Senol S, Akyol E. JOTCSA. 2019; 6(1): 1-14. RESEARCH ARTICLE Study on the Preparation and Drug Release Property of Modified PEG-DA Based Hydrogels Sebnem Senol1 , Emel Akyol1* 1Department of Chemical Engineering, Yildiz Technical University, Istanbul, Turkey. Abstract: The aim of the present study is to develop hydroxyapatite-modified PEG- DA and PEG-DA/HEMA based hydrogels for release of Donepezil HCl for potential treatment of Alzheimer’s disease. [2,2-Dimethoxy-2-phenyl-acetophenone] (Irgacure 651), 1 hydroxycyclohexyl phenyl ketone (Irgacure 184) and 2-hydroxy-4'-(2- hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959) were used as photo- initiators in the synthesis of hydrogels and hydroxyapatite was used for modifying hydrogels. Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM) and digital microscope were utilized to investigate the characteristic properties of hydrogels. Photopolymerization technique was selected for the synthesis of hydrogels. Swelling and drug release studies have been performed under different pH conditions. Keywords: Alzheimer’s Disease, Hydrogels, Photopolymerization, Donepezil HCl, Polyethylene diacrylate, 2-Hydroxyethyl methacrylate. Submitted: November 20, 2018. Accepted: January 03, 2019. Cite this: Senol S, Akyol E. Study on the Preparation and Drug Release Property of Modified PEG-DA Based Hydrogels. JOTCSA. 2019;6(1):1–14. DOI: http://dx.doi.org/10.18596/jotcsa.485817. *Corresponding author. E-mail: [email protected]. INTRODUCTION systems. The purpose of the drug delivery systems is to maintain drug Many new classes of materials have concentration in the blood or in target been used to improve different tissues at prolonging drug-release innovative applications. Hydrogels, times (1-6). being cross-linked three-dimensional polymeric materials, have the ability to Polyethylene glycol diacrylates (PEG- absorb large amounts of water. In DA) based polymers possess recent years, hydrogels have an highly attractive properties that cause increasing demand for drug delivery widely using in variety of applications 1 Senol S, Akyol E. JOTCSA. 2019; 6(1): 1-14. RESEARCH ARTICLE such as tissue engineering, controlled Donepezil is a piperidine-based, drug delivery, and medicine areas. reversible acetylcholinesterase (Ach) Polyethylene glycol diacrylate is non- inhibitor generally used in the volatile, non-toxic, environmentally treatment of Alzheimer patients. friendly, and also tailor-made into Donepezil prevents the hydrolysis of various shapes. Polyethylene glycol the residual Ach in the brain so it is the diacrylate acts as potential stabilizers best pharmacological tool to decrease and matrices for the formation of cognitive deficits in AD patients. functional hydrogels (7-10). Donepezil has been investigated to be sufficient for enhancing of cognitive Poly(2-hydroxyethyl methacrylate) impairment and memory loss in (pHEMA), one of the synthetic water- patients with Alzheimer’s disease. It is soluble polymer, has been largely well efficient when 5 mg of the drug is preferred, especially in various used once daily (22-27). biomedical applications due to its chemical stability (11-12). In this study, we aimed to develop prolonged drug release systems Hydroxyapatite (HAp), enhanced with HAp. We synthesized Ca10(PO4)6(OH)2, is a double salt of tri- PEG-DA/HEMA based hydrogels with calcium phosphate and calcium modified Hap via photopolymerization. hydroxide, and it is the main inorganic Fourier transform infrared component of human bones and teeth. spectroscopy (FT-IR), scanning However, hydroxyapatite has an electron microscope (SEM) and digital excellent biocompatibility and tissue microscope were utilized to investigate bioactivity (13-16). the characteristic properties of hydrogels. Modified PEG-Da/HEMA UV light polymerization is one of the hydrogels were used for prolonging the main methods used in the synthesis of release time. hydrogels in biomedical field. Considerable attention has been EXPERIMENTAL focused on photopolymerization method due to its broad applications. Materials Nowadays, free radical polymerization 2-Hydroxylethyl methacrylate (HEMA), with UV light is utilized in different polyethylene glycol diacrylates applications such as coatings, Mn=700 (PEG-DA), ethylene glycol information storage systems, films, dimethacrylate, 2,2-dimethoxy-2- contact lenses, and biomaterials. In phenyl-acetophenone (Irgacure 651, the photopolymerization, the primary 99% purity), 1-hydroxycyclohexyl radicals were generated from light phenyl ketone (Irgacure 184, 99% absorption of photoinitiator at a purity), 2-hydroxy-4'-(2- suitable wavelength thus hydroxyethoxy)-2- polymerization and into highly cross- methylpropiophenone (Irgacure 2959, linked structures of multifunctional 98% purity), hydroxyapatite (powder, acrylates occurs (17-18). 5 µm and surface area ≥ 100 m2/g), were supplied by Sigma-Aldrich. Alzheimer's disease (AD) is the most Donepezil HCl was a kind gift by Abdi common type of dementia that cause İbrahim Company. Sodium chloride cognitive impairment and memory loss and hydrochloric acid were purchased (19). The number of patients with AD from Merck. Sodium hydroxide and is projected to more than double by monobasic potassium phosphate were 2050. Although the etiology of AD has supplied from J.T Baker. All chemicals been elucidated, multiple questions were used as received without further remain unanswered (20-21). purification. 2 Senol S, Akyol E. JOTCSA. 2019; 6(1): 1-14. RESEARCH ARTICLE Preparation and characterization of PEG-DA/HEMA hydrogels According to hydrogel type, 50% (w/v) PEG-DA/HEMA based hydrogels were PEG-DA, 25% (w/v) PEG-DA- 25% prepared in the presence of a photo- (w/v) HEMA and predetermined ratios initiator (Irg 184, Irg 651, Irg 2959) of photo-initiators were mixed by using and a crosslinking agent (ethylene a magnetic stirrer at 50 rpm. Then, glycol dimethacrylate), as shown in 0.07% (w/v) Donepezil HCl and Table 1. The reactant mixtures were deionized water were added. 0.5% added to petri plates which consist of ethylene glycol dimethacrylate was olive oil, using a micropipette. The then introduced. After reactant mixtures were deaerated by photopolymerization, hydrogels were bubbling nitrogen gas during the washed with n-hexane and dried at reaction. Photopolymerization was room temperature. performed at 365 nm under UV irradiation for a short time. Table 1: Synthesis conditions for the PEG-DA/HEMA based hydrogels. Hydrogels PEG- HEMA EGDM Irg Irg Irg HAp DA A 651 184 2959 Hydrogel 1 50% - 0.5% 1% - - 1% (H1) Hydrogel 2 50% - 0.5% - 1% - 1% (H2) Hydrogel 3 50% - 0.5% - - 1% 1% (H3) Hydrogel 4 25% 25% 0.5% 1% - - 1% (H4) Hydrogel 5 25% 25% 0.5% - 1% - 1% (H5) Hydrogel 6 25% 25% 0.5% - - 1% 1% (H6) The equilibrium swelling ratios of the FT-IR Analyses of Hydrogels swollen hydrogels were measured For the imaging of photo-crosslinked using a gravimetric method in PEGDA-based hydrogels, the deionized water, pH 1.2, 6.8, and 7.4. attenuated total reflectance-FTIR Drug loaded hydrogels were used for (ATR-FTIR) scan was performed with a swelling behavior at 37 °C. At Perkin Elmer Spectrum 100 FTIR predetermined time points, the spectrometer. For each sample, a hydrogels were taken out and weighed spectrum is obtained using the ATR after removal of surface water. utilizing a diamond internal reflection Swelling and release analyses were element mounted on a holder at a repeated three times. A UV–Vis resolution of 4 cm-1 in the range 4000- spectrophotometer (Analytikjena 400 cm-1 for a total of 16 scans. Specord 200/Plus) at 270 nm was used for release studies. FT-IR spectra of the hydrogels are shown in Figure 1. In the PEG-DA The determination of swelling ratio and spectrum, there was an –OH at 3600 −1 −1 preperation of buffer solution cm , a CH2 at 2853 cm , a C=O at procedure has been reported 1728 cm−1, and a C=C at 1628 cm−1. previously in detail (4,28). For the PEG-DA/HEMA based hydrogels, there was an –OH bond at −1 RESULTS AND DISCUSSIONS 3500 cm , a CH2 at 2853 and 2956 cm−1 , a C=O at 1730 cm−1 , a C=C at 3 Senol S, Akyol E. JOTCSA. 2019; 6(1): 1-14. RESEARCH ARTICLE 1610 cm−1, a C–OH at 1059 cm−1. The cm-1 are due to the phosphate being in bands at 1090 and 960 cm-1 are used vibration. FT-IR analyses results for the characterization of phosphate confirm the combination of PEG-DA stretching vibration and the bands and HEMA. observed at 598 and 559 and at 1020 H1 H2 H3 H4 H5 Transmittance % H6 3500 2500 1500 500 Wavenumber (cm-1) Figure 1. FT-IR spectra of the hydrogels. SEM Analysis of Hydrogels showed a surface devoid of pores and The sizes of hydrogels were obtained cracks. Figure 3 shows the effect of by digital microscope (Veho, VMS- 004 incorporation of HEMA and PEG-DA on USB) Microscope (Figure 4). The structure of hydrogels. While textures of the hydrogels were microparticles were formed in the examined by a conventional scanning presence of PEG-DA, the presence of electron microscopy (JEOL JSM HEMA revealed a spherical structure. 6335F). Figure 2 shows the SEM The hydroxyapatite modified PEG-DA micrographs of PEG-DA based hydrogels were very different from and hydrogels using HAp as modified. The PEG-DA/HEMA based hydrogels. SEM morphology of H1 hydrogel 4 Senol S, Akyol E. JOTCSA. 2019; 6(1): 1-14. RESEARCH ARTICLE Figure 2: Scanning electron micrographs of H1 hydrogel. Figure 3: Scanning electron micrographs of H6 hydrogel. 5 Senol S, Akyol E. JOTCSA. 2019; 6(1): 1-14. RESEARCH ARTICLE Figure 4: Digital microscope photos of synthesized hydrogels. Swelling tests based hydrogels. The swelling ratio of In order to investigate the influence of hydrogel decreased significantly with the presence of HAp and pH, swelling the incorporation of HEMA to PEG-DA. kinetics of PEG-DA and PEG-DA/HEMA While the values of swelling based hydrogels were studied.