Influence of degree of crosslinking on 54luorouracil release fkom poly(Z- hydroxyethyl methacrylate) hydrogels

Olga Garcia, Rosa M. Trigo, M. Dolores Blanco and Jo& M. Teijh Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad Complutense de Madrid, E- 28040, Spain

Controlled release of Sfluorouracil (5FU) from poly(Bhydroxyethyl methacrylate) (PHEMA) hydrogels with three different degrees of crosslinking is reported. The swelling kinetic of PHEMA hydrogels in water was studied at different disc thicknesses and temperatures, and the diffusion coefficient and activation energy of the process were obtained. The gels were loaded with 5-FU by immersing them in concentrated aqueous solutions of the drug. The 5-FU release was studied as a function of tempera- ture, disc thickness, disc load and degree of crosslinking of the gels; the diffusion coefficient and activation energy of the release process were also obtained. Biomaterials (1994) 15, (9) 689-694

Keywords: Drug delivery, hydrogels, cross-linking

Received 6 November 1993; accepted 20 December 1993

The study of hydrogels has developed a lot during recent years due to its countless biological applica- tions. There is a special interest in biopolymers having properties that allow the controlled release of drugsl. A hydrogel can be defined as a polymeric material with the special characteristics of being hydrophilic, soft, elastic, able to swell in water and to imbibe large quantities (>20%) of water without the polymeric network going into solution. While in the dehydrated state, they are crystalline and are called xerogels’.

The poly(%hydroxyethyl methacrylate) (PHEMA) hydrogels are widely used in the biomedical field’, 3 due to their easy polymerization, hydrophilic side groups, oxygen permeability4 and high biocompatibil- ity5. Many drugs have been trapped and immobilized in HEMA polymers in order to obtain controlled release systems, for instance, ergotamine627, salicylic acid’* ‘, benzoic acidgS”, tiamine 11, progesterone” and chloroamphenicol’3-‘5, etc.

The usual methods of drug administration (intrave- nous injection and oral tablets) often provide very poor control of the concentrations of such substances in plasma. Good control, that allows maintenance of ideally constant levels of a drug in plasma, can be obtained by a controlled release mechanism in which the active agent is put into the

J olymeric matrix from

which the drug diffuses slowly’ . Citostatic drugs have antiproliferative properties that allow them to act at different biochemical levels on tumoral cells. Neverthe- less, these drugs also affect normal cells, since both the

Correspondence to Dr J.M. Teijbn.

therapeutic and toxic effects of antineoplastic drugs depend not only on their concentration but also on the exposure time of tumoral and normal cells. The release of antineoplastic drugs from hydrogels can be very useful in delivering them in a safe and effective way to the place of action in the organism, and for obtaining a fixed and continuous therapeutic action for a determined period of time, while avoiding secondary actions.

In this study 5-fluorouracil (5-FU) release from PHEMA hydrogels with different degrees of cross- linking has been examined. 5-FU is an analogue of uracil with a fluorine atom at C5; owing to its similar structure to uracil, 5-FU can take part in the metabolism of that pyrimidinic base and prevent thymidine and DNA synthesis. 5-FU is one of the most common antineo- plastic drugs used in clinical biochemistry for the treatment of several malignancies, including carcino- mas of the breast, gastrointestinal tract and ovary17. Owing to its high toxicity, it is a good candidate for controlled release technology in order to obtain a therapeutic effect in situ and minimize the collateral effects of the drug.

MATERIALS AND MJTHODS

Materials

2-Hydroxyethyl methacrylate (HEMA) (Merck, Darmstadt, Germany) was purified by vacuum distilla- tion 14S18-20 at 315-318K and 3.7 x10e3 mm Hg (vacuum pump: Eduar 8) (Eduar, UK). Ethylene glycol

i- 1994 Butterworth-Heinemann Ltd 0142-9612/94/090669-06

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690 5-FU release rate dependency on crosslinking: 0. Garcia et al.

dimethacrylate (EGDMA) (Merck), a,cr’-azoisobutyroni- trile (AIBN) (BDH, UK), dimethyldichlorosilane solution (BDH), KHzP04 and Na2HP04 (Scharlau, Barcelona, Spain) were used as received. The antineo- plastic drug, 5-fluorouracil (5-FU) was supplied by Roche (Madrid, Spain) as a crystalline powder. Bidistilled and deionized water (Mini-Q, Massachu- setts, USA) was used.

Polymerization

Three PHEMA hydrogels were synthesized as a function of degree of crosslinking. Polymerization was carried out in glass test tubes which were siliconized with a dimethyldichlorosilane solution6! 7. The feed mixture comprised the monomer (HEMA), the crosslinking agent (EGDMA) at different concentra- tions (0.5 wt%, z wt% and 5 wt%) and the initiator (AIBN) (0.05 wt%). The amounts of EGDMA and AIBN were related to the total amount of HEMA. The mixture was outgassed by nitrogen for 30 min and was placed in an oven increasing the temperature from 313 K to 353 K gradually for 48 hl8.

After polymerization, solid xerogel cylinders of the three PUMA gels were immersed in distilled water for 2 wk to remove any possible residual monomer. Then they were cut into discs, dried at ambient temperature for 2 d and in an oven at 313K for 1 d until at constant weight,

Swelling of the polymers in water

The swelling experiments of PHEMA discs (without 5- FU) were carried out by placing the xerogel discs into a water bath at constant temperature. The degree of swelling (W,) was obtained by withdrawing the discs, lightly drying with filter paper and weighing quickly in a tared sample bottle, at different times21*22.

Weight of swollen discs - Weight of dry discs

w, = Weight of swollen discs xl00

(1)

The equilibrium degree of swelling (IV,) was reached between 5 and 12 h after immersion of the discs in water, depending on temperature, crosslinking degree and disc thickness.

Loading crf gels

Polymer discs were loaded with 5FU by immersing them in aqueous solutions of the drug at concentra- tions between 1 and 13 mg/ml, in the absence of light, until equilibrium was obtained (1 wk). Then the hydrogel discs containing the drug were dried at ambient temperature for 2 d and in an oven at 313 K for 1 d until at constant weight. The loads of the discs were between 1.6 and 46 kg/m3.

Release of 5-FU from PHEMA hydrogels

Release of 5-FU from the PHEMA discs was carried out by placing each xerogel disc containing the drug on a holder and into a distilled water bath at constant temperature and stirring rate. The volume of water in

the vessel was lOOm1. At various times, aliquots of 50~1 were drawn from the medium to follow the 5-FU release; a maximum of 20 aliquots were taken, so the vessel volume can be considered constant. The drug release always maintained ‘sink’ conditions”, that is the amount of 5-FU released did not exceed 10% of its solubility in water. 5-FU solubility was determined spectrophotome~ically using a Unicam 8700 spectro- photometer at 270 nm, (UnicamAnalytical Systems, Cambridge, UK) and was found to be 13 mg/ml. The highest load of 5-FU was 46 kg/m3 which corresponds to 9 mg 5-FU, so the total drug released into the medium would be 0.9 mgiml, that is, less than 10% of 5-FU solubility.

The concentration of 5-FU was measured by high performance liquid chromatography (HPLC) (Spectra- Physics: SP 8800 HPLC pump, SP 100 ultraviolet detector and SP 4400 computing integrator) (Spectra- Physics, California, USA). The stationary phase was Spherisorb ODS-C1s, 5 pm (ColoChrom, Cagny, France) (220 nm x 4.6mm ID). The eluent was l/75 M

KH2P04-Na2HP04 buffer solution of pH 7.0z3. The flow rate was 1 ml/min and the detector wavelength was 270 nm. 5-FU standards of 0.1-100 pg/ml were run for a calibration curve. This calibration was computed by the integrator. The 5-FU retention time was 5.2 f 0.1 min.

Any degradation was observed. All the xerogel discs with 5-FU were transparent, and all samples showed a single peak in the chromatograph which corresponded to 5-FU”7*24. The release of 5-FU from the three PHEMA hydrogels was studied:

1. at four temperatures (288-310 K); 2. at four different disc thicknesses at 310 K; and 3. at six different 5-FU loads at 310 K.

Additionally, 5-FU release from PHEMA with 5% crosslinker was examined at 298 K.

RESULTS AND DISCUSSION

Swelling of xerogels in water

Xerogel discs of 0.86-1.97mm thickness and 12.22- 14.79 mm diameter were employed in these studies. W, was determined at different times using Equation 2. The values of W, were (36 & l)% for PHEMA contain- ing 0.5% crosslinker (0.3 mol. %), (33 f 21% for PHEMA containing 2% crosslinker (1.3 mol. %) and (29 f l)% for PHEMA containing 5% crosslinker (3.3 mol. %) for temperatures between 288 and 310K. These values are in accordance with the EGDMA concentration of the gel. So when that concentration increases in the feed mixture, W, decreases because the crosslinking degree is higher. These results are consistent with those reported when the influence of crosslinker concentration on W, is observed. For example, for PHEMA gels crosslinked with 0.66 mol. % EGDMA, W, was 39%” and for PHEMA gels crosslinked with 2 mol. % EGDMA, W, was 30%15.

The fractional swelling due to water uptake, F,, for a controlIed diffusion process may be expressed as25:

F, = 4(Rwt/nh’)‘/2 (2)

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5-FU release rate dependency on crosslinking: 0. Garcia et al. 691

where D, is the apparent diffusion coefficient for the transport of water into the gel, t is time and h is the thickness of the xerogel discs. Linearity between F, and t”’ was found for values of F, less than 0.5, at constant temperature T and fixed II, so D, can be obtained from the slope. The experiments of swelling in water were carried out at four temperatures (288-

310K) for each of the three gels. The diffusion coeffi- cients obtained from the straight-line slopes were enhanced when the degree of crosslinking of the gels was lowered (Table I).

A temperature increase results in a greater diffusion coefficient for discs of similar thicknesses and the same crosslinking degree, so that uptake of water into the gel is made easy. In the same way, enhancing the xerogel disc thickness brings about a higher diffusion coefficient at constant temperature and crosslinking degree (Table 1).

When the slopes obtained from Equation 2, FJ’I’, are plotted against h-‘, a straight line is afforded whose slope yields an average D, for the thickness used. Such values are plotted against the crosslinking degree at four temperatures in Figure 2. This average diffusion coefficient decreases with temperature for each gel. Likewise, the diffusion coefficient suffers an exponential change with crosslinking degree of the gels, this behaviour being more pronounced as the temperature decreases. Thus, gels of lower crosslink- ing degree would use a diffusion mechanism for water uptake due to a pore flow mechanism, while gels of higher crosslinking degree would show behaviour intermediate of pore flow transport and flow by water interaction with the matrix’“.

The Arrhenius plot of D, against temperature yields a straight line from which slope the activation energy (E,) can be deduced. The values of E, for water uptake as a function of crosslinking degree of the gels are plotted in Figure 2. The swelling is less favourable when the EGDMA concentration is higher. The E, values are very close for smaller EGDMA concentrations; this may be due to the similar water diffusion behaviour of these gels, which in the 5% crosslinked PHEMA gel swelling is hinder by water-matrix interaction.

Release of 5-FU from PHEMA hydrogels

When the disc thickness is small, diffusion from the gel can be considered as one-dimensional’4~18~z7328. This approach has been followed in determining the diffusion coefficient for the uptake of water and 5-FU release since the thicknesses of the dry discs were between 0.88 and 1.87 mm.

Figure 3 shows that the fractional release of 5-FU, Fs-FU, is linear with the square root of time, t”*, for values of F5.Frr less than 0.5 for the three studied gels. So it is possible to use the equation:

FS-FU = M,/Mx = 4(D,_Fut/~h2)‘12 (3)

where Mt is the amount of 5-FU released at time t; M, is the maximum amount of 5-FU released, that is, the same as that initially in the disc; D~_Fu is the apparent diffusion coefficient for 5-FU delivery from the hydrogels; and h is the thickness of the xerogel discs with 5-FU. This linear dependence yields DS+” from

Table 1 Values of apparent diffusion coefficients for water uptake into PHEMA gels with different crosslinking degree as a function of disc thickness at four temperatures

PHEMA Temperature Thickness (%EGDMA) T (K) h (mm)

Diffusion coefficient D, x 10” (m’/s)

5 310

303

298

288

2 310 1.69 1.36 1.12

303 0.96 1.70 1.35 1.17

298

288

0.97 1.66 1.48 1.22 0.97 1.69 1.41 1.15 0.99

0.5 310

303

298

288

1.94 3.77 1.47 3.39 1.29 3.08 1.05 2.34 1.95 2.97 1.49 2.75 1.20 2.50 1.07 2.27 1.78 2.91 1.47 2.72 1.22 2.39 0.99 1.74 1.86 1.68 1.45 1.41 1.12 1.39 0.99 1.21

3.86 3.44 3.32 3.21 3.40 2.90 2.84 2.33 2.46 2.38 2.31 2.08 1.91 1.78 1.70 1.58

1.97 4.98 1.49 3.83 1.24 3.57 1.03 3.23 1.94 3.21 1.50 3.07 1.18 2.97 0.86 2.33 1.97 2.92 1.55 2.88 1.19 2.72 0.95 2.52 1.97 2.72 1.46 2.51 1.16 2.20 0.87 2.04

the slope. The experiments to determine the release of 5-FU as a function of temperature (between 288 and 310 K) were carried out using discs of similar thickness and load (Table 2).

When the temperature is higher drug release is more favourable, which accords with the increase in D5_FU for all three cases. At one temperature enhanced EGDMA diminishes 5-FU release. Similar behaviour has been observed in chloroamphenicol release from PHEMA hydrogels14. The activation energies for 5-FU release are higher than those for the uptake of water. This suggests that water uptake is the more favourable process, from an energetic viewpoint, than 5-FU release. These differences have been observed for theophyline6 and L-ascorbic acid releasez7.

To determine the influence of disc thickness on 5-FU

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692 5FU release rate dependency on crosslinking: 0. Garcia et al.

3-s-

-; 3.0- .

"E

- 2.!i- -0

x

o* 2.0-

1.5-

1 310K

0

1.0' I I I I I

0 1 2 3 4 5 b

EGDMA (%)

Figure 1 Variation of diffusion coefficients, independent of disc thickness for water uptake, with degree of crosslinking (%EGDMA) of PHEMA gels at four temperatures.

m w

60

10 1 I I I I I 1

0 1 2 3 4 5 6

EGDMA (8)

Figure 2 Dependence of activation energy (E,) on: a, swelling in water and b, 5FU release, with crosslinking degree (%EGDMA) of PHEMA gels.

delivery, the release rate, Fs_Fvt-“2, as a function of h-l was studied; as it was linear for the three gels at 31OK, the diffusion coefficient for drug release, DWIJ, can be obtained from the slope (Figure 4). These diffusion coefficients, which are not dependent on thickness, are plotted against EGDMA concentration in Figure 5a. The gel with greater crosslinking degree, PHEMA 5%, shows a diffusion coefficient that is quite a bit smaller than the others; this means that the antineoplastic release process is slower for this hydrogel. Gels with 0.5% and 2% EGDMA manifest very close behaviour for 5-FU release, which shows in their similar DS-~~

i? I 0.6

IL*

Figure 3 Represe$ation of the fractional release of 5-FU (kFU) vs (time) for three PHEMA gels of different crosslinking degree (h = 1.45 f 0.30 mm, A = 21 f 6 kgfm3, T = 310K). 0, 5% EGDMA; n , 2% EGDMA; A, 0.5% EGDMA.

Table 2 Diffusion coefficients for IFU release from three PHEMA hydrogels at four temperatures

Temperature Diffusion coefficient DgFu x lo’* (m*/s)

(K) PHEMA 5% PHEMA 2% PHEMA 0.5%

310 9.00 12.47 13.73 303 8.94 8.66 10.98 298 6.59 7.38 8.24 288 2.99 4.32 5.63

values. These results are in accord with the E, values determined for 5-FU release from these gels (~~g~~ Zb). In the same way, 5-FU release from PHEMA 5% at 298 K yields a diffusion coefficient of 7.8 x lo-” m’/s’, so the temperature decrease originates a slower rate of 5-FU release. These results are in accordance with those shown in Table 3. So drug release is not affected by disc sizes nor by intrinsic gel composition.

In order to observe the influence of the 5-FU load in its release from the three PHEMA gels at 310 K, and at 298 K for PHEMA 5%, discs of similar thickness at different load were used. From Equation 3 and taking into account that M, = AV = Ash, (where V is the disc volume and S its surface area), it is possible to obtain the expression”:

Fs-FU t1/2 Ah = 3 f = 4(D5-m/n)1!2A

where Mtt-‘/2S-1 is the release rate per unit disc area with drug load. The variation of this parameter with A for the three gels is shown in Figure 6. From the slope of these straight lines, a diffusion coefficient that is not dependent on disc load is obtained. In Figure 5b these diffusion coefficients vs the EGDMA composition of the gels are plotted. These results support the latter that the diffusion behaviour of 5-FU from gels with smaller amounts of crosslinker is very close, as the diffusion

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5-FU release rate dependency on crosslinking: 0. Garcia et al. 693

0 2 4 6 8 10 12 14

10-‘/h (rn-‘)

Figure 4 Plot of release rate of 5-FU (FsFu) vs reciprocal disc thickness (l/h) for the three PHEMA gels at 310K. 0, 5% EGDMA; n , 2% EGDMA; A, 0.5% EGDMA.

0

a

16

8 0 1 2 3 4 5 6

EGDMA (%)

Figure 5 Variation of diffusion coefficients for 5FU release: a, independent of disc thickness and b, indepen- dent of disc load as a function of %EGDMA at 310 K.

coefficient values show, while a crosslinking degree greater than 2% decreases the diffusion rate of 5-FU. Likewise, the release of 5-FU from PHEMA 5% at 298 K yields a diffusion coefficient of 6.96 x lo-” m’fs; thus a lower temperature originates a slower drug release.

Since the diffusion coefficient values for 5FU release as a function of both thickness (Figure 5a) and load (Figure 5b) are not significantly different, an average diffusion coefficient for 5-FU release from each hydrogel can be calculated (Table 3), in the same way as results reported previously6* 7* 27.

Table 3 Average diffusion coefficients for 5-FU release from the three PHEMA gels

Temperature Diffusion coefficient &_ru x 10” (m’/s)

(K) PHEMA 5% PHEMA 2% PHEMA 0.5%

310 9.12 f 0.2 13.81 f 1 14.05 f: 0.8 298 7.38 it.4 - -

5ol------

0 10 20 30 40 50 60

A (kg/in31

Figure 6 Representation of 5-FU release rate per unit disc area (M,f -‘/*S-‘) as a function of disc load (A) for three PHEMA gels of different crosslinking degree at 310K. 0, 5% EGDMA; m, 2% EGDMA; A, 0.5% EGDMA.

Table 4 Diffusion coefficients (D) of substances of different molecular weight (M) from PHEMA gels with diverse equili- brium degree of swelling (W,)

Drug release W, M (Da) D x 10” (m’/s’)

5-Fluorouracil 29 130 0.91 5-Fluorouracii 33 130 1.38 5-Fluorouracil 36 130 1.40 Salicylic acid 27 138 0.50 Salicylic acid 35 138 1.10 Salicylic acid 32 176 1.90 Ergotamine 35 582 0.02

Our results show that the change in crosslinking density of the gels due to an increase in the amount of EGDMA in the feed mixture bears significantly upon 5- FU release. There is evidence of very close diffusion behaviour for smaller degrees of crosslinking, while gels with 5% crosslinker ~oncen~ation exhibit slower release rate. This kind of behaviour has also been observed for chloroamphenicol release from PHEMA hydrogels14, and in general it has been described for the diffusion of small molecular weight solutes from non- porous synthetic hydrogels such as PHEMA. Also, the influence of increased crosslinking appears in both the swelling rate of the gels and the equilibrium swelling degree. These results are in accordance with those

Biomaterials 1994, Vol. 15 No, 9

694 5FU release rate dependency on crosslinking: 0. Garcia eta/.

obtained by Corkhill for PHEMA swelling in water as a function of crosslinker concentration at 295K”. The swelling in water of the gels is faster and more energeti- cally favourable than the release of 5-FU, so the ratio of these diffusion coefficients is 2, which agrees with the activation energy values for both processes.

Experiments carried out to release substances with pharmacological action such as salicylic acid’, ergot- amine” and L-ascorbic acidz7 from PHEMA gels (Table 4) show that the diffusion coefficient values decrease when the molecular weight increases, although in such comparisons the differences in water feed content, crosslinking degree and polymerization conditions must be taken into account. Hence it is very difficult to compare different experiments.

The release of 5-FU from PHEMA hydrogels can be controlled by modifying the degree of crosslinker of the gels to obtain the desired release conditions. The high biocompatibility of PHEMA hydrogels allows in viva implants that would reduce the collateral effects of drugs as toxic and as clinically effective as 5-FU.

ACKNOWLEDGEMENTS

The authors wish to thank Roche Laboratories for the gift of 5-fluorouracil. This work was funded by grant Ref. MAT92-0464-C02-02 from the Comision Intermi- nisterial de Ciencia y Tecnologia.

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