Physical–mechanical, moisture absorption and bioadhesive properties of hydroxypropylcellulose hot-melt extruded films

Biomaterials 21 (2000) 1509}1517

Physical}mechanical, moisture absorption and bioadhesive properties of hydroxypropylcellulose hot-melt extruded "lms Michael A. Repka*, James W. McGinity College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA Received 12 November 1999; accepted 31 January 2000

Abstract The objective of this study was to investigate the moisture absorption, physical}mechanical and bioadhesive properties of hot-melt extruded hydroxypropylcellulose (HPC) "lms containing polymer additives. These additives included polyethylene glycol (PEG) 5%, polycarbophil 5%, carbomer 5%, Eudragit E-100 5%, and sodium starch glycolate (SSG) 5%. Relative humidity (RH) and temperature parameters of the "lms studied included 253C at 0, 50, 80 and 100% RH, and 403C at 0 and 100% RH, stored for 2 weeks. Tensile strength and percent elongation were determined on an Instron according to the ASTM standards. The bioadhesive properties of the HPC/PEG 3350 5% "lm and the polycarbophil 5% containing "lms, with and without PEG, were investigated in vivo on the human epidermis. Although all "lms studied exhibited an increase in percent water content as the percent RH increased, the SSG containing "lm exhibited an almost three-fold increase in percent water content compared to that of the HPC/PEG "lm. The temperature storage condition of 403C/100% RH (versus 253C/100% RH) increased the percent water content of the SSG containing "lm. Percent elongation was highest for "lms containing polycarbophil 5% (without PEG). In addition, the HPC "lm containing polycarbophil 5% exhibited a greater force of adhesion and elongation at adhesive failure in vivo, and a lower modulus of adhesion when compared to the HPC/PEG "lm. A novel approach to determine bioadhesion of "lms to the human epidermis is presented.  2000 Elsevier Science Ltd. All rights reserved. Keywords: Hot-melt; Extruded "lms; Hydroxypropylcellulose; Polycarbophil; Carbomer; Sodium starch gylcolate; Polyacrylate; Physical}mechanical properties; Bioadhesion; In vivo; Novel

1. Introduction Thin "lms for transdermal/transmucosal (TD/TM) drug delivery devices and wound care applications are frequently produced utilizing cast "lms from aqueous or solvent-based systems. Aitken-Nichol et al. discussed numerous disadvantages accompanying these techniques which included environmental concerns, long processing times and high costs [1]. Gutierrez-Rocca and McGinity demonstrated that stable mechanical properties for acrylic cast "lms may not be attained for up to 60 d, which ultimately a!ects the rate of release of drugs incorporated into the "lms [2]. Hjartstam et al. reported that alterations in cellulose "lm structure in#uenced both drug transport and the mechanical properties [3]. In addition, moisture permeability and moisture uptake of TD/TM "lms may in#uence the drug release rate as well as the

* Corresponding author. Tel.: 512-471-4841; fax: 512-471-2746. E-mail address: [email protected] (M.A. Repka).

adhesion of "lms to the epidermis or mucosa. It has been shown that the type and level of plasticizer, temperature, and relative humidity, all a!ect drug release, moisture uptake, and mechanical properties of "lms formed from aqueous dispersions [4}9]. Gutierrez-Rocca and McGinity reported that plasticizers would increase the workability, #exibility, and distensibility of a polymer [2,10]. Plasticizers modify the physical}mechanical properties, by lowering the melt viscosity, glass transition temperature and elastic modulus of a polymeric "lm [2,4]. These physical}mechanical alterations also play an important role in adhesive properties of "lms to solid substrates [11]. Gutierrez-Rocca et al. demonstrated that the mechanical properties for "lms prepared from aqueous latex dispersion Eudragit L 30D containing varying amounts of triethyl citrate, exhibited a reduction in elasticity and an increase in tensile strength at 233C/50% RH with increasing time. It was concluded that the transitional change in mechanical behavior was due to residual moisture in the "lm, since both water and the plasticizer will have a synergistic

0142-9612/00/$ - see front matter  2000 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 2 - 9 6 1 2 ( 0 0 ) 0 0 0 4 6 - 6

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in#uence on the mechanical properties of the cast "lm. Temperature has been shown to signi"cantly in#uence the elongation properties of free "lms cast from aqueous polymeric dispersions [12]. In addition, temperature and humidity a!ect the physical}mechanical properties of "lm coated soft gelatin capsules [13]. Water uptake and certain mechanical properties of "lms produced by either casting or hot melt extrusion may be undesirable or desirable, depending on the application intended. For example, predictable moisture uptake may be advantageous in certain wound care applications and controlled drug di!usion through "lms is dependent on reproducible mechanical properties [4}9]. Hot-melt extrusion has recently sparked much attention in the pharmaceutical "eld [14}19]. Follonier et al. demonstrated that thermally stable drugs, such as diltiazem HCl, could be hot-melt extruded into pellets without signi"cant drug degradation [18]. Melt extrusion has been heralded as a new, continuous formulation process for the production of tablets, granules or pellets [19]. Repka and coworkers recently reported the in#uence of conventional plasticizers and model drugs on physical}mechanical properties of hydroxypropylcellulose "lms prepared by hot-melt extrusion [14]. The researchers reported a large increase in percent elongation when testing was performed perpendicular to #ow versus in the direction of #ow, which may also a!ect the adhesion properties of the "lms. Bioadhesion is generally de"ned as the ability of a biological or synthetic material to &stick' to the skin or a mucous membrane. This results in the adhesion of the material to the tissue for a prolonged period of time [20]. As one would expect, this concept has received considerable attention in the pharmaceutical "eld due to the potential for applications in drug delivery and wound care. A widely used approach to explain the adhesive properties of dermal or transdermal systems is based on the belief that inter-atomic or inter-molecular forces are established at the interface of the adhesive and the substrate (adherent) or skin in these applications [21]. Fundamental thermodynamic quantities, such as surface free energies of both adhesive and adherent, determine the magnitude of the adhesive forces. However, this assembly and thus e!ective adhesion become criteria of good wetting [21,22]. For an adhesive to adhere to a substrate the measured surface energy of the adhesive must be equivalent to or less than that of the adherent, as in the case of the human epidermis [23]. This requirement is a necessary condition but not the only consideration for adhesion. Indeed, numerous mechanisms of adhesion or mucoadhesion have been studied and proposed. These include hydrogen bonding [24], surface energy and contact angle considerations [25}27], polymer chain inter-penetration, and the swelling rate of a polymer interacting with mucin or skin [20].

De Ascentiis and co-workers investigated the in#uence of hydrogen bonding functional groups, ionically charged functional groups, degree of crosslinking, and the size of pendant macromolecular chains of mucoadhesive hydrophilic polymers on the mucoadhesion of these materials to rat intestinal mucosa [28]. Achar and Peppas concluded that cross-linking density did not have an e!ect on the adhesive force, and concluded that chemical interactions that occur at the interface between the acrylic polymer microparticle (}COOH groups) and the mucosa were the predominant bioadhesive contribution [29]. Bioadhesion, however, has been a di$cult phenomenon to measure. Results of adhesion testing can vary widely depending on the factors considered when designing a test and the manner in which the data are collected. Indeed, pH conditions were shown to be important in a study investigating carbomers, and the greatest bioadhesion was demonstrated to occur under acidic conditions [20]. The pK of the carbopols and polycarbophils is reported to be 6.0 ($0.5) and an average baseline of pH of the human skin was reported to be 5.71 (ranging from 4.1 to 6.7) [30]. However, the test method itself can be problematic as well as the speci"c property being measured. Felton and McGinity studied the in#uence of plasticizers in "lm coating formulations on the adhesive properties of an acrylic resin copolymer to solid substrates using a butt adhesion technique [11]. In addition, surface properties of a substrate have been shown to signi"cantly in#uence polymer}substrate interactions, such as force of adhesion, elongation at adhesive failure, and adhesive toughness [31]. In the case of the present study, the substrate studied was the human epidermis. Few, if any studies in the scienti"c literature address the measurement of adhesion (bioadhesion or mucoadhesion) of hot-melt extruded "lms, or even cast "lms, to human skin. Indeed, measurements of adherents and substrates have shown an increase of surface energy with increases in relative humidity and temperature [23]. The objective of our investigation was to study the e!ects of relative humidity, temperature, and various polymer additives on moisture uptake and the mechanical properties of hydroxypropylcellulose hot-melt extruded "lms. In addition, the in#uence of PEG 3350 and polycarbophil on the bioadhesive properties of HPC "lms in vivo on the human epidermis was determined employing a novel test method.

2. Materials and methods 2.1. Materials Hydroxypropylcellulose (HPC) (MW: 1 150 000), (Klucel威 HF), was obtained from Aqualon Company,

M.A. Repka, J.W. McGinity / Biomaterials 21 (2000) 1509}1517

Wilmington, DE. The conventional plasticizer utilized was polyethylene glycol 3350 NF (Carbowax威 3350) (Union Carbide Corp., Danbury, CT). Other additives utilized were Eudragit威 E-100 (RoK hm America Inc, Somerset, NJ), carbomer (Carbopol威 974P) and polycarbophil (Noveon威 AA-1) (BF Goodrich Specialty Chemicals, Cleveland, OH 44141), and sodium starch glycolate (SSG) (Explotab威 Mendell, Patterson, NJ). Scotch威 double-coated tape was supplied by 3M (St. Paul, MN). 2.2. Processing methods 2.2.1. Material preparation and blending Hydroxypropylcellulose, PEG 3350, and other additives were dried at 503C for 24 h prior to mixing. The plasticizer and/or other polymers were incorporated slowly into a liquid}solids Blender威 (Paterson}Kelley Co.) containing the HPC. All additives were blended for 30 min. Batch size for each formulation was 1.0 kg. The composition of the "lms was as follows: (1) HPC 95%#PEG 5%, (2) HPC 95%#polycarbophil 5%, (3) HPC 90%#PEG 5%#polycarbophil 5%, (4) HPC 90%#PEG 5%#carbomer 5%, (5) HPC 90%#PEG 5%#Eudragit E-100 5%, and (6) HPC 90%#PEG 5%#SSG 5%. 2.2.2. Hot-melt extrusion A Killion extruder (Model CKLB-125) was preheated to 1703C melt temperature (Fig. 1). For purging purposes, polyethylene pellets were added to the hopper and passed through the extruder for 5 min (this procedure was repeated for each individual batch). The blend of HPC and plasticizer or additive was placed in the hopper and extruded to obtain a homogenous "lm with a thickness range from 10 to 12 mil, or 0.254}0.305 mm (1 mil"25.4 lm or 0.001 in). The extrusion temperatures for each "lm were dependent on the formulation extruded. The "lms were extruded at their respective optimal temperatures, ranging from 170 to 2003C. The "lm was collected in rolls, labeled, and sealed in 5 mil poly-

Fig. 1. Schematic of an extruder illustrating various functional zones including the hopper, solid conveying zone, melting zone, metering zone, "lm die, chill roll, and take-up roll.

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ethylene bags. Initial testing was commenced after seven days of storage at 253C. 2.3. Analytical methods 2.3.1. Mechanical testing apparatus The physical}mechanical properties of the "lms were determined utilizing an Instron 4201 testing apparatus with a head speed of 10 mm/min. The standard test method for tensile properties of thin plastic sheeting by the American Society for Testing Materials, method D 882-95a was used to investigate the mechanical properties [10]. Six samples from each formulation were tested. The initial grip separation was 100 mm. 2.3.2. Calculations Calculations were performed in the following manner: Force or load (F) Tensile strength (p)" , MA where F is the maximum load and MA is the minimum cross-sectional area of the "lm specimen. Results were converted to megapascal units (MPa). (¸ !¸) *¸ Strain (e)"  " , ¸ ¸   Elongation percent"e;100, ¸ refers to the initial length of the "lm sample and ¸ is  the elongation at the moment of rupture. 2.3.3. Moisture analysis The loss on drying (LOD) for each "lm formulation was performed on a moisture analyzer (Sartorius MA 50). The results were expressed as percent water content of the various "lms. Five samples of each "lm of approximate weight 200 mg were tested. 2.4. Bioadhesion testing Bioadhesive experiments were conducted using a Chatillon digital force gauge DFGS50 attached to a Chatillon TCD-200 motorized test stand (Chatillon Force Measurement, Greensboro, NC) (Fig. 2). To determine that the novel method was feasible for bioadhesive measurements to the skin, three "lms were chosen for testing. Three subjects, two male (ages 19 and 45) and one female (age 33), served as volunteers for the study. The "lm to be tested was secured with double-sided adhesive tape to the upper platen, which consisted of the force gauge "tted with a 1 cm diameter, circular steel plate (modi"ed technique described by Felton and McGinity) [31]. The subject's arm was then stabilized to the lower stationary platen. The area of the subject's arm to be tested (ventral surface of the forearm) was cleansed with isopropyl alcohol and allowed to dry. A "xed

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3. Results and discussion

Fig. 2. Schematic of the Chatillon apparatus used to perform butt adhesion experiments in vivo in human subjects.

Fig. 3. Example of a force}de#ection pro"le obtained from a butt adhesion experiment utilizing hot-melt extruded "lms in vivo using a Chatillon digital force gauge attached to a motorized test stand.

amount (0.5 ml) of de-ionized water was applied to the secured "lm. The contact interval of 180 s was chosen based on preliminary data collected for testing intervals of 30, 60, 120, and 180 s. This interval is consistent with that of Wong and co-workers to provide adequate reproducibility [32]. The upper platen with a 1 cm diameter "lm attached was then lowered to the surface of the arm, allowed to secure contact with a load of approximately 0.8 kg for 180 s and then raised at a constant rate of 2.5 mm/min. The slow rate that the upper platen was raised was chosen since lower rates of deformation have been reported to produce a more even distribution of stress [33]. A personal computer recorded the force (N) and the displacement (mm) at 0.01}0.02 mm intervals. Force}de#ection pro"les were constructed from the data. The force required to detach the "lm on the upper platen from the subject's arm, known as the adhesive force, and the elongation at adhesive failure, equivalent to elongation at break in the tensile testing of the "lms, were determined. The modulus of adhesion, analogous to Young's modulus, was also calculated. Force of adhesion, elongation at adhesive failure, and modulus of adhesion are described and illustrated in Fig. 3.

The mechanical properties of hydroxypropylcellulose "lms were dependent on the plasticizer/polymer composition of the extruded "lm. Without the use of a plasticizing additive, HPC could not be processed into a "lm due to the excessive stress that was placed on the material during processing. After storage for two weeks, the "lm containing HPC and PEG 3350 exhibited a three-fold increase in percent water content as relative humidity increased (7.2% at 0% RH to 21.3% at 100% RH, 253C). However, all other extruded "lms exhibited a six to almost 16-fold increase in percent water content when compared at 0 and 100% RH (253C). As illustrated in Table 1, the "lms containing 5% sodium starch glycolate and stored at 253C showed an increase in moisture content from 3.3% at 0% RH to 51.9% at 100% RH. SSG is used in tablets and capsules as a disintegrant and its swelling capacity in water can be up to 300 times its volume [34]. In contrast, HPC is reported to have a relatively low a$nity for water and absorbs about 12% at 80% RH (233C) [35]. The higher water content attained at 100% RH for the SSG-containing "lms is therefore probably due to sodium starch glycolate's moisture absorption properties. In addition, the "lm consists of a solid dispersion of the superdisintegrant in the cellulose polymer, since SSG does not melt at the processing temperature utilized (1803C), but does char above 2003C [34]. No signi"cant changes in moisture uptake were observed for "lms tested at 0% RH, 403C when compared to the 253C storage data (one-way ANOVA, P'0.05). However, at storage conditions of 403C/100% RH the sodium starch glycolate containing "lms increased the percent water content when compared to that at 253C/100% RH (from 51.9 to 59.8%). This can be explained by the changes that occur at the molecular level concerning cross-linking of the SSG. The e!ectiveness of sodium starch glycolate to absorb water is a!ected by the degree of cross-linkage and the extent of carboxymethylation [34]. Since the SSG-containing "lm is essentially a solid dispersion, it can be reasoned that the "lm's water-absorbing capacity had not reached equilibrium at the 253C temperature condition. These "ndings may be bene"cial when considering wound care applications in addition to drug delivery. The data in Table 2 demonstrate the in#uence of relative humidity (50 and 80% RH) on the tensile strength and percent elongation of the extruded "lms. The tensile strength determined at 80% RH decreased in all "lms tested when compared to that at 50% RH. This observation was anticipated due to the higher moisture content of the "lms stored at the higher relative humidity. As has been previously reported, water itself acts as a plasticizer in hydrophilic polymers, such as polyvinylpyrrolidone, and a change in mechanical properties will

M.A. Repka, J.W. McGinity / Biomaterials 21 (2000) 1509}1517

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Table 1 In#uence of additives on the moisture uptake of hydroxypropylcellulose hot-melt extruded "lms stored for two weeks at various relative humidities and temperatures (n"6) HPC "lms

253C

403C

0% RH

50% RH

80% RH

100% RH

0% RH

100% RH

HPC 95% PEG 5%

7.21 (0.83)

9.35 (0.77)

12.92 (1.20)

18.33 (3.21)

7.27 (0.97)

23.45 (2.33)

HPC 95% Polycarbophil 5%

4.57 (0.11)

11.77 (1.65)

15.58 (0.77)

44.37 (1.36)

7.57 (0.87)

45.60 (2.53)

HPC 90% PEG 5% Polycarbophil 5%

7.29 (0.38)

11.29 (0.36)

15.40 (0.34)

42.61 (1.56)

5.20 (0.73)

40.45 (1.43)

HPC 90% PEG 5% Carbomer 5%

7.38 (1.15)

11.05 (0.82)

14.98 (0.67)

43.17 (0.18)

7.00 (1.08)

41.08 (1.98)

HPC 90% PEG 5% Eudragit E100 5%

5.71 (0.70)

9.03 (1.54)

14.18 (1.36)

46.23 (1.48)

4.74 (0.61)

42.08 (2.56)

HPC 90% PEG 5% SSG 5%

3.29 (0.62)

18.91 (2.39)

24.67 (2.66)

51.87 (1.34)

3.15 (0.10)

59.80 (1.92)

Standard deviation denoted in parentheses.

Table 2 Tensile strength and percent elongation of hydroxypropylcellulose hot-melt extruded "lms tested in the direction of #ow stored at 50 and 80% relative humidity for 2 weeks at 253C (n"6) HPC "lms

Tensile strength (MPa)

Percent elongation

50% RH

80% RH

14.95 (2.23)

9.76 (1.95)

7.10 (0.96)

8.76 (1.30)

HPC 95% Polycarbophil 5%

5.21 (0.29)

2.42 (0.25)

43.18 (4.30)

52.10 (7.70)

HPC 90% PEG 5% Polycarbophil 5%

17.03 (2.29)

11.87 (2.23)

5.99 (0.66)

9.55 (1.08)

HPC 90% PEG 5% Carbomer 5%

13.89 (3.52)

12.13 (2.00)

4.91 (0.65)

5.93 (0.27)

HPC 90% PEG 5% Eudragit E100 5%

12.00 (1.38)

8.09 (0.38)

7.70 (0.23)

10.27 (0.52)

HPC 90% PEG 5% SSG 5%

30.75 (3.98)

16.50 (1.12)

5.40 (0.54)

7.06 (0.91)

HPC 95% PEG 5%

Standard deviation denoted in parentheses.

50% RH

80% RH

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be observed with a change in water content [36]. Plasticizers function by weakening the inter-molecular attractions between polymer chains, which will decrease the tensile strength of "lms [2,9,11]. The highest tensile strength of all the "lms tested was the sodium starch glycolate containing "lm while the "lm containing 5% polycarbophil exhibited the lowest tensile strength. This observation may be attributed to the higher internal stress developed in the sodium starch glycolate solid dispersed "lm and the lowest stress in the "lm containing the polycarbophil [37]. The percent elongation was signi"cantly higher for "lms containing the polycarbophil without plasticizer than any of the other "lms tested. All "lms exhibited an increase in percent elongation when stored at 80% RH for 2 weeks when compared to 50% RH. Thus, a more ductile "lm resulted due to the 30}40% increase in water content when stored at the higher relative humidity condition [2,9]. An interesting "nding was the four- to "ve-fold increase in the percent elongation of the HPC "lms containing polycarbophil 5% compared to the other HPC "lms tested. This may be explained by the fact that in this "lm, only intermolecular interactions occurred between the two longer chained molecules, namely HPC and polycarbophil. The hydroxyl groups on the two polymers form hydrogen bonds. However, since the chains of both

polymers are longer than those of the PEG, there was more latitude for chain unraveling before chain scission. With the incorporation of the PEG 3350, more hydroxyl groups on the HPC and polymer additives become associated with the plasticizer. This competition for reactive sites therefore decreased percent elongation at break. It has also been demonstrated that the temperature of fusion and cooling rate may have a profound e!ect on the solid structure of polyethylene glycol itself [38]. Signi"cant di!erences in the mechanical strength of PEG depend on heat treatment. The mechanical properties of pure PEG molded tablets have been shown to be highly sensitive to thermal history [39]. Since the melting point of the PEG was greatly exceeded, the resultant molecular weight and mechanical properties of the PEG were altered. This fact may also play an important role in the adhesion properties of the various "lms, as described below. Adhesive experiments were conducted in vivo on the human epidermis as described in the methods section. Force}de#ection pro"les were obtained from these experiments on three of the hot-melt extruded hydroxypropylcellulose "lms containing the following: (1) PEG 3350 5%, (2) polycarbophil 5% and PEG 3350 5%, and (3) polycarbophil 5%. These results appear in Fig. 4. The de#ection measurement of the pro"les is expressed in millimeters (mm) and the force is given in N/cm. As

Fig. 4. Force de#ection pro"les of hot-melt extruded hydroxypropylcellulose "lms containing (a) PEG 5%, (b) polycarbophil 5% and PEG 5%, and (c) polycarbophil 5% (n"6).

M.A. Repka, J.W. McGinity / Biomaterials 21 (2000) 1509}1517

stated earlier, these pro"les are similar to stress}strain diagrams commonly generated in the tensile testing of free "lms and allow the visualization of the development of the force within the sample during the adhesion testing. The adhesive force is the force required to remove the extruded "lms from the skin, which is the highest point on the y-axis of the graphs. The elongation at adhesive failure is the distance the upper platen traveled up to the point of "lm and skin separation, denoted on the x-axis. This term is analogous to the elongation at break obtained from the force}de#ection pro"les. As can be seen in Fig. 5a, the force of adhesion of the HPC "lms was highest for the "lms containing 5% polycarbophil (2.05 N/cm$0.08), followed by the polycarbophil plus PEG containing "lm (1.66 N/cm$0.09), and lastly the HPC "lm containing only the PEG (0.64 N/cm$0.05). Thus, the polycarbophil-incorporated "lm without PEG exhibited a three-fold increase in adhesive force, in vivo, when compared to the HPC "lm containing PEG 3350 5%. This may be explained by the fact that the polycarbophils contain a large number of carboxylic acid groups that provide the ability to form hydrogen bonds with the epidermal layer of the skin [20,24]. Since surface characteristics are always important in adhesion, skin physiology is an important factor of bioadhesion. This is in agreement with the work of Wong and coworkers who found the peak detachment force (or adhesive force) to be greater for similar polyacrylates (carbopols) than that of the cellulose's, utilizing chicken pouch tissue, in vitro [32]. The reason for the decrease in adhesive force when PEG 5% was added to the polycarbophil 5% "lm could be explained by the competition for the hydrogen bonding sites by the smaller molecular weight PEG. Repka and co-workers recently reported that the percent elongation was lower for a PEG 8000 than a PEG 400 incorporated HPC "lm [14]. However, the percent elongation of the PEG 400 containing "lm was measured to be 6.8% compared to over 40% for the polycarbophil containing "lm in the present study (in direction of #ow). Thus, many of the reactive sites of the polycarbophil were occupied by the PEG, decreasing available hydroxyl groups for hydrogen bonding with the skin, and therefore decreasing adhesive force. These "ndings are consistent with those of Heinamaki and coworkers [7], who found that ductility (percent elongation) was mainly attributed to the molecular weight of the plasticizer. Rowe also found that as the molecular weight and thus the size of a polyethylene glycol is decreased, the mole fraction of available hydroxyl groups to interact with the hydroxyl groups of the polycarbophil will increase [40]. As can be seen in Fig. 5b, the HPC "lm containing polycarbophil 5% had the greatest percent elongation at adhesive failure of the three "lms tested. This would also be indicative of a greater percent elongation of the polymer "lm itself as discussed above [11,14]. In addition,

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Fig. 5. Force of adhesion (a), elongation at adhesive failure (b), and modulus of adhesion (c) of hydroxypropylcellulose hot-melt extruded "lms containing various additives (n"6).

Fig. 5c illustrates the statistical increase in the modulus of adhesion for the HPC "lm containing PEG, when compared with the HPC "lms containing the polycarbophil. This demonstrates the marked decrease in ductility of the HPC "lms containing the glycol when compared to the "lms containing the polycarbophil additive.

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4. Conclusions The hot-melt extrusion process was shown to be a viable technology for preparing "lms containing HPC with PEG 3350 and other water absorbent polymer additives. All "lms tested in this study exhibited an increase in percent water content with an increase in relative humidity. The HPC "lm containing sodium starch glycolate exhibited the lowest percent water content at 0% relative humidity and the highest percent at 100% RH, which may be bene"cial in both drug delivery and wound care applications (i.e. absorption of exudates). The HPC "lms containing the polycarbophil without plasticizer exhibited a signi"cant increase in the percent elongation compared to other "lms tested (a "ve- to 10-fold di!erence) at both 50 and 80% RH. Force}de#ection pro"les obtained from skin adhesion experiments indicate that the force of adhesion and the elongation at adhesive failure are a function of the polymer additive in the HPC extruded "lms. The polycarbophil 5% containing "lm had the highest force of adhesion and the highest elongation at adhesive failure of the other "lms investigated during in vivo adhesive testing. Results of this study indicate that methods developed utilizing the Chatillon testing apparatus may be employed as a novel technique to determine bioadhesion of "lms to the human epidermis to enhance the development of transdermal and transmucosal systems.

Acknowledgements Michael A. Repka would like to thank the American Foundation for Pharmaceutical Education for its support in this study and other research endeavors. Thanks is also extended to Linda Felton, Ph.D. (College of Pharmacy, University of New Mexico) for her technical advice and to the volunteers who participated in this study.

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