DOI 10.1007/s12272-009-1611-5
College of Pharmacy, Yeungnam University, Gyongsan 712-749, Korea, 2Research Center, Samil Pharmaceutical Co. Ltd.,
Ansan 712-749, Korea, 3Biochemical Engineering College, Beijing Union University, No.18, 3rd Section, Fatouxili, Chaoyang District, Beijing, 100023, China
(Received March 11, 2009/Revisied April 24, 2009/Accepted April 28, 2009)
To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid
dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and
carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of
solid dispersions were investigated using scanning electron microscopy, differential scanning
calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were
evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium
lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers
might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to
amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction.
Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na
should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced
solubility and no convertible crystalline.
Key words: Solid dispersion, Tacrolimus, Sodium carboxylmethyl cellulose, Sodium lauryl
sulfate, Solubility
INTRODUCTION
Tacrolimus isolated from Streptomyces tsukubaensis
is a 23-member macrolide lactone with potent immunosuppressive activity (Kino et al., 1987a, 1987b).
It is a poorly water-soluble compound which gave the
low aqueous solubility of about 1-2 g/mL (Hane et al.,
1992; Honbo et al., 1987; Tamura et al., 2002). Various
oral formulations of tacrolimus such as inclusion
complex (Arima et al., 2001), nanoparticle (Nassar et
Correspondence to: Han-Gon Choi, College of Pharmacy, Yeungnam University, Gyongsan 712-749, Korea
Tel: 82-53-810-2813, Fax: 82-53-810-4654
E-mail: hangon@ynu.ac.kr
or Jong Soo Woo, College of Pharmacy, Yeungnam University,
Gyongsan 712-749, Korea
Tel: 82-53-810-2824, Fax: 82-53-810-4654
E-mail: woojongsoo@ynu.ac.kr
893
894
Aqueous solubility of
tacrolimus (g/mL)
Water
0.67 0.19
- Hydrophilic polymers
Sodium carboxymethyl cellulose
Hydrooxypropyl cellulose
Hydroxypropylmethyl cellulose
7.51 0.29
1.75 0.07
1.95 0.14
- Surfactants
Polyethylene glycol 6000
Polyethylene glycol 4000
Poloxamer 188
Poloxamer 407
Sodium lauryl sulfate
1.00 0.15
1.00 0.12
2.02 0.20
25.57 0.782
476.38 150.61
Switzerland) was used for the preparation of tacrolimus-loaded solid dispersion. First, 0.3 g sodium lauryl
sulfate, 0.2 g citric acid, and 1.2 g (solid dispersion I)
or 24 g (solid dispersion II) CMC-Na were dissolved in
100 mL water, respectively. Then, 3 g tacrolimus presieved through 60 mesh screen was dispersed in this
solution. The resulting dispersion pre-warmed to 60oC
was delivered to the nozzle (0.7 mm diameter) at a
flow rate of 5 mL/min using a peristaltic pump and
spray-dried at 125oC inlet temperature and 65-70oC
outlet temperature. The pressure of spray air was 4
kg/cm2 and the flow rate of drying air was maintained
at the aspirator setting of 10 which indicated the
pressure of aspirator filter vessel -25 mbar. The direction of air flow was the same as that of sprayed products (Choi et al., 2001; Li et al., 2008; Yong et al., 2004).
After excessive amount (about 20 mg) of solid
dispersion I and II were added to 10 mL water, the
solubility test of tacrolimus in the solid dispersions
were carried out using the solubility method as
mentioned above.
Dissolution
The solid dispersions (equivalent to 0.5 mg of
tacrolimus) and 0.5 mg of tacrolimus powder were
inserted into a sinker and placed in the dissolution
apparatus (Shinseang Instrument Co., South Korea),
respectively (Choi et al., 1998). Dissolution test was
performed at 37 0.5oC using the paddle method at
50 rpm with 500 mL 0.005% hydroxypropyl cellulose
solution adjusted to pH 4.5 by phosphoric acid. At
predetermined interval, 3 mL of the medium was
895
896
The amounts of drug dissolved from the solid dispersion II for 15 min increased about 10-fold compared to
tacrolimus powder (23.62 4.40 vs.1.99 0.13%). Thus,
this solid dispersion II was useful for improving the
initial dissolution rate of tacrolimus.
The scanning electron micrographs of tacrolimus
powder, solid dispersion I and II were shown in Fig. 2.
Tacrolimus powder (Fig. 2A) appeared as smoothsurfaced rectangular crystalline in shape (Yamashita
et al., 2003). However, the solid dispersion I (Fig. 2B)
and II (Fig. 2C) gave relatively rough surface and
showed that the hydrophilic polymer and surfactant
might be attached to the surface of the drug.
Thermal behavior of drug powder, carriers, solid
dispersion I and II were shown in Fig. 3. The DSC
curve showed that tacrolimus appeared an endothermic peak at about 130oC corresponding to its melting,
Fig. 2. Scanning electron micrographs (600) : A, tacrolimus powder; B, solid dispersion I; C, solid dispersion II. The solid
dispersion I and II were composed of tacrolimus/CMC-Na/SLS at the weight ratio of 3/1.2/0.3 and 3/24/3, respectively.
transformation of the crystalline form into the amorphous state but due to the attachment of the carriers
to the surface of poorly water-soluble tacrolimus, resulting in changing the hydrophobic drug to hydrophilic form in this solid dispersion.
CONCLUSION
Unlike traditional solid dispersion systems, this
solid dispersion prepared with water, CMC-Na and
sodium lauryl sulfate gave no changed crystalline
form of drug and no environmental pollution. Furthermore, the solid dispersion of tacrolimus/CMC-Na/
sodium lauryl sulfate at the ratio of 3/24/3 improved
about 2,000-fold solubility and 10-fold dissolution of
drug compared to tacrolimus powder. Thus, this solid
dispersion system with water, sodium lauryl sulfate,
citric acid and CMC-Na would be a potential candidate for delivering a poorly water-soluble tacrolimus
with enhanced solubility and no convertible crystalline. Further study on its pharmacokinetics in rats
and stability will be performed.
ACKNOWLEDGEMENTS
This research was supported by the Yeungnam
University research grants in 2008.
REFERENCES
Arima, H., Yunomae, K., Miyake, K., Irie, T., Hirayama, F.,
897
898
Newa, M., Bhandari, K. H., Li, D. X., Kwon, T. H., Kim, J. A.,
Yoo, B. K., Woo, J. S., Lyoo, W. S., Yong, C. S., and Choi, H.
G., Preparation, characterization and in vivo evaluation of
ibuprofen binary solid dispersions with poloxamer 188.
Int. J. Pharm., 343, 228-237 (2007).
Okimoto, K., Miyake, M., Ibuki, R., Yasumura, M., Ohnishi,
N., and Nakai, T., Dissolution mechanism and rate of solid
dispersion particles of nilvadipine with hydroxypropylmethylcellulose. Int. J. Pharm., 159, 85-93 (1997).
Patil, N. S., Mendhe, R. B., Sankar, A. A., and Iyer, H.,
Procedure for chromatography involving sample solvent
with higher elution strength than the mobile phase. J.
Chromatogr. A., 1177 (2), 234-242 (2008).
Sinswat, P., Overhoff, K. A., McConville, J. T., Johnston, K.
P., and Williams, R. O. 3rd., Nebulization of nanoparticulate amorphous or crystalline tacrolimus-single-dose
pharmacokinetics study in mice. Eur. J. Pharm. Biopharm.,
69(3), 1057-1066 (2008).
Tamura, S., Ohike, A., Ibuki, R., Amidon, G. L., and
Yamashita, S., Tacrolimus is a class II low-solubility highpermeability drug: the effect of P-glycoprotein efflux on
regional permeability of tacrolimus in rats. J. Pharm.
Sci., 91(3), 719-729 (2002).
Taylor, L. S. and Zografi, G., Spectroscopic characterization
of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm. Res., 14, 1691-1698
(1997).
Walser, S., Hruby, R., Hesse, E., Heinzl, H., and Mascher,
H., Preliminary toxicokinetic study with different crystal
forms of S (+)-ibuprofen (dexibuprofen) and R,S-ibuprofen
in rats. ARZNEI. FOR., 47, 750-754 (1997).
Watts, A. B., Williams, R. O. 3rd., and Peters, J. I., Recent
developments in drug delivery to prolong allograft survival in lung transplant patients. Drug Dev. Ind. Pharm.,
35 (3), 259-271 (2009).
Yamashita, K., Nakate, T., Okimoto, K., Ohike, A., Tokunaga,
Y., Ibuki, R., Higaki, K., and Kimura, T., Establishment of
new preparation method for solid dispersion formulation
of tacrolimus. Int. J. Pharm., 267, 79-91 (2003).
Yong, C. S., Li, D. X., Oh, D. H., Kim, J. A., Yoo, B. K., Woo,
J. S., Rhee, J. D., and Choi, H. G., Retarded dissolution of
ibuprofen in gelatin microcapsule by cross-linking with
glutaradehyde. Arch. Pharm. Res., 29(6), 520-524 (2006).
Yong, C. S., Yang, C. H., Rhee, J. D., Lee, B. J., Kim, D. C., Kim,
D. D., Kim, C. K., Choi, J. S., and Choi, H. G., Enhanced
rectal bioavailability of ibuprofen in rats by poloxamer
188 and menthol. Int. J. Pharm., 269, 169-176 (2004).