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Enhanced impregnation of hydrogel contact lenses with salicylic acid by addition of water in supercritical carbon dioxide
Accepted Manuscript Title: Enhanced impregnation of hydrogel contact lenses with salicylic acid by addition of water in supercritical carbon dioxide Author: Yuta Yokozaki Junichi Sakabe Yusuke Shimoyama PII: DOI: Reference:
S0263-8762(15)00304-4 http://dx.doi.org/doi:10.1016/j.cherd.2015.08.007 CHERD 1986
To appear in: Received date: Revised date: Accepted date:
3-11-2014 31-7-2015 5-8-2015
Please cite this article as: Yokozaki, Y., Sakabe, J., Shimoyama, Y.,Enhanced impregnation of hydrogel contact lenses with salicylic acid by addition of water in supercritical carbon dioxide, Chemical Engineering Research and Design (2015), http://dx.doi.org/10.1016/j.cherd.2015.08.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Research highlights
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solution.
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Efficiencies of supercritical impregnation with water are higher than aqueous
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hydrogel lens.
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Addition of water in supercritical impregnation increase loading amount in
Release from lenses is resulted by Fickian diffusion and hydrogel swelling.
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Revised manuscript to Chemical Engineering Research and Design
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Short Communication
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Enhanced impregnation of hydrogel contact lenses with salicylic acid
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by addition of water in supercritical carbon dioxide
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Yuta Yokozaki, Junichi Sakabe, Yusuke Shimoyama*
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Ookayama, Meguro-ku, Tokyo 152-8550, Japan
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Department of Chemical Engineering, Tokyo Institute of Technology, 2 – 12 – 1 S1-33,
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* E-mail: [email protected], TEL & FAX: +81 3 5734 3285
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Abstract An impregnation of soft contact lenses with salicylic acid in supercritical CO2
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was enhanced by addition of water. The supercritical CO2 impregnations including
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water were conducted at 40 °C and 11 MPa with 0.34 to 2.18 g L-1 of water amount. The
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contact lenses impregnated in supercritical CO2 including water result in the high
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loading-amount of salicylic acid compared with those without water. The higher amount
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of water in supercritical CO2 impregnation gives the slower release of salicylic acid
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from the lenses. The impregnation efficiency of the contact lenses with salicylic acid in
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supercritical CO2 including water was evaluated from the loading-amount in the lenses
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and the concentration in the supercritical CO2 phase. The efficiencies of supercritical
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CO2 impregnation including water are higher than aqueous solution impregnation. The
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impregnation efficiency of the lenses increases with the water amount in the
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supercritical CO2 impregnation processes. The amount of salicylic acid loaded in the
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lenses also increases with the amount of water dissolved in supercritical CO2. A release
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model using kinetic constant and exponent parameter was applied for modeling the
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release profile of salicylic acid from the contact lenses. The release modeling suggested
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that the release from the contact lenses was resulted from the superimposition of Fickian
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controlled and hydrogel swelling controlled releases.
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Keywords: supercritical CO2 impregnation, enhanced impregnation, addition of water,
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hydrogelcontact lens, release profile
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Introduction
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Although the eye drop method is applied for the around 90 % of the ocular disease
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treatments currently, the only 1 to 5 % of drug in the eye drop can be used
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therapeutically (Hu et al., 2011). Drug delivery systems using hydrogel contact lenses
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for ocular diseases have been developed actively due to their advantages, sustained drug
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release and high bioavailability compared with eye drop (Hu et al., 2011;
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González-Chomón et al., 2011). Some research groups have studied the preparation of
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the ophthalmic drug delivery system using the contact lenses (Ventatesh et al., 2007;
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Ventatesh et al., 2008; Kim et al., 2008; Kappor and Chauhan, 2008(a) and 2008(b);
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Kim et al., 2010). Venkatech et al. (2008) have investigated the molecular imprinted
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hydrogel and the transport permeation of the drug through the hydrogel. Kappor and
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Chauhan (2008(a) and 2008(b)) have studied the mechanism of the release of
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Cyclosporine A from the poly-hydroxy ethyl methacrylate hydrogel with surfactant. The
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additions of surfactant have been capable of the slow and extend release of the drug
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from the hydrogel. The extended release of dexamethasone from the silicone-hydrogel
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lenses has been investigated by Kim et al (2010). Vitamin E was added to the
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silicone-hydrogel for the extended release of dexamethasone. Supercritical CO2 impregnation method can also be a potential technique for the
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preparation of the drug-loaded hydrogel because of the low surface tension on polymer,
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high diffusivity and non-toxic to human body. The hydrogels loaded with ophthalmic
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drug using supercritical CO2 impregnation have been investigated recently (Braga et al.,
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2008; Costa et al., 2010(a) and 2010(b); Braga et al., 2011; Masmoudi et al., 2011). The
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chitosan derivative hydrogels with flurbiprofen and timolol maleate were prepared by
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the impregnation using supercritical CO2 and supercritical CO2 + ethanol mixture
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(Braga et al., 2008). Costa et al. (2010(a)) studied the supercritical CO2 impregnation
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for the drug-loaded contact lenses using a lot of species of the lenses, Hilafilcon B,
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Alphafilcon A, Balafilon A, Nelfilcon A, Vifilcon A, Lotrafilcon A, Methafilcon A,
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Omafilcon A, Galyfilcon A and Lidofilcon A. The impregnation of the poly methyl
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methacrylate lenses with cefuroxime sodium in supercritical CO2 + ethanol mixture was
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investigated by Masmoudi et al. (2011). In the previous work of our group (Yokozaki et
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al., 2014), we studied the effect of the temperature, pressure and depressurization rate of
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supercritical CO2 impregnation on the release profile of salicylic acid from the contact
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lenses. The supercritical CO2 impregnation technique, which attains the hydrogel
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contact lenses with the large loading and sustained release of drug should be developed
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and design for the achievement of the practical application for the ophthalmic drug
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delivery systems.
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In this work, supercritical CO2 impregnation with water was used for the
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preparation of a hydrogel contact lens drug delivery system loading salicylic acid.
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Salicylic acid and Hilafilcon B were used as model solute and contact lens. It is though
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that the addition of water in supercritical CO2 can enhance the mass transfer of CO2 and
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salicylic acid into the hydrogel as explained in the hydrogel foaming using supercritical
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CO2 (Tsioptsias and Panayiotou, 2008; Tsioptsias et al., 2011). The enhancement of CO2
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mass transfer is expected to lead to increase of the amount loaded into the hydrogel. The
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effects of water amount in supercritical CO2 impregnation on the amount of salicylic
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acid loaded into the lenses were investigated. The efficiency of the impregnation in
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supercritical CO2 with water was discussed in the comparison with the aqueous solution
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impregnation. A theoretical model with kinetic constant and release exponent parameter
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was used for discussion about the release profile of salicylic acid from the lenses into
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the aqueous solution.
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2.
Experimental
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2.1. Materials Hilafilcon B, commercial soft contact lenses (SCL) from Bausch & Lomb®., Medalist®
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One-Day Plus (Non-Ionic, 59% water content, 8.6 mm base curve, -0.25 D power, 14.2
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mm diameter and 0.013 g per one lens) were used in this study. Salicylic acid was
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obtained from Wako Pure Chemical Industries, Ltd. The purity was higher than 99.5%.
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Carbon dioxide was supplied from Fujii Bussan Co. Ltd. The purity was higher than
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99.95%. Phosphate buffer solution (PBS) with pH 6.86 at 25 °C purchased form Wako
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Pure Chemical Industries, Ltd. was used as a drug release media.
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Preparation of SCL loading salicylic acid
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2.2.1.
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Supercritical CO2 impregnation
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The supercritical CO2 impregnation including water was conducted by using the
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apparatus slightly modified that used in the previous work (Yokozaki et al., 2014) as
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shown in Fig. 1. This system is composed of a CO2 supply part, a stainless steel
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high-pressure cell, 170 mL and a depressurization part. Carbon dioxide from a gas
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cylinder was liquefied through a cooling unit. The liquefied CO2 was pressurized and
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supplied to the high-pressure cell by a feed pump. A back-pressure regulator was used
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for controlling the pressure in the cell. The temperature inside the cell was controlled by
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the cartridge heater. The inside of the cell was partitioned into two parts by a petri dish.
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Three pieces of SCL and the known amount of salicylic acid were set inside and outside
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of the petri dish respectively. A soaking solution for commercial soft contact lenses
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including sodium chloride and poloxamin was used as the adding water in the
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impregnation also set inside the high-pressure cell. The petri dish was covered with a
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stainless steel wire gauze for preventing powder state salicylic acid from adhering to the
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SCLs. After the impregnation duration for 2 h, the system was depressurized slowly in
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order not to damage the structure of SCLs. The temperature and pressure were set to
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40 °C and 11 MPa in the supercritical CO2 impregnation containing water. The
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depressurization rates were set to 0.1 ± 0.03 MPa min-1. The saturated solubility of
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salicylic acid in supercritical CO2 at 40 °C and 11 MPa is 0.41 g L-1 (Gurdial and Foster,
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1991)). The impregnations were conducted at conditions that the amount of salicylic
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acid 1.2 ± 0.2 g L-1 is set over the saturated solubility in supercritical CO2 and 0.18 ±
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0.01 g L-1 below the saturate solubility. The water amounts in the high-pressure cell
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were controlled from 0 to 2.18 g L-1 in which CO2 + water system forms both the
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homogeneous phase and vapor-liquid two phases. After the impregnation process, SCLs
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were recovered from the high-pressure and then were placed in an oven at 30 °C for 1 h
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in order to dry the lenses. This drying time was optimized by checking the weight loss
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of the lens in various drying time.
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2.2.2. Aqueous solution impregnation
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Impregnations of SCLs with salicylic acid were also conducted in the aqueous
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solution for the comparisons with those prepared by the supercritical CO2 impregnation
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including water. A soaking solution for a commercial soft contact lens was used as the
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medium of the aqueous solution impregnation. The SCLs were placed in 2 mL of the
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solution dissolving salicylic acid at 25°C for 2 h. The concentration of salicylic acid in
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the aqueous solution was 2.0 g L-1. After the impregnations, the SCLs were recovered
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from the solution and placed in the oven at 30 °C for 2 h in order to dry the lenses.
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2.2.3. Rehydration of SCLs
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The dried SCLs loading salicylic acid after the impregnation were placed in 10 mL of
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the saturated salicylic acid PBS, 2.2 g L-1 at 25 °C with gently stirring for 15 min in
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order to rehydrate the lenses. The rehydrated SCLs were recovered from the PBS and
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the excess PBS on the lenses surface was removed by the tissue paper before the release
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test of salicylic acid.
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2.3.
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Drug release profile measurement
The rehydrated SCL were immersed in 10 mL of the PBS in stirred closed vials for 8 h.
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These vials were placed inside a temperature-controlled water bath at 37 °C. The sample
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in 0.3 mL were collected to the pre-determined time intervals, and replaced with the
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equivalent amount of the fresh PBS. The frequencies of the sample collection were once
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every 10, 30, and 60 min at the release time 0 to 3, 3 to 6 and 6 to 8 h, respectively. The
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collected samples were diluted to twice with the fresh PBS. The release amounts of
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salicylic acid were determined from the analysis of the collected samples using UV-vis
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spectrophotometry (JASCO, model V-630, Japan) at 296 nm.
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After the above release measurements, SCLs were kept in 10 mL of the PBS at 37 °C
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in order to leach out the total amount of impregnated salicylic acid in SCLs to the
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aqueous solution. The samples were taken from the solution and analyzed by the UV-vis
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spectrophotometry for quantifying the amount of salicylic acid release from the SCLs.
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In this work, the total amounts of salicylic acid in SCLs were determined from the
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amount released into the PBS for 24 h.
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Modeling of release profile
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The release profile of salicylic acid from the SCL is modeled by the two contributions:
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the initial instantaneous release of salicylic acid adsorbed on the surface of the hydrogel
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matrix of the SCL and the release of salicylic acid incorporated inside the matrix. The
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total amount of salicylic acid in SCL is described by the following equation:
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M tot M ads M dep
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where M denotes the amount of salicylic acid in SCL. The superscripts tot, ads and dep
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mean the total amount, adsorbed amount on the surface and deposited amount inside the
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matrix of the lenses, respectively. The adsorbed amount of salicylic acid on the surface
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of the hydrogel matrix is obtained from the total amount in those by the aqueous
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solution impregnation. The value is 1.75 × 10-4 g per one piece of the lens, which was
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obtained in our previous work (Yokozaki, 2014). The deposited amount of salicylic acid
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can be calculated from the total and adsorbed amounts using the equation (1). The
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release behavior of salicylic acid deposited inside the hydrogel matrix is modeled using
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the kinetic constant k and release exponent parameter n as follows (Ritger and Peppas,
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1987(a) and 1987(b)).
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M tdep kt n dep M
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The subscript t means the release amount at the time t. In this work, the kinetic constant
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k and release exponent n are fitted to the first 60 % release of salicylic acid deposited in
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the SCLs.
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Results and discussion
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The release profiles of salicylic acid from SCLs prepared by supercritical CO2
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including water are presented in Fig. 2. The results of the release profile are for the
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impregnation in case of the over-saturated amounts of salicylic acid in supercritical CO2.
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As shown in Fig. 2, supercritical CO2 impregnation including water and aqueous
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solution impregnation result in the release of salicylic acid from the lenses slower than
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those by the impregnation in supercritical CO2 without water. These results suggest that
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the existence of water in the impregnation processes is needed to reduce the release rate
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of salicylic acid from the hydrogel SCLs. It is thought that the infiltration of salicylic
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acid can be enhanced by the relaxation of the polymer structure of hydrogel SCLs with
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water.
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The modeling results of the salicylic acid release are summarized in Table 1 which
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gives the total and deposited amount of salicylic acid in the lenses, the time taken for
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60 % release of the deposited drug, the kinetic constant and release exponent parameter.
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The time taken for 60 % of release of the deposited salicylic acid decreases with
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increase of the deposited the amount. Except the lens prepared by supercritical CO2
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impregnation without water, the values of the release exponent parameters in the
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equation (2) are between 0.5 and 1.0. This results suggest that the release of salicylic
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acid from the lenses by supercritical CO2 impregnation including water and aqueous
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solution impregnation occurred by the superimposition of Fickian controlled (which
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gives n = 0.5) (Ritger and Peppas, 1987(a)) and hydrogel swelling controlled release
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(which given n = 1.0) (Ritger and Peppas, 1987(b)). Furthermore, the value of the
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release exponent parameters of all the lenses prepared by supercritical CO2
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impregnation including water are around 0.6, on the other hand, that prepared by
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aqueous solution impregnation is more than 0.7. This suggests that the release
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mechanism from lenses prepared by supercritical CO2 impregnation including water is
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more according to the Fickian controlled release compared with that by aqueous
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solution impregnation. In other words, salicylic acid was carried more inside hydrogel
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matrix of SCLs by the impregnation in supercritical CO2 including water .
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Table 2 gives the concentration of salicylic acid in impregnation solution (supercritical
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CO2 or aqueous solution) and the impregnation efficiency. The impregnation efficiency
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E is defined as follows:
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E
M dep C solu
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where C solu is the concentration of salicylic acid in supercritical CO2 or the aqueous
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solution. The salicylic acid concentrations in supercritical CO2 are obtained from the
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solubility of salicylic acid in pure CO2 (Gurdial and Foster, 1991). The efficiency of
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lenses prepared by supercritical CO2 impregnation including water is higher than that by
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aqueous solution impregnation. In addition, as the water amount in supercritical CO2
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impregnation increases, the impregnation efficiency of salicylic acid is also increase.
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This seems to be resulted from the enhancement of the polymer structural relaxation in
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the hydrogel SCLs. According to this tendency, the addition of water into supercritical
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CO2 phase is very important factor for the enhancement of the impregnation of contact
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lens hydrogel. Therefore, relationships of water amount in supercritical CO2
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impregnation processes and the deposited amount in SCLs are presented in Fig. 3. As
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shown in Fig. 3, the amounts of deposited salicylic acid increase linearly up to 0.76 g
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L-1 of the water amount in supercritical CO2 impregnation processes, and are practically
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constant in the range of the water amount, 1.22 to 2.18 g L-1. The increasing and
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constant lines of the deposited amount intersect around 1.1 g L-1 of water in
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supercritical CO2 that is the solubility of water in supercritical CO2 at this experimental
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condition (Sabirzyanov et al., 2002). It is thought that the amount of water dissolved in CO2 increases the amount of
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salicylic acid deposited in the lenses due to the enhancement of CO2 mass transfer into
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the hydrogel and / or the enhancement of salicylic acid solubility in CO2. Unfortunately,
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there is not the knowledge about solubility of salicylic acid in supercritical CO2
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including water. Then the salicylic acid-loaded lenses were prepared by supercritical
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CO2 impregnation with under-saturated amounts of salicylic acid. The release profiles
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of salicylic acid are presented in Fig. 4. Although the amounts of salicylic acid
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dissolved in supercritical CO2 were constant at 0.18 ± 0.01 g L-1, the amount released
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from SCLs increase with the water amount in supercritical CO2 impregnation processes.
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This result can explain that the enhancements of CO2 mass transfer into the hydrogel
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occur clearly on the impregnation of the hydrogel in supercritical CO2.
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Conclusion
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Supercritical CO2 impregnations including water were used for loading of salicylic
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acid into the contact lenses. The contact lenses prepared by supercritical CO2
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impregnation including water result in the slow release rate of salicylic acid compared
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with those by supercritical CO2 impregnation without water. The modeling by using the
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kinetic constant and release exponent parameters suggests that the release mechanism
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from the lenses can be explained by the two contributions of Fickian controlled and
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hydrogel swelling controlled releases. The lenses prepared by supercritical CO2
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impregnation including water are more according to the Fickian controlled release
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compared with that by aqueous solution impregnation. The impregnation efficiency of
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the lenses prepared by supercritical CO2 impregnation incluiding water is higher than
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that prepared by aqueous solution impregnation. In addition, the efficiency increase
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with the water amount in the supercritical CO2 impregnation processes. The amounts of
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salicylic acid deposited in the lenses also increase with the amount of water dissolved in
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supercritical CO2. These effects of water concerning about the enhancement of CO2
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mass transfer into the hydrogel should be significant knowledge for controlling and
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increasing of the loading-amount into the hydrogel contact lenses.
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Acknowledgement
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This work was supported by Grant-in-Aid for Young Scientist (A) on Grants-in-Aid
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for Scientific Research (No. 25709073) of Japan Society for the Promotion of Science,
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Japan.
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Yokozaki, Y., Ng, B., Sakabe, J., Shimoyama, Y., 2014. Effect of temperature, pressure
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17
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submitted.
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Table 1
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The experimental and modeled results of salicylic acid release from contact lenses
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prepared by supercritical CO2 and aqueous solution impregnations. M tot × 104 / g lens-1
M dep × 104 / g lens-1
0.00
< 10
2.07
0.32
0.34
54.8
3.61
0.76
54.6
4.84
1.22
44.8
2.18
44.8
8
n
-
-
1.86
0.063
0.58
3.09
M
0.051
0.61
6.06
4.31
0.066
0.59
6.09
4.34
0.053
0.64
0.036
0.73
pt
ed
an
k
Contact lens prepared by aqueous solution impregnation -
7
cr
t /min *
us
Water amount / g L-1
Ac ce
6
ip t
3
54.8
5.01
3.26
* time taken for 60 % release of deposited salicylic acid.
9
10
11
20 Page 20 of 25
1
2
Table 2
4
The drug impregnation efficiency defined in the equation (3) of supercritical CO2 and
5
aqueous solution impregnations.
6
Supercritical CO2 impregnation
0.00
0.32
0.34
1.86
0.76
3.09
1.22
4.31
M
ed
pt 4.34
Ac ce
E/L
0.41
0.78
0.41
4.54
0.41
7.54
0.41
10.5
0.41
10.6
C sol / g L-1
Aqueous solution impregnation -
8
us
M dep × 104 / g lens-1
an
Water amount / g L-1
2.18 7
cr
ip t
3
3.26
2.0
1.63
9
10
11
21 Page 21 of 25
1
3
pt
ed
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2
Fig. 1.
Supercritical CO2 impregnation apparatus. 1; CO2 bottle 2; dryer 3; back
5
pressure regulator 4; pressure gauge 5; cooling bath 6; feed pump 7; check valve 8;
6
pressure gauge 9; high-pressure cell 10; temperature control unit 11; depressurization
7
valve.
Ac ce
4
8
9
10
22 Page 22 of 25
1
2
ip t
0.0007
cr
0.0006
us
/ g lens
-1
0.0005 0.0004
an
M
tot
0.0003
M
0.0002
0 0
100
pt
3
ed
0.0001
200
300
400
500
time / min
Fig. 2. The release profile of salicylic acid from contact lenses prepared by supercritical
5
CO2 impregnation with ( ● ) 0.00 g L-1; ( ▲ ) 0.34 g L-1; ( ▼ ) 0.76 g L-1; ( ■ )
6
1.22 g L-1; ( ○ ) 2.18 g L-1 amount of water, and ( △ ) aqueous solution
7
impregnation.
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4
8
9
10
23 Page 23 of 25
1
2
ip t
0.0005
cr us
0.0003
an
0.0002
M
M
dep
/ g lens
-1
0.0004
0 0
1.00
1.50
2.00
2.50
Water amount/ g L -1- cell
pt
4
0.50
Ac ce
3
ed
0.0001
5
Fig. 3. Relationship between water amount in high-pressure cell for supercritical CO2
6
impregnation and deposited amount of salicylic acid in contact lenses.
7
8
9
10
24 Page 24 of 25
1
2
ip t
0.0005
us
0.0003
an
0.0002
M
M
tot
/ g lens
-1
cr
0.0004
0 0
100
pt
3
ed
0.0001
300
400
500
time / min
Ac ce
4
200
5
Fig. 4. The release profile of salicylic acid from contact lenses prepared by supercritical
6
CO2 impregnation with ( ● ) 0.34 g L-1; ( ▲ ) 0.76 g L-1; ( ■ ) 2.00 g L-1 amount
7
of water.
25 Page 25 of 25
S0263-8762(15)00304-4 http://dx.doi.org/doi:10.1016/j.cherd.2015.08.007 CHERD 1986
To appear in: Received date: Revised date: Accepted date:
3-11-2014 31-7-2015 5-8-2015
Please cite this article as: Yokozaki, Y., Sakabe, J., Shimoyama, Y.,Enhanced impregnation of hydrogel contact lenses with salicylic acid by addition of water in supercritical carbon dioxide, Chemical Engineering Research and Design (2015), http://dx.doi.org/10.1016/j.cherd.2015.08.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Research highlights
2
us
solution.
5
6
Efficiencies of supercritical impregnation with water are higher than aqueous
cr
ip t
hydrogel lens.
3
4
Addition of water in supercritical impregnation increase loading amount in
Release from lenses is resulted by Fickian diffusion and hydrogel swelling.
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1 Page 1 of 25
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Revised manuscript to Chemical Engineering Research and Design
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Short Communication
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Enhanced impregnation of hydrogel contact lenses with salicylic acid
5
by addition of water in supercritical carbon dioxide
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cr
4
6
Yuta Yokozaki, Junichi Sakabe, Yusuke Shimoyama*
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7
12
13
14
15
ed
11
Ookayama, Meguro-ku, Tokyo 152-8550, Japan
pt
10
Department of Chemical Engineering, Tokyo Institute of Technology, 2 – 12 – 1 S1-33,
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* E-mail: [email protected], TEL & FAX: +81 3 5734 3285
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2 Page 2 of 25
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Abstract An impregnation of soft contact lenses with salicylic acid in supercritical CO2
3
was enhanced by addition of water. The supercritical CO2 impregnations including
4
water were conducted at 40 °C and 11 MPa with 0.34 to 2.18 g L-1 of water amount. The
5
contact lenses impregnated in supercritical CO2 including water result in the high
6
loading-amount of salicylic acid compared with those without water. The higher amount
7
of water in supercritical CO2 impregnation gives the slower release of salicylic acid
8
from the lenses. The impregnation efficiency of the contact lenses with salicylic acid in
9
supercritical CO2 including water was evaluated from the loading-amount in the lenses
10
and the concentration in the supercritical CO2 phase. The efficiencies of supercritical
11
CO2 impregnation including water are higher than aqueous solution impregnation. The
12
impregnation efficiency of the lenses increases with the water amount in the
13
supercritical CO2 impregnation processes. The amount of salicylic acid loaded in the
14
lenses also increases with the amount of water dissolved in supercritical CO2. A release
15
model using kinetic constant and exponent parameter was applied for modeling the
16
release profile of salicylic acid from the contact lenses. The release modeling suggested
17
that the release from the contact lenses was resulted from the superimposition of Fickian
18
controlled and hydrogel swelling controlled releases.
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Keywords: supercritical CO2 impregnation, enhanced impregnation, addition of water,
2
hydrogelcontact lens, release profile
1.
Introduction
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4
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3
Although the eye drop method is applied for the around 90 % of the ocular disease
6
treatments currently, the only 1 to 5 % of drug in the eye drop can be used
7
therapeutically (Hu et al., 2011). Drug delivery systems using hydrogel contact lenses
8
for ocular diseases have been developed actively due to their advantages, sustained drug
9
release and high bioavailability compared with eye drop (Hu et al., 2011;
10
González-Chomón et al., 2011). Some research groups have studied the preparation of
11
the ophthalmic drug delivery system using the contact lenses (Ventatesh et al., 2007;
12
Ventatesh et al., 2008; Kim et al., 2008; Kappor and Chauhan, 2008(a) and 2008(b);
13
Kim et al., 2010). Venkatech et al. (2008) have investigated the molecular imprinted
14
hydrogel and the transport permeation of the drug through the hydrogel. Kappor and
15
Chauhan (2008(a) and 2008(b)) have studied the mechanism of the release of
16
Cyclosporine A from the poly-hydroxy ethyl methacrylate hydrogel with surfactant. The
17
additions of surfactant have been capable of the slow and extend release of the drug
18
from the hydrogel. The extended release of dexamethasone from the silicone-hydrogel
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lenses has been investigated by Kim et al (2010). Vitamin E was added to the
2
silicone-hydrogel for the extended release of dexamethasone. Supercritical CO2 impregnation method can also be a potential technique for the
4
preparation of the drug-loaded hydrogel because of the low surface tension on polymer,
5
high diffusivity and non-toxic to human body. The hydrogels loaded with ophthalmic
6
drug using supercritical CO2 impregnation have been investigated recently (Braga et al.,
7
2008; Costa et al., 2010(a) and 2010(b); Braga et al., 2011; Masmoudi et al., 2011). The
8
chitosan derivative hydrogels with flurbiprofen and timolol maleate were prepared by
9
the impregnation using supercritical CO2 and supercritical CO2 + ethanol mixture
10
(Braga et al., 2008). Costa et al. (2010(a)) studied the supercritical CO2 impregnation
11
for the drug-loaded contact lenses using a lot of species of the lenses, Hilafilcon B,
12
Alphafilcon A, Balafilon A, Nelfilcon A, Vifilcon A, Lotrafilcon A, Methafilcon A,
13
Omafilcon A, Galyfilcon A and Lidofilcon A. The impregnation of the poly methyl
14
methacrylate lenses with cefuroxime sodium in supercritical CO2 + ethanol mixture was
15
investigated by Masmoudi et al. (2011). In the previous work of our group (Yokozaki et
16
al., 2014), we studied the effect of the temperature, pressure and depressurization rate of
17
supercritical CO2 impregnation on the release profile of salicylic acid from the contact
18
lenses. The supercritical CO2 impregnation technique, which attains the hydrogel
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5 Page 5 of 25
contact lenses with the large loading and sustained release of drug should be developed
2
and design for the achievement of the practical application for the ophthalmic drug
3
delivery systems.
ip t
1
In this work, supercritical CO2 impregnation with water was used for the
5
preparation of a hydrogel contact lens drug delivery system loading salicylic acid.
6
Salicylic acid and Hilafilcon B were used as model solute and contact lens. It is though
7
that the addition of water in supercritical CO2 can enhance the mass transfer of CO2 and
8
salicylic acid into the hydrogel as explained in the hydrogel foaming using supercritical
9
CO2 (Tsioptsias and Panayiotou, 2008; Tsioptsias et al., 2011). The enhancement of CO2
10
mass transfer is expected to lead to increase of the amount loaded into the hydrogel. The
11
effects of water amount in supercritical CO2 impregnation on the amount of salicylic
12
acid loaded into the lenses were investigated. The efficiency of the impregnation in
13
supercritical CO2 with water was discussed in the comparison with the aqueous solution
14
impregnation. A theoretical model with kinetic constant and release exponent parameter
15
was used for discussion about the release profile of salicylic acid from the lenses into
16
the aqueous solution.
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2.
Experimental
6 Page 6 of 25
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2.1. Materials Hilafilcon B, commercial soft contact lenses (SCL) from Bausch & Lomb®., Medalist®
3
One-Day Plus (Non-Ionic, 59% water content, 8.6 mm base curve, -0.25 D power, 14.2
4
mm diameter and 0.013 g per one lens) were used in this study. Salicylic acid was
5
obtained from Wako Pure Chemical Industries, Ltd. The purity was higher than 99.5%.
6
Carbon dioxide was supplied from Fujii Bussan Co. Ltd. The purity was higher than
7
99.95%. Phosphate buffer solution (PBS) with pH 6.86 at 25 °C purchased form Wako
8
Pure Chemical Industries, Ltd. was used as a drug release media.
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2
9
Preparation of SCL loading salicylic acid
11
2.2.1.
ed
2.2.
Supercritical CO2 impregnation
pt
10
The supercritical CO2 impregnation including water was conducted by using the
13
apparatus slightly modified that used in the previous work (Yokozaki et al., 2014) as
14
shown in Fig. 1. This system is composed of a CO2 supply part, a stainless steel
15
high-pressure cell, 170 mL and a depressurization part. Carbon dioxide from a gas
16
cylinder was liquefied through a cooling unit. The liquefied CO2 was pressurized and
17
supplied to the high-pressure cell by a feed pump. A back-pressure regulator was used
18
for controlling the pressure in the cell. The temperature inside the cell was controlled by
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7 Page 7 of 25
the cartridge heater. The inside of the cell was partitioned into two parts by a petri dish.
2
Three pieces of SCL and the known amount of salicylic acid were set inside and outside
3
of the petri dish respectively. A soaking solution for commercial soft contact lenses
4
including sodium chloride and poloxamin was used as the adding water in the
5
impregnation also set inside the high-pressure cell. The petri dish was covered with a
6
stainless steel wire gauze for preventing powder state salicylic acid from adhering to the
7
SCLs. After the impregnation duration for 2 h, the system was depressurized slowly in
8
order not to damage the structure of SCLs. The temperature and pressure were set to
9
40 °C and 11 MPa in the supercritical CO2 impregnation containing water. The
10
depressurization rates were set to 0.1 ± 0.03 MPa min-1. The saturated solubility of
11
salicylic acid in supercritical CO2 at 40 °C and 11 MPa is 0.41 g L-1 (Gurdial and Foster,
12
1991)). The impregnations were conducted at conditions that the amount of salicylic
13
acid 1.2 ± 0.2 g L-1 is set over the saturated solubility in supercritical CO2 and 0.18 ±
14
0.01 g L-1 below the saturate solubility. The water amounts in the high-pressure cell
15
were controlled from 0 to 2.18 g L-1 in which CO2 + water system forms both the
16
homogeneous phase and vapor-liquid two phases. After the impregnation process, SCLs
17
were recovered from the high-pressure and then were placed in an oven at 30 °C for 1 h
18
in order to dry the lenses. This drying time was optimized by checking the weight loss
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8 Page 8 of 25
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of the lens in various drying time.
2
2.2.2. Aqueous solution impregnation
ip t
3
Impregnations of SCLs with salicylic acid were also conducted in the aqueous
5
solution for the comparisons with those prepared by the supercritical CO2 impregnation
6
including water. A soaking solution for a commercial soft contact lens was used as the
7
medium of the aqueous solution impregnation. The SCLs were placed in 2 mL of the
8
solution dissolving salicylic acid at 25°C for 2 h. The concentration of salicylic acid in
9
the aqueous solution was 2.0 g L-1. After the impregnations, the SCLs were recovered
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cr
4
from the solution and placed in the oven at 30 °C for 2 h in order to dry the lenses.
11
2.2.3. Rehydration of SCLs
pt
ed
10
The dried SCLs loading salicylic acid after the impregnation were placed in 10 mL of
13
the saturated salicylic acid PBS, 2.2 g L-1 at 25 °C with gently stirring for 15 min in
14
order to rehydrate the lenses. The rehydrated SCLs were recovered from the PBS and
15
the excess PBS on the lenses surface was removed by the tissue paper before the release
16
test of salicylic acid.
17
2.3.
18
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12
Drug release profile measurement
The rehydrated SCL were immersed in 10 mL of the PBS in stirred closed vials for 8 h.
9 Page 9 of 25
These vials were placed inside a temperature-controlled water bath at 37 °C. The sample
2
in 0.3 mL were collected to the pre-determined time intervals, and replaced with the
3
equivalent amount of the fresh PBS. The frequencies of the sample collection were once
4
every 10, 30, and 60 min at the release time 0 to 3, 3 to 6 and 6 to 8 h, respectively. The
5
collected samples were diluted to twice with the fresh PBS. The release amounts of
6
salicylic acid were determined from the analysis of the collected samples using UV-vis
7
spectrophotometry (JASCO, model V-630, Japan) at 296 nm.
an
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1
After the above release measurements, SCLs were kept in 10 mL of the PBS at 37 °C
9
in order to leach out the total amount of impregnated salicylic acid in SCLs to the
10
aqueous solution. The samples were taken from the solution and analyzed by the UV-vis
11
spectrophotometry for quantifying the amount of salicylic acid release from the SCLs.
12
In this work, the total amounts of salicylic acid in SCLs were determined from the
13
amount released into the PBS for 24 h.
14
15
3.
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Modeling of release profile
16
The release profile of salicylic acid from the SCL is modeled by the two contributions:
17
the initial instantaneous release of salicylic acid adsorbed on the surface of the hydrogel
18
matrix of the SCL and the release of salicylic acid incorporated inside the matrix. The
10 Page 10 of 25
1
total amount of salicylic acid in SCL is described by the following equation:
2
M tot M ads M dep
(1)
5
where M denotes the amount of salicylic acid in SCL. The superscripts tot, ads and dep
6
mean the total amount, adsorbed amount on the surface and deposited amount inside the
7
matrix of the lenses, respectively. The adsorbed amount of salicylic acid on the surface
8
of the hydrogel matrix is obtained from the total amount in those by the aqueous
9
solution impregnation. The value is 1.75 × 10-4 g per one piece of the lens, which was
10
obtained in our previous work (Yokozaki, 2014). The deposited amount of salicylic acid
11
can be calculated from the total and adsorbed amounts using the equation (1). The
12
release behavior of salicylic acid deposited inside the hydrogel matrix is modeled using
13
the kinetic constant k and release exponent parameter n as follows (Ritger and Peppas,
14
1987(a) and 1987(b)).
16
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pt
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15
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4
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3
M tdep kt n dep M
(2)
17
18
The subscript t means the release amount at the time t. In this work, the kinetic constant
11 Page 11 of 25
1
k and release exponent n are fitted to the first 60 % release of salicylic acid deposited in
2
the SCLs.
4.
Results and discussion
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4
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3
The release profiles of salicylic acid from SCLs prepared by supercritical CO2
6
including water are presented in Fig. 2. The results of the release profile are for the
7
impregnation in case of the over-saturated amounts of salicylic acid in supercritical CO2.
8
As shown in Fig. 2, supercritical CO2 impregnation including water and aqueous
9
solution impregnation result in the release of salicylic acid from the lenses slower than
10
those by the impregnation in supercritical CO2 without water. These results suggest that
11
the existence of water in the impregnation processes is needed to reduce the release rate
12
of salicylic acid from the hydrogel SCLs. It is thought that the infiltration of salicylic
13
acid can be enhanced by the relaxation of the polymer structure of hydrogel SCLs with
14
water.
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15
The modeling results of the salicylic acid release are summarized in Table 1 which
16
gives the total and deposited amount of salicylic acid in the lenses, the time taken for
17
60 % release of the deposited drug, the kinetic constant and release exponent parameter.
18
The time taken for 60 % of release of the deposited salicylic acid decreases with
12 Page 12 of 25
increase of the deposited the amount. Except the lens prepared by supercritical CO2
2
impregnation without water, the values of the release exponent parameters in the
3
equation (2) are between 0.5 and 1.0. This results suggest that the release of salicylic
4
acid from the lenses by supercritical CO2 impregnation including water and aqueous
5
solution impregnation occurred by the superimposition of Fickian controlled (which
6
gives n = 0.5) (Ritger and Peppas, 1987(a)) and hydrogel swelling controlled release
7
(which given n = 1.0) (Ritger and Peppas, 1987(b)). Furthermore, the value of the
8
release exponent parameters of all the lenses prepared by supercritical CO2
9
impregnation including water are around 0.6, on the other hand, that prepared by
10
aqueous solution impregnation is more than 0.7. This suggests that the release
11
mechanism from lenses prepared by supercritical CO2 impregnation including water is
12
more according to the Fickian controlled release compared with that by aqueous
13
solution impregnation. In other words, salicylic acid was carried more inside hydrogel
14
matrix of SCLs by the impregnation in supercritical CO2 including water .
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Table 2 gives the concentration of salicylic acid in impregnation solution (supercritical
16
CO2 or aqueous solution) and the impregnation efficiency. The impregnation efficiency
17
E is defined as follows:
18
13 Page 13 of 25
1
E
M dep C solu
(3)
2
where C solu is the concentration of salicylic acid in supercritical CO2 or the aqueous
4
solution. The salicylic acid concentrations in supercritical CO2 are obtained from the
5
solubility of salicylic acid in pure CO2 (Gurdial and Foster, 1991). The efficiency of
6
lenses prepared by supercritical CO2 impregnation including water is higher than that by
7
aqueous solution impregnation. In addition, as the water amount in supercritical CO2
8
impregnation increases, the impregnation efficiency of salicylic acid is also increase.
9
This seems to be resulted from the enhancement of the polymer structural relaxation in
10
the hydrogel SCLs. According to this tendency, the addition of water into supercritical
11
CO2 phase is very important factor for the enhancement of the impregnation of contact
12
lens hydrogel. Therefore, relationships of water amount in supercritical CO2
13
impregnation processes and the deposited amount in SCLs are presented in Fig. 3. As
14
shown in Fig. 3, the amounts of deposited salicylic acid increase linearly up to 0.76 g
15
L-1 of the water amount in supercritical CO2 impregnation processes, and are practically
16
constant in the range of the water amount, 1.22 to 2.18 g L-1. The increasing and
17
constant lines of the deposited amount intersect around 1.1 g L-1 of water in
18
supercritical CO2 that is the solubility of water in supercritical CO2 at this experimental
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condition (Sabirzyanov et al., 2002). It is thought that the amount of water dissolved in CO2 increases the amount of
3
salicylic acid deposited in the lenses due to the enhancement of CO2 mass transfer into
4
the hydrogel and / or the enhancement of salicylic acid solubility in CO2. Unfortunately,
5
there is not the knowledge about solubility of salicylic acid in supercritical CO2
6
including water. Then the salicylic acid-loaded lenses were prepared by supercritical
7
CO2 impregnation with under-saturated amounts of salicylic acid. The release profiles
8
of salicylic acid are presented in Fig. 4. Although the amounts of salicylic acid
9
dissolved in supercritical CO2 were constant at 0.18 ± 0.01 g L-1, the amount released
10
from SCLs increase with the water amount in supercritical CO2 impregnation processes.
11
This result can explain that the enhancements of CO2 mass transfer into the hydrogel
12
occur clearly on the impregnation of the hydrogel in supercritical CO2.
13
14
5.
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Conclusion
15
Supercritical CO2 impregnations including water were used for loading of salicylic
16
acid into the contact lenses. The contact lenses prepared by supercritical CO2
17
impregnation including water result in the slow release rate of salicylic acid compared
18
with those by supercritical CO2 impregnation without water. The modeling by using the
15 Page 15 of 25
kinetic constant and release exponent parameters suggests that the release mechanism
2
from the lenses can be explained by the two contributions of Fickian controlled and
3
hydrogel swelling controlled releases. The lenses prepared by supercritical CO2
4
impregnation including water are more according to the Fickian controlled release
5
compared with that by aqueous solution impregnation. The impregnation efficiency of
6
the lenses prepared by supercritical CO2 impregnation incluiding water is higher than
7
that prepared by aqueous solution impregnation. In addition, the efficiency increase
8
with the water amount in the supercritical CO2 impregnation processes. The amounts of
9
salicylic acid deposited in the lenses also increase with the amount of water dissolved in
10
supercritical CO2. These effects of water concerning about the enhancement of CO2
11
mass transfer into the hydrogel should be significant knowledge for controlling and
12
increasing of the loading-amount into the hydrogel contact lenses.
14
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Acknowledgement
15
This work was supported by Grant-in-Aid for Young Scientist (A) on Grants-in-Aid
16
for Scientific Research (No. 25709073) of Japan Society for the Promotion of Science,
17
Japan.
18
16 Page 16 of 25
References
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Braga, M. E. M., Vaz Pato, M. T., Costa Silva, V., Ferreira, E. I., Gil, M. H., Durate, C.
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M. M., de Sousa, H. C., 2008. Supercritical solvent impregnation of ophthalmic drugs
4
on chitosan derivatives, J. Supercrit. Fluids, 44, 245 – 257.
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Braga, M. E., Costa, V. P., Pereira, M. J. T., Fiadeiro, P. T., Gomes, A. P. A. R., Durate,
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C. M. M., de Sousa, H. C., 2011. Effects of operational conditions on the supercritical
7
solvent impregnation of acetazolamide in Balafilcon A commercial contact lenses, Int. J.
8
Pharm., 420, 231 – 243.
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Costa, V.P., Braga, M. E. M., Guerra, J. P., Duarte, A. R. C., Duarte, C. M. M., Leite, E.
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O. B., Gil, M. H., de Sousa, H. C., 2010(a). Development of therapeutic contact lenses
11
using a supercritical solvent impregnation method, J. Supercrit. Fluids, 52, 306 – 316.
12
Costa, V. P., Braga, M. E. M., Duarte, C. M. M., Alvarez-Lorenzo, C., Concheiro, A.,
13
Gil, M. H., de Sousa, H. C., 2010(b). Anti – glaucoma drug – loaded contact lenses
14
prepared using supercritical solvent impregnation, J. Supercrit. Fluids, 53, 165 – 173.
15
González-Chomón, C., Concheiro, A., Alvarez-Lorenzo, C., 2011. Drug-Eluting
16
Intraocular lenses, Materials, 4, 1927 – 1940.
17
Gurdial, G. S., Foster, N. R., 1991, Solubility of o-hydroxybenzoic acid in supercritical
18
cabon dioxide, Ind. Eng. Chem. Res., 30, 575 – 580.
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1
17 Page 17 of 25
Hu, X., Hao, L., Wang, H., Yang, X., Zhang, G., Wang, G., Zhang, X., 2011. Hydrogel
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contact lens for extended delivery of ophthalmic drugs, Int. J. Poly. Sci., Article ID
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814163.
4
Kappor, Y., Chauhan, A., 2008(a). Drug and surfactant transport in cyclosporine A and
5
Brij 98 laden p-HEMA hydrogels, J. Colloid Interf. Sci., 322, 624 – 633.
6
Kappor, Y., Chauhan, A., 2008(b). Ophthalmic delivery of cyclosporine A from Brij-97
7
microemulsion and surfactant-laden p-HEMA hydrogels, Int. J. Pharm., 361, 222 – 229.
8
Kim, J., Conway, A., Chauhan, A., 2008. Extended delivery of ophthalmic drugs by
9
silicone hydrogel contact lenses, Biomaterials, 29, 2259 – 2269.
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an
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ip t
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Kim, J., Peng, C. C., Chauhan, A., 2010. Extended release of dexamethasone from
11
silicone-hydrogel contact lenses containing vitamin E, J. Control. Release, 148, 110 –
12
116.
13
Masmoudi, Y., Azzouk, L. B., Forzano, O., Andre, J. M., Badens, E., 2011. Supercritical
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impregnation of intraocular lenses, J. Supercrit. Fluids, 60 98 – 105.
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Ritger, P.L., Peppas, N.A., 1987(a). A Simple Equation for Description of Solute
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Release I. Fickian and Non-Fickian Release from Non-Swellable Devices in the Form
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of Slabs, Spheres, Cylinders or Discs, Journal of Controlled Release 5, 23 – 36.
18
Ritger, P.L., Peppas, N.A., 1987(b). A Simple Equation for Description of Solute
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pt
ed
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18 Page 18 of 25
Release II. Fickian and Anomalous Release from Swellable Devices, Journal of
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Controlled Release 5, 37-42.
3
Sabirzyanov, A.N., Il’in, A.P., Akhunov, A.R., Gumerov, F.M., 2002. Solubility of Water
4
in Supercritical Carbon Dioxide, High temperature, 40, 231-234.
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Tsioptsias, C., Panayiotou, C., 2008. Foaming of chitin hydrogels processed by
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supercritical carbon dioxide, J. Supercrit. Fluids, 47, 302 – 308.
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Tsioptsias, C., Paraskevopoulos, M. K., Christrofilos, D., Andrieux, P., Panayitou, C.,
8
2011. Polymeric hydrogels and supercritical fluids: The mechanism of hydrogel
9
foaming, Polymer, 52, 2819 – 2826.
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Venkatesh, S., Sizemore, S. P., Byrne, M. E., 2007. Biomimetic hydrogels for enhanced
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loading and extended release of ocular therapeutics, Biomaterials, 28, 717 – 724.
12
Venkatesh, S., Saha, J., Pass, S., Byrne, M. E., 2008. Transport and structural analysis of
13
molecular imprinted hydrogels for controlled drug delivery, Eur. J. Pharm. Biopharm.,
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69, 852 – 860.
15
Yokozaki, Y., Ng, B., Sakabe, J., Shimoyama, Y., 2014. Effect of temperature, pressure
16
and depressurization rate on drug release profile of salicylic acid from contact lenses
17
prepared by supercritical carbon dioxide impregnation, Chem. Eng. Res. Des.,
18
submitted.
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19 Page 19 of 25
1
2
Table 1
4
The experimental and modeled results of salicylic acid release from contact lenses
5
prepared by supercritical CO2 and aqueous solution impregnations. M tot × 104 / g lens-1
M dep × 104 / g lens-1
0.00
< 10
2.07
0.32
0.34
54.8
3.61
0.76
54.6
4.84
1.22
44.8
2.18
44.8
8
n
-
-
1.86
0.063
0.58
3.09
M
0.051
0.61
6.06
4.31
0.066
0.59
6.09
4.34
0.053
0.64
0.036
0.73
pt
ed
an
k
Contact lens prepared by aqueous solution impregnation -
7
cr
t /min *
us
Water amount / g L-1
Ac ce
6
ip t
3
54.8
5.01
3.26
* time taken for 60 % release of deposited salicylic acid.
9
10
11
20 Page 20 of 25
1
2
Table 2
4
The drug impregnation efficiency defined in the equation (3) of supercritical CO2 and
5
aqueous solution impregnations.
6
Supercritical CO2 impregnation
0.00
0.32
0.34
1.86
0.76
3.09
1.22
4.31
M
ed
pt 4.34
Ac ce
E/L
0.41
0.78
0.41
4.54
0.41
7.54
0.41
10.5
0.41
10.6
C sol / g L-1
Aqueous solution impregnation -
8
us
M dep × 104 / g lens-1
an
Water amount / g L-1
2.18 7
cr
ip t
3
3.26
2.0
1.63
9
10
11
21 Page 21 of 25
1
3
pt
ed
M
an
us
cr
ip t
2
Fig. 1.
Supercritical CO2 impregnation apparatus. 1; CO2 bottle 2; dryer 3; back
5
pressure regulator 4; pressure gauge 5; cooling bath 6; feed pump 7; check valve 8;
6
pressure gauge 9; high-pressure cell 10; temperature control unit 11; depressurization
7
valve.
Ac ce
4
8
9
10
22 Page 22 of 25
1
2
ip t
0.0007
cr
0.0006
us
/ g lens
-1
0.0005 0.0004
an
M
tot
0.0003
M
0.0002
0 0
100
pt
3
ed
0.0001
200
300
400
500
time / min
Fig. 2. The release profile of salicylic acid from contact lenses prepared by supercritical
5
CO2 impregnation with ( ● ) 0.00 g L-1; ( ▲ ) 0.34 g L-1; ( ▼ ) 0.76 g L-1; ( ■ )
6
1.22 g L-1; ( ○ ) 2.18 g L-1 amount of water, and ( △ ) aqueous solution
7
impregnation.
Ac ce
4
8
9
10
23 Page 23 of 25
1
2
ip t
0.0005
cr us
0.0003
an
0.0002
M
M
dep
/ g lens
-1
0.0004
0 0
1.00
1.50
2.00
2.50
Water amount/ g L -1- cell
pt
4
0.50
Ac ce
3
ed
0.0001
5
Fig. 3. Relationship between water amount in high-pressure cell for supercritical CO2
6
impregnation and deposited amount of salicylic acid in contact lenses.
7
8
9
10
24 Page 24 of 25
1
2
ip t
0.0005
us
0.0003
an
0.0002
M
M
tot
/ g lens
-1
cr
0.0004
0 0
100
pt
3
ed
0.0001
300
400
500
time / min
Ac ce
4
200
5
Fig. 4. The release profile of salicylic acid from contact lenses prepared by supercritical
6
CO2 impregnation with ( ● ) 0.34 g L-1; ( ▲ ) 0.76 g L-1; ( ■ ) 2.00 g L-1 amount
7
of water.
25 Page 25 of 25