FORMULATION DEVELOPMENT AND EVALUATION OF SOLID LIPID NANOPARTICLES OF BUPRENORPHINE

FORMULATION DEVELOPMENT AND EVALUATION OF SOLID

LIPID NANOPARTICLES OF BUPRENORPHINE

Suryakalyanam Vikas*, S. Poonguzhali, Manohar Babu S.

Department of Industrial Pharmacy, SIMS College of Pharmacy, SIMS Group of Institutions,

Mangaldas Nagar, Guntur,-522001, Andhra Pradesh, India.

ABSTRACT

Buprenorphine is a poorly water soluble drug as it is a BCS Class II

drug and the oral bioavailability is very less due to the extensive first

pass effect. So there is a need to develop a formulation that can

improve the oral bioavailability. In this work, efforts were made to

prepare stable solid lipid nanoparticles for enhancement of oral

bioavailability of Buprenorphine. Drug solubility studies were

performed with various lipids to test the solubility and the glyceryl

monostearate was the lipid in which the drug is more soluble. SLNs

were prepared by the hot homogenization method. For the optimization

of the surfactant the three more formulations were prepared.

Characterization of SLNs was done by measuring particle size, Poly

dispersity index and zeta potential by zeta sizer. The Entrapment

efficiency of the SLNs was found to be in the range of 80 to 95% In- vitro drug release

studies were performed for all these SLNs for 24 hrs in pH 6.8 phosphate buffer. In these

studies the cumulative percentage drug release from all these formulations showed prolonged

release. The formulation (F2) was found to be promising prolonged release. This formulation

(F2) released 77.3 % of drug in 24 hours. The release kinetics of the optimized formulation is

first order and from the higuchi plot the release is by diffusion process and from the

korsemeyers plot the diffusion process is non-fickian diffusion.

KEYWORDS: Buprenorphine, Solid Lipid Nanoparticles, Bioavailability, Glyceryl

monostearate, Solubility studies.

Volume 5, Issue 9, 1387-1397. Research Article ISSN 2277– 7105

*Corresponding Author

Suryakalyanam Vikas

Department of Industrial

Pharmacy, SIMS College of

Pharmacy, SIMS Group of

Institutions, Mangaldas

Nagar, Guntur,-522001,

Andhra Pradesh, India. Article Received on 10 July 2016,

Revised on 01 Aug. 2016, Accepted on 22 Aug. 2016

1. INTRODUCTION

Novel Drug Delivery Systems: Novel Drug Delivery Systems (NDDS) has captured the

interest of both national and international pharmaceutical research organizations. Pioneering

research to devise newer strategies for effectively delivering the drugs in the body or

improvise the existing technologies to enhance their efficiency is the need of the hour. Since

inception, NDDS has seen a foray of transformations right from microencapsulation,

epithelial and transdermal delivery, liposomal vesicles and nanoparticles. The ever improving

delivery systems are not only beneficial to the patients as they are less cumbersome and easy

to abide by but also reduce the complications associated with the induction of the drug in the

body. These novel strategies will effectively potentiate drug administration ensuring safe and

effective therapeutic regimen.[1-4]

The NDDS essentially consists of the drug against the causative agent of the disease being

treated and a carrier system into which the drug is loaded and transported to site of action.

Efforts are now being made to devise carriers that can transport multiple drugs and release

them on command.[5]

Nanoparticulate system

Colloidal particles ranging in size between 10 and 1000 nm are known as nanoparticles. They

are manufactured from synthetic/natural polymers and ideally suited to optimize drug

delivery and reduce toxicity. Over the years, they have emerged as a variable substitute to

liposomes as drug carriers. The successful implementation of nanoparticles for drug delivery

depends on their ability to penetrate through several anatomical barriers, sustained release of

their contents and their stability in the nanometer size. However, the scarcity of safe polymers

with regulatory approval and their high cost have limited the wide spread application of

nanoparticles to clinical medicine.[6, 7]

To overcome these limitations of polymeric nanoparticles, lipids have been put forward as an

alternative carrier, particularly for lipophilic pharmaceuticals. These lipid nanoparticles are

known as solid lipid nanoparticles (SLNs), which are attracting wide attention of formulators

world-wide.[8]

SLNs are colloidal carriers developed in the last decade as an alternative system to the

existing traditional carriers (emulsions, liposomes and polymeric nanoparticles). They are a

substituted by a solid lipid. SLN offer unique properties such as small size, large surface area,

high drug loading and the interaction of phases at the interfaces, and are attractive for their

potential to improve performance of pharmaceuticals, neutraceuticals and other materials.[6-8]

Solid lipid nanoparticles (SLN) are a class of particulate drug carriers made from lipids that

remain in the solid state at room and body temperatures. Lipids utilized for SLN are typically

physiological lipids, including: fatty acids, steroids, waxes, mono-, di-, or triglyceride

mixtures. A wide variety of biocompatible surfactants are used to stabilize SLN; therefore,

SLN have the advantage of physical stability with low toxicity. SLN are becoming

increasingly used for the protection of labile drugs from degradation in the body and for

sustained release.[8]

2. MATERIALS AND METHODS

2.1. Materials used

S. No MATERIAL

1 Buprenorphine

2 Glycerol Monostearate 3 Precirol

4 Stearic Acid 5 Oleic Acid 6 Dyanasan 114 7 Dyanasan 118 8 Compritol ATO 888 9 Tween 80

10 Di-sodium hydrogen phosphate 11 Potassium di-hydrogen phosphate

12 Acetone

13 Iso Propyl Alcohol

2.2. Methods Used

Schematic representation of optimizad formulation of solid lipid nanoparticles.

3. RESULTS AND DISCUSSION

Table No-1: Composition of the formulation

Formulation code

Lipids (%)

Drug (mg) Tween 80 (%)

GMS Precirol Dyanasan

F1 2.5 - - 10 1.5

F2 5 - - 10 1.5

F3 7.5 - - 10 1.5

F4 - 2.5 - 10 1.5

F5 - 5 - 10 1.5

F6 - - 2.5 10 1.5

F7 - - 5 10 1.5

F8 5 - - 10 0.5

F9 5 - - 10 1

F10 5 - - 10 2

Table No-2: Optimized Formulation

Buprenorphine 10 mg

Glyceryl monostearate 2.5% w/v

Tween 80 1.5% w/v

Water 100 ml

Table No-3: Calibration curve of Buprenorphine

CONCENTRATION (µg/ml) ABSORBANCE (nm)

0 0

1 0.1985

2 0.2158

3 0.3866

4 0.5022

5 0.4959

6 0.7288

7 0.7630

8 0.8861

9 0.9713

Table No-4: Solubility studies of the drug in various lipids

S No Lipid Qty Drug Qty Solubility

1 Compritol ATO 1 g

10 mg

Insoluble

2 Precirol 0.35 g Soluble

3 Glyceryl monostearate 0.3 g Soluble

4 Dyanasan 118 0.5 g Soluble

5 Dyanasan 114 0.4 g Soluble

Table No-5: Particle size distribution of Solvent Evaporation method

S. No Surfactant Concentration ( w/v) Size PdI

1 0.5% 1579 1.000

2 1% 993.9 0.309

3 2% 611.3 0.881

Table No-6: Optimization of the lipid concentration

S. No Lipid (%w/v) Size (nm) PDI

1 2.5 241.5 1

2 5 247.55 0.998

3 7.5 773.85 1

Table No-7: Optimization of the surfactant concentration

S. No Tween 80 concentration (% w/v) Size (nm) PDI

F8 0.5 520 0.999

F9 1 400 0.998

F2 1.5 280 0.772

F10 2 350 0.998

Table No-8: Zeta potential data after the Homogenization.

Formulation Zeta potential

F1 -23.9±1.87

F2 -22.7±1.78

F3 -28.1±2.16

F4 -26.3±2.06

F5 -19.9±1.56

F6 -18.5±1.45

F7 -18.1±1.35

Table No-9: Entrapment Efficiency data

Formulation Entrapment efficiency (%)

F1 91.2

F2 95.01

F3 85.68

F4 89.23

F5 90.08

Table No-10: Comparative dissolution data of SLNs of F1, F2 and F3

Table No-11: Comparative dissolution data of SLNs of F4, F5 and F6

Fig No-3: Comparative dissolution profiles of F1, F2 and F3

Time Cumulative % of drug released ± SD

F4 F5 F6

0 0 0 0

1 18.537±1.206 20.238±2.199 15.476±0.390

2 20.934±1.710 26.988±1.615 16.821±0.740

3 22.827±1.047 28.669±1.861 20.621±0.524

4 24.886±1.216 41.866±1.292 23.296±0.649

5 27.543±1.564 44.719±1.163 28.122±0.537

6 30.460±1.674 48.147±1.937 31.656±1.026

7 33.975±1.437 52.178±1.811 36.198±0.652

8 38.432±1.750 54.769±1.556 39.389±1.175

10 44.003±1.857 59.131±1.807 43.928±1.043

12 48.480±2.080 62.406±0.837 47.119±1.179

24 55.242±2.082 65.329±0.974 50.552±1.043

Time Cumulative percentage of drug released ± SD

F1 F2 F3

0 0 0 0

1 20.238±2.170 20.238±0.389 20.238±2.199

2 27.413±2.473 27.923±0.639 26.988±1.615

3 35.306±2.502 30.209±0.594 28.669±1.861

4 39.202±1.624 46.812±0.780 32.881±1.825

5 45.673±1.572 54.631±1.061 41.866±1.292

6 51.389±1.574 55.898±0.685 44.719±1.163

7 55.186±1.420 62.960±0.786 48.147±1.937

8 58.965±1.183 65.250±0.395 52.178±1.811

10 62.999±1.043 67.654±0.641 54.769±1.556

12 66.100±0.829 70.900±0.388 59.131±1.807

Fig No-4: Comparative dissolution profiles of F4, F5 and F6.

Table No-12: Comparative dissolution data of SLNs of F7, F8, F9 and F10.

Fig No-5: Comparative dissolution profiles of F7, F8, F9 and F10

Time Cumulative % of drug released ± SD

F7 F8 F9 F10

0 0 0 0 0

.

Fig No-6: Zero order plot of F2.

Fig No-7: First order plot of F2.

Fig No-9: Korsemeyer peppas plot of F2

Table No-13: Evaluation data of optimized formulation (F2)

Parameters Data observed

Particle size 56.94

Zeta potential -22.7±1.78

Entrapment efficiency 95.01

In vitro dissolution release 77.31

Zero order plot R2=0.646

First order plot R2=0.8332

Higuchi plot R2=0.9152

Korsemeyer peppas plot R2=0.905

Table No-14: Stability Studies at room temperature and refrigerated temperature

Day At room temperature At refrigerated temperature

Size(nm) PDI Zeta potential (mV) Size(nm) PDI Zeta potential (mV)

1 174.73±4.473 0.305±0.097 -28.1±2.16 194.73±4.473 0.405±0.097 -28.1±2.16

30 205.56±8.58 0.309±0.146 -26.3±2.06 294.23±2.898 0.410±0.012 -26.1±2.04

60 210.9±11.49 0.308±0.066 -26.4±2.08 300.0±8.54 0.411±0.031 -26.66±2.12

4. CONCLUSION

Buprenorphine is a poorly water soluble drug as it is a BCS Class II drug and the oral

bioavailability is very less due to the extensive first pass effect. so there is a need to develop a

formulation that can improve the oral bioavailability .In this work, efforts were made to

prepare stable solid lipid nanoparticles for enhancement of oral bioavailability of

Buprenorphine. Drug solubility studies were performed with various lipids to test the

solubility and the glyceryl monostearate was the lipid in which the drug is more soluble.

The preparation of the solid lipid nanoparticles was initially done by solvent evaporation

As the organic solvents are also used in the above process so the method is changed to the hot

homogenization process. Initially, all the process parameters were optimized for the

homogenization time and cycles.

SLNs were prepared by the hot homogenization method. All the seven SLNs were prepared

with the three lipids with each lipid at least two formulations and the formulations with the

optimized lipid is three. For the optimization of the surfactant the three more formulations

were prepared. Characterization of SLNs was done by measuring particle size, Poly dispersity

index and zeta potential by zeta sizer. The Entrapment efficiency of the SLNs was found to

be in the range of 80 to 95% In-vitro drug release studies were performed for all these SLNs

for 24 hrs in pH 6.8 phosphate buffer. In these studies the cumulative percentage drug release

from all these formulations showed prolonged release. The formulation (F2) was found to be

promising prolonged release. This formulation (F2) released 77.3 % of drug in 24 hours. The

release kinetics of the optimized formulation is first order and from the higuchi plot the

release is by diffusion process and from the korsemeyers plot the diffusion process is

non-fickian diffusion. Stability studies were conducted for finally optimized formulation (F2) at

room temperature and 4oC for 2 months; no appreciable changes were noticed in size and zeta

potential.

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