Effective Topical Delivery of Ibuprofen through the Skin
Frank Romanski¹, Erin Zappia², Gabriella Baki², Kenneth Alexander², Norman Richardson¹
¹ BASF Corporation, 500 White Plains Road, Tarrytown, NY 10591
² University of Toledo, College of Pharmacy & Pharmaceutical Sciences, 3000 Arlington Ave, Toledo, OH 43614
[email protected], [email protected], [email protected], [email protected], [email protected]
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To utilize in silico measurements to test skin penetration of free-acid ibuprofen
through the stratum corneum over the course of eight hours
Compare the penetration of sodium ibuprofen versus that of the free-acid ibuprofen
from commercial grade compendial formulations using in vitro Franz-diffusion cell
penetration experiments
Establish the effectiveness of chemical penetration enhancers Kollicream 3C
(cocoyl capryl/caprate), Kollicream® OA (oleyl alcohol), and Kollicream® IPM
(isopropyl myristate), and their resulting effect on the penetration of ibuprofen and
sodium ibuprofen through the skin during both short (one hour) and long term
application (eight hours)
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API grade, compendial Free-acid Ibuprofen and Sodium Ibuprofen, were produced
by BASF Corporation (Florham Park, NJ), and used as supplied
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Chemical penetration enhancers: Kollicream® 3C (cocoyl capryl/caprate),
Kollicream® OA (oleyl alcohol), and Kollicream® IPM (isopropyl myristate) were
also produced by BASF Corporation (Florham Park, NJ), and used as supplied. All
materials were of pharmaceutical, compendial grade and tested to USP/NF and Ph.
Eur. monographs
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Ingredient
Compendial Name
Function
I
DI water
water
solvent
Additional materials utilized in the formulation of the pharmaceutical preparations
included: Kolliwax® GMS II (mono- and di-glycerides), Kolliphor® PS 60 (polysorbate
60), glycerin, deionized water, and Euxyl® 320 as a preservative
A summary of the individual ingredients utilized in this study is shown in Table 1.
Trade Name (Supplier)
Compendial Name
Broad Classification
Kollicream® 3C (BASF)
Cocoyl caprylocaprate, Ph.Eur.
Chemical Penetration
Enhancer
Kollicream IPM (BASF)
Isopropyl Myristate,
USP/NF, Ph.Eur.
Chemical Penetration
Enhancer
Kollicream® OA (BASF)
Oleyl alcohol, USP/NF, Ph.Eur.
Chemical Penetration
Enhancer
®
Kolliphor® PS 60 (BASF)
humectant
Kolliwax GMS II
glyceryl monostearate
consistency factor
10.0
Kollicream 3C
cocoyl capryl/caprate
emollient
10.0
Kolliphor PS 60
polysorbate 60
emulsifier
4.0
III
Euxyl 320
parabens
preservative
0.5
IV
Ibuprofen
ibuprofen
active
1.0
II
Mono- and di-glycerides,
USP/NF, Glyceryl monostearate
type II, Ph. Eur.
Consistency Factor
Speziol® 99.7% (BASF)
Glycerin, USP/NF, Ph. Eur.
Humectant
Euxyl 320 (Schülke)
Parabens, Phenoxyethanol
Preservative
DI Water
Water, Deionized
Water
®
Table 1. Trade and Compendial Names of excipients tested in this study including the broad
classification used for comparative purposes
AAPS-BASF-Romanowski-Skin-Delivery-Ibuprofen-112414.indd 1
5.0
Procedure:
Mix Phase I containing Water and Glycerol
Disperse Phase IV, Ibuprofen into Phase I
Add all components of Phase II to separate beaker
Heat both containers to 80 C - mix to ensure homogeneity
Remove Phase I (with drug) from hot bath - begin homogenization and/or high shear mixing
Pour Phase II to Phase I and allow to homogenize for 5 minutes
Reduce mixing to 200 rpm and allow to cool to 40 C; then add Phase III
Continue mixing until temperature is reduced to 30 C, then remove from mixing; cover, and allow to sit overnight
Table 2. Base cream formulation used to prepare Ibuprofen Formulations; comparisons between
emollients were performed by substituting the 10 wt.% emollient for one of each (Kollicream® 3C,
IPM and OA)
Franz-diffusion cells were utilized for the in vitro testing. Six vertical Franz diffusion
cells were utilized for the in vitro penetration studies. Each was filled with deaearated
phosphate buffer solution (PBS) at a pH of 7.4 and allowed to equilibrate to 37.4°C.
The Strat-M (EMD Millipore, Darmstadt, Germany) synthetic membrane was mounted
between the donor and receptor compartments for a total surface area of ~6.95 cm2.
532+/-50 mg of topical preparation was applied to the membrane surface of the donor
compartment. The donor cells were then sealed with parafilm to prevent evaporation of
the volatile phases. The receptor phases were stirred with magnetic stirring at 125 rpm.
An image of a single Franz cell is shown in Figure 1.
4000
3000
375
Next, the release rate J (µg/cm²hr), was determined by calculating the slope of the line
drawn by plotting the penetration values vs. the square root of the mean time; this is
shown for both free-acid ibuprofen and sodium ibuprofen for penetration enhancers
Kollicream® 3C and Kollicream® OA are shown in Figures 7 and 8.
250
500
125
y = 133.63x - 10.536
0
375
0
2
4
6
8
Time (hours)
Figure 4. In vitro measurements produced using Franz-diffusion cells through the
Strat-M® membrane over eight hours contrasting free-acid ibuprofen and sodium ibuprofen
and Kollicream® 3C (cocoyl capryl/caprate) as the emollient phase
700
NaIBU OA
IBU OA
1000
Ibuprofen
5%
Sodium
Ibuprofen
5%
Sodium
Ibuprofen
+
Kollicream
IPM
Sodium
Ibuprofen
+
Kollicream
OA
Sodium
Ibuprofen
+
Kollicream
3C
Figure 2. Penetration Enhancement vs. Blank after 60 minute incubation on PAMPA™
membrane, dual-mixing (Donor & Receptor) [Emulsion: 45% PEG 400, 2% Polysorbate 60,
40% Water, 5% Na-IBU, 8% lipidic fluid (emollient). Blank has no lipidic fluid]
These results were first analyzed in silico using the ACT formulation software:
Formulating for Efficacy™. By utilizing the Hansen Solubility parameters of each
individual component, the temporal release profile of the three target chemical
penetration enhancers were determined over the course of eight hours. The results of
these measurements are shown in Figure 3.
Ibuprofen penetration through Stratum Corneum
30
20
10
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
Time (hours)
As evident by the penetration of the ibuprofen, upwards of 15 to 30% of the free-acid
ibuprofen had penetrated through the 15µm simulated stratum corneum over the course
of eight hours. In this simulation, clearly the Kollicream® OA (oleyl alcohol) showed the
greater propensity for penetration enhancement over the course of eight hours, while
Kollicream® IPM (isopropyl myristate) showed a close second. These two emollients
showed improvement over Kollicream® 3C. (cocoyl capryl/caprate) However, it is
important to note that the differences between the three emollients was insignificant
using these measurements at the 30 minute or one hour mark, where the previous highthroughput screening results had actually indicated that Kollicream® 3C was the best
penetration enhancer over this time frame. As a result, further in vitro measurements
using the industry standard Franz diffusion cell were initiated to determine the temporal
release profile of the various emollients over a full eight hour timeframe. It is important
to note that the limitations of the in silico measurements are that this only represents
the free-acid ibuprofen, as the Hansen solubility parameters are only related to the nonionized form of the drug, therefore, in vitro experimentation was essential to determine
the differences between the free-acid and sodium salt of ibuprofen through the skin.
125
0
0.75
2.25
3
Sqrt(time, hours)
Figure 6. In vitro measurements plotted as penetration vs. square root mean time
produced using Franz-diffusion cells through the Strat-M® membrane over eight hours
comparing the penetration of free-acid ibuprofen and sodium ibuprofen using
Kollicream® 3C (cocoyl capryl/caprate) as the chemical penetration enhancer
175
0
2
4
6
Penetration (µg/cm²)
■■
175
■■
Figure 5. In vitro measurements produced using Franz-diffusion cells through the
Strat-M® membrane over eight hours contrasting free-acid ibuprofen and sodium ibuprofen
and Kollicream® OA (oleyl alcohol) as the emollient phase
In this comparison, again the penetration of ibuprofen was significantly higher when
dispensed as a sodium salt in comparison to the free-acid form. However, in contrast
to the Kollicream® 3C results, the Kollicream® OA appears to assist in the penetration
at later time intervals, particularly after one and one half hours and continues through
for the full eight hours of penetration, however, the penetration was very low during the
first hour of penetration; this corroborates both the pre-screening results as well as the
in silico measurements indicating that Kollicream® OA showed the best penetration over
eight hours. As a result, it would be assumed that in a faster release formulation, like a
localized cream application, Kollicream® 3C would be the better penetration enhancer,
while Kollicream® OA would be superior for long term penetration for a longer-applied
transdermal product (such as a transdermal patch).
The results of the IPM in vitro study resulted in the compromising of the membrane in
multiple studies, and as a consequence, the in vitro data was not be reported.
At this point, it should be noted that the results indicating the significant improvement in
penetration of sodium ibuprofen versus free-acid ibuprofen is a truly unexpected result.
It is widely known that drugs showing the best penetration through the skin are of the
following criteria: low melting point, moderate lipophilicity (logP), and low molecular
weight. As a consequence, Ibuprofen, with a melting point of 76°C, a molar mass of
206.29 g/mol, and a logP of 3.97 fits quite comfortably in a range that should readily
penetrate through the skin; yet, it has not been proven effective in the US market due
to poor efficacy largely driven by a lack of penetration. Counterintuitively, it is widely
reported in the scientific literature that ionic and charged molecules typically have a
sharp decrease in penetration due to the inherent lipophilic environment of the stratum
corneum, and therefore, it would have been predicted that the free-acid ibuprofen
should show an increase in penetration over the salt form, but this is not the case. To
explain, a representative diffusion model through the skin is shown in Equation 1:
0
0
0.75
1.5
2.25
3
Sqrt (time,hours)
Figure 7. In vitro measurements plotted as penetration vs. square root mean time
produced using Franz-diffusion cells through the Strat-M® membrane over eight hours
comparing the penetration of free-acid ibuprofen and sodium ibuprofen using
Kollicream® OA (oleyl alcohol) as the chemical penetration enhancer
As a result of this calculation, it is clear the skin penetration flux J (µg/cm²hr) for the
free-acid ibuprofen is substantially lower than that of the sodium salt, more specifically,
22.68 (µg/cm²hr) vs. 133.63 (µg/cm²hr) for the sodium salt for penetration enhancer
Kollicream® 3C. On the other hand, the overall skin penetration flux J when ibuprofen
is combined with Kollicream® OA is 147.41 (µg/cm²hr) for the free-acid and 220.0 (µg/
cm²hr) for the sodium salt. This result confirms the hypothesis that the sodium ibuprofen
substantially improves drug penetration of ibuprofen regardless of penetration enhancer.
Over the course of eight hours, it is clear that the use of Kollicream® OA is the superior
chemical penetration enhancer, and can also be used to substantially improve the
penetration of free-acid ibuprofen.
That said, it is important to discuss the common use of many Rx and OTC formulations.
For instance, it is common for patients or consumers to desire more or less immediate
relieve from a topical product. As a result, the full eight hour comparison is quite useful
for a long term application, but for the average consumer using a topical product, the
product may be washed off or displaced by the conclusion of a single hour. Therefore,
a direct comparison of the sodium ibuprofen, free-acid ibuprofen and the two key
penetration enhancers is shown in Figure 9.
NaIBU 3C
IBU OA
NaIBU OA
60 minutes
Conclusions
350
Time (hours)
IBU 3C
By observing the truncated set of data to reflect only the 30 minute and 60 minute
datapoints, it is clear that the Kollicream® 3C penetration enhancers performs better
for a topical product intended for rapid use. In contrast, the Kollicream® OA product
showed considerable less penetration during the first hour, but after one and one
half hours significantly surpasses Kollicream® 3C in terms of overall penetration. In
summary, it would be the conclusion of this work that Kollicream® 3C should be used
as a chemical penetration enhancer for topical formulations, such as creams, gels,
ointments and foams intended for fast relief, while Kollicream® OA would be better
suited for longer-term, transdermal applications. Moreover, it is recommended that
the use of Sodium Ibuprofen far exceeds the possible penetration of ibuprofen over
the free-acid form, and therefore, a pairing of sodium ibuprofen and Kollicream® 3C is
recommended for topical applications, and sodium ibuprofen and Kollicream® OA is
recommended for transdermal applications.
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8
0.0075
Figure 8. In vitro measurements produced using Franz-diffusion cells through the
Strat-M® membrane over one hour comparing the penetration of sodium ibuprofen
and free-acid ibuprofen using chemical penetration enhancers
Kollicream® 3C (cocoyl capryl/caprate) and Kollicream® OA (oleyl alcohol)
NaIBU OA
IBU OA
525
350
0.015
30 minutes
y = 220x - 93.07
y = 147.41x - 61.238
0
1.5
0.0225
0
700
40
Kollicream 3C
Kollicream OA
Kollicream IPM
250
0
525
0
NaIBU 3C
IBU 3C
y = 22.682x + 12.761
2000
Figure 3. In Silico measurements produced using the Formulating for Efficacy™ software
package for three chemical penetration enhancers (Kollicream® 3C, OA and IPM) at 10%
concentration using 5% ibuprofen in an O/W cream
Figure 1. Franz Cell Setup for in vitro penetration studies
NaIBU 3C
IBU 3C
In this first comparison, clearly the sodium ibuprofen showed significant improvement
in penetration over the eight hour experimentation. Furthermore, it is readily apparent
that the penetration of sodium ibuprofen occurs at a significantly faster rate than freeacid ibuprofen, as an adequate concentration of ibuprofen has penetrated through the
membrane after even 15 minutes. Next, the penetration enhancer Kollicream® OA was
tested using identical parameterization, these results are shown in Figure 5.
5000
70.0
glycerol
Polysorbate 60, USP/NF, Ph. Eur., Emulsifier
JPE
Kolliwax GMS II
®
Conc. %
Speziol 99.7%
®
Materials
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Phase
6000
Concentration (µg/mL)
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In a previous study¹ utilizing the PAMPA™ membrane (Pion, Inc. Billerca, MA), sodium
ibuprofen was found to penetrate through this membrane at a significantly faster rate
than free-acid ibuprofen during a high throughput screening experiment for chemical
penetration enhancers. Moreover, the effect of three chemical penetration enhancers,
Kollicream® 3C, IPM, and OA were each found to further improve this penetration versus
a blank sodium ibuprofen formulation. While an interesting and unanticipated result,
these results were only performed for a single time point, 60 minutes, and using a
screening formulation of PEG 400 and Polysorbate 60, and not a commercial formulation.
As a consequence, this study presented here was intended to further corroborate these
results and prove using standard Franz diffusion cells that the use of sodium ibuprofen
significantly improves upon skin penetration in industrially accepted in vitro testing. The
key results of this previous screening study are summarized in Figure 2.
Ibuprofen through S.C. (% total)
Objectives
Topical formulations of free-acid ibuprofen and sodium ibuprofen were prepared
using identical methods. Two separate phases, one oil, one aqueous were separately
prepared and blended prior to homogenization. Ibuprofen or sodium ibuprofen was
dissolved into the aqueous phase containing both deionized water and glycerin. Oil
components Kolliwax® GMS II, the target emollient (one of each Kollicream® 3C, IPM,
and OA), and the surfactant Kolliphor® PS 60 were blended at elevated temperature.
Both the aqueous and oil phases were brought up to 80°C using a temperature control
bath, and once all components were fully melted and homogeneous, the two phases
were mixed and homogenized for 5 minutes at 5,000 rpm. The warm emulsified cream
was then transferred to a four-blade, impeller mixer operating at 200 rpm and cooled
to 40°C, at which point the preservative Euxyl 320 was added. The resulting cream was
further cooled to 30°C under shear and then allowed to sit for 24 hours to adequately
set up the colloidal structure of the cream prior to in vitro testing. A sample of the
formulation is shown in Table 2, below:
Results and Discussion
500
In this case, the where J is the drug flux through the skin (mol/cm2s), which is
dependent on the partition coefficient K, the diffusivity D (cm2/s), the thickness of the
skin h (cm), and the concentration gradient (C0-Ci) (mol/cm3). In the case of sodium
ibuprofen versus free-acid ibuprofen, it is well known that the diffusivity D will decrease
substantially, resulting in a net decrease of skin penetration flux, however, as evident in
this work, the improvement in the concentration gradient ΔC due to the vastly improved
solubility of the sodium ibuprofen in the vehicle provides a larger increase in net driving
force, thus resulting in a net improvement in drug delivery.
Penetration (µg/cm²)
Computational simulations were conducted utilizing the Formulating for Efficacy™
software, available by ACT Solutions (1 Innovation Way, Newark, DE). Simulations were
conducted utilizing the diffusion modeling software module of the software package,
where specifically, 10 wt. % emollient (Kollicream® 3C, IPM, OA) was modeled using
Hansen Solubility Parameters, as well as the test compound 5 wt.% Ibuprofen,
and other excipients. Diffusion was modeled for 8 hours on the stratum corneum
assuming a 10 µm layer of product on the skin and a 15.0 µm thickness of the stratum
corneum. Penetration was recorded as the concentration of ibuprofen that successfully
penetrated through the stratum corneum as a function of time.
0.03
Penetration (µg/cm²)
The ability to effectively deliver non-steroidal anti-inflammatory drugs (NSAIDs) topically
and transdermally offers an increased localization of the drug to the site of pain and
inflammation, while simultaneously reducing systemic absorption. This ultimately
results in more effective treatment for localized pain and inflammation, while reducing
the undesired side effects associated with NSAIDs. In this work, the effective topical
delivery of ibuprofen is discussed. In a previous publication, BASF in collaboration
with Pion, Inc. had ascertained (utilizing the PAMPA™ system) that the common
NSAID ibuprofen can more readily penetrate through the skin when prepared in the
form of a sodium salt. Moreover, the use of chemical penetration enhancers, such as
Kollicream® 3C (cocoyl capryl/caprate), Kollicream® OA (oleyl alcohol), and Kollicream®
IPM (isopropyl myristate) had been shown to also enhance performance over a limited
60 minute penetration study through the synthetic PAMPA™ membrane. The ability of
an ionized drug form to penetrate faster into the skin was unexpected, counterintuitive,
and as a consequence, this work was established to test this finding utilizing both in
silico and with more comprehensive in vitro testing methodologies including the use of
Franz diffusion cells to confirm this result. In this study, in silico measurements using
the Formulating for Efficacy™ software for ibuprofen through the skin using various
penetration enhancers is reported. Subsequently, in vitro studies utilizing Franz diffusion
cells and the synthetic Strat-M® membrane were performed for real topical formulations
containing both free-acid ibuprofen as well as the sodium salt in the presence of
penetration enhancing emollients.
Penetration (µg/cm²)
Methods
Each stable commercial formulation was prepared using the aforementioned technique
and tested on the set of Franz diffusion cells over the course of eight hours. These
experiments were designed to further corroborate the screening study and the in
silico measurements that had shown significant improvement using the sodium salt of
ibuprofen, and the improvement through the use of chemical penetration enhancers.
First, the comparison between sodium ibuprofen and free acid ibuprofen using the
Kollicream® 3C as an emollient and chemical penetration enhancer was conducted;
these results are shown in Figure 4.
Penetration (µg/cm²)
Introduction
0.5 mL of receiver fluid was sampled at the following intervals: 15 minutes, 30 minutes,
45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours,
6 hours 7 hours and 8 hours, and tested using UV spectrophotometry for determination
of ibuprofen concentration. Separate calibration curves were established for freeacid ibuprofen and sodium ibuprofen. Each sample was measured by integrating over
the range of 248 to 252 nm, as was found to be the most accurate response peak for
ibuprofen penetration without outside interference from excipients. Samples are reported
as the average concentration value for each cell, while the error was calculated as the
square root of the sum of squares of the standard deviations for each individual cell.
■■
■■
In silico measurements indicate that three
chemical penetration enhancers, Kollicream®
3C, IPM and OA are effective in assisting the
penetration of ibuprofen through the skin over the
course of 8 hours
It was shown that the sodium salt of ibuprofen
significantly improves the effective topical delivery
of ibuprofen through the skin in comparison with
the free-acid form
It was concluded that the increased solubility of the
ibuprofen sodium improves the penetration at a rate
higher than the corresponding decrease caused
by the ionic compound diffusion; the net result is
significantly better penetration for sodium ibuprofen
In vitro testing has indicated that Kollicream® 3C is
the most effective chemical penetration enhancer
for ibuprofen/sodium ibuprofen during a one hour
time window that represents the typical use of a
topical product
In vitro testing has indicated that Kollicream® OA
is the most effective penetration enhancer for an
extended application of topical ibuprofen/sodium
ibuprofen, and thus would work best with longer
application-use transdermal systems
References
1 Assessment of Transdermal Penetration Enhancement by Topical Pharmaceutical
Excipients Using Skin PAMPA Method, M. Clough, N. Richardson, F. Romanski, N.
Langley, K. Tsinman, O. Tsinman, AAPS National Meeting Meeting, San Antonio, TX,
Nov 11-14, 2014
AAPS National Meeting 2014, San Diego, CA – November 3rd, 2014
10/28/14 7:25 AM