Preparation and Characterization of Repaglinide Loaded Chitosan Polymeric Nanoparticles
U.M. Dhana lekshmi,
P. Neelakanta Reddy
The aim of this study was to formulate and optimize repaglinide (Rg) loaded chitosan (CN) nanoparticles as a sustained release. Repaglinide is a hypoglycemic agent of the meglitinide analog. In present study repaglinide loaded chitosan nanoparticles were prepared by solvent evaporation method in three different ratios. In this method weighed quantity of drug and polymer were dissolved in suitable organic solvent acetone and 2% acetic acid (organic phase). This solution was added drop by drop to the aqueous phase of PVA and homogenized using homogenizer at 18000 rpm followed by magnetic stirring for 2-3 h. The formed Rg-CN nanoparticles were recovered by centrifugation at 25,000 rpm for 15 min followed by washing thrice with petroleum ether and lyophilized. The prepared nanoparticles were evaluated for particle size, Scanning Electron Microscopy (SEM), Fourier Transform Infra Red spectroscopy study (FT-IR), percentage yield, drug entrapment and for in vitro release kinetics. Among the three different ratio 1:4 ratio shown high drug loading (11.22% w/w) and encapsulation efficiencies (97.0%) and nanoparticle recovery (86.40%) with nanosize. Scanning electron microscopy exposed that nanoparticles were spherical in shape with a nearly smooth surface morphology. Particle size was analyzed by Malvern particle size analyzer and shown 48-100 nm range. FT-IR study reveals that, there was no interaction between repaglinide and polymers. Based on the in vitro study, replaglinide released from prepared formulation was slow and sustained over 15 days. Application of the in vitro drug release data to various kinetic equations indicated first order release, swelling and diffusion mechanism from repaglinide nanoparticles.
April 21, 2010; Accepted: June 19, 2010;
Published: February 26, 2011
In the last decade, significant effort was taken to develop nanoparticles,
drug delivery (Fessi et al., 1992; Galindo-Rodriguez
et al., 2004; Oppenheim, 1981; Alonso,
1996; Brigger et al., 2002). Nanoparticles
are submicron sized colloidal polymeric systems. The micro/nanoparticulate drug
delivery systems offer numerous advantages over the conventional dosage forms.
These include improved efficacy, reduced toxicity and improved patient compliance
(Soppimath et al., 2001; Kreuter,
1994; Brannon-Peppas, 1995; Couvreur
et al., 1986). Compared to the traditional micron-sized supports
used in separation process, nanosized carriers possess quite good performance
due to high specific surface area and the absence of internal diffusion resistance
(Chang et al., 2006). In particular, nanoparticles
are able to protect drugs from degradation, to improve permeation/penetration
of the drugs across mucosal surfaces and also to control the release of the
encapsulated or adsorbed drug (Florence et al., 1995;
Takeuchi et al., 2001).
Nanotechnology is now frequently used for various applications in fiber and
textiles (Perelshtein et al., 2008), agriculture
(Speiser, 2008; Lai et al.,
2006), electronics (Huang et al., 2003),
forensic science (Choi et al., 2008), space (Liu
et al., 2007) and medical therapeutics (Bender
et al., 1996; Bonduelle and Foucher, 1992;
Jahanshahi and Babaei, 2008; Kawashima
et al., 2000; Rieux et al., 2006).
These nanoparticle drug formulation reduces the patient expenses and risks of
toxicity (Glen, 2005). Polymeric nanoparticles have been
synthesized using various methods (Reis et al., 2006)
according to needs of its application and type of drugs to been capsulated.
These nanoparticles are extensively used for the nanoencapsulation of various
useful bioactive molecules and medicinal drugs to develop nanomedicine (Panyam
and Labhasetwar, 2003). These nanomedicines have many advantages in the
protection of premature degradation and interaction with the biological environment,
enhancement of absorption into a selected tissue, bioavailability, retention
time and improvement of intracellular penetration (Alexis
et al., 2008).
However, biodegradable nanoparticles are highly preferred and frequently used
to improve the therapeutic value of various water soluble/ insoluble medicinal
drugs and bioactive molecules by improving bioavailability, solubility and retention
time (Shenoy and Amiji, 2005). Such nanoparticles show
promise in drug delivery system and provide controlled/sustained release property,
sub cellular size and biocompatibility with tissue and cells (Panyam
and Labhasetwa, 2003).
Among the various polymers used for the development of sustained release formulations,
one of the most widely used polysaccharides for different pharmaceutical purposes
is chitosan and its derivatives (Thanou et al., 2001;
Morishita and Peppas, 2006; Wilson
et al., 2009). Chitosan is a natural cationic polysaccharide derived
by deacetylation of chitin, a copolymer consisting of combined units of glucosamine
and N-acetyl glucosamine (Lee et al., 1997; Majeti,
2000). In the pharmaceutical field chitosan's advantageous biological properties
have prompted its extensive study as a carrier both of drugs (Bayomi
et al., 1998; Mi et al., 2001) and
of proteins (Calvo et al., 1997). This cationic
polymer has attracted a great deal of attention as a drug delivery carrier because
of its unique properties, such as acceptable biocompatibility (De
Campos et al., 2001), low toxicity (Illum et
al., 2001) and the ability to enhance the absorption of hydrophilic
molecules across the epithelium via the paracellular transport pathway (Schipper
et al., 1999). In the drug delivery field, the vesicles based on
chitosan and derivatives can be used for transdermal, nasal, ocular, oral and
parenteral administration and other application (Thanou
et al., 2001; Thein-Han and Stevens, 2004).
Diabetes mellitus is a major and growing public health problem throughout the
world, with estimated world wide prevalence in 2000 of 150 million people, expected
to increase to 220 million people by 2010. Recent estimates project that the
number of patients diaganosed with type II diabetes will more than double
to 300 million before 2025 (Nagappa, 2008). Diabetes
Mellitus (DM) is defined as a group of metabolic diseases the common feature
of which is an elevated blood glucose level (hyperglycaemia). Chronic hyperglycaemia
is associated with the long-term consequences of diabetes that include damage
and dysfunction of the cardiovascular system, eyes, kidneys and nerves. The
complications of diabetes are often divided into two groups: microvascular (retinopathy,
nephropathy and neuropathy) and macrovascular (ischaemic heart disease, stroke,
peripheral vascular disease). Together, these make diabetes the seventh most
common cause of death in the developed world (McGinity and
ODonnell, 1997). Hence, we have focused the attention on anti diabetic
Repaglinide (Rg), a fast and short acting meglitinide analog with a very short
half-life (1 h) and low bioavailability (50%) (Jain et
al., 2005) was chosen as the drug to overcome the problem due to the
conventional dosage form. In the present study, an attempt has been made to
formulate Repaglinide-loaded CN nanoparticles, which may provide prolonged drug
delivery in the treatment of diabetic disorders and decreases the related side-effects.
MATERIALS AND METHODS
Materials: The research project was performed at Bio Organic Chemistry
Laboratory, Central Leather Research Institute, Chennai during June 2008 to
February 2009. Repaglinide (Rg) was received from Sigma Aldrich, Germany. Chitosan
was received from India sea foods, Cochin. The following materials were obtained
from the indicated suppliers and used as received: Poly Vinyl Alcohol (PVA)
(Sigma Aldrich, Germany), acetone (Ranbaxy Fine chemicals Ltd, New Delhi), glacial
acetic acid (S.R.L,Mumbai) and all other chemicals used were of analytical grade.
Preparation of polymeric nanoparticles: Polymeric nanoparticles were
prepared by solvent evaporation method using CN as coating material and Repaglinide
used as core material. Weighed quantity of drug and polymer were dissolved in
suitable organic solvent Acetone and 2% Acetic acid (organic phase). This solution
was added drop by drop to the aqueous phase of PVA and homogenized using IKA
T 25 Digital Ultra turrax homogenizer, Germany at 18000 rpm followed by magnetic
stirring for 2-3 h. The formed Rg-CN nanoparticles were recovered by centrifugation
(Sigma centrifuge 3K 30) at 25,000 rpm for 15 min followed by washing thrice
with petroleum ether and lyophilized (McGinity and ODonnell,
1997; Govender et al., 1999).
Nanoparticle recovery: The nanoparticle (NP) recovery, which is also
referred to as nanoparticle yield in the literature, calculated using Eq.
1. The individual values were determined (Govender et
Determination of drug incorporation efficiency: Freeze-dried nanoparticles were dissolved in suitable solvent (50 mL) (a common solvent for polymer and the drug). The amount of drug in the solution was measured by ultra violet spectroscopy at 243 nm (Perkin-Elmer Spectrophotometer). Drug content (% w/w) and Drug entrapment (%) were represented by Eq. 2 and 3, respectively.
Particle size analysis: Particle size was determined using Photon Correlation Spectroscopy (PCS) (Malvern S4700 PCS System, Malvern UK). For particle size analysis Rg-CN nanoparticles were first suspended in 100 mL of filtered water (0.2 μm filter, Ministart, Germany) and subjected to sonication for 30 sec and vortex mixing for 10 sec before analysis.
Scanning electron microscopy: The shape and surface morphology of the Rg-CN nanoparticles were examined using Scanning Electron Microscopy (SEM) (JSM-T20. Tokyo, Japan). Appropriate samples of polymeric nanoparticles were mounted on metal stubs, using double-sided adhesive taps. Samples were gold coated and observed for morphology, at acceleration voltage of 15 KV.
Fourier transform infrared spectroscopy: Infrared spectroscopy was conducted using a Avatar 320-FT IR spectrophotometer and the spectrum was recorded in the region of 4000-400 cm-1. The procedure consist of dispersing a sample (drug, polymer and Rg-CN nanoparticle preparation) in potassium bromide pellet (200-400 mg) and compressing into discs by applying a pressure of 5 tons for 5 min in a hydraulic press. The pellet was placed in the light path and the spectrum was obtained.
In vitro release study: The in vitro release of Rg-CN nanoparticles
was carried out in triplicate in stirred dissolution cells at 37.4°C by suspending
2 mL of Rg-CN nanoparticle suspension into a beaker containing 100 mL of release
media (phosphate buffer saline pH 7.4). The correct in vitro conditions
to study the release behavior of a hydrophobic drug were maintained (Avinash
et al., 2007). Drug release was assessed by intermittently sampling
the receptor media (5 mL) at predetermined time intervals, each time 5 mL of fresh
phosphate buffer saline pH 7.4 was replaced. The amount of repaglinide released
in the buffer solution was quantified by a UV spectrophotometer at 243 nm.
Evaluation of in vitro release kinetics: In order to investigate the mechanism of release the data were analyzed with the following mathematical models: zero-order kinetic Eq. 4, first-order kinetic Eq. 5 and Higuchi kinetic Eq. 6.
The following plots were made: Qt vs. t (zero order kinetic model), ln (Q0 - Qt) vs. t (first-order kinetic model) and Qt vs. t1/2 (Higuchi model), where Qt is the percent of drug released at time t, Q0 is the initial amount of drug present in the microspheres and K0, K1 and K h are the constants of the equations. Further, to confirm the mechanism of drug release, the first 60% of drug release was fitted in Korsmeyer- Peppas model Eq. 7:
where Mt/Má are the fraction of the drug release
at time t, K p is the rate constant and n is the release exponent.
The n value is used to characterize different release mechanisms and is calculated
from the slope of the plot of log of fraction of drug released (Mt/Má)
vs. log of time (Costa and Lobo, 2001).
RESULTS AND DISCUSSION
Formation of polymeric nanoparticles: The Repaglinide loaded chitosan
polymeric nanoparticles were prepared by solvent evaporation method according
to Jain et al. (2005) in three different ratio
of polymer (1: 2, 1: 3 and 1: 4). Solvent evaporation method is one of the easiest
method when compare to other techniques. A suspension of chitosan polymer and
Repaglinide drug in suitable solvent acetone and 2% acetic acid forms the organic
phase. This organic phase was poured into an aqueous phase containing PVA. The
organic solvents used in these preparations rapidly partitioned into the external
aqueous phase and the polymer precipitated around the drug. The subsequent evaporation
of the entrapped solvent led to the formation of Repaglinide loaded chitosan
polymeric nanoparticles. Specifically the polymer coated or covered around the
shaped drug led to spherical shaped polymeric nanoparticles.
Effect of drug content and drug entrapment: The percentage entrapment
efficiency was varied by varying the characteristics of polymer, drug, surfactant
and cross linking agent etc., Normally the low entrapment efficiency was due
to high affinity of drug and polymer in different solvents (drug in organic
solvent and polymer in aqueous solvent and vice-versa) during the nanoparticle
preparation and the drug loading content and entrapment efficiency were mainly
affected by the polymer and drug ratios. Peng et al.
( 2007) also reported that the improved encapsulation efficiency may be
due to the greater proportion of polymer with respect to the amount of drug.
In our Rg-CN nanoparticle preparation, the drug and the polymer were dissolved
in organic phase and greater proportion of polymer were added to the drug. Hence,
there was no chance in the diffusion of drug away from the polymer. The percentage
drug entrapment of Repaglinide in the formulations was found to be good at all
levels of drug loading. The high entrapment efficiency of Repaglinide is believed
to be due to its poor aqueous solubility, high affinity of drug and polymer
in the same solvent (organic solvent) and increased polymer ratio. Present report
was found to be similar to that of early findings (Jain
et al., 2005).
The researchers (Niwa et al., 1994) attributed
the decreased drug entrapment with increasing theoretical drug loadings to an
enhanced drug leakage into the aqueous phase (if drug is water soluble) or into
the organic phase (if drug is water insoluble) at high loadings. This would
also lead to an enhanced drug loss. Compared to 1:3, 1:4 ratios the 1:2 ratio
shown high drug content and it produced an enhanced drug leakage which influences
the absolute release profiles and responsible for an increased initial burst.
Avinash et al. (2007) have reported that increase
in drug content in the particles influences the absolute release profiles such
as the cumulative amount of drug released at any time and the induction period
increases. The increase in drug content increased the amount of drug close to
the surface which is responsible for an increased initial burst. The increase
in drug in the core of nanoparticles is responsible for a prolonged drug release
from the polymer.
In the Rg-CN nanoparticles preparation, according to the result of efficiency of recovery and drug entrapment of nanoparticles among the three different ratios, 1:4 ratio was selected as the best ratio compare to 1:2 and 1:3 because these ratios leads to a low drug entrapment which implied high drug wastage during the preparation and 1:4 ratio shown low drug wastage. These polymeric nanoparticles were prepared at three consecutive times for reproducibility and result elicited in Table 1.
Rg-CN preparation of 1:4 ratio shown 11.22% w/w drug content, 97.0% drug entrapment
and 86.40% nanoparticle recovery which revealed increased drug entrapment, nanoparticle
recovery and particle size. Douglas et al. (1987)
have reported that high nanoparticle recovery is required for reducing manufacturing
costs and its size and morphology important for quality control and bio distribution.
Morphological characterization of polymeric nanoparticles: Figure
1 shown that the Rg-CN preparation has smooth spherical shaped appearance.
The surface of formulated nanoparticles depends on two factors according to
Fessi et al. (1992) and Galindo-Rodriueg
et al. (2004). A saturated solution of polymer produced smooth and
high yield nanoparticles. The undissolved polymer produced irregular and rod
shaped particles. The diffusion rate of solvent is too fast and the solvent
may diffuse into the aqueous phase before stable nanoparticles are developed
or formed causing the aggregation of nanoparticle preparation. In this study
a portion of the CN preparations possessed sparingly soluble property; the addition
of 2% acetic acid to acetone in the CN preparation reduces the fast diffusion
rate. This condition is suitable for spherical shaped nanoparticle formation.
Due to the solubility and diffusion rate the Rg-CN preparation exposed good
spherical appearance (Fig. 1).
|| Percentage of nano particle recovery, drug content, entrapment
and wastage for three ratios (1:2, 1:3, 1:4)
Particle size and poly dispersity index: Nanoparticle size determined
by PCS was shown in Fig. 2. Birnbaum et
al. (2000) have reported that particle size of nanoparticles was larger
than those obtained by the quantitative analysis of the SEM. The contrast of
the Electron Microscope (EM) pictures allows only the visualization of the nanoparticle
core, whereas the hydrodynamic radius of the particles is measured by PCS. Particle
size is often used to characterize nanoparticles, because it facilitates the
understanding of the dispersion and aggregation. Due to large surface area and
attractive force between the particles more chance of aggregation is possible
in small sized particles. The surfactant may aid in reducing aggregation of
the particles once the nanoprecipitates are formed. The addition of PVA in Rg-CN
preparation could reduces the aggregation formation which is conformed by result
of low poly dispersity index. Birnbaum et al. (2000)
have reported that PVA appeared as the most suitable surfactants in reducing
aggregation of the particles which suspends immediately after formation. The
particle size data shown that nanoparticles produced were of sub micron size
and of low poly dispersity index ( 48-100 nm and 0. 280PI) which indicated a
relatively narrow particle size distribution for Rg-CN preparation.
FT-Infrared Spectroscopy (FTIR): FTIR spectra of pure repaglinide, polymer and repaglinide loaded polymeric nanoparticle were shown in Fig. 3. Infrared spectra of chitosan sample studied displayed several characteristic vibration properties in the region. A band at 3419 cm-1 corresponds to the combined peaks of the NH2 and OH group stretching vibration in chitosan. The band at 1657 cm-1 is attributed to the CONH2 group. The 1598 cm-1 peak of the c (NH2) bending vibration is sharper than the peak at 1657 cm-1, which shows the high degree of deacetylation of the chitosan. A shift from 3419 to 3427 cm-1 is shown and the peak is sharper in the chitosan nanoparticles, which indicates that the hydrogen bonding is enhanced. The intensities of (CONH2) band at 1657 cm-1 and (NH2) band at 1598 cm-1, which can be observed clearly in pure chitosan, FTIR of repaglinide shown peaks at 3320 (NH stretching), 2947(CH stretching), 1728 (C = O), 1604 (C = C), CH deformation at 1460-1438 cm-1. Similar peaks were seen in repaglinide loaded CN nanoparticle preparation. Hence, the study confirmed that there is no interaction between drug and polymer.
|| PCS of Rg-CN nanoparticle
|| FTIR of polymer, drug and Rg-CN nanoparticle
|| In vitro release of Repaglinide from polymeric nanoparticles
of 1:4 ratio
|| Release kinetics data of Rg-CN polymeric nanoparticle
In vitro release study: The in vitro release of repaglinide from CN polymeric nanoparticles were shown in Fig. 4. The drug released from CN polymeric nanoparticle preparations were 14.80% upto15 days. The release of replaglinide mainly depended upon the polymer concentration. The release rate of the drug from the nanoparticles was found to decrease drastically on increasing the polymer concentration. The decreased percentage of drug release indicates that this polymer may form a more compact wall and it indicates that they have sustained drug release for a prolonged period of time.
In vitro release kinetics study: The data obtained for in
vitro release was fitted into equations for zero order, First order, Korse
meyer , Hixson-crowell and the Higuchi release model (Fig. 5-9).
The interpretation of data was based on the value of the resulting regression
coefficient (Table 2). The zero order rate describes the systems
where the drug release rate is independent of its concentration (Fig.
5). The first order which describes the concentration dependant release
(Fig. 6). Higuchi model describes the release of drugs from
an insoluble matrix as a square root of a time dependant process based on Fickian
|| Zero order kinetics data of Rg-CN nanoparticle preparation
|| First order kinetics data of Rg-CN nanoparticle preparation
|| Higuchi equation data of Rg-CN nanoparticle preparation
|| Hixson-Crowell equation data of Rg-CN nanoparticle preparation
Figure 7 exposed the higuchi kinetics (Sood
and Pachangnula, 1998; Merchant et al., 2006).
The release constant was calculated from the slope of the appropriate plots
and the regression co efficient (r2) was determined and results tabulated
in Table 2.
||Korsmeyer-Peppas eqation data of Rg-CN nanoparticle preparation
In this Rg-CN preparation, release profile of the repaglinide was fit into
various kinetic models to find out the mechanism of drug release. Among this
highest correlation coefficient was shown in first order followed by Higuchi
and Hixson Crowell (Fig. 8) equations. The release rates were
calculated from the slope of respective plots. The data obtained was also fit
in to the Korsmeyer-Peppas (Fig. 9) in order to find out the
n value, to describe the drug release mechanism. The n value of 0.503 for Rg-CN
preparation indicates the mass transfer. It follows a non-Fickian model or anomalous
transport,indicating the drug release is controlled by more than one process.
That is superposition of both phenomenon, the diffusion-controlled and swelling-
controlled release. Merchant et al. (2006) have
reported the similar findings. In Rg-CN there was significant difference in
the R2 values of zero-order equation and Hixson-Crowell eqation.
Hence the erosion mechanism was not involved in the release pattern. From these
results we concluded that the release of Repaglinide from the CN matrix was
predominently controlled by First order, diffusion and swelling mechanism.
Repaglinide loaded chitosan nanoparticles were successfully prepared by solvent evaporation method. The surface morphology of these Rg-CN preparations was found to be smooth. These Rg-CN preparations shown high drug loading and encapsulation efficiency with nanosize. Rg loaded CN polymeric nanoparticles with a small size and a narrow size distribution were obtained. In vitro release kinetics studies shown that Rg loaded CN nanoparticles were capable of releasing the drug in a slow sustained manner. The nanoparticles may improve the oral absorption of repaglinide due to high surface to volume ratio, high bio distribution. Therefore, the bioavailability of drug may be improved and may help to reduce the dose of the drug and frequency of administration. From the present investigation it may be concluded that the repaglinide loaded chitosan nanoparticles is an effective carrier for the design of a controlled drug delivery system of poorly water soluble drugs like repaglinide.
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