Formulation and Optimization of Polymeric Nano

Formulation and Optimization of Polymeric Nano

FORMULATION AND EVALUATION OF NANOPARTICULATE DRUGDELIVERY SYSTEM OF LACIDIPINE

M.Pharm Dissertation Protocol Submitted to

RajivGandhiUniversity of Health Sciences, Karnataka

Bangalore– 560 041

By

Mr. HEMEN BORO B.Pharm

Under the Guidance of

Mr. SHANTHAKUMAR G.SM.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

RAJIVGANDHIUNIVERSITY 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
6.0
7.0
8.0
/ 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. 1nm = 10-9 m).
Nanotechnology can be termed as the synthesis, characterization, exploration and application ofnanosized (1-100nm) materials for the development of science. It deals with the materials whosestructures 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 withdelivery 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) Targeted drug delivery
(4) Bioavailability enhancement
DRUG PROFILE :
LACIDIPINE7

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.
DESCRIPTION8:
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, reducingperipheral vascular resistance and lowering blood pressure.It undergoes extensive first-pass 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.

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 :
  • RameshGet al.,have developed and optimized the microemulsion based transdermaltherapeutic 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.,haddeveloped nanocrystals of nifedipine using methocelE15 as polymer by using an highpressure homogenizer. Since sampletemperature increases in HPH all operations were carried outusing 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
  • JawaharN 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. Invitro studies were determined by the bulk equilibrium reverse dialysis bag technique. This study suggest that the feasibility of formulating ramipril loaded PLGA nanoparticles canbe used to improve the therapeutic efficacy of ramipril in the treatment of hypertensive disorder.11
  • Pandya MVet al.,investigated the increase in the solubility and dissolution rate of simvastatin by the preparation of nanosuspensions withPluronic F127 and ZrO2 beads using a wet-milling technique . The results showed that nanosuspensions prepared with the higher concentrations of PluronicF127 and the higher quantitiesof 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 fastonset of therapeutic drug effect.12
  • Maincent Pet al.,reported isradipinewas 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
  • Suganeswari M et al., hadprepared 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 andhigher 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 thatsustained release of some formulation last up to 24 h. This has showed promising advantages of Frusemide nanoparticles over conventional dosage forms.17
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.
  1. To carryoutin vitro dissolution studies of lacidipine nanosuspension.
  2. To carry out stability studies on the most satisfactory formulation.
MATERIALS AND METHODS:
7.1 - Source of Data
  1. Journals such as,
  2. Indian Drug.
  3. Indian Journal of Pharmaceutical Sciences.
  4. Indian Journal of Pharmaceutical Education and research.
  5. European Journal of Pharmaceutical Sciences.
  6. International Journal of Pharmaceuticals.
  7. Drug Development & Industrial Pharmacy.
  8. Journal of Controlled Release.
  9. African journal of pharmaceutical sciences
  10. Journal of Nanomedicine.
  11. American association of pharmaceutical scientists.
  12. Review articles
  13. World Wide Web.
  14. J-gate@Helinet.
  15. Science Direct, Pub medand biomed central.
  16. Library: Acharya and B M Reddy College of Pharmacy.
  17. E-library: Acharya and B M Reddy College of Pharmacy.
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.
7.2Method of collection of data:
  1. Preformulation studies of drug & selected polymer
  2. Solubility studies.
  3. Melting point determination.
  4. Purity of the drug
  5. Compatibility studiesby FTIR/DSC.
  6. Preparations of nanosuspension by high shear homogenization/ultrasonication/ precipitation/media milling or any suitable / developed method.18
  7. The resultant product is freeze dried using lyophilizer and final product thus obtained will be subjected to evaluation parameters.
  8. 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.
  1. To carry out in vitro dissolution study of formulated nanosuspension.
  2. 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”.
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
  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.
7British Pharmacopoeia. Monograph: Medicinal and Pharmaceutical Substances: Lacidipine. British Pharmacopoeia Commission . London. 2009: Vol-I &II: 1-5.
  1. 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 : Pharmacokinetics.Html.
  2. 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.
  3. 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.
  4. Jawahar N, Eagappanath T, Nagasamy V,JubieS, Samanta MK. Preparation and characterisation of PLGA-nanoparticles containing an anti-hypertensive agent. Int. J. Pharmtech. Res. 2009;1(2):390-3.
  5. 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.
14.SuganeswariM, Shering A, Azhagesh RK, BharathiP,SathishB. 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.
9. / Signature of the candidate / HEMEN BOROB.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. SHANTHAKUMAR G.S M.Pharm, Ph.D
Assistant Professor
11.2 Signature
11.3 Co-Guide ( If any) / -NA-
11.4 Signature / ----
11.5 Head of the Department / Dr. SHIVANAND KALYANAPPAM.Pharm, Ph.D
Professor & HOD
Department of Pharmaceutics
11.6 Signature
12. / 12.1 Remarks of
thePrincipal
12.2 Signature / Dr. DIVAKAR GOLI M.Pharm, Ph.D
Professor and Principal

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