Electrically controlled drug delivery system using polyelectrolyte gels

Journal

of Controlled Release, 14 (1990)

Elsevier Science Publishers

253

253-262

B.V., Amsterdam

ELECTRICALLY CONTROLLED DRUG DELIVERY SYSTEM USING POLYELECTROLYTE GELS K. Sawahata, M. Hara, H. Yasunaga and Y. Osada Department of Chemistry, lbaraki University, Mite 3 10 (Japan) (Received March 15, 1990; accepted in revised form July 9, 1990) Keywords: polyelectrolyte

gels; insulin; dry delivery system; chemomechanical

system; artificial muscle

Electrically stimulated drug delivery systems usingpolyelectrolyte gel and microparticles are experimentally demonstrated. The principle of the systems is based on the chemomechanical shrinking and swelling of polymer gels under an electric field. It was found that bioactive materials, such as pilocarpine hydrochloride, glucose and insulin, are successfully released from the gel by switching the electric field alternately on and off. The release mechanism of these compounds is briefly discussed.

INTRODUCTION

In recent years much attention has been given to developing drug delivery systems (DDS ) involving, for example, the utilization of various carrier membranes to afford prolonged delivery times with a minimal change of delivery velocity. However, in considering the DDS from a future therapeutic viewpoint, it is desirable to develop an “active” DDS device which is capable of sensing the needs of the body and delivering an appropriate dose of drug at the appropriate moment to the required part of the body. With this aim in mind, a targeted drug carrier capable of binding with the antigen using specific antibodies has been developed recently [ 11. The principle of this system is to use a vector molecule possessing specific affinity towards specific molecules or cells in the specific organ. Kim and coworkers developed a crosslinked gel of concanavalin A (ConA), a plant lectin to which was chemically bound the glycosylated form of insulin. When the blood glucose level rises, glucose enters the gel and

0168.3659/90/$03.50

0 1990 -

displaces glycosylated insulin (81) from ConA. The gl is then released through the membrane into the body [ 2-41. Crosslinked polymer gels which switch on and off the supply of drug or biomolecules in response to changes in temperature and/or pH [ 4 ] have also been developed. Hoffman and coworkers recently developed a temperature sensitive polymer containing enzyme [ 5,6]. This gel swells at temperatures below 37°C and allows enzyme reaction. However, above this temperature the gel collapses and prevents diffusion of substrate to the enzyme molecules entrapped in the gel. Thus, the rate of enzyme reaction is temperature-sensitive. Kim et al. prepared a similar temperaturesensitive hydrogel containing insulin [ 71. The release rate of the drug was regulated by changing the temperature. It can also be necessary to make a DDS which releases a drug in response to environmental pH. For example, acid-labile drugs have to be protected from the strongly acid environment of the stomach. Thus, a coating has been made which permits release only in the higher pH en-

Elsevier Science Publishers

B.V.

254

vironment of the gut, and a pH-sensitive, swelling-controlled release system was made using a hydrophobic polyelectrolyte gel by Siegel et al. [ 81. Virtually no release was observed at neutral pH, but steady release occurred at lower pH. Horbett and coworkers immobilized glucose oxidase and catalase into a hydrogel. Response to pH change caused by enzyme reaction caused the hydrogel to swell and brought about an enhanced release of insulin [9-l 11. A system which undergoes shape change and develops contractile force in response to outside stimuli is called a “chemomechanical (or mechanochemical) system”. This refers to thermodynamic systems capable of transforming chemical energy directly into mechanical work or, conversely, transforming mechanical into chemical potential energy [ 12,131. A chemomechanical system using a polyelectrolyte gel which contains drug molecules may provide new possibilities to realize another type of active DDS. We have previously reported that water-swollen polyelectrolyte gels immersed in water shrink under an electric field and recover their original size when the electric field is turned off [ 14,151. When drug molecules or other bioactive molecules are entrapped within the gel, which is caused to shrink reversibly by means of electric stimulus, the drug outflow from the gel can be switched on and off, since the diffusion rate is altered by the solvent flow. In addition, the contractile stress appearing in the network polymer will also “squeeze” out the swelling fluid together with drug molecules when the gel shrinks and the reticular size is changed. Thus, this kind of shape change may be used for the active delivery or release of drugs and other biomolecules. This paper is concerned with a preliminary experimental approach to developing an electro-stimulated active-drug delivery system made up of a slightly crosslinked polyelectrolyte gel containing drug molecules or other active agents. Pilocarpine hydrochloride (Pil) , insulin, raffinose and glucose were used as the active agents to be delivered. The gels were

mostly based on synthetic vinyl polymers. In addition, we chose to use microparticle gels incorporating lightly crosslinked sodium salt of poly (acrylic acid) (Na + PAA). It was demonstrated that the gels could release these biomolecules in response to switching on and off the electric field.

EXPERIMENTAL Materials

Methacrylic acid (MAA) (Tokyo Kasei), acrylic acid (AA) (Tokyo Kasei), and dimethylaminopropylacrylamide (DMAPAA) (Kojin Co Ltd.) were distilled under vacuum. The boiling points of these compounds were 329 K and 387 K, respectively, under reduced pressure. NJV’ -Methylenebis (acrylamide ) (MBAA) (Wako Chemical) and potassium persulfate (Wako Chemical) were used as crosslinking agent and radical initiator, respectively. They wee used after recrystallization from water. Sodium alginate (Wako Chemical ) , raffinose ( Wako Chemical ) , pilocarpine hydrochloride (Pil) (Kant0 Chemical) and insulin (bovine pancreas; mol. wt. 5735 g/mol, from Sigma) were used without further purification. Methods Preparation

of gel

Crosslinked water-swollen poly (methacrylic acid) (PMAA) gel was prepared by radical polymerization of a 3.0 mol dmp3 aqueous solution of MAA under a nitrogen atmosphere at 50°C for 20 h. Potassium persulfate and 2.0 mol% of N.N’-methylenebis(acrylamide) were used as radical initiator and crosslinking agent. crosslinked similar manner a In a poly (DMAPAA) (PDMAPAA) gel was prepared by polymerizing a 3.0 mol dm-3 aqueous solution of DMAPAA in the presence of 3.0~ lop2 mol dmp3 MBAA. In this case the

255

polymerization was carried out at 333 K using 3.0 x lo-* mol dmm3 potassium persulfate as an initiator. An alginic acid gel (Ca-ALG gel) was prepared by immersing a Visking tube (diameter 4.2 cm) containing 5.0 wt% sodium alginate solution in a large amount of 5.0 wt% calcium chloride solution for 1 week. Prior to use the gels were all immersed in a large amount of water for at least 1 week to remove unreacted monomer and initiator and equilibrated in water (in some cases immersed in salt solution of designated concentration), and then dried under vacuum until they reached constant weight. The

Carbon

degree of swelling (DS) was calculated by weighing dry (IV,) and water swollen ( W,) gels; DS = W,/ W+ NaPAA microparticles were prepared according to a published procedure [ 161, i.e., by the inverse emulsion polymerization of a solution of 136 mmol of the sodium salt of acrylic acid and 0.065 mmol of MBAA in 68.5 cm3 of cyclohexane in the presence of 0.048 g of Span 80 (sorbitan mono-oleate). The suspension was stirred at 180-200 rpm under a nitrogen atmosphere, and the polymerization was carried out at 60°C for 6 h. Potassium persulfate (0.03 g) was used as a radical initiator. Following poly-

Y--+--i

lcm.

1-x 1 cm

(b)

arbon

electrode

ilectrode cm

1 X 4 cm

PAA microparticle

PDMAPAA

gel

Fig. 1. Apparatus used for release measurement. (a) Gel in contacts with both electrodes; (b) gel microparticles in contact with anode; (c) gel apart from both electrodes.

256

merization, the microparticles were washed repeatedly with methanol and equilibrated in distilled water for 1 day. The microparticles obtained were spherical, and the diameter of the swollen spheres in distilled water was between 150 and 300 pm. The particles were then dyed by immersing them in a 10V4 mol drn3 aqueous solution of methylene blue, and washed. Incorporation of dye facilitated the observation of shape changes under a microscope. Entrapment of raffinose and Pi1 was carried out by immersing the dry cubic gel in a large amount of 0.25 mol dme3 raffinose or 0.83 mol dm-” Pi1 solution for a week. Insulin was incorporated into PDMAPAA and Ca-ALG gels by equilibration in 0.01 wt% (1.7~ lop5 mol dm-” insulin solution at 274 K for 1 week. The amount of drug entrapped was monitored via the decrease in concentration of the impregnating solution using a polarimeter (JASCO DIP 140) or spectrophotometer (Hitachi U3200 ).

Measurements

A piece of crosslinked gel (PMAA: 10~10~10 mm; Ca-ALG: 5~5x5 mm; PDMAPAA: 5x5 ~5 mm) was inserted between a pair of carbon electrodes connected to a d.c. source in 30 ml of water (Fig. la). The amount of drug released into water was monitored as a function of time using a spectrophotometer or a polarimeter. NaPAA microparticles containing Pi1 were placed in a quartz cell containing 4 ml of water (Fig. lb). With the aid of two carbon electrodes, a constant voltage was applied from a d.c. source. The solute concentration in the water was monitored spectrophotometrically by measuring the change in absorption at 510 nm or by polarimetry as a function of time. A release test of insulin was carried out by placing a piece of gel (3 X 3 mm) containing insulin in water. The electrodes were placed out of contact with the gel at a distance of 9 mm from each other (Fig. lc ).

RESULTS AND DISCUSSION Release of raffinose and Pil from PMAA

gel

As reported in previous papers, a water-swollen polymer gel inserted between a pair of electrodes undergoes shrinkage under a d.c. electric field and reduces its weight owing to loss of water [ 15-171. Several experimental facts exist to support the interpretation that the chemomechanical behavior observed is essentially an electrochemical phenomenon. They are: (1) the absolute absence of contraction for a neutral (non-charged) hydrogel; (2) swelling at the anode and contraction at the cathode when the gel is negatively charged, and the reverse observation for the positively charged polyelectrolyte gel; (3) a direct relationship between the rate of contraction and the amount of electrical current. Direct support, however, for the presumed electrokinetic nature is provided by the observation of migration of water (electroosmosis) and of charged ions (electrophoresis) towards the electrode bearing a normal charge opposite in sign to the net charge borne by the gel. The observed chemomechanical behavior of the hydrogels led us to conclude that the external electric field interacted with charged molecules in the gel and induced electrokinetic coupling, namely electroosmosis of water and electrophoresis of charged molecules. These gels are stable under the applied electric field. However, any local pH change near the electrodes due to hydrolysis of water should be taken into account even through this is not a major factor for gel shrinkage. On the basis of the observed phenomenon, a polyelectrolyte gel containing a drug or a biomolecule ) was interposed between a pair of electrodes and a d.c. was applied. We can now expect gel shrinkage and concomitant drug outflow with water. Thus, a preliminary release test was carried out using PMAA gel containing raffinose at various temperatures. The change in raffinose concentration in water as a function

257

of time is shown in Fig. 2a-c. An increase in concentration of raffrnose was observed as soon as the electric field was applied, although insignificant and spontaneous “leakage” of raffinose out of the gel was seen in the absence of an electric field. The rate of raffinose release during the “on” period, for example at 25°C

(Fig. 2b) was 12 times larger than that in the “off” period. The rates of electro-induced raffinose release increased with increasing temperature, and they were calculated as (1.8,3.8 and4.0)X10-5moldm-3s-‘at5,25and40”C, respectively; the rate during the “off” period

on

Time

/ h

off

0

1

2

3

4

5

Time I h

Time

/ h

Fig. 2. Time profiles of raffinose release from PMAA gel: (a) 5 ’ C; (b ) 25 ’ C; (c ) 40 ’ C; electric field strength = 12 V cm-‘; current density= 5.3 mA cm-‘. PMAA gel 10 X 10 x 10 mm in water, amount of raffinose entrapped 2.5 X 10m3mol.

258

changed less over the corresponding temperature range. Figure 3 shows the logarithmic dependence of the rate of raffinose release on the reciprocal temperature. From this figure we can roughly evaluate the value of the activation energy of raffinose release; this was calculated as 25 kJ mol-’ for the current “on” time and 19 kJ mol-’ for the “off” time. The activation energy for the “off” period refers to diffusion of raffinose out of the gel. In contrast, the activation for the “on” period corresponds to the response of shrinking of the gel plus diffusion of raffinose caused by compression of the gel. Thus, the release rate of raffinose in the “on” period is largely governed by forced convection. However, further experimental investigation is necessary for quantitative understanding of the process. In a similar manner, a release test of Pi1 was carried out using PMAA gel, and the result is shown in Fig. 4. An increased rate of Pi1 release

-5 DC:on

a

-10

c -! 0C:off

-15 I

I

3

4 l/T

( x10--3)

Fig. 3. Logarithmic dependence of the rate of raffinose release on the reciprocal temperature.

0

1

2 Time

3

4

I h

Fig. 4. Time profile of Pi1 release from PMAA gel at 5°C; field strength= PMAA

12 V cm-‘;

current

density 5.3 mA cm-‘.

gel 10 X 10X 10 mm in water,

amount

of Pi1 en-

trapped 8.3 X lo-” mol.

was also observed, and the ratio of the release rates in the “on” and “off” periods was 7 at 5°C. Release of Pil from NaPAA

microparticles

Microparticles of the crosslinked sodium salt of poly (acrylic acid) with a diameter of 150300 pm undergo reversible shrinkage when a d.c. electric field is applied [ 161. The rate of volume change is proportional to the current density. The shrinkage is rapid, and a 96% volume change took place within 50 s with application of a d.c. of 0.3 mA cme2. The shrinkage of the particles in the present case is explained by the same reasoning as previously, i.e. a negatively charged microparticle moves to the anode, and the sodium counter-ions of the particle move to the cathode owing to electrophoretic migration. In other words, an electric field gradient will produce a steady diffusion of mobile cations and carry sodium ions away from carboxylate ions. Carboxylate anions, in turn, are largely undissociated. The carboxyl groups in this state become much less hydrated, and the gel consequently contracts. Figure 5a and b shows the changes in concentration of Pi1 released from NaPAA micropartitles as a function of time. A rapid and sharp increase in concentration of Pi1 was observed when the electric field was applied. The rate of

259 (a) 3.0

0 0

10

20 Time

30

40

i min

(b) 8.0

.________I______

0

10

_;_--

20

30

---

_____-_-,---i ‘ 40

50

Time / min

Fig. 5. Time profiles of Pi1 release from PAA microparticles; fieldstrength: (a) 3.3 Vcm-‘; (b) 5.6 Vcm-‘; (c) 5.6 V cm-‘; current density: (a) 8.8pA cmM2; (b) 25fi cmT2; (c) 25 PA cmm2 in the presence of 5.1 X 1O-4mol 1-r of Pi1 in the external solution. Weight of dry microparticles 7.4 x 10e5 g, water 4 ml, amount of Pi1entrapped 2.5 x 10e7 mol. Dotted lines indicate the spontaneous release of Pi1 without application of d.c.

Pi1 release during the field “on” time was 9.8x 10e7 mol dmm3 s-l, which exceeded 5.4fold the rate during the “off” time (1.8 x low7 mol dme3 s-i). The rate of release increased with increasing electric field, and the rate of Pi1 release at 5.6 V cm-’ was about 4 times that at 3.3 V cm-‘. This factor coincided with the ratio of the rate of contraction of microparticles at 5.6 and 3.3 V cm-” 1161. The spon~neous release curve in Fig. 5 shows the zero order is associated with relatively low concentration of Pi1 in the gel and low velocity of Pi1 release. When the Pi1 concentration in the gel becomes relatively low compared with that in the external solution due to repeated “on” and “off’ cycles, a reverse flow from the external solution back into the gel is observed (Fig. 5~). This experimental result may be associated with the fact that the microparticle recovers its original size when the electric field is switched off. While the initial Pi1 concentration inside the gel particle is fairly high, a back-flow of the Pi1 from the external solution is unlikely to occur. However, when the alternate “on” and “off” cycles are repeated and the concentration of Pi1 inside the gel becomes low (and that of the external solution becomes high), a counter flow takes place from the external solution back into the gel. Thus, in order to achieve a constant outflow of the drug from the microparticles the concentration gradient must be made high enough to prevent this back-flow. It should be noted that Pi1 is a ionizable molecule and undergoes electrophoretic migration toward the cathode under an electric field. In order to confirm that Pi1 release occurred due to chemomechanical shrinkage of the gel particle and not to electrophoresis, glucose was entrapped into the gel and a release test of glucose was carried out. Glucose has no ionizable moiety and sustains no electrophoretic transport. As shown in Fig. 6, glucose initially “flashed out” of the particles on applying an electric field, and the release rate of glucose in the first “on” period was 45 times larger than that in the following “off” time. Thus it is evident that the re-

260

0

15

30 Time

45 / min

60

75

Fig. 6. Time profiles of glucose release from PAA microparticles; field strength 10 V cm-‘; current density 0.9 mA cm-’ Weight of dry microparticles 1.2 x 10m4 g, water 4 ml, amount of glucose entrapped 6.0 x lo-’ mol. Fig. 8. Dependence of the rate of Pi1 release on voltage. Weight of dry microparticles 1.2 x lo-” g, water 4 ml, amount of Pi1 entrapped 4.0~ lo-@ mol.

0

0 0.2

"E

0.'

0

10

, 20

.I ,I .I . 30 40 50 60 70 Time / min.

' ci 0 G :: -0.1 : 80

90

100

Fig. 7. Time profile of Pi1 release and electric current; field strength 5.6 V cm-‘; current density 50 ,uA cm-‘. The cell shown in Fig. lb was used. Weight of dry microparticles 1.2X 10m5g, water 4 ml, amount of Pi1 entrapped 4.0 X 10e8 mol.

lease occurred by means of chemomechanical change in the size of the particles, associated with forced convection. The rate decreased gradually with repeated application of electric field, presumably due to rapid consumption of the glucose. Time profiles of amount of Pi1 release and current applied are shown in Fig. 7. The rather steady release and back-flow of Pi1 are repeated after the first “on” period. A less intense second flow of Pi1 is also seen, and this may possibly be related to the counter e.m.f. that appears after switching off the current. In addition, it can be seen that an outflow of Pi1 always takes place

with a certain time-lag after switching on the electric current, implying that the Pi1 release occurs only after the particle has undergone a certain dimensional change. Figure 8 shows the dependence of the rate of Pi1 release on the voltage applied. Significant and linear increase in the rate of Pi1 release is seen with an increase in the potential gradient from 1.7-2.8 V cm-‘; however, the effect later tends to saturate. No release of Pi1 occurred at all below 1.1 V cm-‘, since chemomechanical shrinkage of the microparticle occurs by the electrokinetic process described before, and below the threshold voltage which induces the electrochemical reaction (electrolysis of water), no contraction of the particle takes place. Release of insulin from PDMAPAA

gel

As is well known, an artificial device for delivering insulin for a prolonged period of time at a constant level in the body is extremely important. Most current insulin therapies involve subcutaneous injections one or more times each day. However, subcutaneous injection results in localized insulin accumulation, which eventually leads to local hypertrophy and fat deposits under the skin. At the same time, insulin injec-

261

tion therapy for diabetics suffers problems in controlling the glucose level. Insulin levels become higher than normal levels immediately after injection and become lower later. This rather poor control of glucose level induces a variety of degenerative conditions, including retinopathy, nephropathy, cardiovascular complications and others. We have previously reported that a polymer gel prepared from a weak polyacid, for example PMAA, when immersed in water or in salt solution is able to expand when two polarized electrodes face each other at a certain distance from the gel [ 181 (Fig. lc ) . The phenomenon was explained in terms of the similar ion-transport process i.e., mobile cations migrate by electrophoresis towards the cathode and penetrate into the swollen PMAA network. This induces an ionization of carboxyl groups and causes the part of the gel facing the anode to swell. The reverse observation was made for a gel prepared from a polybase, such as PDMAPAA, i.e., the anions travel toward the anode and ionize the amino group of the gel, which induces swelling of the part of the gel facing the cathode. In the case of the gel immersed in water, the electric field forces out hydrogen ions toward the cathode and induces the ionization of carboxyls. Thus, polymer gels prepared from a weak polyelectrolyte undergo asymmetric swelling when they are placed in fluid facing the electrodes and at a certain distance. This swelling process of the gel was utilized in controlling the release of insulin. In this case the principle is different from the previous examples, because the agent is released due to expansion of the gel network, which allows the drug to diffuse out more easily. Insulin is a protein with a molecular weight of 5735 g mol-‘. In order to achieve enhanced release of such macromolecules out of the gel, the expansion of the crosslinked network structure (swelling of the gel) is more suitable than contraction. Insulin was entrapped into the PDMAPAA gel by the same procedure and electro-stimulated control of delivery was made, As seen in

Fig. 9, a periodic and constant “on” and “off” release of the protein molecule was obtained by numerous alternate applications of an electric field. The response of the gel is quite sharp and no leakage of the insulin during the “off” time was observed. This is because the insulin molecules [ 191 are largely ionized in the polybase gel (isoelectric point of insulin = 5.30435 [ 191 and can undergo electrostatic interaction with the amino groups of PDMAPAA. When the insulin is entrapped in a polyanion gel such as PMAA or Ca-ALG and a release test is carried out in a similar manner, a considerable amount of leakage is observed. So far as the authors know, little work has been done on the control of drug delivery by electrical stimulus [ 131. This kind of DDS has the advantage that the release rate can be easily controlled just by switching on and off the electric field and by changing the ma~itude of the electric current. Detailed analysis of the diffusion process and the more complete “cut-off”

0

20

40 Time

60 80 / min

100

120

Fig. 9. Time profile of insulin release from PDMAPAA gel by alternate “on” and “off” periods at 3.3 V cm-‘; current density 1.3 mA cm-*. PDMAPAA gel 3 x 3 x 3 mm, water 3 ml, amount of insulin entrapped 2.4 x lo-” mol. Duration of “on” periods: first 5: 1 min; following 5: 2 min; last 3: 3 min.

262

control of release without further investigation.

leakage remain

for

8

9

CONCLUSIONS

An electrically stimulated DDS using polyelectrolyte gels was demonstrated. The principle of the controlled delivery of the bioactive agent is based on the chemomechanical shape change (both shrinkage and contraction of the gel) under an electric field. It has been shown that, in principle, the velocity and amount of release can be controlled by the intensity of the electric field applied.

10

11

12

13

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