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Citation: Nowak, A.; Ossowicz-
Rupniewska, P.; Konopacki, M.;
Muzykiewicz-Szyma´nska, A.;
Kucharski, Ł.; Rakoczy, R. Assessing
the Influence of a Rotating Magnetic
Field on Ibuprofen Permeability from
Diverse Pharmaceutical Formulations.
Sci. Pharm. 2024,92, 4. https://
doi.org/10.3390/scipharm92010004
Academic Editor: Susi Burgalassi
Received: 18 November 2023
Revised: 12 December 2023
Accepted: 21 December 2023
Published: 29 December 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Scientia
Pharmaceutica
Article
Assessing the Influence of a Rotating Magnetic Field on Ibuprofen
Permeability from Diverse Pharmaceutical Formulations
Anna Nowak 1, Paula Ossowicz-Rupniewska 2, * , Maciej Konopacki 3, Anna Muzykiewicz-Szyma ´nska 1,
Łukasz Kucharski 1and Rafał Rakoczy 3, *
1Department of Cosmetic and Pharmaceutical Chemistry, Pomeranian Medical University in Szczecin,
Powsta´nców Wielkopolskich Ave. 72, 70-111 Szczecin, Poland
2Department of Chemical Organic Technology and Polymeric Materials, Faculty of Chemical Technology and
Engineering, West Pomeranian University of Technology in Szczecin, Piastów Ave. 42, 71-065 Szczecin, Poland
3Department of Chemical and Process Engineering, Faculty of Chemical Technology and Engineering, West
Pomeranian University of Technology in Szczecin, Piastów Ave. 42, 71-065 Szczecin, Poland
*Correspondence: possowicz@zut.edu.pl (P.O.-R.); rrakoczy@zut.edu.pl (R.R.)
Abstract: This study introduces a novel approach for enhancing the transdermal permeability of
ibuprofen through the skin by utilising a rotating magnetic field (RMF). The core objective is to
systematically evaluate the influence of a 50 Hz RMF on ibuprofen’s skin permeability across various
formulation types, each employing distinct physical forms and excipients. The experimental setup
involved Franz cells with skin as the membrane, exposed to a 50 Hz RMF in conjunction with specific
formulations. Subsequent comprehensive analysis revealed a notable increase in the transdermal
transport of ibuprofen, irrespective of the formulation employed. Notably, the differences in the
initial 30 min of permeation were particularly pronounced. Crucially, this investigation establishes
that the application of a 50 Hz RMF resulted in a remarkable over-sevenfold increase in ibuprofen
permeability compared to the control group without RMF exposure. It is noteworthy that in all
semi-solid pharmaceutical formulations tested, RMF effectively reduced the delay time to zero, un-
derscoring the efficiency of RMF in overcoming barriers to transdermal drug delivery. This research
positions the application of RMF as a highly promising and innovative technology, significantly
enhancing the transdermal penetration of anti-inflammatory and analgesic drugs through the skin.
The demonstrated effectiveness of RMF across diverse formulations suggests its potential in transder-
mal drug delivery, offering a novel and efficient strategy for improving therapeutic outcomes in the
administration of ibuprofen and potentially other pharmaceutical agents.
Keywords: electromagnetic field; rotating magnetic field; active pharmaceutical ingredients;
nonsteroidal anti-inflammatory drugs; ibuprofen; transdermal drug delivery; skin barrier
1. Introduction
The delivery of pharmaceutical agents through biological barriers, including the skin,
is an intriguing facet of active substance transport. This non-invasive approach offers
numerous advantages, such as bypassing hepatic metabolism, reducing degradation risks
in the gastrointestinal tract, and minimising unwanted interactions with food components
or other medications. It is particularly valuable in managing chronic diseases by reducing
the dosing frequency for drugs with short biological half-lives. However, the skin’s barrier
properties pose inherent challenges, restricting substance permeability [1–8].
Various strategies have been devised to enhance the transport of therapeutic sub-
stances through the skin, including molecular modifications, formulation selection, and
barrier property alterations. Non-invasive techniques utilising magnetic fields have also
been explored, offering promise for efficient drug delivery without the need for invasive
procedures [9–11].
Sci. Pharm. 2024,92, 4. https://doi.org/10.3390/scipharm92010004 https://www.mdpi.com/journal/scipharm
Sci. Pharm. 2024,92, 4 2 of 11
Traditional methods in this field often employ constant magnetic fields, necessitating
the use of strong magnets near the biological barrier to create a magnetic field gradient.
While effective, they require separating active substances from magnetic carriers, which
can be challenging. In contrast, a pulsed magnetic field, exemplified by the dermaportation
system, surrounds the biological membrane with a magnetic coil. This approach limits the
magnetic field’s influence on the biological barrier, but it does not affect active substances,
limiting its effectiveness [12].
It is noteworthy that there is a conspicuous gap in the existing body of research
concerning the utilisation of a rotating magnetic field in drug delivery. This unconventional
method harnesses electric fields induced by the magnetic field, propelling active substances
and facilitating their movement across biological barriers, such as the skin. The potential
of the rotating magnetic field to augment drug transport introduces a novel dimension
to pharmaceutical science, holding the promise of overcoming prevailing limitations and
enhancing therapeutic outcomes.
The impetus behind our exploration of this novel approach lies in its apparent novelty
and the perceived unexplored potential it presents. The unique ability of the rotating
magnetic field to induce electric fields led us to hypothesise that this method could of-
fer a distinct and efficient mechanism for propelling active substances across biological
barriers. This anticipation of transformative benefits prompted our investigation into the
potential advantages of the rotating magnetic field, adding a layer of scientific curiosity to
its exploration.
In this study, we thoroughly examine the impact of the rotating magnetic field on the
permeability of ibuprofen from various pharmaceutical formulations. This investigation
highlights the method’s potential as a non-invasive drug delivery approach with broad
clinical applications. The novelty of our research lies in the application of a rotating mag-
netic field to enhance drug permeability through the skin. Specifically, we employed a
50 Hz rotating magnetic field, and commercially available preparations containing ibupro-
fen served as our model drug. The rotating magnetic field method offers distinct advantages
over traditional permeability-enhancing techniques, particularly in its non-invasiveness,
unique mechanism of action, and practical considerations.
2. Results
Owing to its numerous advantages, transdermal drug delivery stands as an intriguing
alternative to the oral route. Regrettably, this method of drug administration is not without
its share of challenges, primarily linked to the restricted passage of active pharmaceutical
ingredients (API) through the protective skin barrier. This study presents research findings
that explore the application of a rotating magnetic field in enhancing the permeability of
ibuprofen through the skin. Four different commercially available formulations containing
ibuprofen were employed in the investigation. The study examined the permeability
of ibuprofen through pigskin both in the presence (MF—magnetic field) and absence
(C—control) of exposure to a rotating magnetic field. A comparative analysis of the
permeability results between the magnetic field-assisted and control conditions is illustrated
in Figure 1.
The permeability of the active substance in tests using a rotating magnetic field is
significantly higher, regardless of the formulation used. It is clear that the permeability
itself depends on the type and composition of the formulation. The highest permeability,
regardless of the tested time point, was obtained for CP_gel_1_MF; after 24 h of testing,
236.099
µ
g/cm
2
IBU permeated from this preparation (Figures 1and 2). In the case of this
preparation, the largest difference between the control sample and the test in the presence
of a magnetic field is visible—an increase of approximately 144 to 695%, depending on the
measurement point. The lowest permeability was obtained for the control permeation from
the patch (CP_patch_1_C), 50.993
µ
g/cm
2
IBU after 24 h of testing, an increase compared
to the control sample of approximately 37 to 127%. Analysing all time points at which
the acceptor fluid was collected for analysis, the highest penetration was observed for
Sci. Pharm. 2024,92, 4 3 of 11
CP_gel_1_PM and CP_gel_2_PM. These compounds form a separate group that differs
significantly from the others (Figure 3).
Sci. Pharm. 2023, 91, x FOR PEER REVIEW 3 of 11
of a magnetic field is visible—an increase of approximately 144 to 695%, depending on the
measurement point. The lowest permeability was obtained for the control permeation
from the patch (CP_patch_1_C), 50.993 µg/cm
2
IBU after 24 h of testing, an increase
compared to the control sample of approximately 37 to 127%. Analysing all time points at
which the acceptor fluid was collected for analysis, the highest penetration was observed
for CP_gel_1_PM and CP_gel_2_PM. These compounds form a separate group that differs
significantly from the others (Figure 3).
Figure 1. IBU permeation profiles from different formulations with (MF) and without (C) rotating
magnetic field exposure. The values are the means with standard deviation; n = 3.
CP_gel_1_C
CP_gel_1_MF
CP_cream_1_C
CP_cream_1_MF
CP_gel_2_C
CP_gel_2_MF
CP_patch_1_C
CP_patch_1_MF
-20
0
20
40
60
80
100
120
140
160
180
200
220
Average
Ave rage ± S tandard e rror
Average ± Standard deviation
Figure 2. Box-plot of cumulative mass of IBU throughout the entire 24 h study with and without
rotating magnetic field exposure.
Figure 1. IBU permeation profiles from different formulations with (MF) and without (C) rotating
magnetic field exposure. The values are the means with standard deviation; n= 3.
Sci. Pharm. 2023, 91, x FOR PEER REVIEW 3 of 11
of a magnetic field is visible—an increase of approximately 144 to 695%, depending on the
measurement point. The lowest permeability was obtained for the control permeation
from the patch (CP_patch_1_C), 50.993 µg/cm
2
IBU after 24 h of testing, an increase
compared to the control sample of approximately 37 to 127%. Analysing all time points at
which the acceptor fluid was collected for analysis, the highest penetration was observed
for CP_gel_1_PM and CP_gel_2_PM. These compounds form a separate group that differs
significantly from the others (Figure 3).
Figure 1. IBU permeation profiles from different formulations with (MF) and without (C) rotating
magnetic field exposure. The values are the means with standard deviation; n = 3.
CP_gel_1_C
CP_gel_1_MF
CP_cream_1_C
CP_cream_1_MF
CP_gel_2_C
CP_gel_2_MF
CP_patch_1_C
CP_patch_1_MF
-20
0
20
40
60
80
100
120
140
160
180
200
220
Average
Ave rage ± S tandard e rror
Average ± Standard deviation
Figure 2. Box-plot of cumulative mass of IBU throughout the entire 24 h study with and without
rotating magnetic field exposure.
Figure 2. Box-plot of cumulative mass of IBU throughout the entire 24 h study with and without
rotating magnetic field exposure.
In the case of ibuprofen and other pain-relief medications, expeditious skin permeation
is desirable to expedite the therapeutic response. This urgency arises from the fact that
swift and enhanced permeation leads to a more rapid reduction in inflammation within
the underlying tissues [
13
]. Figure 4displays the permeation rate calculated for each
time interval. Typically, the highest permeation rate into the acceptor fluid was observed
in samples obtained during the initial phase of the experiments, particularly within the
first hour. Consequently, this suggests that the pain-relief effect will manifest promptly
under such conditions. The highest permeation rate into the acceptor fluid for semi-solid
Sci. Pharm. 2024,92, 4 4 of 11
formulations, when subjected to a magnetic field, was consistently observed within the
initial hour of the experiments. Consequently, this implies a notably rapid onset of the
pain-relief effect. In contrast, the control trial, which reached its maximum penetration rate
between 3 and 6 h, would entail a prolonged waiting period for patients, and there is even
the possibility of the drug being inadvertently rubbed off the skin before it fully penetrates.
Interestingly, even after the same time frame, the test utilising a magnetic field maintained
a slightly higher permeation rate than the control test. Comparatively, peak permeation
rates were achieved over an extended testing period when examining solid formulations.
In this instance, akin to the semi-solid variant, testing in the presence of a magnetic field
led to an increase in permeation rate, albeit with the highest rate being reached after a more
extended period, specifically after 6 h. Importantly, when employing a medical patch, there
is no risk of unintentionally removing the medication from the skin surface until it has been
intentionally taken off.
Sci. Pharm. 2023, 91, x FOR PEER REVIEW 4 of 11
0 20 40 60 80 100 120 140 160
Cumulative pe rmeation mass [µg /c m
2
]
CP_ge l_2_MF
CP_ge l_1_MF
CP_ge l_2_C
CP_crea m_1_MF
CP_pa tch_1_C
CP_pa tch_1_MF
CP_crea m_1_C
CP_ge l_1_C
Figure 3. Cluster analysis graph for the mean accumulated mass of IBU throughout the 24 h study
with and without rotating magnetic field exposure. The compounds that penetrate best throughout
the 24 h study form a separate cluster (red circle).
In the case of ibuprofen and other pain-relief medications, expeditious skin
permeation is desirable to expedite the therapeutic response. This urgency arises from the
fact that swift and enhanced permeation leads to a more rapid reduction in inflammation
within the underlying tissues [13]. Figure 4 displays the permeation rate calculated for
each time interval. Typically, the highest permeation rate into the acceptor fluid was
observed in samples obtained during the initial phase of the experiments, particularly
within the first hour. Consequently, this suggests that the pain-relief effect will manifest
promptly under such conditions. The highest permeation rate into the acceptor fluid for
semi-solid formulations, when subjected to a magnetic field, was consistently observed
within the initial hour of the experiments. Consequently, this implies a notably rapid onset
of the pain-relief effect. In contrast, the control trial, which reached its maximum
penetration rate between 3 and 6 h, would entail a prolonged waiting period for patients,
and there is even the possibility of the drug being inadvertently rubbed off the skin before
it fully penetrates. Interestingly, even after the same time frame, the test utilising a
magnetic field maintained a slightly higher permeation rate than the control test.
Comparatively, peak permeation rates were achieved over an extended testing period
when examining solid formulations. In this instance, akin to the semi-solid variant, testing
in the presence of a magnetic field led to an increase in permeation rate, albeit with the
highest rate being reached after a more extended period, specifically after 6 h.
Importantly, when employing a medical patch, there is no risk of unintentionally
removing the medication from the skin surface until it has been intentionally taken off.
The ibuprofen content in the acceptor fluid collected at 0.5 h and 24 h of permeation
is summarised in Table 1. When we analyse the permeation of IBU separately under the
influence of a rotating magnetic field (RMF) and without RMF, it becomes evident that in
the presence of RMF, the cumulative mass determined after 0.5 h of permeation exhibited
the following order: CP_gel_1_MF > CP_cream_1_MF > CP_gel_2_MF > CP_patch_1_MF.
Notably, CP_gel_1_MF had the highest concentration, with a cumulative mass of IBU
measuring 18.163 ± 2.564 µg/cm2. A similar trend persisted for the cumulative mass
determined after 24 h of testing in the presence of RMF, where CP_gel_1_MF also
demonstrated the most significant result, specifically 236.099 ± 26.206 µg/cm2. Conversely,
a slightly different paern emerged in the absence of RMF. Without RMF, the highest
result after 0.5 and 24 h, seen for CP_gel_2_C, amounted to 4.446 ± 1.601 and 113.618 ±
6.159 µg/cm2, respectively.
Figure 3. Cluster analysis graph for the mean accumulated mass of IBU throughout the 24 h study
with and without rotating magnetic field exposure. The compounds that penetrate best throughout
the 24 h study form a separate cluster (red circle).
Sci. Pharm. 2023, 91, x FOR PEER REVIEW 5 of 11
Figure 4. Permeation rate of IBU from different formulations with and without rotating magnetic
field exposure during the 24 h permeation, α = 0.05 (mean ± SD, n = 3).
Table 1. Cumulated mass of IBU from different formulations after 0.5 h and 24 h of the examination
with and without rotating magnetic field exposure; different leers indicate significant differences
between the results obtained using RMF and the control sample; p < 0.05, mean ± SD, n = 3. The
statistically significant difference was estimated by ANOVA using Tukey’s test.
Formulation Cumulative Permeation Mass
After 0.5 h [µg/cm
2
] After 24 h [µg/cm
2
]
Using RMF
CP_gel_1_MF 18.163 ± 2.564
b
236.099 ± 26.206
b
CP_gel_2_MF 9.687 ± 1.368
b
161.329 ± 29.206
a
CP_cream_1_MF 12.477 ± 1.083
b
122.387 ± 9.457
b
CP_patch_1_MF 3.352 ± 0.815
a
69.706 ± 5.054
b
Control samples without the use of RMF
CP_gel_1_C 2.470 ± 0.890
a
96.681 ± 8.988
a
CP_gel_2_C 4.446 ± 1.601
a
113.618 ± 6.159
a
CP_cream_1_C 3.555 ± 0.761
a
73.092 ± 11.716
a
CP_patch_1_C 2.091 ± 0.038
a
50.993 ± 5.524
a
a
compounds characterised by significantly lower permeation;
b
compounds characterised by
significantly higher permeability. The groups after 1 h and after 24 h were analysed separately.
The results of ex vivo permeation experiments evaluating ibuprofen efficiency are
summarised in Table 2. Permeation parameters were calculated, including flux, apparent
permeability coefficient, lag time, diffusion coefficient in the skin, skin partition
coefficient, percent drug permeated after 24 h, and enhancement factor. There was a
noticeable contrast in the steady-state flux depending on exposure to the magnetic field
applied during the research. Ibuprofen exhibited the least penetration (3.01 ± 0.38 µg/cm
2
)
when the rotating magnetic field was not utilised (CP_patch_1_C). This observation is
consistent across all diffusion parameters. Conversely, all the tested semi-solid
formulations showed higher percutaneous flux, with steady-state flux measurements of
4.43 ± 0.36 µg/cm
2
for CP_cream_1_C, 9.26 ± 1.80 µg/cm
2
for CP_gel_1_C, and 18.74 ± 4.45
µg/cm
2
for CP_gel_2_C, respectively. This parameter exhibited significant increases when
RMF was employed, particularly in the case of CP_gel_1_MF, yielding the best results
(30.54 ± 3.42 µg/cm
2
). In the case of CP_gel 1, a significant difference was also
Figure 4. Permeation rate of IBU from different formulations with and without rotating magnetic
field exposure during the 24 h permeation, α= 0.05 (mean ±SD, n= 3).
Sci. Pharm. 2024,92, 4 5 of 11
The ibuprofen content in the acceptor fluid collected at 0.5 h and 24 h of permeation
is summarised in Table 1. When we analyse the permeation of IBU separately under the
influence of a rotating magnetic field (RMF) and without RMF, it becomes evident that in
the presence of RMF, the cumulative mass determined after 0.5 h of permeation exhibited
the following order: CP_gel_1_MF > CP_cream_1_MF > CP_gel_2_MF > CP_patch_1_MF.
Notably, CP_gel_1_MF had the highest concentration, with a cumulative mass of IBU mea-
suring
18.163 ±2.564 µg/cm2.
A similar trend persisted for the cumulative mass determined
after 24 h of testing in the presence of RMF, where CP_gel_1_MF also demonstrated the most
significant result, specifically 236.099
±
26.206
µ
g/cm
2
. Conversely, a slightly different pattern
emerged in the absence of RMF. Without RMF, the highest result after 0.5 and 24 h, seen for
CP_gel_2_C, amounted to 4.446 ±1.601 and 113.618 ±6.159 µg/cm2, respectively.
Table 1. Cumulated mass of IBU from different formulations after 0.5 h and 24 h of the examination
with and without rotating magnetic field exposure; different letters indicate significant differences
between the results obtained using RMF and the control sample; p< 0.05, mean
±
SD, n= 3. The
statistically significant difference was estimated by ANOVA using Tukey’s test.
Formulation
Cumulative Permeation Mass
After 0.5 h [µg/cm2] After 24 h [µg/cm2]
Using RMF
CP_gel_1_MF 18.163 ±2.564 b236.099 ±26.206 b
CP_gel_2_MF 9.687 ±1.368 b161.329 ±29.206 a
CP_cream_1_MF 12.477 ±1.083 b122.387 ±9.457 b
CP_patch_1_MF 3.352 ±0.815 a69.706 ±5.054 b
Control samples without the use of RMF
CP_gel_1_C 2.470 ±0.890 a96.681 ±8.988 a
CP_gel_2_C 4.446 ±1.601 a113.618 ±6.159 a
CP_cream_1_C 3.555 ±0.761 a73.092 ±11.716 a
CP_patch_1_C 2.091 ±0.038 a50.993 ±5.524 a
a
compounds characterised by significantly lower permeation;
b
compounds characterised by significantly higher
permeability. The groups after 1 h and after 24 h were analysed separately.
The results of ex vivo permeation experiments evaluating ibuprofen efficiency are
summarised in Table 2. Permeation parameters were calculated, including flux, apparent
permeability coefficient, lag time, diffusion coefficient in the skin, skin partition coefficient,
percent drug permeated after 24 h, and enhancement factor. There was a noticeable contrast
in the steady-state flux depending on exposure to the magnetic field applied during the
research. Ibuprofen exhibited the least penetration (3.01
±
0.38
µ
g/cm
2
) when the rotating
magnetic field was not utilised (CP_patch_1_C). This observation is consistent across all dif-
fusion parameters. Conversely, all the tested semi-solid formulations showed higher percu-
taneous flux, with steady-state flux measurements of 4.43
±
0.36
µ
g/cm
2
for CP_cream_1_C,
9.26
±
1.80
µ
g/cm
2
for CP_gel_1_C, and 18.74
±
4.45
µ
g/cm
2
for CP_gel_2_C, respectively.
This parameter exhibited significant increases when RMF was employed, particularly in
the case of CP_gel_1_MF, yielding the best results
(30.54 ±3.42 µg/cm2).
In the case of
CP_gel 1, a significant difference was also demonstrated between the penetration with and
without a magnetic field, analysing all time points during the 24 h study (Table 3).
Furthermore, the permeability coefficient (K
P
), a quantitative measure of the rate at
which a molecule can traverse the skin barrier, was also determined. K
P
takes into account
factors related to both the drug and the barrier, considering their interactions and eliminating
the impact of compound concentration. For the tested formulations, K
P
values ranged
from
0.88 ±0.07 ×103cm/h
for CP_cream_1_C to 3.75
±
0.89
×
10
3
cm/h for CP_gel_2_C
when RMF exposure was applied. In contrast, they ranged from 1.85
±
0.60
×
10
3
cm/h
Sci. Pharm. 2024,92, 4 6 of 11
for CP_cream_1_MF to 6.11
±
0.68
×
10
3
cm/h for CP_gel_1_MF when magnetic fields
were used.
Table 2. Permeation parameters of IBU from different formulations using RMF (f = 50 Hz,
Bmax ≈34 mT) or without RMF.
Sample JSS,
µg cm−2h−1
KP·103,
cm·h−1LT, h D·104,
cm2·h−1KmQ%24h EF0.5h EF24h
Using RMF
CP_gel_1_MF 30.54 ±3.42 6.11 ±0.68 * * * 4.72 7.35 2.44
CP_gel_2_MF 27.823 ±2.97 5.56 ±0.59 * * * 3.23 2.18 1.42
CP_cream_1_MF
9.27 ±0.98 1.85 ±0.60 * * * 2.45 3.51 1.67
CP_patch_1_MF
6.54 ±0.95 4.57 ±0.66 0.21 ±0.08 19.51 ±1.62 0.12 ±0.01 4.88 1.60 1.37
Control samples without the use of RMF
CP_gel_1_C 9.26 ±1.80 1.87 ±0.36 1.32 ±0.32 3.17 ±0.97 0.30 ±0.12 1.93 1.0 1.0
CP_gel_2_C 18.74 ±4.45 3.75 ±0.89 1.37 ±0.35 3.32 ±0.94 0.62 ±0.29 2.27 1.0 1.0
CP_cream_1_C 4.43 ±0.36 0.88 ±0.07 0.32 ±0.04 12.93 ±0.82 0.03 ±0.01 1.46 1.0 1.0
CP_patch_1_C 3.01 ±0.38 2.11 ±0.26 0.23 ±0.09 18.14 ±1.98 0.06 ±0.01 3.57 1.0 1.0
J
SS
—steady-state flux; K
P
—permeability coefficient; L
T
—lag time; D—diffusion coefficient; K
m
—skin partition
coefficient; Q—the percentage of the applied dose; EF—enhancement factor; * LT< 0.
Table 3. Significant differences in the cumulative mass of IBU, taking into account all time points
during the entire 24 h permeation, were estimated by the Mann–Whitney test.
CP gel 1 C CP gel 2 C CP cream 1 C CP patch 1 PM
CP gel 1 PM Z = −2.3629
p= 0.0181 *
CP gel 2 C Z = −1.5228
p= 0.1278
CP cream C Z = −1.7325
p= 0.0831
CP patch 1 PM Z = −1.3127
p= 0.1862
* Value is significantly different (p< 0.05).
Significantly, a profound effect of the rotating magnetic field on the lag time was
observed. All semi-solid samples exhibited no lag time, indicating that the substance
commenced penetrating the skin almost immediately. In practical terms, this suggests
that the substance can permeate the barrier almost instantly upon application, which can
be pivotal in achieving a rapid drug response. This contrasts with the control sample,
where the release time ranged from 0.32 to 1.37 h. The lag times for the patch were similar,
approximately 0.2 h. Additionally, the percentage of the permeated applied dose was
determined, revealing the highest enhancement in ibuprofen penetration when using a
magnetic field for the CP_gel_1 formulation and the lowest enhancement for CP_patch_1.
3. Discussion
The study presented explores the potential of a rotating magnetic field (RMF) in
enhancing the permeability of ibuprofen through the skin. The results indicate a significant
impact of RMF on the permeation of ibuprofen, with promising implications for transdermal
drug delivery.
As is known, transdermal drug delivery is a valuable alternative to oral administration
due to its numerous advantages, including controlled release, reduced side effects, and
Sci. Pharm. 2024,92, 4 7 of 11
improved patient compliance. However, the skin barrier presents a challenge, limiting
the passage of active pharmaceutical ingredients (API) into the bloodstream. The use of
a rotating magnetic field (RMF) significantly improved the permeability of ibuprofen, re-
gardless of the formulation used. The highest permeability was observed for CP_gel_1_MF,
indicating that the specific formulation played a role in the extent of permeation. In the
case of ibuprofen and similar pain-relief medications, rapid skin permeation is desirable
for achieving a swift therapeutic response. The study demonstrated that the highest perme-
ation rates occurred within the initial hours, particularly within the first hour, suggesting a
prompt onset of pain relief. In contrast, the control group, without the assistance of RMF,
exhibited a delayed onset of permeation, reaching the maximum penetration rate between
3 and 6 h. This could lead to a longer waiting time for patients and a risk of the drug being
rubbed off before full penetration. The study considered various permeation parameters,
which offered insights into the mechanisms involved in the permeation process. One
significant observation was the complete elimination of lag time in all semi-solid samples
when RMF was employed. This implies that the substance began permeating the skin
almost immediately, which could be critical for achieving a rapid therapeutic effect. In
contrast, control samples exhibited lag times ranging from 0.32 to 1.37 h.
The results suggest that the choice of formulation plays a crucial role in drug per-
meation. CP_gel_1_MF demonstrated the highest concentration and permeability, while
CP_patch_1_C showed the lowest permeation. The results of the experiments, particularly
the differences in permeability observed between the various formulations and the impact
of a rotating magnetic field (RMF), can be analysed in the context of the ingredients used
in the different preparations. All semi-solid products used in this research are available
in the active version of 50 mg/g. The presence of isopropyl alcohol and poloxamer 407 in
CP_gel_1, which are known for their solubilising and penetration-enhancing properties,
may contribute to the enhanced permeability when exposed to RMF. Similar to CP_gel_1,
CP_gel_2 also contains isopropyl alcohol and another alcohol, ethanol. The inclusion of
ethanol and isopropyl alcohol could contribute to the better solubility of ibuprofen, possibly
leading to higher permeation rates when using RMF. The greater permeability enhancement
using gel formulations is most likely related to the lower viscosity of these systems. In
the case of CP_cream_1, the presence of glycerol monostearate and xanthan gum might
affect the formulation’s texture and, subsequently, its permeability properties. In contrast
to the semi-solid forms, this formulation is in solid patch form and contains 200 mg of
the active substance per patch. The excipients include various polymers and materials
to form the adhesive, coating, and protective layers. The solid form of this preparation
naturally has different permeation characteristics compared to the semi-solid formulations.
The use of RMF played a significant role in enhancing the permeability of all formulations.
However, the specific composition of each formulation, including the excipients and their
solubilising properties, has contributed to the observed differences in permeability. For
example, CP_gel_1 exhibited the highest permeability when RMF was applied, and this
might be attributed to the presence of isopropyl alcohol and poloxamer 407, which are
known for their permeation-enhancing properties.
In our investigation, the composition of the formulation containing isopropyl alcohol
and poloxamer 407 was found to significantly impact the skin permeability of ibuprofen. To
provide a comprehensive understanding of this phenomenon, we delve into the mechanistic
details of how the application of the rotating magnetic field (RMF) contributes to the
controlled modulation of skin permeability. The RMF, operating at a frequency of 50 Hz,
induces electric fields that interact with the formulation components, resulting in a series
of dynamic changes. Firstly, the electric fields influence the solubility of ibuprofen within
the formulation, affecting its overall availability for transdermal transport. Additionally,
the RMF alters the diffusion kinetics of the drug through the formulation, impacting the
rate at which ibuprofen permeates the skin. Moreover, the interaction between the RMF
and the formulation components plays a crucial role in the drug’s interaction with the skin
barrier. This intricate interplay affects the skin’s permeability characteristics, providing
Sci. Pharm. 2024,92, 4 8 of 11
a controlled and modulated environment for drug transport. These insights contribute
to a more robust understanding of the observed changes in skin permeability induced by
the combination of the active pharmaceutical ingredient and the formulation base in the
presence of the rotating magnetic field.
In summary, the composition of the formulations, including the choice of excipients,
played a crucial role in determining the permeability of ibuprofen through the skin. The
use of a rotating magnetic field further enhanced this permeability, making it a potential
method for improving transdermal drug delivery. Additional studies and clinical trials
may be needed to explore the safety and efficacy of these formulations and the impact of
RMF in clinical applications.
The findings have practical implications for transdermal drug delivery, especially
for pain-relief medications where rapid onset is critical. The implications of our findings
bear direct relevance to transdermal drug delivery, particularly in the context of pain-relief
medications where achieving a rapid onset is of paramount importance. The application of
a rotating magnetic field (RMF) emerges as a potential strategy to enhance the efficiency
of drug delivery through the skin. In practical terms, this study underscores the promis-
ing role of RMF in improving the permeability of ibuprofen, thereby offering potential
advancements in the efficacy of transdermal drug delivery. RMF can potentially be utilised
to enhance the efficiency of drug delivery through the skin. In conclusion, this study show-
cases the potential of a rotating magnetic field in improving the permeability of ibuprofen,
which is promising for enhancing the efficacy of transdermal drug delivery. The choice of
formulation and the application of RMF are crucial factors that impact the extent and speed
of drug permeation. Further research and clinical trials may be needed to fully evaluate the
safety and effectiveness of this approach in clinical settings.
4. Materials and Methods
4.1. Materials
All the reagents and solvents were obtained from commercial sources and utilised with-
out further purification. AmBeed (Arlington Hts, IL, USA) supplied (R,S)-ibuprofen (IBU)
(2-(4-isobutylphenyl)propanoic acid) (IBU). Baker (Radnor, PA, USA) supplied acetoni-
trile. POCH (Gliwice, Poland) delivered the methanol and the procurement of potassium
dihydrogen phosphate (p.a.) from Merck (Darmstadt, Germany). Sigma-Aldrich (Stein-
heim am Albuch, Germany) was the supplier of the PBS tablets. A local abattoir supplied
porcine hide.
Four commercial preparations (CP) containing ibuprofen were selected for experimen-
tation, each available in different formulations, either semi-solid or solid, and distinguished
by the presence of various excipients: (1) CP_gel_1 (semi-solid form)—active substance
content: 50 mg/g. Excipients: isopropyl alcohol, solketal (2,2-dimethyl-4-hydroxymethyl-
1,3-dioxalate), poloxamer 407, medium-chain triglycerides of saturated fatty acids (Miglyol
812), lavender oil, orange oil, purified water. (2) CP_gel_2 (semi-solid form)—active
substance content: 50 mg/g. Excipients: ethanol (96%), isopropyl alcohol, hydroxyethylcel-
lulose, levomenthol, Reflex 12122 flavour (methyl salicylate), diethylene glycol monoethyl
ether, macrogolglycerides caprycaproates (Makrogol 400), glycerol, sodium hydroxide (10%
aqueous solution), purified water. (3) CP_cream_1 (semi-solid form)—active substance
content: 50 mg/g. Excipients: triglycerides of medium-chain saturated fatty acids, glycerol
monostearate, macrogol-30-glycerol monostearate, macrogol-100-glycerol monostearate,
propylene glycol, sodium methyl parahydroxybenzoate, xanthan gum, lavender oil, orange
oil, purified water. (4) CP_patch (solid form)—active substance content: 200 mg/patch.
Excipients: adhesive layer: macrogol 400, macrogol 20000, levomenthol, block copolymer
Styrene-Isoprene-Styrene 22, polyisobutylene (PIB) 55k, polyisobutylene (PIB) 1100k, ester
of hydrogenated rosin with glycerol, liquid paraffin. Coating layer: ethylene terephthalate,
woven. Protective layer: siliconised ethylene polyterephthalate.
Sci. Pharm. 2024,92, 4 9 of 11
4.2. Exposure to Rotating Magnetic Field (RMF)
Experiments were conducted using a set of reactors equipped with an external electro-
magnetic field generator. The current study system was composed of two identical reactors
(one with the exposure of a rotating magnetic field and the second without the control
process) connected to the same heat source, which prevented any temperature fluctuation
impact. The utilised system of reactors is presented in Figure 5.
Sci. Pharm. 2023, 91, x FOR PEER REVIEW 9 of 11
saturated fay acids, glycerol monostearate, macrogol-30-glycerol monostearate,
macrogol-100-glycerol monostearate, propylene glycol, sodium methyl
parahydroxybenzoate, xanthan gum, lavender oil, orange oil, purified water. (4) CP_patch
(solid form)—active substance content: 200 mg/patch. Excipients: adhesive layer:
macrogol 400, macrogol 20000, levomenthol, block copolymer Styrene-Isoprene-Styrene
22, polyisobutylene (PIB) 55k, polyisobutylene (PIB) 1100k, ester of hydrogenated rosin
with glycerol, liquid paraffin. Coating layer: ethylene terephthalate, woven. Protective
layer: siliconised ethylene polyterephthalate.
4.2. Exposure to Rotating Magnetic Field (RMF)
Experiments were conducted using a set of reactors equipped with an external
electromagnetic field generator. The current study system was composed of two identical
reactors (one with the exposure of a rotating magnetic field and the second without the
control process) connected to the same heat source, which prevented any temperature
fluctuation impact. The utilised system of reactors is presented in Figure 5.
Figure 5. Schematic of experimental reactor setup: (1) tank; (2) 3-phase coils; (3) phase inverter; (4)
PC; (5) process chamber; (6) Franz diffusion cells; (7) pump; (8) plate heat exchanger; (9) precise
thermostat; (10) oil heat exchanger; (11) 3-way valve.
The experimental setup was composed of two identical reactors. Each reactor consists
of a stainless steel tank (1), inside which a set of 3-phase coils was placed, powered by the
AC through the phase inverter (3) connected to PC (4), allowing control of the current–
voltage and other properties. In the current studies, we utilised currents of 100 V and 50
Hz. The rotating magnetic field (RMF), a specific form of electromagnetic field, was
created by powering those coils with maximal magnetic induction at Bmax = 34 mT. A
transparent process chamber (5) is placed axially in the centre of the coils. A holder with
Franz diffusion cells (6) is placed inside the process chamber. This holder is rinsed in the
process water circulated by the pump (7) through the plate heat exchanger (8). On the
other side, this heat exchanger is supplied by hot water from the precise thermostat, which
Figure 5. Schematic of experimental reactor setup: (1) tank; (2) 3-phase coils; (3) phase inverter;
(4) PC; (5) process chamber; (6) Franz diffusion cells; (7) pump; (8) plate heat exchanger; (9) precise
thermostat; (10) oil heat exchanger; (11) 3-way valve.
The experimental setup was composed of two identical reactors. Each reactor consists
of a stainless steel tank (1), inside which a set of 3-phase coils was placed, powered by the
AC through the phase inverter (3) connected to PC (4), allowing control of the current–
voltage and other properties. In the current studies, we utilised currents of 100 V and
50 Hz. The rotating magnetic field (RMF), a specific form of electromagnetic field, was
created by powering those coils with maximal magnetic induction at Bmax = 34 mT. A
transparent process chamber (5) is placed axially in the centre of the coils. A holder with
Franz diffusion cells (6) is placed inside the process chamber. This holder is rinsed in the
process water circulated by the pump (7) through the plate heat exchanger (8). On the
other side, this heat exchanger is supplied by hot water from the precise thermostat, which
maintains the temperature at a constant level with only slight changes of 0.1 Celsius. It
should be highlighted that the single thermostat is a heat source for both reactors. According
to Figure 5, therefore, any temperature fluctuations will not affect differences in results
comparing these two reactors. It should be noted that the powered coils are generating
additional heat because of the electric resistance of the wires. Therefore, we rinsed those
coils in a non-toxic silicon oil with electric insulator properties. The silicon oil is circulated
through an external loop equipped with another heat exchanger (10). Therefore, the tap
water can cool down part of the oil stream to remove excessive heat from the system. The
oil flow in this external loop is controlled by a 3-way valve (11) with an electric engine
connected to the temperature sensor and controller, which allows constant oil temperature.
Permeability studies were conducted using Franz diffusion cells (Phoenix DB-6,
ABL&E-JASCO, Wien, Austria) equipped with diffusion areas of 1 cm
2
. The accep-
Sci. Pharm. 2024,92, 4 10 of 11
tor chamber, filled with a PBS solution (pH 7.4), maintained a constant temperature of
37.0
±
0.1
◦
C. As the permeable membrane, pig skin with a thickness of 0.05 cm and suitable
impedance was employed. The fresh porcine skin was washed in PBS buffer pH 7.4 and
then dermatomed to the needed thickness. The skin samples were stored in aluminium
foil in a freezer at
−
20
◦
C for three months to preserve their skin barrier properties. Before
use, the skin samples were thawed slowly at room temperature for 30 min. Next, the
skin was mounted on the donor chamber. The integrity of the skin has been examined
by checking its impedance, which was measured using an LCRmeter4080 (Conradelec-
tronic, Wernberg-Köblitz, Germany). Each donor chamber contained 1 g of a semi-solid
formulation or a patch segment. The experiments extended over 24 h, and samples were
collected and analysed at specific time intervals: 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, and 24 h.
The API content in the samples was quantified using HPLC via the standard curve method.
The HPLC system (Knauer, Berlin, Germany) consisted of a 2600 UV detector, a Smartline
model 1050 pump, and a Smartline model 3950 autosampler operated with ClarityChrom
2009 software. A 125 ×4 mm chromatographic column packed with Hyperisil ODS (C18)
of 5
µ
m particle size was used. The mobile phase was a mixture of 0.02 mol/dm
3
potassium
dihydrogen phosphate, acetonitrile, and methanol (45/45/10, v/v/v) adjusted to pH 2.5
with orthophosphoric acid. The spectrophotometric detector was set at 220 nm, with a
1 cm3/min flow rate. The column temperature was maintained at 25 ◦C, and the injection
volume was 20 µL.
The kinetic profiling of ex vivo infinite-dose steady-state percutaneous absorption was
characterised using Fick’s laws of diffusion, as is common practice [
14
–
16
]. Key permeation
parameters, including flux (J
SS
), diffusion coefficient (K
P
), lag time (L
T
), diffusion coefficient
(D), and skin partition coefficient (Km), were determined.
4.3. Statistical Analysis
The results are expressed as the mean
±
standard deviation (SD). We employed a
one-way analysis of variance (ANOVA) for the analysis. Specifically, to assess the sig-
nificance of differences between individual groups regarding the cumulative mass after
24 h of permeation and the cumulative mass in the skin, the Tukey test (
α
< 0.05) was
utilised. A cluster analysis was carried out to determine similarities between all prepa-
rations tested, i.e., those exposed to a magnetic field and those not exposed, considering
all time points of acceptor fluid uptake. On this basis, groups of compounds with similar
permeation were presented. Furthermore, the Mann–Whitney test was used to determine
significant differences in cumulative mass between compounds subjected to magnetic field
exposure and those without exposure, considering all time points of acceptor fluid uptake.
All statistical calculations were performed using Statistica 13 PL software 13.3 (StatSoft,
Kraków, Poland).
Author Contributions: Conceptualisation, P.O.-R. and R.R.; investigation, P.O.-R.; methodology, A.N.
and M.K.; formal analysis, A.N., M.K., A.M.-S. and Ł.K.; writing—original draft preparation, A.N.
and P.O.-R.; writing—review and editing, P.O.-R. and R.R.; visualisation, A.N. and M.K.; supervision,
P.O.-R. and R.R.; project administration, P.O.-R.; funding acquisition P.O.-R. All authors have read
and agreed to the published version of the manuscript.
Funding: This research was funded by the National Centre for Research and Development, grant
number LIDER/53/0225/L-11/19/NCBR/2020.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author.
Conflicts of Interest: The authors declare no conflicts of interest.
Sci. Pharm. 2024,92, 4 11 of 11
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