# Fast Drug Release Using Rotational Motion of

Authors: Tetsu Mitsumata; Yusuke Kakiuchi; Jun-Ichi Takimoto
Journal: Research Letters in Physical Chemistry
 (2008)

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## Abstract

Accelerated drug release has been achieved by means of the fast rotation of magnetic gel beads. The magnetic gel bead consists of sodium alginate crosslinked by calcium chlorides, which contains barium ferrite of ferrimagnetic particles, and ketoprofen as a drug. The bead underwent rotational motion in response to rotational magnetic fields.   In the case of bead without rotation, the amount of drug release into a phosphate buffer solution obeyed non-Fickian diffusion. The spontaneous drug release reached a saturation value of 0.90 mg at 25 minutes, which corresponds to 92% of the perfect release.   The drug release was accelerated with increasing the rotation speed.   The shortest time achieving the perfect release was approximately 3 minutes, which corresponds to 1/8 of the case without rotation.   Simultaneous with the fast release, the bead collapsed probably due to the strong water flow surrounding the bead.   The beads with high elasticity were hard to collapse and the fast release was not observed.   Hence, the fast release of ketoprofen is triggered by the collapse of beads.   Photographs of the collapse of beads, time profiles of the drug release, and a pulsatile release modulated by magnetic fields were presented.


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## Body

## 1. Introduction

Many systems of
drug release have been fabricated using polymer gel. Polymer gel is a material
of open system, and is able to transport drug molecules through crosslinked
network of the gel. According to this, spontaneous slow (sustained)
release can be achieved. The sustained
release is caused by the osmotic pressure differenceπin−πout at the inside and outside of the gel [1]   Furthermore,
a novel drug delivery system (DDS) was developed by means of various stimuli-responsive
polymers. Polymer gels synthesized with the
stimuli-responsive polymers undergo a volume phase transition in response to
stimuli such as temperature, solvent, or pH. When the gel achieved the volume phase transition, additional pressures are generated on the gel. Owing
to the additional pressure contributed from the mixing πmix and
elastic πel energies
[1], the drug release is accelerated. Thus, the accelerated release of drugs is attributed
to the volume contraction triggered by the additional pressures.Various stimuli-responsive gels responding to
temperature, pH, electric field, chemicals, and UV light have been employed to
fabricate the novel drug delivery system. Poly(N-isopropylacrylamide) (PNIPA) gel is well known for a temperature-sensitive
gel which exhibits a volume phase transition originating from the lower
critical solution temperature. PNIPA
gel copolymerized with alkyl methacrylates demonstrates complete on-off release
of indometacin in response to stepwise temperature changes between 20 and 30°C
[2, 3]. The regulated drug release is explained by
the squeezing mechanism [4]. A pulsatile release of ketoprofen occurs when the gel was cycled in buffer solutions between pH 3.0 and pH 6.5 [5]. It has been shown
that protein lysozyme is released from the carboxy methyl dextran hydrogel
membranes in the pH range of 6.5–9.0 [6]. Electrically stimulated drug
release of pilocarpine hydrochloride, glucose, and insulin has been fabricated
using chemomechanical shrinking and swelling of polyelectrolyte gels under
electric fields [7]. A sharp pulsatile release of glucose from a
microcapsule of plant lectin has also been demonstrated based on the concept of
competitive binding [8]. An on-off
modulation for protein permeation by UV irradiation has been constructed by an
azoaromatic polymer membrane [9]. In the
present study, we attempted to construct the new system of drug delivery using
magnetic gels responding to magnetic fields.It has been
reported that the magnetic gel undergoes a variety of motion under magnetic
fields. For example, the magnetic gel
consisting of magnetic fluids shows elongation by means of the gradient of
magnetic field [10, 11], and
it has been applied for a fluid valve [12]. Carrageenan
magnetic gel containing magnetic particles presents an isotropic deformation
under uniform magnetic fields [13]. Recently, we found that the magnetic gel
consisting of sodium alginate and barium ferrite particles demonstrates a
rotational motion in response to rotational magnetic fields [14, 15]. Using the rotational motion of the magnetic
gel, we have succeeded in the fast and controllable release of ketoprofen from
the magnetic bead. The release behavior
is briefly reported and the mechanism of the fast release is discussed.


## 2. Experimental Procedures

### 2.1. Synthesis of Magnetic Beads

The bead of magnetic
gels consists of Sodium alginate (Wako Chemicals, Osaka, Japan) as gel
matrices, barium ferrite (BaFe12O19) (Sigma-Aldrich Co., Mo, USA) as magnetic particles,
and (2RS)-2-(3-Benzoylphenyl)propanoic
acid (ketoprofen) (Saitama Daiichi
Pharmaceutical Co., LTD., Saitama,
Japan) as drugs. The
chemical structure of ketoprofen is shown in the inset of Figure 2. A pre-gel solution consisting of sodium
alginate (0.3 wt.%), barium ferrite (3.0 wt.%), and ketoprofen (9.0 wt.%) was
prepared. The ketoprofen was dissolved
in methanol before mixing these chemicals. The magnetic gel beads were obtained by dropping the pre-gel solution in
a methanol/water mixed solvent containing CaCl2 (3.0 wt.%). The concentration of methanol in the mixed
solvent was 30 vol.%. The obtained
beads were stocked in a beaker filled with pure water. The mean diameter of a magnetic particle was
determined as 15μm by using a Particle size analyzer (Mastersizer 2000, Malvern Instruments, Malvern, UK). The bead was irradiated by a 1 T magnetic
field for 1 minute in order to give the bead a remanent magnetization.


### 2.2. UV Measurements

The absorbance
at 280 nm was measured using a UV spectrometer (Shimazu UVmini-1240). The measurement was carried out using a flow
cell at room temperature. The total
volume of the sample space of the flow cell including a flow tube was 34.9 mL. The flow rate was constant to be 46 mL/min. We evaluated the amount of drug released
from the gel by the absorbance at 280 nm. The absorbance (Abs) showed linear
relationship with the concentration of ketoprofencKP;Abs=284.06×cKP. The data presented in this paper is the drug
release in a phosphate buffer solution. The buffer solution was prepared by dissolving potassium hydrogen
phosphate (0.8 wt.%, Wako Chemicals) and sodium dihydrogenphosphate (1.5 wt.%,
Wako Chemicals) in pure water.


### 2.3. Microscope Observations

Microscope observations were
carried out using a microscope (Digital microscope VHX-900, VH-Z00R, Keyence Co., Osaka, Japan).


## 2.1. Synthesis of Magnetic Beads

The bead of magnetic
gels consists of Sodium alginate (Wako Chemicals, Osaka, Japan) as gel
matrices, barium ferrite (BaFe12O19) (Sigma-Aldrich Co., Mo, USA) as magnetic particles,
and (2RS)-2-(3-Benzoylphenyl)propanoic
acid (ketoprofen) (Saitama Daiichi
Pharmaceutical Co., LTD., Saitama,
Japan) as drugs. The
chemical structure of ketoprofen is shown in the inset of Figure 2. A pre-gel solution consisting of sodium
alginate (0.3 wt.%), barium ferrite (3.0 wt.%), and ketoprofen (9.0 wt.%) was
prepared. The ketoprofen was dissolved
in methanol before mixing these chemicals. The magnetic gel beads were obtained by dropping the pre-gel solution in
a methanol/water mixed solvent containing CaCl2 (3.0 wt.%). The concentration of methanol in the mixed
solvent was 30 vol.%. The obtained
beads were stocked in a beaker filled with pure water. The mean diameter of a magnetic particle was
determined as 15μm by using a Particle size analyzer (Mastersizer 2000, Malvern Instruments, Malvern, UK). The bead was irradiated by a 1 T magnetic
field for 1 minute in order to give the bead a remanent magnetization.


## 2.2. UV Measurements

The absorbance
at 280 nm was measured using a UV spectrometer (Shimazu UVmini-1240). The measurement was carried out using a flow
cell at room temperature. The total
volume of the sample space of the flow cell including a flow tube was 34.9 mL. The flow rate was constant to be 46 mL/min. We evaluated the amount of drug released
from the gel by the absorbance at 280 nm. The absorbance (Abs) showed linear
relationship with the concentration of ketoprofencKP;Abs=284.06×cKP. The data presented in this paper is the drug
release in a phosphate buffer solution. The buffer solution was prepared by dissolving potassium hydrogen
phosphate (0.8 wt.%, Wako Chemicals) and sodium dihydrogenphosphate (1.5 wt.%,
Wako Chemicals) in pure water.


## 2.3. Microscope Observations

Microscope observations were
carried out using a microscope (Digital microscope VHX-900, VH-Z00R, Keyence Co., Osaka, Japan).


## 3. Results and Discussion

Figure1 shows the time course of the shape of magnetic gel beads showing
rotational motion. As seen in Figure 1(a),
the bead was turbid and it had a shape of sphere with rough surface. Sodium alginate was soluble in water;
however ketoprofen was insoluble in water, but soluble in methanol. Immediately after mixing the sodium alginate
aqueous solution and ketoprofen/methanol one, the mixed solution was clouded. The solution was stable in emulsion and it did not show any
precipitation. It is considered that
the emulsion directly gelled by an addition of calcium chloride. The diameter of the bead decreased with an
elapse of the rotation time (Figures 1(b)–1(d)). The bead was collapsed and disappeared 3 minutes after starting
rotation. This strongly suggests that
the bead is easy to collapse by the strong water flow induced by the rotation. Only magnetic particles tied each other and
remained in the buffer solution. Magnetic particles embedded in the bead did not disperse in the solution
and made a string because each particle has magnetic poles.Figure 1
Schematic
illustration of the geometry of magnetic gel bead and permanent magnet. Photographs
representing the collapse of magnetic gel beads by rotational motion with 5000 rpm: (a) 0 minute, (b) 0.5 minute, (c) 1.0 minute, (d) 1.5 minutes.Figure 2
Time profile
of the ketoprofen release for a magnetic gel bead (sodium alginate: 0.3 wt%,
ketoprofen: 5 wt%, barium ferrite: 3 wt%). The bead rotated (5000 rpm) at the time
indicated by the arrow.Figure2 shows the effect of rotation on the time profile of the ketoprofen
release from the beads. The bead was
not rotated till 5 minutes and was rotated at the time indicated by the
arrow. Ketoprofen was soluble in not
only methanol but also phosphate buffer solution (pH~6). Below the time of 5 minutes, the gradual increase
in the ketoprofen release was due to spontaneous release from the bead. The bead maintained its spherical shape and
the size was not changed. At 5 minutes,
it was observed that the ketoprofen release dramatically increased simultaneous
with the rotation. Furthermore, the
bead was observed to be collapsed remarkably by rotation as shown in the
photographs in Figure 1. Therefore, the
increase in the ketoprofen release is not attributed to the squeezing effect of
drug molecules by volume changes, which has been employed in the drug delivery
of polymer gels. Probably the bead was
collapsed by strong water flow at the interface between the bead and water
generated by the rotation; as a result, the ketoprofen was rapidly released
from the bead. Beads were rich in
elastic modulus when the concentration of sodium alginate increased. The beads with high elasticity were hard to
collapse, and the amount of ketoprofen release has not reached high value seen in Figure 2. The rapid release of ketoprofen was not seen
in a magnetized bead without rotation. This
means the rapid release was not caused by the collapse due to the magnetic
attractive force between magnetic particles. For
example, when the concentration of sodium alginate was 2 wt.%, the amount of
ketoprofen released from the gel was 0.16 mg at 5 minutes, which equals
entirely the value without rotation. These results strongly suggest that the fast
release of ketoprofen is triggered by the collapse of beads.Figure3 shows the time profiles of the amount of ketoprofen released from the
beads with various rotation rates. Generally, drug release from swellable polymer Mt can be described by the following empirical equation [16]:(1)MtM∞=ktn,where M is the drug release at equilibrium state. Also, k, t, and n are the rate constant, time,
and the order of drug release, respectively. In the case of Fickian diffusion, the diffusion obeys Fick’s second law
and the order n in (1) is equal to 0.5. In the case of bead without rotation, the
drug release was explained by the above empirical equation. The order n was estimated to be 0.6, indicating anomalous (non-Fickian)
diffusion. The saturation value of the
ketoprofen released from the bead was approximately 0.90 mg, which was seen at
25 minutes after starting rotation. When
the rotation speed was 2500 rpm, the drug release increased and reached the
saturation value at 12 minutes. At 5000 rpm of the maximum rotation speed, the drug release was further accelerated and
achieved the saturation at only 3 minuttes. All beads collapsed before the
ketoprofen release reaches to the saturation value. A bead was ground by a mortar and dissolved
in the buffer solution in order to estimate the maximum value (perfect release)
of ketoprofen in the bead; the estimated value was 0.97±0.03 mg. This value was in good agreement with the
saturation values seen in Figure 3. This means that the most of ketoprofen embedded
in the bead (>90%) was released into the buffer solution by the fast
rotation.Figure 3
Time profiles of the ketoprofen release for the
beads with various rotation rates; (∘): 0 rpm,  (□): 2500 rpm, (⋄): 5000 rpm (sodium
alginate: 0.3 wt%, ketoprofen: 9 wt%, barium ferrite: 3 wt%).Figure4 shows the pulsatile release of ketoprofen from the beads upon changes of on/off rotation. Increase in the ketoprofen release during the
first 2 minutes is clearly caused by the spontaneous release. It is considered that the release rate due
to the spontaneous release corresponds to 4.0×10−2 g/g/min.   After 2 minutes, a pulsatile drug release
synchronized with the rotation of beads was observed. The drug delivery system undergoing
pulsatile release has been mainly constructed by using temperature responsive
gels. In the temperature responsive
drug delivery, the temperature of the environment surrounding the gel has to be
changed by heating. Accordingly, it must
take a considerable
time to modulate the drug release. The
drug release controlling by electric stimulus can be modulated within several
minutes, however the system needs electrical wires to supply electric power to
the gel. The drug delivery system
presented here showed drug release without lag time because the magnetic force directly
acts on the gel. Although it is
needless to say that the collapse of beads by water flow also plays an important
role of the first release.   Thus the pulsatile release by using magnetic field was
demonstrated by the present study.Figure 4
Release of
ketoprofen from the beads in response to stepwise rotation speeds between 0 and
5000 rpm (sodium alginate: 0.3 wt%, ketoprofen: 9 wt%, barium ferrite: 3 wt%).


## 4. Conclusion

Drug delivery system controlled
by magnetic fields has been constructed by means of the fast rotation of
magnetic gel beads. The
magnetic gel bead consists of sodium alginate crosslinked by calcium chlorides,
which contains barium ferrite of ferrimagnetic particles, and ketoprofen as a
drug. The bead underwent rotational motion in response to rotational magnetic
fields. In the case of bead without
rotation, the amount of drug release showed non-Fickian diffusion. When the bead was rotated, the drug release
rapidly increased and reached the perfect release shortly. The drug release was accelerated with
increasing the rotation speed. The
shortest time achieving perfect release was approximately 3 minutes, which
corresponds to 1/8 of the time without rotation. Simultaneous with the fast
release, the bead was collapsed probably due to the strong water flow
surrounding the bead. The beads with high elasticity were hard to
collapse and the fast release was not observed. Hence, the fast release of ketoprofen is triggered
by the collapse of beads, not by the squeezing effect of drug that has been
employed in the drug delivery of polymer gels in the past. We
also succeeded in pulse release of the drug controlled by the magnetic field. The drug delivery system presented here has
an advantage of the drug release without ragtime because the magnetic force
directly acts on the gel. In addition,
no electric wires for modulating the drug release are needed for this system. If the magnetic bead can be delivered to the
target such as cancer tissues, intensive drug release only around the target
will be possible. Magnetic beads presented here would have a great potential
as a new capsule of drugs without harmful side effects.



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*Source: 671642-2008-03-26.xml*