Formulation and evaluation of sustained release microspheres of

FORMULATION AND EVALUATION OF
SUSTAINED RELEASE MICROSPHERES
OF FENOFIBRATE
Done by
Mini Mol.P.V
Reshma Fathima.K
Under the Guidance of
Ms.Sreethu K Sreedharan

CONTENTS
 Introduction
 Literature Review
 Objective And Plan of Study
 Materials And Equipments
 Methodology
 Results And Discussion
 Summary And Conclusion
 References
2

INTRODUCTION
 A well designed controlled drug delivery system can
overcome some of the problems of conventional
therapy and enhance the therapeutic efficacy of a
given drug. To obtain maximum therapeutic efficacy,
it becomes necessary to deliver the agent to the
target tissue in the optimal amount in the right
period of time there by causing little toxicity and
minimal side effects.
3

 There are various approaches in delivering a therapeutic
substance to the target site in a sustained controlled
release fashion.
 One such approach is using microspheres as carriers for
drugs.
 Microspheres are characteristically free flowing powders
consisting of proteins or synthetic polymers which are
biodegradable in nature and ideally having a particle size
less than 200 μm.
 This is the important approach in delivering therapeutic
substance to the target site in sustained and controlled
release fashion.
4

 Microspheres are sometimes referred to as
microparticles. Microspheres can be manufactured
from various natural and synthetic materials.
 Polyethylene, polystyrene and expandable
microspheres are the most common types of
polymer microspheres.
 Polystyrene microspheres are typically used in
biomedical applications due to their ability to
facilitate procedures such as cell soeting and
immunio precipitation
5

Mechanism of Drug Release
 Most of the drug delivery through micro particles
inhibits a matrix type internal solid dispersion
morphology structure.
 The drug may be insoluble in the polymeric matrix
and the drugs are released by erosion. Initially water
diffuses into the matrix dissolving the resulting
adjacent to the surface of the device.
 The resulting osmotic pressure is relieved by forming
a channel to the surface releasing a defined amount
of drug in the initial drug burst.
6

Materials Used
 Microspheres used usually are polymers. They are
classified into two types
1. Synthetic polymers
2. Natural polymers
Synthetic Polymers:
a)Non biodegradable polymers:
Polymethyl methacrylate (PMMA), Acrolein, Glycidyl
methacrylate, Epoxypolymers
7

b) Biodegradable polymers:
 Lactides, their glycolides and their copolymers,
PolyalkylCyano Acrylate.
Natural polymers
 These are obtained from different sources like
proteins, carbohydrates and chemically modified
carbohydrates.
 Proteins: Albumin, Gelatin, And Collagen,
Carbohydrates: Agarose, Carrageenan, Chitosan, Starch.
8

Methods
 Single emulsion technique
 Double emulsion technique
 Polymerization
 Phase separation/ Coacervation
 Spray drying
 Solvent extraction
 Emulsion Solvent Evaporation
 Wet emulsion technique
 Hot Melt Microencapsulation
9

Pharmaceutical Applications
 Ophthalmic Drug Delivery Polymer
 Gene delivery Gene delivery systems
 Intratumoral and local drug delivery
 Oral drug delivery
 Nasal drug delivery
 Buccal drug delivery
 Gastrointestinal drug delivery:
 Peroral drug delivery
 Vaginal drug delivery
 Transdermal drug delivery
 Colonic drug delivery
 Multiparticulate delivery system
10

LITERATURE REVIEW
 Naeem. M, Kiran. B et al., 2013 developed the
fenofibrate loaded liposphere system. An attempt
was made to improve aqueous solubility of FNO by
aid of stearic acid and Paraffin oil. Significant
improvement in the aqueous solubility of the drug in
the FNO lipospheres supports the applicability of
lipospheres as a tool for improving aqueous
solubility of the BCS class-II drugs10.
11

 Modi, Tayade et al 2006., developed the Solid
dispersion (kneading) technique for the
enhancement of the dissolution profile of valdecoxib
using solid dispersion with PVP and the preparation
of fast-dissolving tablets of valdecoxib by using a
high amount of superdisin- tegrants. A phase
solubility method was used to evaluate the effect of
various water-soluble polymers on aqueous solu-
bility of valdecoxib. Polyvinyl pyrrolidone (PVP K-
30) was selected and solid dispersions were prepared
by the method of kneading14.
12

Drug Profile
 DRUG : Fenofibrate
 CATEGORY : Hypolipidaemic drug
 MOLECULAR STRUCTURE :
 MOLECULAR FORMULA : C20 H21ClO4
 DESCRIPTION: white crystalline solid, odourless.
 MELTING POINT: 79-82°C
13

 SOLUBILITY: Soluble in organic solvents such as ethanol,
methanol, DMSO, and DMF. Sparingly soluble in aqueous
buffers.
 MECHANISM OF ACTION: it is a fibrate class
hypolipidaemic drug. It enhances activity of the enzyme
lipoprotein lipase, which degrades VLDL level resulting in
lowering of triglycerides. They also increase HDL levels.
Fibrates also inhibits coagulation and promote
thrombolysis, which also accounts for their beneficial
effects.
 ADVERSE EFFECTS: GI upsets, skin rashes, headache,
muscle cramps blurred vision.Adverse events occurs in
about 1% of the patients treated with fenofibrate. Skin
rashes were the most frequent event causing
discontinuation of therapy.
14

 PHARMACOKINETICS: pharmacokinetics
significantly affected by food intake. The high fat
breakfast will significantly affecting the rate of
absorption of fenofibrate more than the standard
breakfast and fasted conditions specifically AUC
from zero to infinity and peak plasma
concentration (Cmax) is increased.
 DOSE: Orally available as 140mg, 160 mg and
200mg tablets and capsules.
 STORAGE: Store below 30ºC.
15

OBJECTIVE AND PLAN OF STUDY
 The sustained release dosage forms are designed
to achieve a prolonged therapeutic effect by
continuously releasing medication over extended
periods of time after administration of a single
dose.
 The ideal drug delivery system will possess two
main properties
»It will be a single dose for the whole duration of treatment.
»It will deliver the active drug delivery at the site of action.
16

MATERIALS AND EQUIPMENTS USED
SL.N
O
MATERIALS SUPPLIED BY
1 Fenofibrate
Alkem pharmaceuticals Pvt
Ltd,mumbai
2 Gelatin Nice chemicals,Banglore
3 Methanol Nice chemicals,Banglore
4 Tween 20 Prowess lab chemicals
5 Liquid paraffin Prowess lab chemicals
6 Formaldehyde Nice chemicals,Banglore
7 Hydrochloric acid Nice chemicals,Banglore
8 Monosodium phosphate Nice chemicals,Banglore
9 Disodium phosphate Nice chemicals,Banglore
SL.N
O
INSTRUMENTS MANUFACTURER
1 Electronic weighing balance Shimadzu BL220H,Japan
2 Magnetic stirrer Remiequipments Pvt Ltd
3 Optical microscope Dolar US 4
4 UV-Spectroscopy Shimadzu 1600,Japan
5 FTIR Shimadzu 8400,Japan
6 Dissolution test apparatus Electro Lab,TDT 08L (USP)
7
Differential Scanning
Calorimetry
Shimadzu D.S.C TA60 WS
Thermal Analyzer
8 Scanning Electron Microscopy DSC-823e, Mettler Toledo
17

 Preformulation Studies
 Identification of drug
FTIR (fourier transforms infrared spectra)
DSC Analysis
Physical Appearance
Melting point
 Drug excepient compatability studies
 Spectrophotometric Scanning of fenofibrate and polymer
Preparation of standard stock solution
Construction of calibration curve
METHODOLOGY
18

• Formulation
 Preparation of Drug Polymer phase
 Preparation of Oily Phase
 Preparation of Gelatin microspheres of fenofibrate
Formulation Drug(mg) Polymer(mg)
Tween20(
ml)
F1 200 1000 1
F2 200 1500 1
19

• Evaluation Studies
 Bulk characterization
 angle of repose
θ = tan−1 h r
 bulk density
Bulk Density =
weight of sample in gm
volume occupied by the sample
 tapped density
Tapped Density =
weight of sample in gm
volume occupied by the sample after tapping
20

 Carr´s Index (CI)
Carr’s Index =
tapped density−bulk density
tapped density
 Percentage yield (%Y)
% Yield =
practical yield
theoretical yield
×100
 Percentage Drug Entrapment(%DE)
% Drug Entrapment =
practical drug content
theoretical drug content
× 100
21

 Morphology
By using SEM analysis
 Invitro Cumulative Percentage Drug Release Study
The FNO release from the microspheres was evaluated by using the US
Pharmacopoeia Dissolution Apparatus-II Paddle (XVIII) in 900ml mixture of
PBS pH 6.8 with 1% SLS in 9:1 at 37°C ± 0.5 temperature. The rotational
speed of dissolution apparatus was maintained at 100rpm. Each run was
carried out in triplicates.
Accurately weighed 243mg of microspheres were filled in a “0” size
capsule to get the final weight of 475mg each of the capsules was transformed
into dissolution media. The 5ml samples were withdrawn at predetermined
time intervals with dissolution media replacement and were filtered through
0.45µm whatman filter paper. The drug content was determined
spectrophotometrically at 290nm on shimadzu UV/ Vis- spectrophotometer.
22

RESULTS AND DISCUSSION
IR spectrum of Fenofibrate
IR spectrum of
Gelatin
23

IR spectrum of
Fenofibrate +
Gelatin
Frequency (cm-1)
FNO
Frequency (cm-1)
Physical mixture
Interpretation
3036 3039 Alkanes
3220 3211
Monosubsituted benzene
ring
3437 3439 Phenols
3526 3514 1,4-Disustituted phenol
1416 1417 -CH3 group
1622 1625 Carboxylic group
1796,1224 1796,1225 Aromatic ester
1220 1225 -CH2Cl
IR Spectral peaks of
Fenofibrate and
physical mixture
24

SEM Analysis of fenofibrate and
microspheres
25

DSC analysis of prepared
microspheres
DSC Curve of
Fenofibrate
26

Standard curve
CONCENTRATION ABSORBANCE
0 0.00
10 0.553
20 0.996
30 1.545
40 2.015
50 2.497
27

Bulk characterization
Sl.no Parameter
Fenofibrate microspheres
F1 F2
1 Angle of repose 24.11 25.22
2 Bulk density 0.26 0.31
3 Tapped density 0.33 0.39
4 Carr’s index 20 22
5 Hausner’s ratio 1.25 1.30
28

 Percentage yield
The percentage yield was calculated as per the equation and it was found to be
74 % and 76% in formulation F1 and F2 respectively.
 Percentage Drug Entrapment
% Drug entrapment of drug entrapped within the polymer matrices were in the range
of 70-97 %. An entrapment efficiency depends on the drug solubility in the solvent
system used for processing.
 In-vitro drug release study:
The drug release from microspheres in phosphate buffer pH 6.8 has been shown in
Figure . Cumulative % drug release from F1and F2, were in the range of 60 and 68%
within 12hours respectively. No formulation is showing burst release which indicates
the absence of free particles on the surface of microspheres which further confirmed by
SEM study. The trail revealed that low level of gelatin (25%) failed to produce
microsphere with acceptable physical characteristic where as high level of stearic acid
(100%) resulted in liposphere that exhibited high percentage of drug release. As the
level of paraffin oil increases the particle size of liposphere increases due to tackiness
which in turn decrease the % drug release from the liposphere
29

Dissolution values of F1 Dissolution Values of F2
Sl.n
o
Time
(hr)
Absorbanc
e
Concentrati
on (µg/ml)
Amount of
drug
released
% drug
release
Cumulativ
e % drug
release
1 0 0 0 0 0 0
2 0.5 0.009 0.0611 0.0611 4.07 4.07
3 1 0.020 0.1919 0.1919 12.79 12.87
4 2 0.038 0.4058 0.4058 27.05 27.31
5 3 0.045 0.4890 0.4890 32.60 33.14
6 4 0.052 0.5722 0.5722 38.15 38.79
7 5 0.060 0.6673 0.6673 44.49 45.25
8 6 0.067 0.7506 0.7506 50.04 50.93
9 7 0.072 0.8099 0.8099 53.99 54.99
10 8 0.073 0.8219 0.8219 54.79 55.87
11 10 0.075 0.8456 0.8456 56.37 57.47
12 12 0.079 0.8932 0.8932 59.15 60.17
Sl.n
o
Time
(hr)
Absorban
ce
Concentrati
on (µg/ml)
Amount of
drug
released
%
drug
releas
e
Cumulati
ve % drug
release
1 0 0 0 0 0 0
2 0.5 0.009 0.0574 0.0574 5.45 5.45
3 1 0.013 0.1068 0.1068 7.25 7.29
4 2 0.019 0.1962 0.1962 14.41 14.49
5 3 0.028 0.2869 0.2869 19.13 19.34
6 4 0.035 0.3702 0.3702 24.68 25.06
7 5 0.050 0.5485 0.5485 36.57 37.06
8 6 0.062 0.6911 0.6911 46.07 46.80
9 7 0.074 0.8338 0.8338 55.59 56.51
10 8 0.081 0.9169 0.9169 61.13 62.24
11 10 0.086 0.9764 0.9764 64.09 65.26
12 12 0.090 1.0239 1.0239 66.26 67.39
30

SUMMARY AND CONCLUSION
Following concclusions have been drawn from the present study:
 In the preformulation studies, it was found that Fenofibrate is having poor flow
property. Hence in the present study, the resulting microsphere considerably improved
flow properties.
 The analytical mehod used in the present study was found to be suitable for the
estimation of Fenofirate, which was indicated by the high regression values obtained
in the standard plot.
 The yellowish white microspheres were obtained by using emulsion – coacervation
method and the percentage yield was found to be 74% for F1 and 76 % for F2.
 Scanning electron microscopy of Fenofibrate microsphere was also performed and
the surface morphology were studied.
32

 Sustained release property of microsphere were also
enhanced by incorporating the microsphere in enteric
coated capsules.
 The percentage drug entrapment were in the range of 70-
97%.
 The invitro drug release study showed that the
microspheres were released 60 and 67% of drug at 12 hrs
in formulation F1 and F2 respectively.
 Gelatin can be effectively used for the preparation of
sustained release Fenofibrate microsphere. In
conclusion, the present study demonstrated the
successful preparation of once daily sustained release
microsphere of Fenofibrate.
33

REFERENCES
 Ramteke. K. H, Jadhav.V. B, Dhole. S. N, [2012], Microspheres as
carriers used for novel drug delivery system, IOSRPHR, 2(4),
44-48.
 Sahil, Akanksha, Premjeet, Bilandi, Kapoor, [2011], Microsphere a
review, IJRPC, 1(4).
 Prabus. L, Shirwaikar A, Kumar, [2009], Formulation and
evaluation of sustained release microspheres of rosin containing
aceclofenac, ARS Pharm, vol 50, 51-62.
 Gangadhar.C. B, Sunder. R, Varma. M, Raju. M, Saikiran. M,
[2010], Formulation and evaluation of indomethacin microspheres
using natural and synthetic polymers as controlled release dosage
forms, International journal of drug discovery, 2(1), 8-16.
 Barhate. D, Rupnar. S, Sonvane. M, Pawar. R, Rahane. D, [2009],
Formulation and evaluation of floating microspheres of ketorolac
trometSSSamol, International journal of pharmaceutical research
and development online,1 (9), ISSN: 0974-9446.
34

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