Stability Studies on Piroxicam Encapsulated Niosomes - IngentaConnect

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Stability Studies on Piroxicam Encapsulated Niosomes Zehra Ceren Ertekin1, Zerrin Sezgin Bayindir2 and Nilufer Yuksel2* 1

Department of Analytical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Tandogan, Ankara, Turkey; 2Department of Pharmaceutical Technology, Faculty of Pharmacy, Ankara University, 06100 Tandogan, Ankara, Turkey Abstract: Drug delivery systems which yield ideal treatments are currently the center of interest for researchers. Niosomes have numerous advantages over other drug delivery systems. However, stability issue is not clear yet and is a serious drawback for niosomes. In this study, the stability of niosomes was the center of interest. Piroxicam which was chosen as the model drug was loaded to niosomes. Niosomes were prepared by thin-film method and different forms (aqueous dispersion, lyophilized powder and lyophilized powder with cryoprotectant) of the original niosome formulation were prepared. The samples were stored either at 5°C±3°C or 25°C±2°C/60% RH±5% RH for 3 months. The drug leakage percent, particle size and distribution, zeta potential, drug release profiles were determined and niosomes were visualized under optic microscope. Niosome formulation provided sustained release of piroxicam. The drug leakage from stored niosomes was observed at the level of 1.56-6.63 %. Individual vesicle images were obtained for all samples by optical microscope. However, particle size of niosomes was increased upon storage. The zeta potential values were neither related to time nor physical form. Drug release profiles and amounts were quite similar for all forms of niosomes and the original formulation but a slight decrease was noticed on drug release amounts by time. This indicates that niosomes become more rigid by time. Although the ideal storage was obtained with lyophilized niosomes at 5±3°C in this study, the usage of suitable cryoprotectant and optimized lyophilization process should be further evaluated.

Keywords: Drug release, lyophilization, niosomes, piroxicam, span 40, stability. INTRODUCTION Today besides the studies on the discovery of potent and safe active agents there are tremendous researches on the modification of drug formulations to provide more effective and safer treatments. The researches particularly focus on the drug delivery systems which can improve the pharmacokinetic and biological distribution of active agents. Vesicular drug delivery systems appear to be unique and industrially feasible systems. The major problem that limits the usage of vesicular systems is their poor stability. The assembly of bilayered vesicular systems from nonionic surfactants was discovered by the cosmetic research industry in 1970s [1]. The bilayered spherical vesicles formed from nonionic surfactants and cholesterol in the aqueous medium are known as niosomes (non-ionic surfactant vesicles) [2]. Although it has been more than 40 years since their first usage today there is no marketed drug in niosome form. One of the main reasons for this can be the unclear stability properties of niosomes. The literature considers niosomes as liposome analogs and emphasize that they have superior stability compared to liposomes [3, 4]. Despite this consideration the studies do not give sufficient information on niosome stability [2]. For the introduction of *Address correspondence to this author at the Department of Pharmaceutical Technology, Faculty of Pharmacy, Ankara University, 06100 Tandogan, Ankara, Turkey; Tel: +90312 2033155; Fax: +90312 2131081; E-mail: [email protected]

1875-5704/15 $58.00+.00

niosomes to the drug market adequate shelf life is necessary. Formulation parameters (types of surfactant, the presence or absence of membrane stabilizing and charge inducing agents), charge of the final formulation, the structure of the loaded drug, particle size and physical state of the niosomes, storage temperature and time, thermodynamic conditions must be kept under control for the stability of niosomes [5]. The main stability problems with niosomes are aggregation, fusion, swelling and drug leakage [6]. For improved stability it is recommended to store niosomes and liposomes in dry powder form rather than aqueous dispersion form [5, 7, 8]. In order to obtain dry niosomes techniques such as lyophilization, spray drying, spray freezing and supercritical freezing can be used [8]. The present study was designed to prepare niosome formulations and investigate their stability. The niosomes were loaded with a model active agent, piroxicam, which is an oxicam derivative, nonsteroidal anti-inflammatory drug. There are several studies on piroxicam loaded niosomes prepared with different surfactants but there were not any evaluations from the stability respect [9, 10]. Piroxicam has poor water solubility (0.0198 mg/ml) [11, 12] and it is negatively charged in physiological pH [13]. In this study lyophilization approach was used to obtain niosomes in dry powder form. Piroxicam loaded niosomes were lyophilized with/ without cryoprotectant and their stability was monitored for 3 months by comparing with aqueous niosome dispersion at 5±3°C and 25±2°C.

© 2015 Bentham Science Publishers

Stability Studies on Piroxicam Encapsulated Niosomes

Current Drug Delivery, 2015, Vol. 12, No. 2

MATERIALS AND METHODS

%Entrapment efficiency (%EE) = (a-b/a)x100

Materials

a: the amount of drug used in niosome preparation (g)

Piroxicam was obtained from Synopharm (Hamburg, Germany). Cholesterol and dicetyl phosphate (DCP) were purchased from Sigma-Aldrich (Milwaukee, WI, USA). Span 40 was bought from Fluka (Buchs, Switzerland). Chloroform, methanol, sorbitol, Tween 80, sodium hydroxide, sodium chloride were purchased from Merck (Darmstadt, Germany). Hydrochloric acid was obtained from Riedel de Haën (Seelze, Germany). Ultra-pure water purified by MilliQ Plus System (Millipore Corp., Molsheim, France) was used in all experiments.

b: the amount of unloaded drug in the supernatant (g)

Preparation of Piroxicam Loaded Span 40 Niosomes Piroxicam was loaded in niosomes by film hydration method. In a 100-ml round-bottom flask surfactant:cholesterol: dicetylphospate and piroxicam were dissolved in 100 ml of chloroform in certain molarities given in Table 1. Chloroform was then evaporated at 45°C, 60 rpm in a rotary evaporator (Buchi 200, BÜCHI Labortechnik AG, Switzerland). The residue of chloroform was removed by further incubation of the flask under vacuum overnight. The dried lipid film was hydrated with 100 ml of ultrapure water (Millipore Mili-Q-Gradient A10, USA) at 60°C by 15 min of vortexing and 45 min of bath sonication (Ultrasonic LC 30, Germany). The obtained niosomal dispersion was ultracentrifuged (Beckman Optima XL-100K, Germany) at 45 000 rpm for 1 hour at 5°C in order to separate the unloaded piroxicam from drug loaded niosomes [14, 15]. The precipitate containing the niosomes encapsulating piroxicam was redispersed in 100 ml of ultrapure water. Table 1.

The composition of piroxicam loaded niosomes.

Organic phase

Aqueous phase

Molarity (x10-3)

Weight

Span 40

2.97 M

270 mg

Cholesterol

2.97 M

115 mg

Dicetyl phosphate

2.50 M

135 mg

Piroxicam

0.75 M

25 mg

Chloroform

100 ml

Water

q.s. 100 ml

Determination of Piroxicam Encapsulation Efficiency After ultracentrifugation of the niosomes to separate the unloaded drug, the amount of free piroxicam in the supernatant was determined by diluting the supernatant with ultrapure water. The piroxicam concentration was estimated by UV spectrophotometer (Schimadzu 1202 UV Visible, Japan) at λmax 360 nm by using the calibration line of piroxicam in the ultrapure water. The linearity range of the analytical 2 method was 2-18 µg/ml and determination coefficient (r ) value was 0.999. The results of piroxicam encapsulation was calculated by using Equation 1 [16].

193

Eq. (1)

Measurement of Particle Size and Distribution of the Niosomes Dynamic light scattering (DLS) method was used to determine the particle size and distribution of niosomes by using Zetasizer (Malvern Zetasizer Nano ZS, Malvern Instruments, UK). The equipment performs the analysis with a HeNe Laser (633 nm) at scattering angle of 175º at 25 ºC. Before the analysis 25 µL of niosomes was diluted to 10 ml with ultrapure water and filtered through Whatman no:42 ashless filter paper (n=3). Measurement of Zeta Potential The surface charge of the niosomes was measured with Zetasizer (Malvern Zetasizer Nano ZS, Malvern Instruments, UK) and the equipment automatically calculated the results by using the Smoluchowski equation [16]. In vitro Release of Piroxicam from Niosomes The drug encapsulated niosomes were evaluated for their drug release behavior by the dialysis method with slight modification [17]. Dialysis membranes (molecular weight cut off 12 000 Da) were hydrated with water by overnight incubation prior to the release experiments. Piroxicam loaded niosomes containing 230 μg piroxicam were placed into the dialysis membrane and closed at both ends. The bags were submerged into a bottle containing the 50 ml of release medium (simulated gastric fluid (pH 1.2) containing 0.1 % (v/w) Tween 80) [18, 19]. The bottles were placed inside a water bath and shaken at 100 rpm 37 ºC. Aliquots of 3 ml release medium were withdrawn from the release medium at selected time points and replaced with fresh medium (n=3). The absorbance of piroxicam in the collected samples was directly analyzed spectrophotometrically. Piroxicam amount was calculated by comparing the absorbance values with a standard solution of piroxicam having a known concentration in dissolution medium as described in USP 30 [20]. Stability of Niosomes in Storage Conditions The stability of piroxicam loaded niosomes in different physical states and storage conditions was examined. The stability test was performed in two different conditions as mentioned in ICH stability guidelines [21]. The formulations were introduced into glass flacons and incubated in refrigerator at 5±3°C and climatic chamber at 25±2°C, relative humidity 60±5 %. The niosomes were stored as (a) aqueous dispersion, AD; (b) lyophilized niosomal powder-LP; and (c) lyophilized niosomal powder containing sorbitol as a cryoprotectant-LP-C. Preparation of AD Samples Freshly prepared niosomes were transferred in 8 ml glass flacons and sealed using crimtop vial caps with rubber septa.

194 Current Drug Delivery, 2015, Vol. 12, No. 2

Ertekin et al.

Preparation of LP Samples The niosomes placed in glass flacons were frozen at −40 °C for 2 hours. The frozen samples were lyophilized using Christ Gamma 2-16 LSC freeze dryer (Harz, Germany). The process was performed at a pressure of 12 Pa for 24 h. After lyophilization step samples were sealed as LP samples. Preparation of LP-C Samples Sorbitol at an amount of ten times the amount of niosome solid content was added to the niosome dispersion. The samples were lyophilized by following the protocol used for the preparation of LP samples. The Stability Tests

The vesicles observed in optic microscope confirmed the formation of niosomes (Fig. 1). The presence of multi lamellar vesicles was attributed to the usage of film hydratation technique and absence of high energy input to the system such as probe sonication or homogenization. DLS measurement demonstrated that particle size and poly dispersity index were 175±1.567 nm and 0.469±0.006. The particle size distribution was trimodal as it was observed in previous studies (Fig. 2) [17]. After the separation of unloaded piroxicam the zeta-potential of the niosomes was also measured to indicate their surface potential. The niosomes were negatively charged and the zeta potential was -36.5±0.26 mV. This value was considered to be within the range sufficient for obtaining stable and aggregation resistant systems [23, 24].

In the stability test the drug leakage, in vitro drug release, particle size and zeta potential of the samples were evaluated. The samples were analyzed at the end of second and third months. Prior to the analysis the lyophilized niosomes were reconstructed with ultrapure water to their original volume. The leakage ratio of piroxicam was determined by comparing the drug content in niosomes before and after storage. The samples were ultracentrifuged at 45 000 rpm for 1 hour at 5°C in order to separate the leaked piroxicam and the leaked piroxicam amount was measured spectrophotometrically. The leakage percent was calculated by using Equation 2. % Leakage = (a/b)x100

Eq. (2)

a: the amount of drug measured in the supernatant (g) b: the initial amount of drug encapsulated in niosomes (g) The rest of the stability tests were performed as described above. The statistical evaluation of the data was made by using one-way ANOVA (SPSS 9.0, USA). RESULTS AND DISCUSSION Characterization of Niosomes Piroxicam was encapsulated into niosomes with an efficiency of 92.57±0.36 %. The lipophilic nature of piroxicam and usage of Span 40 which has low HLB value increased the encapsulation efficiency. Due to its hydrophobic nature Piroxicam is expected to locate between the hydrophobic chains in the niosome bilayer [22].

Fig. (1). The optic microscope image of piroxicam loaded niosomes.

The in vitro drug release profiles of pure piroxicam and piroxicam loaded niosomes are given in (Fig. 3). The release rate of pure piroxicam was increased after encapsulation of the active agent into niosomes. Instead of the rapid drug release observed in the case of pure piroxicam, the dissolution profile of piroxicam was improved after niosomal encapsulation. Within the first 30 minutes the piroxicam release percents were 26.9 % and 10.43 % in case of pure piroxicam

Size Distribution by Volume

Volume (%)

15

10

5

0 1

10

100 Size (d.nm)

Fig. (2). The particle size distribution of piroxicam loaded niosomes.

1000

10000



and niosomes. As seen the main drug release from pure piroxicam occurs in the first hour. Between the 1st and 24th hours the total drug release percent was 18.54 % and 70.75 % for pure and encapsulated piroxicam. The enhanced drug release via niosomes was attributed to the solubilizing effect of niosomes. Under this circumstances enhancement of piroxicam bioavailability can be expected by niosomal encapsulation compared to classical tablet and capsule forms. 100

pure piroxicam

niosome

Drug Release %

90 80 70

60 50 40 30 20 10 0 0

5

10

15

20

25

195

incubation demonstrated that the system will stabilize itself by time (Fig. 4). The particle size and zeta potential are two important parameters that characterize colloidal drug delivery systems and their effects on the stability of the carriers is a well established relationship [29, 30]. In order to prevent the aggregation of colloidal systems it is necessary to provide some barrier between the particles such as steric or static barriers or introducing a charge on the surface of the vesicles. Zeta potential is an indicator for the size of this barrier. If all of the particles have large enough zeta potential the particles may repel each other strong enough to so that they will not have the tendency of coming together. However, this phenomenon is an assumption and there are several other parameters that affect the colloidal stability such as particle size, viscosity, chemical interactions within the system, storage conditions etc. As the ratio of gravitational forces to Brownian forces increase the particle size of the colloids becomes more dominant on the stability of the systems because the electrostatic interactions do not provide sufficient protection against precipitation [31].

Time (h) AD

Fig. (3). The in vitro drug release profiles of pure piroxicam and piroxicam loaded niosomes. Drug Leakage %

Under the stability test conditions drug leakage was observed for all of the niosomal formulations (Fig. 4). Although the niosome formulations contain cholesterol which increase the rigidity of niosomes and form less leaky niosomes [25], drug leakage was observed during the stability test. The remaining amounts of drug in niosomes at 25oC were between 93.37±0.16 % and 98.44±0.02 % and quite high. The formulations can be considered as stable from the drug encapsulation respect. After 3 month incubation the amount of the encapsulated piroxicam was decreased in the order of LP>LP-C>AD. Contrary to expectations, the high drug leakage in LP-C can be explained by the assembly of solid dispersion medium by sorbitol through hydrogen bonds from hydroxyl groups of sorbitol to double bound oxygen atoms in piroxicam which enhances the drug solubility, thus the leakage. The presence of cryoprotectants during lyophilization of liposomes was also shown to lead decreased encapsulation efficiency in former studies [26, 27]. The leakage was also attributed to the cryoprotectants act of mechanism on niosomal structure. Both the crystal formation during the freezing step of the lyophilization and interaction of cryoprotectants with the vesicle membrane during the water sublimation lead drug leakage. The leakage was relatively low at 5°C ranging between 1.68-3.60 % and this was expected because the drug leakage increases with temperature due to enhanced fluidity of the niosome membrane [28] . A storage temperature of 5°C was found to be more appropriate to minimize drug leakage from niosomes. This outcome is compatible with the literature mentioning that it is more suitable to store niosome formulations at refrigerator temperature [5, 28]. The drug leakage was decreased in the 3rd month compared to 2nd month. The decrease of drug leakage by

LP-C 4

LP-C

2

LP 0

AD 2 Month

25 ºC

3 Month

AD LP

4

Drug Leakage %

Stability of Niosomes

LP

6

LP-C

3 2

LP-C

1

LP

0

AD 2 Month

3 Month

5 ºC

Fig. (4). The drug leakage from niosomes stored at 25oC or 5oC. The particle size of the original formulation, 175±1.567 nm, was increased in all of the formulations after storage (Table 2). After reconstruction of lyophilized niosome powders, aggregation was not observed but the particle size analyzer gave poor sample quality notice. This might be due to possible aggregation of the vesicles or vesicle growth, because adequate sample quality was obtained after bath sonication of the samples. As the storage time extended, the sonication


Table 2.

Ertekin et al.

The particle size and polydispersity index of the niosomes during the stability test.

Mean Particle Size±SE (nm) 175±1.567

0 month °

AD

LP

LP-C

Polydispersity Index±SH 0.469±0.006

25 C

°

°

5C

25 C

5 °C

2 month

259.1±3.4

235.8±1.71

0.497±0.02

0.505±0.02

3 month

257.2±5.63

261.9±5.41

0.501±0.03

0.414±0.02

2 month

218.2±2.61

332±34.38

0.459±0.01

0.416±0.05

3 month

242±6.69

287.6±6.21

0.519±0.02

0.549±0.03

2 month

326.5±8.18

ND*

0.452±0.04

ND

3 month

416.2±24.35

276.1±19.12

0.393±0.04

0.573±0.04

* Not determined.

Fig. (5). The optic microscope images of piroxicam loaded niosomes obtained during the stability tests.

duration necessary for obtaining good sample quality was increased. Besides, the drug leakage that was observed during the storage caused by the migration of the drug in the external phase might cause the fusion of the vesicles, thus increase the niosome size. It was reported that upon hydration of lyophilized vesicular systems with reduced sugar concentrations, they may be destabilized and reassemble as their origin or form larger vesicles [32]. However the optical microscopy images showed the presence of individual vesicles (Fig. 5). After hydration of lyophilized vesicular systems, the assembly of larger vesicles with higher polydispersity index was also demonstrated by several researchers [24, 26]. It is recommended to optimize the lyophilization parameters (such as cryoprotectant type and amount, niosome

composition, freezing rate and temperature etc.) to retain the niosome properties [24, 26]. The zeta potential of the samples was changed between -22 mV and -51 mV which was initially -36.5 mV (Table 3). These values are assumed to provide adequate repulsion between vesicles to prevent the aggregation and provide stable colloidal systems [33]. But if the difficulty of obtaining good quality sample for the particle size measurements is also considered the systems can not be designated as stable. Solely the electrostatic repulsion is not an enough parameter to prevent aggregation and explain the stability of colloidal systems. The zeta potential changes were minimum for LP-C samples and independent from storage temperature (Table 3).


Table 3.


25 ºC

-22.03±0.03

-43.47±0.06

5ºC

-40.13±0.019

-41.7±0.19

25 ºC

-53.2±0.047

-43.5±0.98

5ºC

-22.43±0.081

-39.6±0.15

25 ºC

-45.23±0.66

-34.93±0.33

formation of larger niosomes during the storage period. It is well-known that small particle size increases the total surface area of vesicular systems [34] thus, the surface available for drug release and the length of the diffusional barrier in niosome structure also increase and result in enhanced drug release [35]. This phenomenon may be an explanation for slow drug release which comes with niosome growth upon storage. Other explanations would be possible increase on the rigidity of niosome membrane or interaction of the drug with the niosome membrane components [25, 36]. In general the stable release patterns were reached after the second month and the overall drug release at the end of 4th hour was not significantly different (p>0.001) (Fig. 7).

5ºC

-44.2±0.20

-37.93±0.24

CONCLUSION

The zeta potential changes observed during the stability test.

Storage temperature AD

LP

LP-C

Second month

Third month

In the current study which is focused on the stability of niosomes, three forms were investigated: aqueous dispersion lyophilized niosomes and lyophilized niosomes with a cryoprotectant. Although the drug leakages from niosomes were within acceptable limits in all forms, LP niosomes which were directly lyophilized were found to be the most appropriate form to prevent the drug leakage. The outcomes of this study showed that lyophilization would be beneficial for improved stability of niosomes, but the usage of cryoprotec-

80 70 60 50 40 30 20 10 0

80

Drug release %

Drug release %

The drug release rates from the formulations kept at both 5oC and 25oC were investigated for four hours to observe the changes in initial fast release portion comparing to the release profile given in (Fig. 3). The drug release decreased in the second and third months compared to the initial drug release data but the physical form of the samples did not influence this decrease significantly (p>0.05) (Fig. 6). The decrease on the amount of the released drug may be due to

0

50

100

150

Time (min)

O month

2 month

200

60 40 20 0

250

0

80

80

60

60

40 20 0 0

50

LP-C 25 ºC

100

150

Time2 (min) O month month

200

50

AD 5 ºC

3 month

Drug release %

Drug release %

AD 25 ºC

O month

150

Time (min) 2 month

200

250

3 month

20 0 0

250

50

LP 5 ºC

3 month

100

40

100 O month

150

Time (min) 2 month

200

250

3 month

80

80 70 60 50 40 30 20 10 0

Drug release %

Drug release %

197

0

LP 25 ºC

50

100

150

Time (min)

O month

2 month

200 3 month

250

60 40 20 0 0

LP-C 5ºC

50 O month

Fig. (6). The in vitro drug release profile of niosome formulations stored at 25C or 5 C.

100

150

Time (min) 2 month

200 3 month

250


Ertekin et al.

Fig. (7). The percentage of drug released in 4 hours.

tant has to be separately evaluated for the cryoprotectant type by considering its interaction with both the surfactant and the drug. Under these circumstances the temperature of 5°C is suggested as an appropriate storage condition for niosomes. CONFLICT OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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Received: January 04, 2014

Revised: May 02, 2014

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Accepted: July 21, 2014

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PMID: 25056419