. 41-46. 8. J. R. Robinson, Bioadhesive compositions and methods of treatment therewith, Intern. Patent Class. AOlN 25/26, 25/34 (1985).

Received October 27, 1987 Accepted April 12, 1988