Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 73 No. 3 pp. 731ñ737, 2016
ISSN 0001-6837
Polish Pharmaceutical Society
KINETICS STUDY ON KETOPROFEN RELEASE FROM MINI TABLETS
AND MULTI-COMPARTMENT SYSTEMS
TOMASZ STAWARSKI1*, EDMUND SIERADZKI2, EMILIA GA£ECKA2 and KAROLINA BINEK2
Department of Drug Technology and Pharmaceutical Biotechnology, 2Department of Applied Pharmacy
and Bioengineering, Medical University of Warsaw, Banacha 1, 02-097 Warszawa, Poland
1
Abstract: Thanks to multi-compartment systems it is possible to modify drug release. Two types of mini tablets
containing 12.5 mg of ketoprofen were made: mini tablets of immediate (IR) and sustained (SR) release. Some
of the tablets of immediate release were coated with an enteric coating, thereby obtaining a delayed release
effect (IRc). For each tablet type, release profiles were tested in three media: 0.1 M HCl, phosphate buffer pH
4.5 and phosphate buffer pH 6.8. Based on the obtained results, three appropriate multi-compartment models
have been constructed and tested. The factor limiting the amount of available ketoprofen at the absorption place
is pH of the environment. It was observed that the increase in pH caused the increase of ketoprofen solubility.
Constructed multi-compartment systems allowed to change the composition and the dose of medicinal substances easily. Thanks to this it is possible to adjust the release profile of the active substance to the individual
patient, which meets the expectations of personalized medicine.
Keywords: multi-compartment system, modified release, mini tablets, coated tablets, ketoprofen
Abbreviations: BCS ñ Biopharmaceutical Classification System, EMA ñ European Medicines Agency, IR ñ
immediate release mini-tablet, IRc ñ immediate release mini-tablet, coated enterically, NSAID ñ non-steroidal
anti-inflammatory drugs, SR ñ sustained release mini-tablet
medicinal substances of different places of release
are used, such a drug form can successfully compete
with other forms, either in monotherapy or in combination therapy (5ñ7).
Multi-compartment system is superior to traditional drug forms in terms of more efficient control
of release and absorption place. As a result, a better
control of the concentration of medicinal substance
in blood or tissues is obtained, leading to improved
safety of pharmacotherapy (8ñ10). Furthermore, this
kind of system provides the possibility to model the
profile of medicinal substance release and absorption by placing in one capsule e.g., mini tablets of
different compositions or of different coatings (5,
11, 12). Control of the rate of medicinal substance
release is achieved inter alia through the use of
polymer coatings of varied thickness, soluble at different pH valueso or through the use of excipients,
delaying disintegration of the tablet or the release of
the medicinal substance (11ñ13).
One of the main areas where modified release
of medicinal substance is often used is the treatment
of pain and inflammations. Ketoprofen (the II class
In the twenty-first century pharmaceutical
technology the dominating tendency is to seek a
drug form which would provide a desired therapeutic effect with a minimum of side effects. Therefore,
scientists create drug forms which both provide the
correct dose of the medicinal substance to a specific
organ and ensure its release for a specified period of
time (1ñ3). In clinical practice the use of sustained
release preparations (8ñ12 h) enables the use of
a lower daily dose, which results in smaller variation
of the concentration of medicinal substance in the
blood. In order to obtain immediate and sustained
release, the drug form technology has been enriched
with newly developed multi-compartment systems
whose structure makes it possible to meet the abovementioned requirements. Thanks to this universal
drug form it is possible to overcome many of the
disadvantages arising from the use of conventional
drug forms (4). The drug dose is divided into many
sub-units ñ containers, each of which behaves like
an individual form, providing medicinal substance
in a predetermined place and in a predetermined
way. If in the multi-compartment system several
* Corresponding author: e-mail: tomasz.stawarski@wum.edu.pl; phone/fax: +48 (22) 5720647
731
732
TOMASZ STAWARSKI et al.
of BCS system) (14) is a representative of the group
of non-steroidal anti-inflammatory drugs (NSAID)
(15) and it is widely used in the treatment of pain, in
cases of inflammation and rheumatic diseases (16).
When administered in the drug form of unmodified
release, it is rapidly absorbed, achieving the maximum concentration in blood within 0.5 to 2 h (17,
18). After this time, its concentration decreases rapidly to a very low level, thus in the long-term treatment it is necessary to take multiple doses of the
drug per day in order to maintain the therapeutic
concentration (9).
Multi-compartment systems enable the release
of desired amount of active substance in a selected
section of the gastrointestinal tract (19, 20), according to a determined dosing schedule. Thanks to them
it is often possible to reduce the quantity of drug
doses to one per day (21).
The aim of the study was to construct and test
a multi-compartmentment system, consisting of
mini tablets of ketoprofen, enclosed in a capsule of
hypromellose. The mini tablets obtained by the
usage of different technologies and having different
properties, created multi-compartment systems in
suitable configurations. These systems allowed to
change the composition and the dose of medicinal
substances easily. It was also possible to modify the
release profiles of applied substance.
MATERIALS AND METHODS
In the first stage of the study, using a tablet
press (EK0 - Korsch) with a stamp having a diameter of 5 mm, two types of mini tablets with ketopro-
fen (Lee Pharma) as a model substance were prepared: immediate release mini tablets (IR) of a
weight of 50 mg and the medicinal substance content of 12.5 mg as well as sustained release mini
tablets (SR) of a weight of 60 mg and ketoprofen
content of 12.5 mg. Both kinds of mini tablets were
prepared using direct compression. Part of the
immediate release mini-tablets were coated with
enteric coating (ACRYL- EZE PINK, Colorcon),
which resulted in mini tablets releasing drug substance with a delay (IRc). Mini tablets/cores were
coated according to the W¸rster method
(UNIGLATT, Glatt) (22). Weight gain of the tablets
in the coating process was about 16%. The composition of the tablet mass of IR and SR mini tablets
and its properties are shown in Table 1.
Release profiles were tested for each type of
mini tablets, pursuant to the EMA (European
Medicines Agency) guidelines, in three media: 0.1
M HCl, phosphate buffer pH 4.5 and phosphate
buffer pH 6.8. In addition, release test in the phosphate buffer pH 6.8 over the course of 12 h was carried out for SR tablets. Concentration of ketoprofen
in the tested samples was determined spectrophotometrically (spectrophotometer UV 300 UV:Visible,
Unicam) at a wavelength λ = 259 nm. The correlation coefficients for standard curves drawn for ketoprofen in particular media were respectively:
2
● 0.1 M HCl (r = 0.9995)
2
● phosphate buffer, pH 4.5 (r = 0.9979)
2
● phosphate buffer, pH 6.8 (r = 0.9912)
The obtained results made it possible to calculate the amount of released ketoprofen for each
series of mini tablets. Based on the obtained results,
Table 1. The composition of the tablet mass of IR and SR mini-tablets and its properties.
Ingredients
Mini-tablets IR
Ketoprofen
12.5 mg
Microcrystalline cellulose
Mini-tablets SR
12.5 mg
29.2 mg
Silica colloidal
37.5 mg
(Prosolv 90HD, JRS Pharma)
Sodium starch glycolate
(Prosolv Easy Tab, JRS Pharma)
óóóóóó-
Hypromellose K4M (Colorcon)
óóóóóó-
18.0 mg
Sodium stearyl fumarate
0.3 mg
Total
50 mg
60 mg
Hardness [N]
TBH-420TD Erweka
103.1 ± 1.17
133.5 ± 3.24
Friability
TA3 Erweka
0.04%
0.17%
Disintegration time [s]
ZT71 Erweka
60 ± 2
óóóóóóó
Kinetics study on ketoprofen release from mini tablets and...
733
Figure 1. Amounts of released ketoprofen (% ± SD) from mini tablets over 120 min in various media (n = 12)
multi-compartment systems were constructed, by
placing mini tablets in a capsule of hypromellose.
The amount of released ketoprofen from the
mini tablets and multi-compartment system were
tested in vitro in the dissolution apparatus with a
paddle (DT 70, Erweka), using the acceptor fluid
replacement method (23). To avoid floating of
multi-compartment systems on the surface of acceptor fluids aggravating elements (Sinkers) were used.
The rotation speed of the agitator was 50/min while
the water temperature in the bath was 37 ± 1OC. The
volume of acceptor fluids was 900 mL. The following two acceptor fluids had been used in the study of
multi-compartment systems:
● 0.1 M HCl - imitating the environment prevailing
in the stomach,
● phosphate buffer, pH 6.8 ñ simulating the conditions in the small intestine.
Three types of multi-compartment systems
were prepared, containing, respectively:
● IR + IRc ñ 2 immediate release mini tablets and
2 immediate release coated mini tablets. This
model simulates the pulsatile release model in
which half of the dose is released in the stomach
and the other half in the small intestine;
● IR + 3SR ñ 1 immediate release mini tablet and 3
sustained release mini tablets. This corresponds to
a classic model of a drug of sustained action,
wherein part of the substance, in initial dose form,
is released in the stomach, and the other part as
a maintenance dose is slowly released and
absorbed in the small intestine;
IRc + 3SR ñ 1 immediate release coated mini
tablet and 3 sustained release mini-tablets where
only a small, insignificant portion of ketoprofen is
released from matrix tablets in the stomach while
both, the initial dose and maintenance dose are
released in the small intestine. This model can be
proposed for the treatment of patients with damaged gastric mucosa and enables to avoid its irritation.
Studies on ketoprofen release from multi-compartment systems had been performed up to the 120th
minute with the use of 0.1 M HCl as acceptor fluid
and afterwards the releasing medium was changed
to phosphate buffer pH 6.8.
●
RESULTS AND DISCUSSION
Use of Prosolv Easy Tab and Prosolv 90HD
made it possible to carry out direct compression the fastest and cheapest method of tabletting.
Obtained mini tablets with ketoprofen were characterized by high hardness (103 ± 2.26 N for IR mini
tablets and 133.5 ± 3.24 N for SR mini tablets) and
low friability (0.04% and 0.17%, respectively). It
should be noted, that a considerable hardness of IR
mini tablets did not lead to unfavorable prolong of
their disintegration time (60 + 2 s) (Table 1).
Results of dissolution testing show clearly, that
the pH is the critical factor determining the quantity
of ketoprofen, which may be dissolved in the medium, after release from the mini tablets. Solubility of
ketoprofen increases substantially with increasing
734
TOMASZ STAWARSKI et al.
pH (16, 24). In 0.1 M HCl, after 120 min, was dissolved 20% of ketoprofen, released from IR mini
tablets. In the phosphate buffer pH 4.5 was dissolved almost 70% and in phosphate buffer pH 6.8
about 90%. The results of ketoprofen release from
mini tablets are given in Figures 1 and 2.
The effect of pH on the dissolution rate of ketoprofen is also significant. In the first 30 min of the
study, was dissolved in a medium, respectively:
●
●
●
In 0.1 M HCl - 6.09% of ketoprofen, representing
about 30% of the total amount of ketoprofen, dissolved within 120 min.
In buffer pH 4.5 - 34.26%, representing approximately 50% of the total amount of ketoprofen,
dissolved within 120 min.
In buffer pH 6.8 - 81.95%, which is almost 90%
of the dose of ketoprofen, which completely dissolved during the test.
Figure 2. Amount of released ketoprofen (% ± SD) from SR mini tablets in buffer pH 6.8 over 12 h (n = 12)
Figure 3. Amounts of released ketoprofen (% ± SD) from multi-compartment systems (n = 12)
Kinetics study on ketoprofen release from mini tablets and...
735
Figure 4. Comparison of amounts of released ketoprofen (% ± SD) from IR and IRc mini tablets over 120 min in buffer pH 6.8. All data
are shown as the mean values ± standard deviation. (*, # - statistically significant differences in Shapiro ñ Wilk test, p < 0.05).
This clearly shows that a relatively small
change in pH in the stomach may have a significant
impact on the solubility and absorption of ketoprofen, and through it, on the time, after which a therapeutic effect is observed (16). The situation when
the pH of the stomach is higher than the physiological, can take place, inter alia, during long term use
of proton pump inhibitors (omeprazole, pantoprazole), as well as during the concomitant use of ketoprofen and antacids (magnesium hydroxide, aluminum hydroxide) (25).
In studies of ketoprofen release from sustained
release mini tablets (SR), the effect of pH on the dissolution rate of released ketoprofen is also observed.
However, the main factor, controlling the amount of
ketoprofen released into the medium is the diffusion
rate through the swollen matrix. The amount of dissolved ketoprofen increases with an increase of pH,
but in any medium, an increase of its concentration
is quite uniform. There is no rapid dissolving of substantial amount of the active substance in the first 30
min of the release, as it was observed in the IR mini
tablets studies. In the initial stage, when the mini
tablet absorbs the medium and forms a matrix, we
can see the graph curve slightly flattened (Fig. 2).
Only when the diffusion rate of ketoprofen to the
medium stabilizes, the curve is steeper and close to
a straight line.
In the study on the multi-compartment system
#3 (Fig. 3), where the SR mini tablets are one of the
components of the system, the effect of pH change
on the release rate of ketoprofen is also clearly visi-
ble. For 120 min, about 7% of ketoprofen, originating from IR and SR mini tablets was dissolved,
which is an initial dose. When in the 120th minute the
medium was changed (the vertical, dashed line) to
phosphate buffer pH 6.8, the rest of the initial
dosage rapidly dissolved. The remainder of ketoprofen contained in SR mini-tablets was released more
slowly than would be apparent from the results,
obtained in the study on SR mini tablets in a phosphate buffer pH 6.8 (Fig. 2). From 150th to 240th
minute of testing, the curve has a flatter course than
in the distal section. This means, that ketoprofen
releases from the matrix slower, despite the relatively long residence of SR mini-tablets in the buffer,
with the best observed solubility of the active substance. It seems that this is due to soaking minitablets by hydrochloric acid during their residence in
0.1 M HCl solution. Formed matrix, restricts the
exchange of ketoprofen with the surrounding buffer.
It was not until 240th minute that the curve is of
steeper course, which may indicate a change in the
permeability of the matrix. This leads to the suspicion that in a clinical conditions similar phenomenon may occur. When a tablet administered to a
patient is surrounded by chyme with a low pH, the
diffusion rate of active substance from the dosage
may be lower than in vitro. Summary of the results
of the active ingredient release from multi-compartment systems, as well as types of analyzed multicompartment systems are given in Figure 3.
Comparison of the amounts of released ketoprofen from the IR and the IRc mini tablets, shows
736
TOMASZ STAWARSKI et al.
significant difference in the release rate of ketoprofen in phosphate buffer pH 6.8 (Fig. 4). The percentage of the released ketoprofen at 30th and 60th
min is higher for IR mini tablets than for IRc mini
tablets, although the compositions of both are the
same, and the envelope covering the core of the IRc
mini tablet dissolved very quickly. Amounts of
ketoprofen released in the 90th and 120th min of a
study are similar, and the differences between them
are statistically insignificant. The observed phenomenon indicates that the presence of the enteric coating on the core has an impact on the release rate of
ketoprofen. All data are shown as the mean values ±
standard deviation and were evaluated with
Statistica 10.0 (StatSoft, Poland).
The proposed design of multi-compartment
systems, based on the results of the mini tablets
ketoprofen dissolution testing, makes it easier to
design the composition of the dosage form. Thanks
to this it is possible to adjust the release profile of
the active substance to the individual patient, which
meets the expectations of personalized medicine
(26). Preparation of the proposed form of drug in the
present embodiments, can be also less expensive
than developing a complex form of the drug in tablet
form (27, 28). In addition, dividing the total dose
into smaller subunits accelerates the release of the
active substance compared to the release of the same
dose, contained in one tablet (29). This is particularly important in the treatment with NSAID and helps
to avoid local irritation of the gastric mucosa by
slowly disintegrating tablet.
CONCLUSIONS
The factor limiting the amount of available
ketoprofen at the absorption place is pH of the environment. A relatively small change in pH in the
stomach may have a significant impact on the solubility and absorption of ketoprofen, and through it,
on the time, after which a therapeutic effect is
observed. Multi-compartment systems are superior
to traditional drug forms in terms of more efficient
control of release and absorption place. Preparation
of the proposed form of drug in the present embodiments, can be also easier and less expensive than
developing a complex form of the drug in tablet
form.
REFERENCES
1. Graf W., Fraunberger B., Yang T., Kerling F.,
Pauli E., Stefan H.: Int. J. Clin. Pharmacol.
Ther. 47, 439 (2009).
2. Mourad J.J., Waeber B., Zannad F., Laville M.,
Duru G., AndrÈjak M.: J. Hypertens. 22, 2379
(2004).
3. Hiremath P.S., Saha R.N.: Int. J. Pharm. 362,
118 (2008).
4. Ko≥odziejczyk M.K., Zgoda M.M.: Polim.
Med., 40 (2), 21 (2010).
5. Ishida M., Abe K., Hashizume M., Kawamura
M.: Int. J. Pharm. 359, 46 (2008).
6. Goole J., Deleuze Ph., Vanderbist F., Amighi
K.: Eur. J. Pharm. Biopharm. 68, 310 (2008).
7. Aubert J., Mulder C.J.J., Schrˆr K., Vavricka
S.R.: SelfCare 2 (S1), 1 (2011).
8. El-Kamal A.M., Sokar M.S., Al Gamal S.S.,
Naggar V. F.: Indian J. Pharm. Sci. 65, 399
(2003).
9. Meka L., Kesavan B., Kalamata V.N., Eaga
C.M., Bandari S., Vobalaboina V.: J. Pharm.
Sci. 98, 2122 (2009).
10. Marwa H.A., Omaima A.S., El-ghamry Hanaa
A., El-nahas Hanan M.: IJPSR 2, 2195 (2011).
11. Greb E.: Pharm. Tech. 38, 38 (2010).
12. Funaro C., Mondelli G., Passerini N., Albertini
B.: Pharm. Technol. Drug Delivery 11, 38
(2010).
13. Stawarski T., Sieradzki E., Baran B., Stawarska
A.: Curr. Issues Pharm. Med. Sci. 26, 160
(2013).
14. Marzec A.: Investigations of biological availability and equivalence., p. 168, Oinpharma Sp.
z o.o., Warszawa 2007 (in Polish).
15. Rohilla S., Rohilla A., Marwaha R.K., Nanda
A.: Int. Res. J. Pharm. 2, 53 (2011).
16. Kokki H.: Pediatr. Drugs 12, 313 (2010).
17. Rençber S., Karavana S.Y., ÷zyazici M.:
FABAD J. Pharm. Sci. 34, 203 (2009).
18. Zafar F., Shoaib M.H., Yousuf R.I.: IJPSRR 13
(2), 58 (2012).
19. Subhabrota M., Souvik R., Subhadeep C.:
DARU 19, 47 (2011).
20. Luppi B., Bigucci F., Zecchi V., Cerchiara T.:
Drug Deliv. 16, 24 (2009).
21. Roda A., Sabatini L., Mirasoli M., Baraldini M.,
Roda E.: Int. J. Pharm. 241, 165 (2002).
22. Bauer K.H., Frˆmming K-H. F¸hrer C.: Technologie Mit Einf¸rung in die Biopharmazie. p.
365, MedPharm Polska, Wroc≥aw 2012 (in
Polish).
23. Janicki S., Sznitowska M., ZieliÒski W.:
Pharmaceutical and biological bioavailability of
drugs., p. 45, Oúrodek Informacji Naukowej
ÑPolfaî Sp. z o.o., Warszawa 2001 (in Polish).
24. Veys E.M.: Scand. J. Rheumatol. Suppl. 90,
Suppl. 1 (1991).
Kinetics study on ketoprofen release from mini tablets and...
25. Neuvonen P.J.: Br. J. Clin. Pharmacol. 31, 263
(1991).
26. Jain S.S., Agarwal H.V., Jagtap P.S., Neha M.
Dand N.M. et al.: Res. J. Pharm. Technol. 5,
449 (2012).
27. Tajane S.R., Kholwal B.B., Suryawanshi S.S.,
Tarkase K.N.: IJPSR, 3, 358 (2012).
737
28. Ruchi J., Ashutosh B., Preeti K.: Int. J. Univ.
PBS 3(2), 64 (2014)
29. Stawarski T., Sieradzki E., Bartos N.: Farm.
Pol. 70, 231 (2014).
Received: 19. 03. 2015