Fabrication of Nano-composites from the Radix of Angelica gigas Nakai by Hot Melt Extrusion Mediated Polymer Matrixs

INTRODUCTION

Radix of Angelica gigas Nakai is an important herbal medicine in Korea and has several pharmacological properties to menopausal syndromes, anemia, abdominal pain, inhibition of breast cancer, and amenorrhea (Nam et al., 2018).

A. gigas Nakai has been studied extensively and found to contain a variety of substances including coumarins (Ryu et al., 1990). Coumarins are composed of decursin and decursinol angelate, which has long been used as a traditional medicine for the treatment of anemia, as a sedative, and as an anodyne or a tonic agent (Yook, 1990).

Most of the decursin and decursinol angelate metabolized to decursinol, more hydrophilic, it is low bioavailability and water solubility due to poorly and slowly absorbed across the gut and via the blood following oral and intravenous administrations (Kim et al., 2009).

Many herbal medicines such as Radix of A. gigas Nakai are used in functional food products; however, there is currently a great deal of concern over possible absorption, tissue distribution, metabolism, and elimination following oral administration associated with such pharmaceutical active compound in animal model and human body.

This point was explained that pharmaceutical active compound have strong intermolecular covalent bonds in the crystal lattice, the diverse range of structural components, the high bonding capacity within the molecules, and the large molecular weight of the endproduct make it less functional. (Khaledi, 1997; Khoddami et al., 2013).

Also, pharmaceutical industry is facing the challenge of having more and more pooly soluble drug molecules that have to developed into dosage forms so that high and reliable drug absorption can be guaranteed on being administered to patients (Breitkreutz, 1998).

Usually the drug company will seek a way to modify the molecule in a way that it become more soluble, different approach such as physical modification (salts, amorphous solid dispersions, and particle size reduction) and carrier or delivery systems (co-solvent, micelles, microemulsion, and nanopaticles) to overcome the solubility issues and enhancing the drug molecule's bioavailability of drug molecule (Perriea and Rades, 2010).

Janssens and Van den Mooter (2009) defined that solid dispersion is formulation of pooly souble compounds as solid dispersions might lead to particel size reduction, improve wetting, reduced agglomeration, changes in the physical state of the drug and possibly dispersion on an molecular level, according to the physical state of the solid dispersion.

Solid dispersion are system where one component is dispersed in a carrier (usualluy polymeric and often amorphous), it used ways to improve the solubility and hence the bioavailability of drug (Newman et al., 2012). Solid dispersion are prominent nowadays when preparation method such as hot-melt extrusion. In hot-melt extrusion (HME), extruder's screw the materials is mixed and dispersed at the same time, HME does by applying shear stress to the drug and the polymer, it generated energy by friction in order to overcome the crystal lattice energy to transform the drug into its amorphous form and to soften the polymer (Qi et al., 2011).

The application of food grade polymer in food and drug industry is getting special attention for the development of control delivery system. Hydroxypropyl ethylcellulose (HPMC) is a water soluble cellulose mainly used as a carrier material for the control release of active ingredients.

HPMC is hydrophilic and biocompatible polymer having capabilities of the hydration and gel forming which is prolong the releasing time of the active ingredients (Kadajji and Beageri, 2011). HPMC is extensively used in the food industry as a stabilizer, as an emulsifier, as a protective colloid, and as a thickener (BeMiller and Whistler, 1996).

HPMC is used as a raw material for coatings with moderate strength, moderate moisture and oxygen barrier properties, elasticity, transparency, and resistance to oil and fat (Kadajji and Beageri, 2011). It forms gel upon heating with gelation temperature of 75 - 90℃ during extrusion. By reducing the molar substitution of hydroxyl propyl group, the glass transition temperature of HPMC can be reduced to 40℃ (Deshmukh et al., 2017).

Recently, in order to produce sustaind release matrix tablets, hot melt extrudates of ethyl cellulose as a releasecontrolling polymer and HPMC as a hydrophillic drug relase modifier together with different drug such as iburofen and metoprolol tartrate were molded in to tablets using extruder (Vervaet et al., 2008; Quinten et al., 2008).

Another food grade carrier, alginate is a natural hydrophilic polysaccharide extracted from brown seaweed (Yang et al., 2011). This biopolymer is considered biocompatible, biodegradable, non-toxic and its use as food additive has been generally recognized as safe by Food and Drug Administration (Andersen et al., 2012).

As a food ingredient, the applications of alginate are based on three main properties: thickening, gelling, and film forming due to presence of reactive sites, such as hydroxyl and carbonyl groups along the backbone (Zia et al., 2015).

Application of alginate in food industry is being increasing due to its dynamic chemical and biological properties (Zia et al., 2015). In addition to alginate is increasingly used to encapsulate active compound, acting as a carrier for controlled delivery system and protective coating for fruits and vegetables (Qin et al., 2018).

Previously a group of researcher prepared nanocomposite of radix of A. gigas Nakai based on polymer and biopolymer to enhanced solubility and bioavailability (Piao et al., 2015), oral cancer therapy (Nam et al., 2017), control delivery system (Lee et al., 2016), brest cancer therapy (Lee et al., 2017a).

Researchers have discovered the compatible polymeric material for the preparation of hydrogel matrix in order to enhance solubility (Baird and Taylor, 2012; Shit and Shah, 2014). From the nutraceutical point of view, polymer control the rheological characteristics of food materials and prolong the releasing time.

In this regards, nano-composite of radix of A. gigas Nakai were prepared based on HPMC (HP55, CN40H and AN6) and Na-Alg to enhance solid dispersion of the active compound. This nano composite would be potentially enhance the nanonization, water solubility and amorphization of the active compound from A. gigas Nakai extrudate.

MATERIALS AND METHODS

RESULTS AND DISCUSSION

1. Physical-chemical characteristics of extrudate solid formulations (ESFs) mediated various HPMCs and Na- Alg polymer

1) Particle size reduction

In our study, the particle size of the ultrafine powder of radix of A. gigas Nakai was recorded at 1,467㎚, whereas the particle size was reduced to 585㎚ at the ESFs without polymer adding. Among the ESFs mediated polymers such as HPMCs (HP55, CN40H and AN6) and Na-Alg, the least particle size (323㎚) was achieved in the HP55-ESF (Table 1).

Table 1

Particle size and diffusion coefficient of extrudate solid formulations (ESFs) mediated various HPMCs and Na-Alg polymer.

Previously it is reported that HME extrusion is the most suitable process to form nano particle size (Maniruzzaman et al., 2012; Lee et al., 2017b). The particle size reduction strategy results in increased surface area, decreased diffusional distance, and increased dissolution rates (Repka et al., 2007; Merisko-Liversidge and Liversidge, 2008).

In the case of a limited dissolution rate, decreasing the particle size of the crystal form of active compounds can improve solubility. By downsizing the particle size, the surface will increase, this usually improves the wettability and hence dissoltion kinetics. Down sizing particles lead to molecular dispersed system.

HP55-ESF has the lowest particle size among ESFs mediated other HPMCs polymers and Na-Alg polymer, physical and chemical propertises of the HP55 might have direct influence to reduce the particle size.

Melt viscosity is important factor for determined extrudability of a polymer, polymer with a high molecular weight exhibit high melt viscosity and are difficult to extrude (Chokshi et al., 2005). Higher viscosity which means a higher shear stress with higher extrusion temperature might even lead to higher impurity level of ingredient in extrudated materials (Ghebremeskel et al., 2007) may cause degradation of active compounds and polymer. The high viscosity are not suitable.

For instant, HP55 possess 27 - 35% of phthalyl with viscosity of 32 - 48 cSt, pH < 5.5 where as CN40H and AN6 possess 19 - 24 % and 28 - 30% of methoxyl with viscosity of 4000 and 6 cSt, pH 5 - 8, respectively. On the other hand, Na-Alginate viscosity is 300 cSt and pH > 7.

Previous research have investigated the mechanism of hydrophilic HMPC effect on the particle size of the active compound (Miranda et al., 2007).

2) Solubility analysis

The results in Table 2 show that water solubility was improved in HP55-ESF (61.5%) compared to ultrafine powder of radix of A. gigas Nakai (34.4%), acetic acid not treated ESF control (38.4), acetic acid treated ESF control without polymer (47.2%).

Table 2

Water solubility analysis of extrudate solid formulations (ESFs) mediated various HPMCs and Na-Alg polymer.

According to the Noyes-Whitney equation, particle size has a direct effect on the dissolution rate. The reduction of particle size increases the diffusional coefficient and nanonization.

In addition, an acidic solution (H+) increases the concentration gradient as well as enhances the dissolution rate through ionization process (Szekeres and Tombácz, 2012).

Amorphous nanoparticles exhibit very high saturation solubility compared to the crystalline form (Murdande et al., 2010). The HME process tends to make more channels to enhance the permeability and penetration of water into the core of the material’s matrix (Piao et al., 2015). Preparation of amorphous solid dispersion is a promising way to improve solubility. Cystalline compound exhibit poor water solubility, since the lattice energy must be overcome in order for dissolution (Li et al., 2013; Chuah et al., 2014).

The solubility of amorphous substances is higher solubility than the thermodynamically stable crystalline forms, because their internal bonding forces are weak. Solutions obtained from amorphous forms are supersaturated, and crystallization occurs once a crystal of the stable form develops (Gangurde et al., 2015).

In order to improve solubility, HPMC polymer carriers have been used because they readily generate amorphous forms and may be able to retain the amorphous nature of the compound (Leuner and Dressman, 2000). The higher solubility achieved in the HP55-ESF among ESFs mediated other HPMCs polymers and Na-Alg polymer. The reason might be due to the physicochemical characterization of the HP55 polymer.

3) XRD, DSC and FT-IR analysis

Fig. 1 shows the XRD diffractogram of the ESFs mediated other HPMCs polymers and Na-Alg polymer. The presence of a large number of peaks of different intensities in the diffractogram suggests the presence of unidentified complex substances in the ESFs mediated other HPMCs polymers and Na-Alg polymer. The HP55- ESF/CN40-ESF showed sharp diffraction peaks at angles between 25° and 30° with a lower degree of diffraction among the formulations. Application of pressure and agitation through an extrusion channel to mix materials together, subsequently forcing them out through a die to form an amorphous solid (Wilson et al., 2012).

Fig. 1

XRD diffractogram of extrudate solid formulations (ESFs) mediated various HPMCs and Na-Alg polymer.(A); UFP; ultrafine powder from radix of A. gigas Nakai, (B); ESF-control: acetic acid not treated extrudate solid formulations control, (C); ESF-AA; acetic acid treated extrudate solid formulations without polymer, (D); ESF-Na-Alg; acetic acid treated extrudate solid formulations with polymers, sodium aliginate (5% w/w), (E); ESF-HP55; acetic acid treated extrudate solid formulations with polymers, HP55 polymer (10% w/w), (F); ESF-CN40H; acetic acid treated extrudate solid formulations with polymers, CN40H (10% w/w), (G); ESF-AN6; acetic acid treated extrudate solid formulations with polymers, AN6 (10% w/w).

In the DSC analysis, it is determined the glass transition temperature (Tg) (Fig. 2). The extrudate solid formulations (ESFs) mediated various HPMCs and Na-Alg polymer had a lower ΔH value of Tg (> 10 J/g) than ultrafine powder of radix of A. gigas Nakai (ΔH of 146 J/g). It is well known that amorphous materials have a lower Tg compared to crystalline materials (Yoshioka et al., 1994).

Fig. 2

Glass transition energy of extrudate solid formulations (ESFs) mediated various HPMCs and Na-Alg polymer.UFP; ultrafine powder from radix of A. gigas Nakai, ESFcontrol: acetic acid not treated extrudate solid formulations control, ESF-AA; acetic acid treated extrudate solid formulations without polymer, ESF-Na-Alg; acetic acid treated extrudate solid formulations with polymers, sodium aliginate (5% w/w), ESF-HP55; acetic acid treated extrudate solid formulations with polymers, HP55 polymer (10% w/w), ESF-CN40H; acetic acid treated extrudate solid formulations with polymers, CN40H (10% w/w), ESF-AN6; acetic acid treated extrudate solid formulations with polymers, AN6 (10% w/w). Mean values ± SD from triplicate separated experiments are shown. *Value marked by different letters in each column are significantly different by t-test (p<0.05) compared ultrafine powder from radix of A. gigas Nakai (UFP).

The ΔH of Tg of the extrudate solid formulations (ESFs) mediated various HPMCs and Na-Alg polymer appeared as very weak transitions, as more crystalline materials act as physical crosslinks that restrain the mobility of the amorphous regions (Zeleznak and Hoseney, 1987). The lowest ΔH was achieved in CN40-ESF where ΔH was recorded at 1.3 J/g.

DSC analyzes the system has been widely used to study the termal properties of materials used for example in hot melt extrusion. DSC can be used for the determination of Tg coupled with endothermic and exothermic phase transformation. The decreased Tg in the DSC scan of the HME indeicated that the drug is present in an amorphous or molecularly dissolved state rather than crystalline form (Singhal et al., 2011)

It is previously reported that the Tg of the formulation can be reduced to 40℃ by reducing the molar substitution of hydroxyl propyl group of HPMC (Deshmukh et al., 2017).

FT-IR spectroscopy investigated the new compounds produced in the ESFs, since it can detect a range of functional groups according to molecular structure (Cocchi et al., 2004; Tita et al., 2011). The spectra are presented in Fig. 3, which shows that the splitting peak in 1,700 - 3,500㎝⁻¹ in ESFs, however, no splitting peak were observed in ultrafine powder from radix of A. gigas Nakai at the same range. Moreover, it is also observed that polymer matrix has no effect to produce new compound but HME.

Fig. 3

FTIR chromatogram of extrudate solid formulations (ESFs) mediated various HPMCs and Na- Alg polymer.(A); UFP; ultrafine powder from radix of A. gigas Nakai, (B); ESF-control: acetic acid not treated extrudate solid formulations control, (C); ESF-AA; acetic acid treated extrudate solid formulations without polymer, (D); ESF-Na-Alg; acetic acid treated extrudate solid formulations with polymers, sodium aliginate (5% w/w), (E); ESF-HP55; acetic acid treated extrudate solid formulations with polymers, HP55 polymer (10% w/w), (F); ESF-CN40H; acetic acid treated extrudate solid formulations with polymers, CN40H (10% w/w), (G); ESF-AN6; acetic acid treated extrudate solid formulations with polymers, AN6 (10% w/w).

In the ESFs, there is a strong peak in wavelength of 2,800 - 3,000㎝⁻¹, which correspond to alkane C-H stretching. Alkynes, benzene and its derivatives stretching occurred near 3,300㎝⁻¹ in all ESFs except ultrafine powder of radix of A. gigas Nakai. The other prominent peaks at 1,700 - 1,500㎝⁻¹ for all ESFs possess the characteristics of methylene and methyl bending. The peak region between 3,500 - 3,000㎝⁻¹ is related to C-H, OH compounds (SP2), which we attribute to the nature of the organic compounds in the ESFs. Peak regions at < 2,000㎝⁻¹ represent the carbonyl group compounds and the =C bonds in the aromatic rings and aromatic CH bonds on substituted rings (Silverstein et al., 2006). The peaks in the region < 1,500㎝⁻¹ are related to carbon– oxygen bonds (CO) in ethers, esters, and carboxylic acids and are indicative of a wide variety of metabolites, such as tannins, flavonoids, and anthraquinones (Correia et al., 2011).

2. Analytical investigation of extrudate solid formulations (ESFs) mediated various HPMCs and Na-Alg polymer

Among extrudate solid formulations (ESFs) mediated various HPMCs and Na-Alg polymer, ESF-HP55 showed the highest phenolic compound content (TPC; 2,136㎎· GAE/100g, TF: 180㎎·COU/100g, decursin; 200㎎/100g, decursinol angelate: 182㎎/100g, DPPH scavenging activity; 93%) (Table 3). The high level of compression and shear forces exerted on the crystalline structure of phenolic molecules lead to their disruption and defibration and the formation of an amorphous structure (Jurišić et al., 2015) (Fig. 4).d

Table 3

Total phenolic content, total flavonoid and antioxidant activity of extract in extrudate solid formulations (ESFs) mediated various HPMCs and Na-Alg polymer.

Fig. 4

Schematic illustration of extrudate solid formulations (ESFs) mediated various HPMCs and Na-Alg polymer and solid dispersions by hot melt extrusion process.

The physical crosslinking process by HME destructured the fiber matrix and caused phenolic compounds to be released into solution (Yu et al., 2002). HME increases the reactive surface areas of compounds and destructure the fiber matrix, thus causing enhanced decursin and decursinol angelate to be released into solution (Fig. 5). Therefore, the most likely explanation for the enhanced active compound extraction from the extrudate sample is the disruption of cell wall structure (Piao et al., 2015).

Fig. 5

Contents of decursin and decursinol angelate of extrudate solid formulations (ESFs) mediated various HPMCs and Na-Alg polymer.UFP; ultrafine powder from radix of A. gigas Nakai, ESF-control: acetic acid not treated extrudate solid formulations control, ESF-AA; acetic acid treated extrudate solid formulations without polymer, ESF-Na-Alg; acetic acid treated extrudate solid formulations with polymers, sodium aliginate (5% w/w), ESF-HP55; acetic acid treated extrudate solid formulations with polymers, HP55 polymer (10% w/w), ESF-CN40H; acetic acid treated extrudate solid formulations with polymers, CN40H (10% w/w), ESFAN6; acetic acid treated extrudate solid formulations with polymers, AN6 (10% w/w). Mean values ± SD from triplicate separated experiments are shown. *Value marked by different letters in each column are significantly different by t-test (p < 0.05) compared ultrafine powder from radix of A. gigas Nakai (UFP).

In this study HP55 polymer enhanced the extraction efficiency of phenolic compound. It is explanied that due to hydrophilic characteristics and sol-gel behaviour of the HMPC polymer, extraction was facilitated (Kjoniksen et al., 2005). It is reported that HME enhances the dissolution rate of poorly water-soluble compounds (Hulsmann et al., 2000). Moreover, Hagi and Hatami (2010) determined higher levels of flavonoid were produced by the use of an acid-mediated solution from vegetables and medicinal plants.

ACKNOWLEDGEMENTS

This work was supported by the Kangwon National University (2017520170416).

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