Preparation and Characterization of Novel Self Nano Emulsifying Drug Delivery System of Allopurinol

 

Priyal Patel*, Shilpa Solanki, Ashok Mahajan, Falgun Mehta, Kautuk Shah

Babaria Institute of Pharmacy, BITS Edu Campus, Vadodara - Mumbai NH#8, Varnama,

Vadodara - 391240 Gujarat, India.

*Corresponding Author E-mail: priyalpatel02@gmail.com

 

ABSTRACT:

The aim of research was to develop self nanoemulsifying drug delivery technology containing low aqueous soluble drug allopurinol for improving solubility, dissolution and bioavaibility. Preliminary screening were carried on the basis of maximum solubility of allopurinol in oil, surfactant, co-surfactant and pseudo-ternary phase diagram was constructed to identify the ratio of surfactant and co-surfactant for nanoemulsion formulation using water titration method. Based on the solubility study, Labrafil M 1944 CS, Cremophor RH 40, Transcutol used as oil, surfactant, and co-surfactant respectively. Pseudo-ternary phase diagram was constructed to identify the ratio of surfactant and co-surfactant for nanoemulsion formation by water titration method. As per the ternary phase diagram ratio of Smix in 2:1 was identified with maximum emulsification area. SNEDDS composed of 35 % Labrafil M 1944 CS, 43.34% Cremophor RH 40, 21.66% Transcutol. Globule size was found to be 25.42 nm, and zeta potential value was -9.26 mV. Prepared SNEDDS were evaluated for globule size, viscosity, emulsification time, cloud point, dilution test and thermodynamic stability study. Prepared liquid SNEDDS then converted into solid SNEDDS via extrusion/spheronization technique using Aerosil 200, lactose monohydrate and Croscarmellose sodium. The pellets containing SNEDDS possessed good flow properties and mechanical strength and other rheological parameters. Self nanoemulsifying pellet exhibited uniform size and shape. Friability, dissolution time and disintegration of pellets formulation shown promising results. Time required for 80% drug release of self nanoemulsifying pellet was found to be 26 min, which was significantly lower than liquid SNEDDS, plain drug containing pellet and marketed preparation of Allopurinol (ZYRIK).

 

KEYWORDS: Allopurinol, solid-self nanoemulsifying drug delivery system (S-SNEDDS), Self nanoemulsifying Pellet (SNEP), pseudo-ternary phase diagram, Extrusion/Speronization.

 

 


1.    INTRODUCTION:

“Allopurinol is classified as a xanthine oxidase inhibitor. It reduces of uric acid level in the body. It is one of the best gouty medicines. Allopurinol is used to prevent gout attacks, not to treat them once they occur1,2. “A hypoxanthine analogues has a different biological activities and pharmacological actions such as pain in upper part of stomach, loss of appetite, peeling, and red skin rash4,5. However, allopurinol was reported to have 0.48mg/ml solubility in water due to that it absorbed slightly in GI tract.

 

Aullopurinol is first line drug therapy used in chronic gout and hyperuricemia. and It is weakly acidic (pKa 9.4) in nature, which has poor water solubility. The major site for absorption of ALP is duodenum and upper jejunum, whereas its absorption gets slower and incomplete in the lower jejunum6,7,8. The biological half-life of drug is 1 - 3 hour than converted to oxipurinol, its active metabolite so technically actual bioavaibility is not identified. Reported oral bioavaibility was up to 70%9,10. various approaches have be investigated to improve the solubility of allopurinol. These approaches include Allopurinol suppositories and injectables, gastro retentive drug delivery system of allopurinol, solid dispersions of allopurinol.”

 

“The present study was proposed to fabricate and prepare Allopurinol loaded SNEDDS with the intention of increasing its solubility and achieving higher bioavailability. To accomplish this, the allopurinol was screened for drug solubility in various oils, surfactants and co-surfactants11,12.”

 

2.    MATERIALS AND METHODS:

2.1 Materials:

Allopurinol was obtained from Centurian Pvt Ltd, Vadodara. Materials like Acrysol EL 135, Acrysol K 140 was obtained from Corel Pharma Chem,. India. Castor oil, Mentha oil, Jojoba oil, Cremophor EL, Cremophor RH 40, Span 80, Span 20, and Avicel was obtained from Chemdyes Corporation. Labrafil M 1944 CS was obtained from Gattefosse Inc, USA. Olive oil, Linseed oil and Mustard oil was obtained from Genuine chemical co, India. Isopropyl mystirate, Isopropyl palmitate and Isopropyl alcohol was obtained from Aatur Instruchem., India. Tween 20, PEG 200, PEG 400, Propylene glycol and Lactose monohydrate was obtained from Suvidhinath Laboratorie. India. Cross-carmellose sodium, Aerosil 200, Aerosil 300 and Tween 80 was obtained from Astron Chemicals, India. Crosspovidone was obtained from Signet Chemical Corporation Pvt Ltd, India. Silicon dioxide 350 was obtained from Thrien Enterprise. India. Captex, Capmul MCM was obtained from Abitec USA. Transcutol was obtained from Ozone International Pvt. Ltd, India.

 

2.2. Methods:

2.2.1. Solubility studies:

In order to identify the right composition of SNEDDS components with good solubilizing capacity for allopurinol, “saturation solubility was performed in different oils, surfactants and co-surfactants by adding an excess amount of drug into 2ml of each vehicle in screw capped greiner tubes.” The obtained mixtures were mixed continuously for 2 min using cyclo mixture (Remi equipment). The mixtures were kept for 48 h in a rotatry flask shaker for effective mixing followed by equilibrium for 12 h.13,14 The equilibrated samples were removed and centrifuged at 3000rpm for 15 min to remove the precipitated allopurinol. The supernatant solution was filtered through a miliporee membrane filter (0.45m) then methanol was added for dilution.The concentration of Allopurinol was identified using UV Spectrophotometer at 250nm. Entire solublities were don in triplicate.15,16,17

 

2.2.2 Construction of Pseudo-ternary phase diagram:

Water titration method was used to build the phase diagram consisting oil, water, surfactant and co surfactant for investigation of concentration component of SNEDDS. Ternary phase diagram using a Gibbs triangle was the most suitable methods to study the phase behavior of such systems.18,19 On the basis of solubility and emulsification study, Labrafil M 1944 CS, Chremophor RH 40 and Transcutol were selected as oil, surfactant and co-surfactant, respectively. Surfactant was mixed with cosurfactant in fixed weight ratios (1:1, 3:1, 2:1, 1:2). For each phase diagram, the ratio of oil to Smix was varied as 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8 and 1:9 (w/w). Aliquots of each Smix were then mixed with oil at room temperature (25°C). Phase studies was carried out by adding drop wise water, resulting system was examined bluish tone, hazyness. No heating was applied during the preparation. The endpoint of nanoemulsion domain at a given ratio was determined when the system became hazy after addition of water.21 Then using chemix software, the phase behaviour of the system was mapped on phase diagram with the apices representing oil, water and smix. The ternary phase diagram showing maximum nanoemulsion region was taken as the criteria for the selection.20,21

 

Table 1: Solubility of Allopurinol in different vehicles.

Solubility of Allopurinol in different oil, surfactant, co-surfactant

Oils

Solubility of Allopurinol (mg/ml) ± SD

Surfactant

Solubility of Allopurinol (mg/ml) ± SD

Olive Oil

28.66± 0.307

Tween 20

33.60±0.323

Castor Oil

23.32± 0.125

Tween 80

36.42±0.12

Linseed Oil

9.08± 0.03

Span 20

10.83±0.21

Mustard Oil

26.07± 0.06

Span 80

11.45±0.24

Acrysol EL 135

51.27± 0.13

Cremophor RH

39.48±0.12

Acrysol K 40

25.93± 0.18

Cremophor EL

37.97±0.12

Captex

21.24± 0.32

Co-surfactant

Jojoba Oil

23.73± 0.31

PEG 200

9.49±0.32

Mentha Oil

26.29± 0.29

PEG 400

17.57±0.12

Peceol

9.87± 0.04

Capmul MCM C8

7.04±0.12

Labrafil M 1944 CS

55.23± 0.14

Transcutol

27.97±0.125

Isopropyl palmitate

17.93± 0.32

Propylene glycol

10.43±0.01

Isopropyl mystirate

19± 0.39

 

 

 

2.2.3 Formulation of liquid SNEDDS system:

The liquid SNEDDS were prepared by Allopurinol (100 mg) in a suitable blend of oil, surfactant, and co-surfactant at 25°C as per phase diagram. The final mixture was vortexed until a clear solution was obtained.22,23

 

2.2.4 Preparation of solid SNEDDS formulations:

Based on all characterization and evaluation tests of liquid SNEDDS formulas, optimized batch was added with Aerosil 200 and lactose monohydrate and mixed in a kneader until the liquid SNEDDS were completely adsorbed to form a dry fine mixture. Crosscarmelose sodium as a superdisintigrant was uniformly blended with above fine mixture for about 5 Minute. A suitable dough like mass for extrusion process was prepared by adding drop by drop required water. The wet mass was extruded in a screw extruder. The extrudates were spheronized on a spheronizer. The produced pellets were then air dried.24,25

 

Table 2: Composition of optimized liquid SNEDDS formulation

Formulation (v/v)

Percentages

Labrafil M 1944 CS (%)

35

Cremophor RH 40 (%)

43.34

Transcutol (%)

21.66

 

2.3 Characterization of the Solid SNEDDS:

2.3.1 Globule size Analysis and Polydispersibility Index (PDI):

“The droplet size has paramount importance in self-emulsification tendency because rate and extent of drug release depends on it as well as absorption prior to measurement 1mL of different liquid SNEDDS was diluted 10 times with distilled water. The globule size and polydispersibility index of the formed nanoemulsions were determined by dynamic light scattering (DLS) using a photon correlation spectrometer (Zetasizern)26,27

 

2.3.2 Surface morphology of solid SNEDDS pellets:

Scanning electron microscopy images of solid pellets loaded with optimized batch of SNEDDS was shown in Figure: 4. SEM images were evaluated further.28,29

 

2.3.3 Differential scanning calorimetry of solid SNEDDS:

“Differential scanning calorimetry technique was used to investigate the thermal behavior of pure allopurinol and the physical state of Allopurinol in solid SNEDDS using (DSC Q200 v24.2 build 107, TA Instruments).30

 

2.3.4 Drug release studies:

In vitro drug release studies of allopurinol from pellets loaded with SNEDDS were performed using USP dissolution apparatus II with 900 ml of 0.1N HCL as a dissolution medium at 37±0.5°C. Paddle speed was kept at 100rpm. Allopurinol-loaded solid SNEDDS (equivalent to 100mg of Allopurinol) and 100mg of Allopurinol pellet were placed in a dissolution tester (Electrolab TDT-08L). An aliquot (5ml) of the sample was collected, filtered and analyzed for quantification of Allopurinol by UV visible spectrophotometer at predetermined time intervals. The sink condition was maintained by replacement of fresh media.31,32

 

2.3.5 Stability study:

Stability study was carried out as per ICH guidelines. The optimized samples were stored in a humidity chamber with relative humidity of 75±5% and temperature of 40°±2 °C or at room temperature for 1 month. Physical characteristics and drug content were investigated for stored samples. The similarity factor (f2) was used for the evaluation of the drug release.33,34

 

2.3.6 Statistical analysis:

The pharmacokinetic data of the two formulations were compared by the Student’s t-test. A p-value of less than 0.05 was considered as statistically significant.35,36

 

3.    RESULT AND DISCUSSION:

3.1 Solubility study:

The components system including_ oil, surfactant and cosurfactant must be carefully chosen to design SNEDDS with optimum acceptable physiochemical characteristics. The main aim of performing drug solubility in various vehicles used in SNEDDS was to provide a robust self emulsifying region with large boundary size in the ternary phase diagram and to form nano droplet size globules to increase solubility and bioavailability. The solubility of Allopurinol in different vehicles like essential oils, surfactants and co-surfactants was shown in Table No 1. It was found that Allopurinol exhibited highest solubility in Labrafil M 1944 CS (55.23±0.14mg/ml) and Acrysol EL 135 (51.27±0.13mg/ml). So both oils were selected as an oil phase for further investigation because of its solubilizing potential of Allopurinol. Among various surfactants example like Cremophor® EL, Cremophor® RH 40, Span 20, Span® 80, Tween® 20, and Tween® 80 were screened for the emulsification ability of the selected oil phase. The criteria for the selection of surfactant are its drug solubility, HLB value, non toxic nature. On the basis of % (percentage) of transmittance and ease of emulsification, Surfactant selection was done. Cremophor RH 40(97.23±0.55) and Cremophor EL (91.7±0.34) exhibited highest percentages tramittance of Allopurinol. Whereas various Co-surfactant example like PEG 400, PEG 200, Capmul® MCM C8, Propylene Glycol, Transcutol were selected based on the ability to form clear nanoemulsion and stable at a minimum concentration. On the basis of % transparency and ease of emulsification Transcutol (99.9±0.1) exhibited highest percentages tramittance of Allopurinol. Based on the solubility study these ingredients were selected for further studies.37,38

 

3.2 Construction of phase diagram:

Pseudo a ternary phase diagram was constructed to obtain self nanoemulsifying region with appropriate concentration ranges of components in the areas of forming nanoemulsion. Based on solubility study data, Labrafil M 1944 CS were used as oil phase, whereas based on the percentages transmittance data revealed Cremophor RH 40 was selected as surfactants; and Transcutol used as co-surfactants for constructing different phase diagram in order to investigate the best self emulsifying region. It was significantly found that that surfactant concentration less than 30% shown turbid emulsions. It was noted that spontaneous emulsion formation within self-emulsifying region increased as the percentage of co-surfactant in the liquid SNEDDS formulation raised. There was no significant difference observed between the two co-surfactants. The minimum ratio of surfactant and co- surfactant phase for self-emulsification was around 50–75%. When the sum of the surfactant and co-surfactant ratio was above 60% of the SNEDDS formulation, self-emulsification efficiency was good. The phase diagrams were mapped at surfactant/cosurfactant ratios (1:1, 1:2, 2:1 and 3:1). The size of the nanoemulsion region in the diagrams was compared, the larger the size the greater the self- nanoemulsification efficiency. Pseudoternary phase diagrams showed that the zone of nanoemulsion (the black area) was largest in formulae prepared with Cremophor RH40-Transcutol HP mixture (Smix) at 2:1 ratio as shown in Figure No. 1. Thus, fixing the surfactant/cosurfactant ratio at 2:1 was a better choice from a stability point of view. At Smix 2:1, and when cosurfactant was added with surfactant in equal amounts, a higher nanoemulsion region was observed, perhaps because of the further reduction of the interfacial tension and increased fluidity of the interface at Smix 2:1.39,40

 

4.     Characterization of liquid SNEDDS:

In SNEDDS, the primary means of self-emulsification assessment was visual evaluation22. “The rate of emulsification and droplet size distribution was investigated for checking efficiency of self-emulsification. The droplet size of the emulsion was a crucial factor in self-emulsification performance because it determines the rate and extent of drug release as well as absorption23. It was observed that increasing the surfactant concentration (from 20% to 50% v/v) in SNEDDS formula (Table 2) decreased the z-average diameter of emulsion formed but above 65% with Labrafil M 1944 CS the z-average diameter slightly improved. The effect of the cosurfactant (Transcutol) concentration on the z-average diameter in SNEDDS was similar to that of the surfactant (Labrafil M 1944 CS) at concentrations of from10% to 25% v/v. A decrease in z-average diameter was observed with an increase in the co-surfactant concentration of Transcutol from 20% to 25%, if co-surfactant concentration was less than z-average diameter was increases.” It was observed that the formulation composition ratio given in Table 3 gave smaller z-average diameter than other SEDDS formulations tested and chosen for further studies.41,42

 

Figure 1: Pesudoternary phase with different ratio of Smix

 


 

Table 3: Optimized formula for SNEDDS

Formulation number

Formulation components (%)

Mean particle size (nm)

PDI (polydispersity index)

Oil

Surfactant

Co-surfactant

1

25

50

25

28.45

0.198

2

30

46.67

23.33

32.13

0.072

3

35

43.34

21.66

25.42

0.208

4

40

40

20

63.96

0.384

5

45

36.67

18.33

38.23

0.436

6

50

33.34

16.66

69.48

0.548

7

55

30

15

96.45

0.496

8

60

26.67

13.33

102.8

0.436

9

65

23.34

11.66

206.9

0.667

10

70

20

10

-

-

 


 

Figure 2: Globule size of optimized batch

 

Figure 3; Zeta potential of optimized batch

 

4.1 Solid state characterization of solid SNEDDS:

The surface morphology of SNEP formulation of Allopurinol was determined using scanning electron microscope. Blank adsorbant mixture of Aerosil 200 and lactose monohydrate was shown in Figure No 4 (A) and after adsorbing SNEDDS on adsorbant was shown in Figure No 4 (B). Figure No 4 (A) appeared with rough surface and porous particle. However, Figure No 4 (C) appeared as smooth surface of aerosil 200 and lactose monohydrate, indicating that the liquid SNEDDS either adsorbed or coated inside the pores of adsorbent powder mixture. The image of the self nanoemulsifying pellets containing Allopurinol had the same outer macroscopic morphology consisting of well separated spherical particles.43

 

Figure 4: SEM photograph of adsorbent mixture (B) SEM photograph of adsorbent mixture after adsorbing SNEDDS (C) SEM photograph of SNEP

 

DSC Thermograms of pure Allopurinol, blank SNEP (without Allopurinol) and Allopurinol SNEP were obtained using differential scanning calorimeter as shown in Figure 5. The thermogram of pure Allopurinol exhibited a sharp endothermic peak at about 384 ̊C, corresponding to its melting point as shown in Figure 5. Blank SNEP showed no specific peaks near to Allopurinol endothermic peak as presented in Figure 5 (B). In case of Allopurinol SNEP formulation, the endothermic peak of_ Allopurinol was absent as shown in Figure 5 (C). The change in melting behaviour of Allopurinol can be attributed to the inhibition of its crystallization and solubilisation of Allopurinol in SNEP. Therefore, it could be concluded that Allopurinol in the solid SNEDDS was in the amorphous form. It is known that transforming the physical state of a drug to the amorphous or partially amorphous state leads to a high-energy state and high disorder, resulting in enhanced solubility. As a result, it was expected that the solid particles would also have enhanced solubility.

 


 

 

Figure 5: (A) Pure Allopurinol

 

Figure. 5: (B) Blank SNE

 

Figure 5: (C) Allopurinol SNEP

 


4.2 In vitro dissolution test:

In vitro drug release studies were performed for liquid SNEDDS, Plain drug containing pellet, solid SNEDDS in cpasule and marketed formulation (Zyric), shown in Figure No: 6. As the emulsification time was below 26 second a maximum percentage of the drug released within 80 sec from the solid SNEDDS; however, the dissolution studies were conducted for 1 h to release profile, ensuring that the solid SNEDDS shown the improvement of in vitro dissolution than other formulation.

 

Table No 4: Comparative dissolution profile between SNEP, liquid SNEDDS, plain drug containing pellet, and Marketed formulation Allopurinol (Zyric)

Time in minute

SNEP in capsule

liquid SNEDDS

plain drug containing pellet

Marketed formulation (Zyric)

0

0

0

0

0

10

45.17

36.71

30.51

28.47

20

74.03

69.68

59.45

50.35

30

84.89

75.66

68.38

62.32

40

89.25

85.25

76.18

73.19

50

93.74

91.33

80.51

79.59

60

96.26

95.16

93.67

92.46

 

 

Figure 6: Comparison of SNEP, SNEDDS, Pellets containing plain drug and marketed preparation of Allopurinol (Zyric)

 

As per the in Figure 6.and using %CDR results, the selected SNEP in capsule had a faster drug release than liquid SNEDDS, plain drug containing pellet and marketed preparation (Zyric). Crosscarmelose sodium enhanced water absorption into the pellets and improve interfacial surface between liquid SNEDDS and dissolution medium. Secondly the result could be related to the role of fine solid components of pellet formulations like adsorbent (aerosil 200) which act as porous carrier to enhance the dissolution profile. It has been shown that finely divided solid particles can be used as emulsifying agents and emulsion stabilizer.

 

5.    CONCLUSION:

In this study, the solid SNEDDS of Allopurinol was prepared by Adsorption to solid carriers technique, using water-insoluble Aerosil 200 as a solid carrier. The solid SNEDDS Pellet consisted of well-sperical shape with smooth surface and preserved the self-emulsification performance of the liquid SNEDDS. Solid SNEDDS Of DSC measurements and SEM analysis suggested that Allopurinol in the solid SNEDDS may be in the molecular dispersion state. In vitro dissolution test showed that the solid SNEDDS had a faster in vitro release rate than the marketed formulation. Thus, this solid self-nanoemulsifying system may provide a useful oral solid dosage form for poorly water-soluble drug, Allopurinol.

 

6.    CONFLICT OF INTEREST:

There is no conflict of interest generated out of this research work.

 

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Received on 13.12.2019            Modified on 23.03.2020

Accepted on 18.06.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(4):2108-2114.

DOI: 10.52711/0974-360X.2021.00373