Formulation and Evaluation of Candesartan Niosomal Suspension

 

Sunder Raj Manvi1, V. R. M. Gupta2, K. Srikanth2*, N. Devanna3

1F R & D, Abdi Ibrahim, Istanbul, Turkey

2Dept. of Pharmaceutics, Pulla Reddy Institute of Pharmacy, Annaram, Andhra Pradesh, India.

3Dept. of Chemistry, JNTUA, Ananthapur, Andhra Pradesh, India.

*Corresponding Author E-mail: ksrikanthgupta@yahoo.co.in

 

ABSTRACT:

Objective of the present research work is to develop the liquid dosage form (niosomal suspension) of candesartan. Niosomes have been prepared using two different non ionic surfactants by thin film hydration technique and are characterized for size, shape, entrapment efficiency, invitro drug release and stability. SEM studies have been carried out which shown that the niosomes are spherical in shape with smooth surface. All the vesicles appeared in the size range of 8.1– 11.3µm. % entrapment efficiency has been carried out by dialysis method and the results are confirmed with centrifugation method. Niosomes prepared using spans showed good results than the niosomes prepared using tweens. Among all formulations, FS603 has shown highest entrapment efficiency [71.2%]. Diffusion studies were carried out to study the drug release pattern from all formulations and are revealed that increase in the concentration of surfactant decreases the drug release from niosomes, in all formulations prepared using spans and tweens. Among all formulations, FS603 has shown better sustained release, which is desirable for enhancing the bioavailability. Hence, FS603 has been optimized as best formulation and carried stability studies as per ICH guidelines and are revealed that the niosomes are stable for long time at refrigerated temperature.

 

KEYWORDS: Niosomes, Mean residence time, Bioavailability, Solubility, Non ionic surfactants.

 


INTRODUCTION:

Candesartan is an angiotensin II receptor antagonist and is used mainly for the treatment of hypertension. It is poorly water soluble drug, and its absorption from oral route is also poor, as a result, failure in providing effective plasma drug profile on conventional oral administration. The large dose and frequent administration of candesartan may lead to hypotension1.

 

Literature substantiated that the liposomal concept has good advantages like sustained drug release, targeted drug delivery, as drug carrier, not affected by Reticulo endothelial system and enhance the mean residence time in blood, etc2. Lipid constituents are used in manufacturing of liposomes, Due to the presence of lipid constituents, they are more susceptible to rancidity which leads to destabilization of liposomes. Because of this the liposomal technology advantages are limited3.

 

To enhance the stability of vesicle, liposomal technology has been slightly modified by replacing the lipid constituent with non-ionic surfactants.

 

The resultant vesicles were said to be Niosomes and showed more stability than the liposomes4. The niosomes will have similar advantages as of liposomes and also greater stability, researchers adopting this technology not only for above mentioned applications but also using for enhancing the bioavailability of poorly soluble drugs by enhancing their MRT of drugs in the bio-environment5. Researchers also proved that the carrier system serves to protect the drug from degradation and protects the host from unwanted immunological or pharmacological effects6.

 

Apart from this there is no commercial liquid dosage form available for candesartan, comfortable to all patients. This initiated the authors to make an attempt to develop the candesartan niosomal suspension.

 

MATERIALS AND METHODS:

Materials

Candesartan obtained as a gift sample from Dr. Reddy’s laboratories, Hyderabad. Cholesterol, Spans and Tweens purchased from Loba Chemicals, Mumbai. All used solvents were HPLC grade.

 

Method

Preparation of niosomes

All niosomal formulations were prepared by slight modification in lipid film formation technique reported by Jain et al7.


Table 1. All formulations with their particle size and entrapment efficiency

S.No

Formulation

Drug: Cholesterol: Surfactant

Particle size, µm

% Entrapment efficiency

Dialysis method

Ultra centrifugation method

1

FS1

Span - 60

1.0: 1.0:0.5

8.1

57.6

58.4

2

FS2

1.0:1.0:1.0

6.4

62.3

61.2

3

FS3

1.0:1.0:1.5

3.9

71.2

73.6

4

FT1

Tween - 20

1.0: 1.0:0.5

15.1

38.4

40.7

5

FT2

1.0:1.0:1.0

13.5

46.3

44.9

6

FT3

1.0:1.0:1.5

11.3

58.1

57.3

 

Table 2. Percentage drug release from all formulations.

S.No

Time, Hrs

% DRUG RELEASE FROM FORMULATIONS

 

FS1

FS2

FS3

FT1

FT2

FT3

Candesartan suspension

1

0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

2

1

16.6

8.0

5.8

28.9

18.2

23.0

32.3

3

2

22.9

15.5

11.1

41.4

38.4

28.1

51.6

4

3

31.3

25.6

17.4

51.2

48.2

38.5

69.9

5

4

38.6

30.4

22.6

59.1

52.4

43.9

88.8

6

5

40.6

36.5

27.4

62.2

58.4

49.3

94.4

7

6

48.7

44.6

35.3

66.4

61.9

58.1

96.1

8

7

56.2

50.9

41.1

71.6

66.4

63.1

97.3

9

8

61.9

56.8

48.5

78.8

72.5

69.6

 97.4

 

 

 

 

Fig.1. SEM photographs of an optimized formulation

 


Three different weight ratios of API: cholesterol: surfactant were taken in a round bottom flask and dissolved in 10 ml chloroform. The API, cholesterol and surfactant film was formed by the evaporation of chloroform using rotary flash evaporator (Buchi type) and then, the resulted film was hydrated with 10 ml of double distilled water for about 30 min. Temperature was maintained at 60±2°C. This was lead to the formation of milky white niosomal suspension. The resulting niosomal suspension was subjected to bath sonication to decrease the size of niosomes.

 

CHARACTERIZATION

Vesicle Morphology and Size Analysis8

The prepared niosomal formulations were characterized for their morphology using Scanning Electron Microscopy (SEM). The results of SEM are shown in Fig. 1. The vesicles size was determined by using optical microscope in triplicate. The results were tabulated in table 1. 

 

Entrapment Efficiency9

For determination of entrapment efficiency, the unentrapped drug in niosomal formulation was separated using dialysis method. 1ml of niosomal suspension was placed in donor compartment and dialysis was carried out in 100 ml of phosphate buffer (PBS, pH 7.4). After every 30 min, 2ml of sample is withdrawn and concentration of unentrapped drug present in the sample was determined using UV spectrometer. The dialysis was carried out till the samples show constant results. % entrapment efficiency of all formulations was tabulated in table 1. 

 

Entrapment efficiency

=

Total amount of drug

-

Amount of

unentrapped drug

 

Fig 2. Drug release from niosomal formulations prepared using span – 60

 

In vitro Release Studies10

In vitro release studies of all niosomal suspensions and conventional niosomal suspension (10mg/ml) were performed using exhaustive dialysis method and the results were tabulated in table 2. Two side open ended glass tube was taken and one side has been closed with semi permeable membrane. The fabricated tube was used as donor compartment, in which 1ml of suspension was taken and placed in receptor compartment containing 100 ml phosphate buffer with polysorbate - 20. The dialysis was carried out at 50 rpm at 37°C for 8hrs. Every hour 2ml of sample was withdrawn and same volume of fresh sample was replaced. The samples were analyzed using UV spectrophotometer at 218nm. The results were shown graphically in fig 2 and 3.

 

Fig 3. Drug release from niosomal formulations prepared using tween – 20

 

Stability Studies11

In the present study, the stability of the vesicles was determined by slightly modifying procedure given by Solanki et al. The size and shape of vesicles were measured immediately after manufacturing and after 30 days at 4-8±1°C and 25±2°C. The results were tabulated in table 3.

 

Table 3. Stability studies as per ICH guidelines

Stability studies

S.

No

 

 

 

Storage conditions

Immediately after manufacturing

After 30days

Particle size, µm

Shape

Particle size, µm

Shape

1

Refrigerared temp

3.9

Spherical

4.1

Spherical

2

Room

temp

 3.9

Spherical

4.6

Spherical

 

RESULTS AND DISCUSSION:

All developed formulations were characterized for surface morphology, particle size, entrapment efficiency, in vitro drug release and stability.

 

In all formulations, the niosomes appeared spherical in shape. The size of niosomes in all formulations was found in the range of 3.9 – 11.3µm.  It has been observed that the increase in the surfactant concentration decreases the particle size. This may be due to decrease in the surface tension with increase in surfactant concentration.

 

% entrapment of drug is more in formulations prepared with the spans than the formulations prepared using tweens. The % entrapment efficiency in all formulations was found in the range of 38.4 – 71.2%. The highest % entrapment efficiency was exhibited by FS3 formulation and least was found in FT1 formulation. Though the particle size of FS3 formulation is less, it exhibited more % entrapment efficiency. This may be due to formation of more number of niosomes per sq.mm area.

 

In vitro drug release from all formulations was carried out by exhaustive dialysis method. All niosomal formulations showed sustained drug release when compared with that of conventional suspension. Among all niosomal formulations, FS3 showed effective sustained release of candesartan. Hence this formulation was considered as optimized formulation and stability studies were carried out as per ICH guidelines for the same. The size of vesicles was increased more in formulations stored at room temperature (25±2°C) than formulations stored at refrigerated temperature (4-8±1°C). 

 

CONCLUSION:

In vitro results stated that the carrier system is adoptable to develop the liquid dosage form for candesartan. It is necessary to study further, for complete development. 

 

REFERENCES:

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8.        Abdelkader H, Ismail S, Kamal A, Alany RG. Preparation of niosomes as an ocular delivery system for naltrexone hydrochloride: Physicochemical characterization. Pharmazie. 65(11); 2010: 811-817.

9.        M. Abraham Lingan, A. Abdul Hasan Sathali, M. R. Vijaya Kumar, A. Gokila. Formulation and evaluation of topical drug delivery system containing clobetasol propionate niosomes. Sci. Revs. Chem. Commun. 1(1); 2011: 7-17

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Received on 28.10.2012          Modified on 10.11.2012

Accepted on 20.11.2012         © RJPT All right reserved

Research J. Pharm. and Tech. 5(12): Dec. 2012; Page 1570-1572