Drug-loaded Pectin Microparticles Prepared by ...

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Naresuan University, Phitsanulok 65000 Thailand. *author for correspondence [email protected] Keywords: Pectin, Microparticles, Solid Dispersion, ...

Advanced Materials Research Vol. 506 (2012) pp 282-285 © (2012) Trans Tech Publications, Switzerland doi:10.4028/www.scientific.net/AMR.506.282

Drug-loaded Pectin Microparticles Prepared by Emulsion-Solvent Evaporation P. Sriamornsak1,2,*, S. Konthong2, K. Burapapadh1,2 and S. Sungthongjeen3 1

Department of Pharmaceutical Technology, and 2 Pharmaceutical Biopolymer Group (PBiG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000 Thailand 3 Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000 Thailand *author for correspondence [email protected]

Keywords: Pectin, Microparticles, Solid Dispersion, Emulsion-Solvent Evaporation

Abstract. The aim of this study was to develop the pectin-based microparticles by emulsion-solvent evaporation technique. The effects of concentration and type of pectin and addition of glutaraldehyde on size, size distribution, drug crystalline state and drug dissolution from microparticles were investigated. The results showed that a model drug, indomethacin, could be encapsulated in microparticles. Higher molecular weight of pectin caused a larger in size of microparticles than the lower one. A high degree of esterification is preferred to stabilize the pectin microparticles. The powder x-ray diffractograms showed that all microparticles led to amorphous products while their physical mixture still showed the crystalline state of drug. Drug dissolution from the microparticles containing indomethacin and pectin was increased, resulting from the formation of an amorphous solid dispersion. Addition of glutaraldehyde, however, resulted in slower drug dissolution, compared to the formulations without glutaraldehyde or drug alone. Introduction Poor solubility of drugs causes subsequently poor bioavailability after oral administration of many drugs. The use of microparticles for oral administration to increase the bioavailability of poorly water-soluble drugs due to an enhancement of the intestinal absorption of the drug is well documented (1). It has been also found that the absorption in the gastrointestinal tract is improved by a small particle size. Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic and antipyretic activities. Indomethacin may cause serious adverse effects and should not be used as a simple analgesic or antipyretic. Indomethacin is a poorly soluble, highly permeable (Class II) drug. Its oral absorption is often controlled by the dissolution rate in the gastrointestinal tract. In this study, the indomethacin-loaded microparticles are prepared by using emulsion-solvent evaporation method. Pectin, a biodegradable polymer, was used as wall component of microparticles. Pectin is extracted from plant cell walls, especially in apple pomace and citrus fruits. It has commonly been used as a gelling agent, a thickening agent and a colloidal stabilizer in food industry. Its applications in the pharmaceutical industry were increased in the last decade (2). In addition, pectin is capable of reducing the interfacial tension between an oil phase and a water phase and can be effective in the preparation of emulsions (3,4). The aim of this study was to investigate the effects of type and concentration of pectin and the addition of glutaraldehyde on the size, size distribution, drug crystalline state and drug dissolution from pectin microparticles.

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Experimentals Indomethacin was purchased from P.C. Drug Center Co., Ltd. (Thailand). Three types of pectin with different molecular weights (MW) and degrees of esterification (DE), i.e., low methoxy pectin (LMP) with MW of 70 kDa and DE of 38%, amidated low methoxy pectin (ALMP) with MW of 150 kDa and DE of 29% and degree of amidation of 20%, and high methoxy pectin (HMP) with MW of 200 kDa and DE of 70%, were donated by Herbstreith & Fox KG (Germany). All other chemicals were of analytical grade and used as received without further purification. The pectin microparticles were prepared by emulsion-solvent evaporation method. Two concentrations (0.5 and 0.75% w/w) of pectin in water were prepared. Indomethacin was dissolved in chloroform and poured into the pectin dispersion. The mixtures were homogenized by homogenizer at 8,000 rpm for 30 minutes. Glutaraldehyde (1% v/v), a cross-linking agent, was then added and stirred for 20 minutes. The solvent presented in emulsions was evaporated by rotary evaporator (model R-3 Rotavapor, Buchi Laboratory Equipment, Switzerland). The obtained microparticles were characterized by a laser scattering particle size distribution analyzer (model LA-950, Horiba, Japan) and an inverted microscope (model Eclipse TE2000-s Nikon, Japan). The crystallinity of drug in microparticles was analyzed by a powder x-ray diffractometry (PXRD; model Miniflex II, Rigaku Co., Japan) at 30 kV, 15 mA over the range of 5-45° 2θ by the scanning speed of 4 degrees/min using CuKα radiation wavelength of 1.5406 Å. The dissolution of indomethacin from microparticles were performed in phosphate buffer pH 7.4 (900 mL) using USP dissolution apparatus II (model DT70, Erweka, Germany) at 37±0.5°C and a speed of 75 rpm. The absorbance of drug solution was measured at 318 nm using UV spectroscopy (model T60, PG Instruments, UK). Each dissolution study was performed in triplicate. 100

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Without glutaraldehyde

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70 60 50 40 30 20 10 0 0.10

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Figure 1. (a) Size of pectin microparticles prepared from HMP, and the morphology of microparticles prepared from HMP (b) without and (c) with glutaraldehyde. Results and Discussion Sizes and size distribution of the microparticles obtained from emulsion-solvent evaporation highly depended on the type and concentration of pectin (Fig. 1a). The microparticles obtained from HMP showed the largest size owing to its high MW (200 kDa). This might be due to long chain polysaccharide lying on the water-chloroform interface loose the structure of microparticles. LMP and ALMP which were smaller in molecular sizes than HMP formed smaller microparticles (data not shown). Glutaraldehyde was used for cross-linking pectin molecules to form tighter structure pectin molecules of microparticles. The significant decreasing of microparticle size was found when adding glutaraldehyde in the HMP microparticles. In ALMP and LMP microparticles, addition of glutaraldehyde caused different results. However, the particles size could be decreased to 16 µm when glutaraldehyde was added. The DE of HMP (70%) played a major role in emulsion stability.

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Hydrophobic part of pectin results in stable particles size. The decrease in size of microparticles was owing to partial evaporation of chloroform. The morphology of microparticles prepared from HMP (2% w/w) were spherical with smooth surface (Figs. 1b and 1c). The size of microparticles prepared from HMP (2% w/w) with no glutaraldehyde was about 60 µm while the addition of glutaraldehyde caused tighter and smaller microparticles (about 30 µm). The powder x-ray diffraction analysis was used to clarify the crystalline form of indomethacin in microparticles. The diffractograms showed that indomethacin powder was highly crystalline and all types of pectin were present as an amorphous form (Fig. 2). Their physical mixture still showed a crystalline form of indomethacin. The microparticles prepared from different types of pectin (0.5% w/w) showed that the drug was completely amorphous (Fig. 2). Similar results were obtained when using 0.75% w/w of different types of pectin. The disappearance of the peaks may be due to the inhibition of indomethacin crystallization by pectin. (b)

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(c)

Figure 2. Powder x-ray diffractograms of microparticles prepared from (a) LMP, (b) HMP, (c) ALMP. The concentration of pectin was 0.5% w/w (a)

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Figure 3. Dissolution profiles of indomethacin from microparticles (with glutaraldehyde) prepared from different types of pectin; (a) 0.5% w/w pectin (at ratio 1:10), and (b) 0.75% w/w pectin (at ratio 1:15). The dissolution profiles of microparticles obtained from emulsion-solvent evaporation method were carried out in phosphate buffer pH 7.4 (Fig. 3). The amount of drug dissolution from microparticles prepared from different types of pectin could be ranked as ALMP>HMP>LMP when

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using 0.5% w/w pectin while the drug dissolution of microparticles using 0.75% w/w of various pectin classified as LMP>HMP>ALMP. It is observed that the drug dissolution from microparticles prepared from various pectins was slower than the indomethacin powder. This is probably due to the impact of glutaraldehyde, a cross-linking agent, which hardened the microparticles and consequently slowed the drug dissolution. Fig. 4 shows the dissolution profiles of indomethacin from microparticles prepared from ALMP with and without glutaraldehyde. The drug dissolution from microparticles without glutaraldehyde was considerably faster than those with glutaraldehyde and indomethacin powder alone when using 0.5% w/w pectin while drug dissolution from microparticles using 0.75% w/w pectin, without glutaraldehyde, was faster than those with glutaraldehyde but slower than indomethacin powder. The higher drug dissolution from the microparticles without glutaraldehyde might be resulted from the formation of an amorphous solid dispersion. Addition of glutaraldehyde, however, resulted in slower drug dissolution, compared to the formulations without glutaraldehyde or drug alone. (b)

(a)

Figure 4. Dissolution profiles of indomethacin from microparticles prepared from ALMP with and without glutaraldehyde; (a) 0.5% w/w pectin (at ratio 1:10), and (b) 0.75% w/w pectin (at ratio 1:15). Conclusions Indomethacin could be encapsulated in the microparticles prepared by using pectin as a wall component. Higher molecular weight of pectin caused a larger in size of microparticles than the lower one. Powder x-ray diffractograms showed that the drug in microparticles was in an amorphous form while the physical mixture still showed the crystalline state of drug. Drug dissolution from the microparticles containing indomethacin and pectin was increased. Addition of glutaraldehyde, however, resulted in slower drug dissolution, compared to the formulations without glutaraldehyde. Acknowledgment The authors thank the Thailand Research Fund and Office of Small and Medium Enterprises Promotion, Thailand, for the financial support (grant number IUG5080020). References [1] [2] [3] [4]

G.G. Liversidge, K.C. Cundy: Int J Pharm, Vol.125(1995), p.91. P. Sriamornsak: Silpakorn U Int J, Vol.3(2003), p.206. P. Sriamornsak: Expert Opin Drug Del, Vol.8(2011), p.1009. K. Burapapadh, M. Kumpugdee-Vollrath, D. Chantasart, P. Sriamornsak: Carbohydr Polym, Vol.82(2010), p.385.