DSpace at VNU: An investigation of effects of modification processes on physical properties and mechanism of drug release for sustaining drug release from modified rice

DSpace at VNU: An investigation of effects of modification processes on physical properties and mechanism of drug releas...

Vuong Duy Ngo, Thinh Duc Luu, Toi Van Vo, Van-Thanh Tran, Wei

Duan, Phuong Ha-Lien Tran, Thao Truong-Dinh Tran

PII: S0928-4931(16)30412-X

DOI: doi: 10.1016/j.msec.2016.04.098

Reference: MSC 6478

To appear in: Materials Science & Engineering C

Received date: 28 December 2015

Revised date: 15 April 2016

Accepted date: 29 April 2016

Please cite this article as: Vuong Duy Ngo, Thinh Duc Luu, Toi Van Vo, Van-Thanh Tran, Wei Duan, Phuong Ha-Lien Tran, Thao Truong-Dinh Tran, An investigation of effects of modification processes on physical properties and mechanism of drug release

for sustaining drug release from modified rice, Materials Science & Engineering C (2016),

doi: 10.1016/j.msec.2016.04.098

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.

ACCEPTED MANUSCRIPT

An investigation of effects of modification processes on physical properties and mechanism of drug release for sustaining drug release from modified rice

Vuong Duy Ngo1, Thinh Duc Luu1, Toi Van Vo1, Van-Thanh Tran3, Wei Duan2, Phuong

Ha-Lien Tran2,* and Thao Truong-Dinh Tran1,*

Thao Truong-Dinh Tran (ttdthao@hcmiu.edu.vn)

Phuong Ha-Lien Tran (phuong.tran1@deakin.edu.au)

ACCEPTED MANUSCRIPT

Abstract

The aim of this study was to investigate the effect of modification processes on

physical properties and explain the mechanism of sustained drug release from modified rice

(MR) Various types of Vietnamese rice were introduced in the study as the matrices of

sustained release dosage form Rice was thermally modified in water for a determined

temperature at different times with a simple process Then tablets containing MR and

isradipine, the model drug, were prepared to investigate the capability of sustained drug

release Scanning electron microscopy (SEM) was used to determine different morphologies

between MR formulations Flow property of MR was analyzed by Hausner ratio and Carr’s

indices The dissolution rate and swelling/erosion behaviors of tablets were evaluated at pH

1.2 and pH 6.8 at 37 ± 0.5°C The matrix tablet containing MR showed a sustained release as

compared to the control The SEM analyses and swelling/erosion studies indicated that the

morphology as well as swelling/erosion rate of MR were modulated by modification time,

drying method and incubation It was found that the modification process was crucial because

it could highly affect the granule morphologies and hence, leading to the change of

flowability and swelling/erosion capacity for sustained release of drug

Keywords: modified rice, flow property, sustained release, morphology, incubation

ACCEPTED MANUSCRIPT

1 Introduction

Hydrophilic polymer matrices have been widely used in formulations of sustained release (SR) systems to achieve slow release of drug over an extended period of time [1-4] due to low cost, ease of manufacture and relative independence of the physicochemical and physiological conditions of the gastrointestinal tract [5, 6] Generally, the hydrophilic polymer hydrates when it exposes to dissolution medium to form the gel layer as the barrier controlling drug release Hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), xanthan gum, sodium alginate, poly (ethylene oxide) and crosslinked homopolymers and copolymers of acrylic acid are commonly used as hydrophilic matrices [7-11]

Rice has been widely used in food industry and direct food use [12] Despite promising characteristics of a safe material with starch component adding up to almost 90%

of milled rice [13], its application in pharmaceutical industry is still limited Recently, starch has been considered as a promising biomaterial in pharmaceutical industry due to the unique physicochemical and functional characteristics [14-16] Native starches have been well explored as binders and disintegrants in solid dosage forms; however, the utilization is restricted due to poor flowability Meanwhile, modified starches have been investigated for applications of sustained release agents as hydrophilic matrices [17-21] in drug delivery systems Starch-based biodegradable polymers used in preparation of microspheres or hydrogels have been studied for drug delivery [22, 23] Starch like rice starch could be modified by chemical, physical or enzymatic methods to have distinctive properties Mechanism of drug release from modified rice matrices would be a result of the passage of drug molecules controlled by the matrix structure and gel layer formation

The granular structure and swelling ability in cold water of native starches have been investigated by physical modifications such as extrusion, drum-drying and a controlled

ACCEPTED MANUSCRIPT

pregelatinization-spray-drying [17] However, few studies have investigated thermal modification on physical properties and changes of drug release mechanism from modified rice in details so far The study introduced various types of Vietnamese rice as possible carriers for sustained release of drug in a simple process with common apparatuses The potential rice was selected for further use in investigation of effects of modifying time, incubation method, and drying method on the flow property, granule morphology, swelling and erosion capacity of modified rice-based tablets Hence, dissolution profiles of tablets, analysis of flowability, SEM images as well as swelling and erosion studies were carried out

ACCEPTED MANUSCRIPT

phosphate (KH2PO4) was purchased from Wako Pure Chemical Industries (Japan) Aerosil

200 was from Jebsen & Jessen Chemicals Holding Pte Ltd (Singapore) Mannitol (Pearlitol®) was purchased from Roquette Pharma Company, France

2.2 Methods

2.2.1 Modification of rice

Four varieties of glutinous rice were milled and sieved by 500 μm sieve Then, 15 g of each type of glutinous rice was dispersed in 150 mL of distilled water and incubated at 90 °C for 4 h The swelling rice was then heated in an oven at 120 °C with different times The mucilage was dried in the oven at 60 °C or freeze-dried at –52 °C The modified rice (MR) was finally passed through 500 μm sieve The detailed conditions for MR were described in

the Table 1

Table 1 Method of rice-based tablet formulations

Formulation

Modified Temperature ( o C)

Modifying time (h)

Incubation time (h)

ACCEPTED MANUSCRIPT

at - 52 °C

NT 10 h freeze-drying

at - 52 °C

NT 12 h freeze-drying

NT 8 h without incubation

2.2.2 Preparation of prolonged release tablet

Solid dispersion of isradipine was prepared by melting method Briefly, mixture of polymer (PEG:HPMC=1:1) and drug at the ratio 8:1 was melted at 160 oC Drug was dispersed in the melted polymer Aerosil® 200 was used as a sorbent of solid dispersion (Aerosil® 200: solid dispersion = 1:3) The resultant mixture was passed through a 500 μm sieve and thoroughly mixed with MR and mannitol Finally, MgS was blended with the above mixture which was then compressed into tablets of diameter 8mm using a single punch-press machine (TDP 1.5, China) Hardness of the tablets was controlled at 30 ± 5 N Each 150 mg tablet contained 60 mg solid dispersion of isradipine, 20 mg MR, 68.5 mg mannitol and 1.5

mg MgS

2.2.3 Dissolution studies

The tablets were introduced to an in vitro dissolution test at 37 ± 0.5 °C using type II

apparatus dissolution tester (DT70 Pharmatest, Germany) at 50 rpm To evaluate capability of sustained drug release, each dissolution vessel contained 750 ml of 0.1N hydrochloric acid (pH 1.2) for 2 h and then the pH of the medium was adjusted to pH 6.8 by adding 250 mL of 0.2 M sodium phosphate solution, preheated to 37 °C (2 M hydrochloric acid or 2 M sodium hydroxide was used for minor pH adjustment) [24] 1ml of sample was collected from the media at 1, 2, 6, 10, 14, 18, and 24 h 100 µl sample solutions were diluted for HPLC test

2.2.4 High performance liquid chromatography (HPLC) analysis

ACCEPTED MANUSCRIPT

The quantification of isradipine was performed using Ultimate 3000 HPMC Thermoscientific Inc., USA The mobile phase contained Methanol: Water: Acetonitrile mixture at the ratio 46 %, 20 % and 34 %, respectively with a flow rate of 1.00 ml/min and the running time was 4 min The UV/VIS detector was set at a wavelength of 325 nm 20 µL

of sample was injected to HPLC system

2.2.5 Flow property test

The Carr’s compressibility index and the Hausner ratio were calculated to provide a measure of the flow properties and compressibility of MR powders However, firstly bulk and tap densities of MRs were determined before and after 1250 taps, respectively, using the tap density tester (SVM, ERWEKA GmbH, Germany)

The Hausner ratio and Carr’s index was determined as follows:

Hausner ratio =tapped densitybulk density (1)

Carr index =(tapped density−bulk density)tapped density X 100 (2)

2.2.6 Scanning Electron Microscopy (SEM)

Samples were stuck onto conductive carbon adhesive tape The morphology was then

examined under the scanning electron microscope (Hitachi’s S-4800 FE-SEM, Japan)

2.2.7 Swelling and erosion studies

The rate of MR swelling was determined by equilibrium weight gain method [25] Tablets were accurately weighed (W0) and put in sinkers to conduct the swelling test using the USP II apparatus (50 rpm, 37 °C, and a 900 mL dissolution medium of buffer pH 1.2 and buffer pH 6.8) with a dissolution tester (DT70 Pharmatest, Germany) Sinkers of tablets were carefully removed from the media after 1, 2 and 6 h and the tablets were lightly blotted with

ACCEPTED MANUSCRIPT

tissue paper to remove excess surface water and then reweighed (Wt) The percent water uptake or swelling rate due to absorbed liquid was estimated at each time point using Eq (3): Matrix swelling (%) = (3)

Wt: weight at time t (1 h, 2 h, 6 h)

W0: initial weight

Matrix erosion study was performed by a method of Roy and Rohera [26] After the swelling study, the wet samples were then dried in an oven until the samples were completely dried and finally weighed until a constant weight was achieved (Wd) The percentage matrix erosion at time t was estimated from Eq (4)

Matrix erosion (%) = (4)

W0: initial weight

Wd: weight after drying

3 Results and discussion

3.1 Dissolution studies

3.1.1 Effect of types of rice

The drug release behaviors depend on type of the matrix, capability of swelling, diffusion and erosion process [27] Hydrophilic polymers are commonly used to control release of drug due to their capability of swelling in the presence of water and forming a gel-like substance To compare effect of types of rice on dissolution rates, the samples (NT, NB,

VL, HV) were prepared under the following conditions: incubating at 90 ºC for 4 h, heating at

120 ºC for 8 h, and then drying in an oven (F1, F2, F3, F4) The NT tablets showed more

sustained release rates than NB, VL and HV tablets (Figure 1) Specifically, after 1 h the

drug dissolution release of NT, NB and VL tablets were 24.6 %, 26.45 % and 28.4 %, respectively, while the dissolution rate of HV tablets was 35.3 % After 2 h, the dissolution

(Wt−W0)/W0 x 100

(W0−Wd)/W0 x 100

18 h, indicating that NT would be a potential rice to prolong the release of drug Physical modification of rice would lead to changes of granular structures and conversion of native rice into cold water-soluble rice or small-crystallite rice [28] Mechanism of drug release from such gel-forming matrices would elucidate those different release patterns Hence, NT was selected for further studies

ACCEPTED MANUSCRIPT

Figure 1 Effects of types of rice incubated at 90 ºC for 4 h, heated at 120 ºC for 8 h, and dried in the oven on drug dissolution (n=3)

3.1.2 Effect of modifying time and drying method

To investigate the effect of modifying time on dissolution rate, NT samples were prepared by the following conditions: incubating at 90 ºC for 4 h, heating at 120 ºC in 8 h, 10

h and 12 h, and finally drying in the oven or freeze drier Figure 2 shows the effect of time in

the modification process followed by drying in the oven on the dissolution rate of tablets By increasing the time of heating from 8 h to 10 h and 12 h (F1, F5 and F6, respectively), the modified rice could not retard the dissolution rate Conversely, the increased time reduced the ability of sustained drug release from the tablets At the time points from 2 h to 6 h, there was

an explosion of the drug release from NT heated in 10 h (increased from 33.4 % to 75.0 %) and NT heated in 12 h (increased from 33.9 % to 98.5 %), while the dissolution rate of NT heated in 8 h was moderately increased from 28.4 % to 49.3 % The drug release was increased slowly in the next hours until the end of the dissolution Similar results were also observed with the samples which were dried by freeze-drying method (F7, F8 and F9)

(Figure 3) These results indicated that the longer modifying time may cause the higher

dissolution rate and it would be a critical factor to consider for being optimized in the thermal modification process

ACCEPTED MANUSCRIPT

Figure 2 Effects of modifying time on dissolution rate of tablets of NT incubated at 90

ºC for 4 h, heated at 120 ºC and dried in the oven (n=3)

ACCEPTED MANUSCRIPT

Figure 3 Effect of modifying time on dissolution rate of tablets of NT incubated at 90 ºC

for 4 h, heated at 120 ºC and dried by freeze drier (n=3)

For further investigation of the effect of drying method on drug release rate, two NT samples which were modified in 8 h and 12 h (dried by the freeze-drying and oven method)

were compared to each other in dissolution profiles (Figure 4) For 12 h modifying time,

generally NT tablets using freeze-drying method (F9) was expressed lower drug dissolution release than the tablets dried in the oven (F6) However, the dissolution rate of NT tablets which were under 8h of modifying time and then introduced to the freeze-drying (F7) was higher than the tablets dried in the oven (F1) Therefore, appropriate modifying time and drying method would be needed for the formation of controlled release formulations Effect

of drying method on the drug release will be investigated in the erosion and swelling studies (section 3.3)

NT 8 h freeze drying

NT 10 h oven drying

NT 12 h freeze drying

ACCEPTED MANUSCRIPT

Figure 4 Effects of freeze-drying and oven drying on dissolution rate of tablets of NT

incubated at 90 ºC for 4 h and heated at 120 ºC (n=3)

3.1.3 Effect of incubation method

To investigate the role of incubation for MR, the NT sample in water was directly heated at 120 ºC for 8 h and dried in the oven This MR was compared with the sample which was prepared in the same condition except for the additional incubation step before heating

the rice (F10 compared to F1) Figure 5 shows the effect of incubation method in the

modification process on the dissolution rate of tablets For incubation method, there was a sustained release after 2 h, increasing from 28.6 % to 49.3 % in the range of time points from

2 to 6 h Then drug release was increased slowly at a constant rate during the next 18 h Meanwhile, from 2 h to 6 h, dissolution rate of the method without incubation was significantly enhanced, which was twofold enhancement from 38.6 % to 84.2 % These results proved that the incubation method is one of the most important steps in modification process for sustaining drug release

NT 8 h freeze drying

NT 8 h oven drying

NT 12 h freeze drying

NT 12 h oven drying