Preparation of stable aqueous suspension of a hydrophobic drug with polymers

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Abstract

Pharmaceutical preparation of a hydrophobic aldose reductase inhibitor 5-(3-ethoxy-4-pentyloxyphenyl)-2,4-thiazolidinedione (CT112) was investigated. CT112 dissolved in a basic solution with different kinds of polymers was neutralized by acid to obtain a suspension preparation. In particular, the addition of a polymer, hydroxypropyl methyl cellulose (HPMC) provided a stable CT112 suspension with a homogeneous particle size, and there seemed to be an optimal concentration of HPMC for the stable suspension. The addition of polysorbate 80 brought higher CT112 solubility in water, but did not provide a stable suspension. X-ray diffraction, IR spectrum, and thermal analysis revealed that the particles in the suspension with HPMC had lower degree of crystallinity, less hydrophobic particle surface, and lower melting point and decreased fusion enthalpy than the suspension without HPMC. These results suggested that the highly stable CT112 suspension could be attained by the adsorption of the polymer.

Introduction

Ocular medical treatments sometimes require pharmaceutically difficult ophthalmic preparations, which contain unstable drugs or highly hydrophobic drugs. The difficulty should be overcome to cure the diseases especially for the treatment of serious and sight-threatening ocular diseases. Diabetic corneal disease (keratopathy), involving serious ocular pain and recurrent corneal erosion, is one of these ocular diseases. There are no special medicines for the disease except for conventional corneal protecting agents or pain relievers. This disease may be caused by the accumulation of sorbitol in the corneal cells due to the accelerated aldose reductase [1], and has been shown to be relieved by an aldose reductase inhibitor, 5-(3-ethoxy-4-pentyloxyphenyl)-2,4-thiazolidinedione (CT112) [2], [3]. The effect was also demonstrated for diabetic animal models [4].

CT112 is a potent aldose reductase inhibitor and it is very insoluble in water, freely soluble in alkaline solution, but is relatively easily hydrolyzed in alkaline solution. Therefore, aqueous suspension is desirable preparation for a stable ophthalmic medicine. Its characteristics, having square-platy crystal form, are highly hydrophobic, and difficult to disperse in water. It easily forms aggregates in water.

For this kind of hydrophobic drugs, surfactants and water-soluble polymers are usually used to expect that they adsorb on the particle surface, form protective colloid, increase the wettability and solubility in water, and help the dispersion of the particles in water [5]. Theoretical approach for preparing suspension was described by Martin [6]. The purpose of this study is to investigate possible preparations of a stable suspension of CT112 by adding various surfactants and water-soluble polymers. General pharmaceutical methods like suspension dispersibility, particle size and shape, and aggregate formation were used to evaluate the preparation of stable suspension. Additionally, physical determinations were also used to find the role of a polymer in a stable suspension.

Section snippets

Materials

CT112 (5-(3-ethoxy-4-pentyloxyphenyl)-2,4-thiazolidinedione) for the experiment was chemically synthesized in Senju Pharmaceutical Co., Osaka, Japan [7]. The structure is given in Fig. 1. CT112 is white, flaky crystal, and very insoluble in water. As water-soluble polymers and surfactants, polyvinylalcohol EG-05 (PVA), polyvinylpyrrolidone K-30 (PVP), hydroxypropyl methyl cellulose 65SH-50 (HPMC), polyethyleneglycol 4000 (PEG), carboxy methyl cellulose sodium (CMC), β-cyclodextrin (β-CyD), and

Results and discussion

Since CT112 is quite insoluble in water, and it is soluble in basic solution and easily re-precipitate upon neutralization by acid, the effect of polymers, surfactants and some dispersing agents on the particle shape and the dispersibility of the re-precipitated CT112 particles was examined. The particle shapes observed by a microscope soon after the re-precipitation are shown in Table 1. PVA and PVP gave spherical particle shape, and HPMC gave amorphous particle shape. PEG, CMC, polysorbate

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