FORMULATION AND EVALUATION OF NANOPARTICULATE DRUG DELIVERY
SYSTEM OF LACIDIPINE
M.Pharm Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore– 560 041
By
Mr. HEMEN BORO B.Pharm
Under the Guidance of
Mr. SHANTHA KUMAR G.S M.Pharm, Ph.D
Assistant Professor
Department of Pharmaceutics,
Acharya & B.M. Reddy College of Pharmacy,
Acharya Dr. Sarvepalli Radhakrishanan Road,
Soldevanahalli, Chikkabanavara (Post)
Hesaraghatta Main Road, Bangalore – 560 090.
2012-2014
1
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE.
ANNEXURE - II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1.
Name of the Candidate
and Address
MR. HEMEN BORO
C/O THUNU BORO
NEAR ST.CLARET SCHOOL
VILL-MILANNAGAR(VIP)
P.O:GUWAHATI AIRPORT
GUWAHATI-781015, ASSAM.
2.
Name of the Institution
ACHARYA & B.M. REDDY COLLEGE OF
PHARMACY,
ACHARYA Dr. SARVEPALLI RADHAKRISHANAN
ROAD, SOLDEVANAHALLI, HESARAGHATTA MAIN
ROAD, CHIKKABANAVARA POST.
BANGALORE-560090
3.
Course of Study and Subject
M. Pharmacy
(Pharmaceutics)
4.
Date of Admission
16 -07-2012
5. TITLE OF THE PROJECT:-
FORMULATION AND EVALUATION OF NANOPARTICULATE DRUG
DELIVERY SYSTEM OF LACIDIPINE
2
6.0
BRIEF RESUME OF THE INTENDED WORK:
6.1 NEED FOR THE STUDY:
Hypertension is estimated to cause 4.5% of current global disease burden & is as prevalent
in many developing countries.1 Hypertension is defined as a sustained diastolic blood pressure
greater than 90 mm Hg accompanied by an elevated systolic blood pressure(>140 mm Hg).
Hypertension results from increased peripheral vascular smooth muscle tone, which leads to
increased arteriolar resistance & reduced capacitance of the venous system. Elevated blood
pressure is an extremely common disorder 2 in more than 40% (and up to 50%) of adults in many
countries are estimated to have high blood pressure.3
The word ‘nano’ is derived from Latin word, which means dwarf. Nano size refers to one
thousand millionth of a particular unit thus nanometer is one thousand millionth of a meter (i.e.
-9
1nm = 10 m).
Nanotechnology can be termed as the synthesis, characterization, exploration and
application of nanosized (1-100nm) materials for the development of science. It deals with the
materials whose structures exhibit significantly novel and improved physical, chemical, and
biological properties ,phenomena, and functionality due to their nano scaled size.4 As 40% or more
of the new chemical entities are coming are having the problem of physical/chemical
/pharmaceutical/pharmacology. Nanoparticles can solve this problem as it.5
(i)
Increased surface area
(ii)
Enhanced solubility
(iii)
Increased rate of dissolution
(iv)
Increased oral bioavailability
(v)
More rapid onset of therapeutic action,
(vi)
Less amount of dose required
Nanosuspensions are colloidal dispersions of nanosized drug particles stabilized by
surfactants. They can also be defined as a biphasic system consisting of pure drug particles
dispersed in an aqueous vehicle in which the diameter of the suspended particle is less than 1 μm
in size. Problems associated with delivery of poorly water-soluble drugs and lipid-soluble drugs
can be solved by formulating nanosuspension.6
Advantages :
(1) Physical Long-term Stability
(2) Increase in Saturation Solubility and Dissolution Velocity of drug
3
(3) Targeted drug delivery
(4) Bioavailability enhancement
DRUG PROFILE :
LACIDIPINE 7
H3C
H3C
H
N
CH3
O
O
O
O
CH3
CH3
H3C
O
O
CH3
MOLECULAR FORMULA: C26H33NO6
MOLECULAR WEIGHT: 455.6 g/mol
CHARACTERISTICS: A white to pale yellow crystalline powder. It melts at about 178°c.
Practically insoluble in water; freely soluble in acetone; sparingly soluble in absolute ethanol.
DESCRIPTION 8:
Pharmacotherapeutic group: Dihydropyridine derivatives
Lacidipine is a specific and potent calcium channel antagonist with a predominant selectivity for
calcium channels in the vascular smooth muscle. Its main action is to dilate peripheral arterioles,
reducing peripheral vascular resistance and lowering blood pressure.It undergoes extensive firstpass metabolism in the liver. Absolute bioavailability averages about 10 %. Elimination half-life
of lacidipine after single oral doses of 4, 6 and 8mg was approximately 7.5 h.
Due to low bioavailability of lacidipine in the body, water insolubility & low half life, the present
titled has been selected. The present purpose of my research work is to enhance water solubility,
bioavailability and to formulate and evaluate nanosuspension which can overcome earlier
problems of lacidipine.
4
6.2 REVIEW OF LITERATURE:
Literature survey was carried out on the proposed topic with the facility of internet and
helinet and referring scientific journal. The survey reveals that, no work has been reported on the
proposed topic and some related research work are coated below :

Ramesh G et al.,have developed and optimized the microemulsion based transdermal
therapeutic system for lacidipine (LCDP). The bioavailability studies in rabbits
showed
significant (p < 0.05) improvement in bioavailability, after transdermal administration of
microemulsion gel compared to oral suspension.9

Hecq J et al., had developed nanocrystals of nifedipine using methocel E15 as polymer by
using an
high pressure homogenizer. Since sample temperature increases in HPH all
operations were carried out using an heat exchanger, placed ahead of the homogenizing valve,
with sample temperature maintained. This study showed that formulation of nifedipine as
nanoparticles has met great success in regards to dissolution rate and saturation solubility
enhancement. 10

Jawahar N et al., have prepared and characterized PLGA nanoparticles of ramipril loaded
by nanoprecipitation method using tribloere (Pluronic RF-68). The particles were
characterized for drug content, particle size and particle morphology by TEM. In vitro studies
were determined by the bulk equilibrium reverse dialysis bag technique. This study suggest
that the feasibility of formulating ramipril loaded PLGA nanoparticles can be used to improve
the therapeutic efficacy of ramipril in the treatment of hypertensive disorder.11

Pandya MV et al.,investigated the increase in the solubility and dissolution rate of
simvastatin by the preparation of nanosuspensions with Pluronic F127 and ZrO2 beads using
a wet-milling technique . The results showed that nanosuspensions prepared with the higher
concentrations of PluronicF127 and the higher quantities of ZrO2 reduced the particle size and
enhanced the dissolution rate of the formulation. These results show that the prepared
nanosuspensions significantly improved the in vitro dissolution rate, thus possibly enhancing
the fast onset of therapeutic drug effect.12

Maincent P et al., reported isradipine was encapsulated by the nanoprecipitation method
using polymers including PECL, poly(d,l-lactide) and poly(d,l-lactide-co-glycolide). The
amorphous state of PLA and PLAGA non-loaded nanoparticles and the semi-crystalline state
of PCL were demonstrated with XRD and DSC. Results showed that the obtained
nanoparticles are good candidate’s delivery system for oral administration.13
5

Suganeswari M et al., had prepared and characterized nanoparticles containing atorvastatin
calcium:D1N , amlodipine besylate:D2N loaded by nanoprecipitation method using tribloere
(Pluronic F68).
The amlodipine has potency to promote the activity of atorvastatin.
Therefore, atorvastatin and amlodipine combination were used for this research. This
research showed a new way towards the formulation of nanoparticles of atrovastin &
amlodipine..14

Arunkumar N et al.,prepared & evaluated atrovastin nanosuspension using homogenisation
method. Through the various studies it was found that crystalline atorvastatin was converted
to amorphous form and exhibit improved dissolution and higher solubility. The increase in
drug dissolution rate and solubility can be expected to have significant impact in the oral
bioavailability of the drug.15

Singh A et al., have developed losartan potassium loaded chitosan nanoparticles by ionic
gelation of chitosan with tripolyphosphate anions with different core: coat ratio and
evaluated for drug content, loading efficiency, particles size, zeta potential, in vitro drug
release and stability studies. The developed formulation overcomes and could possibility be
advantageous in terms of sustained release dosage forms of losartan potassium.16

Gaikwad A et al.,had prepared frusemide nanoparticles using ten different drug to carrier
ratio, and characterized for particle size, shape, percentage yield, drug entrapment, stability
studies, zeta potential, FT-IR study, in-vitro drug release and release kinetics. The FTIR
study confirmed that there was no interaction between drug and polymer. No appreciable
difference was observed in the extent of degradation of product during 60 days in the
nanoparticles. Zeta potential of formulation supports the minimum interaction between the
particles. The in-vitro drug release study revealed that sustained release of some
formulation last up to 24 h. This has showed promising advantages of Frusemide
nanoparticles over conventional dosage forms.17
6
6.3 - Objective of the Study
Following are the objectives of the present study
1. To carry out identification and preformulation study of drug and selected polymers.
2. To
formulate
nanosuspension
by
high
pressure
homogenization/ultrasonication/
precipitation/media milling or any suitable / developed method.
3. Evaluation of formulated nanosuspension for various parameters like:
 Particle size analysis and shape morphology.
 Entrapment efficiency.
 Drug content estimation.
 Zeta potential.
4. To carry out in vitro dissolution studies of lacidipine nanosuspension.
5. To carry out stability studies on the most satisfactory formulation.
7.0
MATERIALS AND METHODS:
7.1 - Source of Data
6. Journals such as,
a. Indian Drug.
b. Indian Journal of Pharmaceutical Sciences.
c. Indian Journal of Pharmaceutical Education and research.
d. European Journal of Pharmaceutical Sciences.
e. International Journal of Pharmaceuticals.
f. Drug Development & Industrial Pharmacy.
g. Journal of Controlled Release.
h. African journal of pharmaceutical sciences
i. Journal of Nanomedicine.
j. American association of pharmaceutical scientists.
7. Review articles
8. World Wide Web.
9. J-gate@Helinet.
10. Science Direct, Pub medand biomed central.
11. Library: Acharya and B M Reddy College of Pharmacy.
12. E-library: Acharya and B M Reddy College of Pharmacy.
7
Materials
Drug
: Lacidipine
Polymer
: PVP, Eudragit RS100, Eudragit RL100, Ethyl Cellulose, PEG etc.
Stabiliser
: Methyl cellulose, Lecithins,Poloxamer etc.
Surfactant
: Polysorbates, Oleic acid Etc.
Solvent
: Ethanol, Chloroform, Acetone, Ether, Water Etc.
7.2 Method of collection of data:
1. Preformulation studies of drug & selected polymer
a. Solubility studies.
b. Melting point determination.
c. Purity of the drug
d. Compatibility studies by FTIR/DSC.
2.
Preparations
of
nanosuspension by high shear homogenization/ultrasonication/
precipitation/media milling or any suitable / developed method.18
3. The resultant product is freeze dried using lyophilizer and final product thus obtained will
be subjected to evaluation parameters.
4. Evaluation of the various properties of lacidipine nanosuspension.
 Entrapment efficiency.
 Drug content estimation.
 Particle size and shape morphology by SEM.
 Zeta potential by using zeta sizer.
5. To carry out in vitro dissolution study of formulated nanosuspension.
6. To carry out stability studies on the most satisfactory formulation.
7.3 Does the study require any investigation or interventions to be
Conducted on patients or other humans or animals?
“NO”
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
“NA”.
8
8.0
REFERENCES:
1.
Judith A. World health organisation/international society of hypertension on management
of hypertension. Lippincott Williams & Wilkins. 2003; 21:1-10.
2. Harvey AR, Champe PC . Lippincott’s illustrated reviews: Pharmacology.2nd edition .
Lippincott Williams & Wilkins. London. 2002: 179.
3. New data highlights in hypertension, diabetis incidence, [online][cited 08-12-12];available
from http://www.who.int/mediacentre/news/releases/2012/world-health-stastics.html.
4. Jain NK. Pharmaceutical Nanotechnology. National. Sci. Dig. Lib. 2008: 02-19.
5. Vishvajit K, Jagdale A, Deepali M, Vilasrao kJ. Nanosuspension: A novel drug delivery
system. Int. J. Pharm. Biosci. 2010; 1(4) : 352-60.
6. Patravale VB, Abhijit AD, Kulkarni RM . Nanosuspensions: A promising drug delivery
strategy. J. Pharm. Pharmacol. 2004; 56 : 827-40.
7
British
Pharmacopoeia. Monograph: Medicinal and Pharmaceutical Substances:
Lacidipine. British Pharmacopoeia Commission . London. 2009: Vol-I & II: 1-5.
8.
Lee, Rhoda C, Bryson, Harriet M. Lacidipine; A review of its pharmacodynamic &
pharmacokinetic properties & theraputic potential in the treatment of hypertension [cited
28-11-12]Available
From
:http://www.Adisonline.com/Lacidipine
Pharmacokinetics.
Html.
9. Gannu R, Reddy PC, Vamshi VY, Kumar YS, Rao YM. Enhanced bioavailability of
lacidipine via microemulsion based transdermal gels: Formulation optimization, ex vivo
and in vivo characterization. Int. J. Pharm. 2010; 388: 231–41.
10. Hecq J, Deleers M, Fanara D, Vranckx H, Amighi K. Preparation and characterization of
nanocrystals for solubility and dissolution rate enhancement of nifedipine. Int. J. Pharm.
2005; 299: 167–77.
11. Jawahar N, Eagappanath T, Nagasamy V, Jubie S, Samanta MK. Preparation and
characterisation of PLGA-nanoparticles containing an anti-hypertensive agent. Int. J.
Pharmtech. Res. 2009; 1(2): 390-3.
12. Pandya1 MV, Patel JK, Patel JD. Formulation and optimization of nanosuspensions for
enhancing simvastatin dissolution using central composite: design. Dissolution. Tech.
2011; 3(2): 40-6.
13.Philippe M, Martine LV, Laurence F, Young K, Maurice H. Preparation and
characterization of nanoparticles containing an antihypertensive agent. Eur. J. Pharm.
Biopharm. 1998; 46(2): 137-43.
9
14.Suganeswari M, Shering A, Azhagesh RK, Bharathi P, Sathish B. Preparation,
characterization and evaluation of nanoparticles containing hypolipidemic drug and
antihypertensive drug. Int. J. Pharm. Biological. Archives. 2011; 2(3): 949-53.
15.Arunkumar N, Deecaraman M , Rani C , Mohanraj KP, Venkates KK. Preparation and
solid state characterization of atorvastatin nanosuspensions for enhanced solubility and
dissolution . Int. J. Pharm. Tech. Res; 2009; 1(4): 1725-30.
16. Singh A, Deep A. Formulation and evaluation of nanoparticles containing losartan
potassium. Int. J. Pharm. Res. Tech. 2011; 1(1): 17-20.
17. Gaikwad A, Tamizhrasi S, Sorti A , Gavali P , Mehare G. Formulation and in vitro
characterization of polymethacrylic acid nanoparticle containing frusemide. Int. J. Pharm.
Tech. Res; 2010; 2(1): 300-4.
18. Ravichandran R. Nanotechnology-based drug delivery systems. Nanobiotech. 2009; 5:
17–33.
10
Signature of the candidate
9.
HEMEN BORO B.PHARM
10.
Remarks of the guide
The topic selected for dissertation is satisfactory. Adequate
equipments and chemicals are available to carry out project
work.
11.
Name and designation of
11.1 Guide
Mr. SHANTHA KUMAR G.S M.Pharm, Ph.D
Assistant Professor
11.2 Signature
11.3 Co-Guide ( If any)
11.4 Signature
11.5 Head of the Department
-NA-
----
Dr. SHIVANAND KALYANAPPA M.Pharm, Ph.D
Professor & HOD
Department of Pharmaceutics
11.6 Signature
12.
12.1 Remarks of
the Principal
12.2 Signature
Dr. DIVAKAR GOLI M.Pharm, Ph.D
Professor and Principal
11