Formulation and Evaluation of Solid Lipid Nanoparticles of Atenolol

Formulation and Evaluation of Solid Lipid Nanoparticles of Atenolol

FORMULATION AND EVALUATION OF SOLID LIPID NANOPARTICLES OF ATENOLOL

M.Pharmdissertation protocol submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore-560041

By

Mr. M.VISWANATH REDDYB.Pharm

Under the Guidance of

Ms.JAYANTHIM.Pharm

Asst.Professor

2011-2013

Department of Pharmaceutics,

Acharya & B.M.Reddy College of Pharmacy,

Soladevanahalli, Chikkabanavara Post,

Hesaraghatta main road, Bangalore-560 090.

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

ANNNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 / Name and address of candidate / Mr.M.VISWANATH REDDY
H:NO-2-89, VELPANUR(POST),VELGODU(MANDAL),KURNOOL(DIST),ANDHRA PRADESH-518535.
2 / Name of institution / ACHARYA & B.M. REDDY COLLEGE OF PHARMACY
SOLADEVANAHALLI, HESARAGHATTA MAIN ROAD, CHIKKABANAVARA POST,
BANGALORE-560090.
3 / Course of study and subject / M.Pharm
(Pharmaceutics)
4 / Date of admission / 4thJanuary 2012
5 / Title of the project / FORMULATION AND EVALUATION OF SOLID LIPID NANOPARTICLES OF ATENOLOL.
6.0 / BRIEF RESUME OF THE INTENDED WORK:
6.1NEED FOR THE STUDY:
Nanotechnology is defined as the science and engineering carried out in the nanoscale thatis 10−9 m. Nanotechnology is a multidisciplinary scientific undertaking, involves creation and utilization of materials, devices, or systems on the nanometre scale1. For the past few decades, there has been a considerable research interest in the area of drugdelivery using particulate delivery systems as carriers for small and large molecules. Nanoparticles present a promising drug delivery system of controlled and targeted release. Nanoparticles have been used as a physical approach to alter andimprove the pharmacokinetic and pharmacodynamic properties of various types of drugmolecules. They have been used in vivo to protect the drug entity in the systemic circulation,restrict access of the drug to the chosen sites and to deliver the drug at a controlled andsustained rate to the site of action. Various polymers have been used in the formulation ofnanoparticles for drug delivery research to increase therapeutic benefit, while minimizing side effects.
The word "Nano" is derived from the Greek word Dwarf. It means "a billionth." A nanoparticle is a billionthof a meter.Nanoparticles are the colloidal particulate systems with size ranging between 1-1000 nm2.
But nanoparticles have some disadvantages such as:
1)Involves higher manufacturing costs which may in turn lead to increase in the cost of formulation.
2)Involves use of harsh toxic solvents in the preparation process.
3)May trigger immune response and allergic reactions.
4)Nanoparticles have less stability3.
Solid lipid nanoparticles are at the forefront of the rapidly developing field of nanotechnology with several potential applications in drug delivery, clinical medicine and research as well as in otherfields. Due to their unique size-dependent properties, lipid nanoparticles offer the possibility to develop new therapeutics. The ability to incorporate drugs into nanocarriers offers a new prototype in drug delivery that could be used for secondary and
tertiary levels of drug targeting. Hence, solid lipid nanoparticles hold great promise for reaching the goal of controlled and site specific drug delivery and hence have attracted wide attention of researchers.
Solid lipid nanoparticles (SLNs) are particles of nanometre dimensions with a solid lipid matrix. They are oily droplets made from lipids which are solid at room temperature and stabilised by surfactants4.
Solid lipid nanoparticles have following advantages over nanoparticles like:
1)Improve stability of pharmaceuticals.
2)High and enhanced drug content.
3)Better control over release kinetics of encapsulated compounds.
4)Much easier to manufacture than bipolymericnanoparticles.
5)Very high long-term stability.
6)Enhances the drug entrapment efficiency5.
Novel drug delivery systemis an opportunity for formulation scientists to overcome many challenges associated with Antihypertensive drug therapy, thereby improving the managementof patients with hypertension. Hypertension or high blood pressure is a condition in which the blood pressure in either arteries or veins is abnormally high. Hypertension is one the major cause of death and disability in the world. Today, approximately 1 billion people worldwide have high blood pressure, and this number is expected to increase to 1.56 billion people by the year 2025.About 1 of every 4 adults being afflicted with hypertension6.
Classes of drugs used in the treatment of hypertension are: Beta adrenergic blockers, calcium channel blockers, ACE inhibitors, diuretics, Alpha blockers.Atenolol is a beta adrenergic blocker which has less permeability and low lipophilicity. The bio-availability of atenolol is 50% and has protein binding of 6-16%7.So by coating atenolol with lipids permeability will be increased and hence enhances the bio-availability.
Hence present study is proposed to enhance bioavailability of atenololby formulating it intosolid lipid nanoparticles.
6.2 REVIEW OF LITERATURE:
  • Verger MLet al., reported in this article that Isradipine was encapsulated by the nanoprecipitationmethod using polymers including poly(epsilon-caprolactone), poly(d,l-lactide)and poly(d,l-lactide-co-glycolide) and was characterised by SEM and DSC. The colloidal suspensions displayed a sustained release profile in comparison with the drug release profile of isradipine in a PEG solution. From this investigation, they suggest that these nanospheres will be a good candidate delivery system for oral administration, to reduce the initial hypotensive peak and to prolong the antihypertensive effect of the drug8.
  • Hecq Jet al., reported in this article thatucb-35440-3 is a new drug entity under investigation at UCB S.A. It is poorly soluble in water hencenanocrystals are achieved to enhance the solubility and dissolution characteristics.From the in vivo studies they observed the dissolution rate of ucb-35440-3 increased significantly at pH 3.0, 5.0 and 6.5 for ucb-35440-3 nanoparticles. However, the pharmacokinetic profile obtained yielded lower systemic exposure than the un-milled compound9.
  • Chitosannanoparticles have gained more attention as drug delivery carriers because of their better stability, low toxicity, simple and mild preparation method, and providing versatile routes of administration. Tiyaboonchayfrom hisobservations, he investigated the available preparation techniques involved chitosannanoparticles, the application of explored chitosannanoparticles, and their mechanism of action10.
  • GavandeSDet al., reported in this article the nanoparticle preparation method by ionic relation between a polycationic and a polyanionic polymer under magnetic stirring and to achieve drug loading into the matrices of gelatine-based nanoparticles through incubation of the drug-gelatine solution preceding to preparation and cross-linking of the nanoparticlesin situ. From the discussion, they provide a various ideas regarding selection of polymer for different type of diseases11.
  • Acharya Met al., reported in this article about the nanotechnology to improve drug delivery and to overcome some of the problems of drug delivery for cancer treatment. They can be formulated by aptamer conjugation for targeted delivery to the lymphatic system, brain, arterial walls, lungs, liver, spleen, or made for long-term systemic circulation. Thus, in pharmaceutical applications, size, shape and morphology of the solid particles are important because they can affect the solubility as well as bioavailability of the drug particles12.
  • Jawahar Net al., reported in this article the design and characterization of Poly (D,L-Lactide-co-Glycolide) (PLGA) nanoparticles containing ramipril an anti-hypertensive agent loaded by nanoprecipitation method using tribloere polymeric stabilizer (PluronicRF-68). The particle size obtained for the prepared nanoparticles range from 20nm to 340nm and also an increased in encapsulation efficiency (68-75%). The drug release from the ramiprilnanoparticles was 72%. They conclude that, the feasibility of formulating ramipril loaded PLGA nanoparticles can be used to improve the therapeutic efficacy of ramipril in the treatment of hypertensive disorder13.
  • VikasK et al.,discussed about the Novel drug delivery systems to overcome the challenges associated with antihypertensive drug therapy. Most of these drugs have short half-life, low bioavailability, poor permeability and undesirable side effects. So, to overcome these problems various anti hypertensive drug delivery systems have been developed for achieving sustained drug release kinetics. From results, they discussed the highlights of novel drug delivery systems which are effective in treatment for hypertensive patients on anti-hypertensive drug therapy14.
  • Aswathi RG et al.,reported in this article the synthesis of 5-fluorouracil (5-FU) loaded biocompatible fluorescent zeinnanoparticles. Zein is the storage protein in corn kernels. Synthesis of zeinnanoparticles of around 800 nm in size and was conjugated with quantum dot Zns:Mn. The nanoparticle was in turn encapsulated with the drug 5-FU. In vitro drug release studies were also performed. The biocompatibility of the nanoparticle showed that nanoparticles at higher concentrations are compatible for cells and are expected to be promising agents for the targeted delivery of drugs15.
  • Ding Det al., reported the formulation of cisplatindicholodiamino platinum (CDDP)-loaded gelatine-poly(acrylic acid) (GEL-PAA) nanoparticles by polymerizing acrylic acid in the presence of gelatine in aqueous solution followed by incorporating CDDP into the formed GEL-PAA nanoparticles through polymer metal complex formation of CDDP with carboxylic groups in the nanoparticles.In vivo antitumor activity indicated that the nanoparticle formulation was superior in anticancer effect to free CDDP on murine hepatic H22 tumour-bearing mice model through intra peritoneal (i.p) administration and displayed a dose-dependent antitumor efficacy16.
  • Kenneth Oet al., reported the development of a nano particulate formulation based on gelatine or its admixtures with other polyelectrolytes, nanoprecipitation conditions for the delivery of proteins and peptide drugs. The plan of the work was to achieve drug loading into the matrices of gelatine-based nanoparticles through incubation of the drug-gelatine solution prior to formation and cross-linking of the nanoparticles in situ. Results obtained showed the formation of very smooth and spherical particles with a unimodel distribution17.
  • Young Het al., reported in this article, Chitosan (CS)–poly(acrylic acid) (PAA) complex nanoparticles,which are well dispersed and stable in aqueous solution, have been prepared by template polymerization of acrylic acid (AA) in chitosan solution.The experiment of in vitro silk peptide (SP) release showed that these nanoparticles provided a continuous release of the entrapped SP for 10 days, and the release behaviour was influenced by the pH value of the medium18.
  • MukerjeeSet al.,reported in this article that solid lipid nanoparticles are at the forefront of the rapidly developing field of nanotechnology. The different types of nanocarrierswhich were based on solid lipid like solid lipid nanoparticles, nanostructured lipid carriers, lipid drug conjugates and analytical techniques are also discussed. Aspects of solid lipid nanoparticles route of administration and their biodistribution are also incorporated19.
  • Ekambaram Pet al.,reported in this article, the alternative carrier system to tradition colloidal carriers, such as emulsions, liposome’s, and polymeric micro and nanoparticles. Ramipril is an antihypertensive agent and it has many side effects. To overcome the side effects and to improve the bioavailability of ramipril, solid lipid nanoparticles of ramipril are prepared by using lipids with stabilizers20.
  • Viswajith Aet al.,reported in this article that, Solid lipid nanoparticles (SLNs) are alternative drug delivery system to colloidal drug delivery system such as liposome, lipid emulsions. They discussed the preparation method, characterization, route of administration of solid lipid nanoparticles(SLN), advantages, different preparation method which are suitable for large scale production and application of SLNs21.

7.0 / 6.3 OBJECTIVE OF THE STUDY:
The main objective of the present study is to:
  1. To carry out preformulation studies.
  2. To carry out preparation of Solid lipid nanoparticles(SLN) of atenolol.
  3. To carry out characterization of the prepared SLNs by:
  1. Particle Size Analysis.
  2. Surface morphology.
  3. Zeta potential.
  4. Percentage (%) Yield.
  5. Drug entrapment efficiency.
  1. To carry outIn-vitro release studies of the prepared SLNs.
  2. To carry out stability studies of solid lipid nanoparticleson the most satisfactory formulation.
MATERIALS AND METHODS:
7.1 SOURCE OF DATA:
Review of literature from:
A.Journals such as
  1. International Journal of Pharmaceutics.
  2. European Journal of Pharmaceutics and Biopharmaceutics
  3. European Journal of Pharmaceutical sciences.
  4. Asian journal of Pharmaceutics.
  5. Journal of Nanoparticle Research.
B. bank.com
MATERIALS:
1)DRUG: Atenolol.
2)SOLID LIPIDS: The lipids used will be triglycerides, partial glycerides, fatty acids, steroids and waxes.
3)SURFACTANTS:The surfactants used will be Anionic, Cationic, and Zwitterionic.
7.2 METHOD OF COLLECTION OF DATA21:
1. Preformulation studies:
  1. Identification testof drug by FTIR/UV.
  2. Compatibility testing for drug and lipids.
  1. Preparation of solid lipid nanoparticles will be conducted by one of the following methods:
  1. High shear homogenization.
  2. Hot homogenization.
  3. Cold homogenization.
  4. Ultrasonication.
  5. Solvent emulsification/evaporation.
  6. Spray drying method.
  1. Characterization of obtained solid lipid nanoparticles by:
  1. Particle size analysis by SEM/LD.
  2. Surface morphology by TEM.
  3. Zeta potential is measured by zeta potentiometer.
4. Evaluation parameters:
  1. Percentage yield.
  2. Drug entrapment efficiencywill be done by ultracentrifugation, centrifugation filtration/gel permeation chromatography.
  3. In vitro dissolution studies.
5. To carry out stability studies of solid lipid nanoparticles on the most satisfactory formulation.
7.3DOES THE STUDY REQUIRE ANY INVESTIGATIONTO BECONDUCTED ON PATIENTS OR OTHERHUMANS OR ANIMALS?
“NO”
7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR
INSTITUTION IN CASE OF 7.3?
“NOT APPLICABLE”
8.0 / REFERENCES:
  1. Ravichandran R. Nanotechnology-Based drug delivery systems. Nanobiotechnol 2009; 5:17-33.
  1. MohanrajVJ, Chen Y. Nanoparticles – A review. Tropical J Pharm Res 2006; 5(1): 561-73.
  1. Advantages and disadvantages of nanoparticles. Nanoparticles [Online]. 2010 Oct 03 [Cited 2012 Apr 30]; available from:URL:
  1. Jain N, Jain R, Thakur N, Gupta BP, Jain DK, Banveer Jet al., Nanotechnology: A safe and effective drug delivery system. Asian JPharm Clinical res 2010; 3(3):1-8.
  1. Ekambaram P, Sathali AS,Priyanka K.Solid lipid nanoparticles: A review.Sci Revs ChemCommun 2012; 2(1):80-102.
  1. Hypertension etiology. Hypertension statistics [Online]. 2010 [Cited 2012 May 5]; available from: URL:
  1. Wander GS, Chhabra ST, Kaur K.Atenolol drug Profile. Supplement Japi 2009; 57:13-16.
  1. Verger ML, Fluckigera L, Kim Y,Hoffmana M, Maincent P. Preparation and characterization of nanoparticles containing an antihypertensive agent. EurJPharmBiopharm 1998; 46:137-43.
  1. Hecq J, Deleers M, Fanara M, Vranckx H, Boulanger P, Le Lamer S et al., Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base. Eur J PharmBiopharm 2006; 64:360-68.
  1. Tiyaboonchai W.ChitosanNanoparticles: A promising system for drug delivery.Naresuan University Journal 2003; 11(3): 51-66.
  1. Sunil G, Hemant S, Prajakta U, Dheeraj B, DineshK. Biodegradable nanoparticle: Emerging research area for novel drug delivery. JPharm Res 2012; 5(1):169-73.
  1. Acharya M, patel M, Raval J. Nanoparticulate drug delivery system using drug polymer and aptamer conjugation. Am JPharmtech Res 2011; 1(4):88-107.
  1. Jawahar N, Eagappanath E, Venkatesh N, JubieS, SamantaMK. Preparation and characterisation of PLGA-Nanoparticles containing an anti-hypertensive agent. Int JPharmTech Res 2009; 1(2):390-93.
  1. Vikas K, Arvind S, Ashish S,Gourav J, Vipasha D. Recent advances in NDDS (Novel Drug Delivery System) for delivery of anti-hypertensive drugs. Int J Drug Dev Res 2011; 3(1):252-9.
  1. Aswathy RG, Sivakumar B, BrahatheeswaranB, Fukuda T, Yoshida Y, Maekawa Tet al., Biocompatible fluorescent zeinnanoparticles for simultaneous bio imaging and drug delivery application. Adv Nat Sci: NanosciNanotechnol2012; 3:1-7.
  1. Ding D, Zhu Z, Liu Q, Wang J,Hua Y, Jiang X et al.,Cisplatin-loaded gelatine-poly (acrylic acid) nanoparticles: Synthesis, antitumor efficiency in vivo and penetration in tumours. Eur JPharmBiopharm2011; 79:142-9.
  1. Ofokansi K, Winter G, Fricker G, Coester C. Matrix-loaded biodegradable gelatin nanoparticles as new approach to improve drug loading and delivery. Eur JPharmBiopharm 2010; 76:1-9.
  1. Hua Y, Jianga X, Ding Y, Gea H, Yuanb Y, Yanga C. Synthesis and characterization of chitosan–poly (acrylic acid) nanoparticles. Biomaterials 2002; 23:3193-201.
  1. Mukherjee S, Ray S, ThakurRS.Solid lipid nanoparticles: A modern formulation approach in drug delivery system.Indian JPharmSci 2009;(4):349-58.
  1. Ekambaram P, Abdul HS. Formulation and Evaluation of Solid Lipid Nanoparticles of Ramipril.J Young Pharm 2011; 3(3):216-20.
  1. Vishvajit A, deepali, Jagdale M, vilasrao J. Solid lipid nanoparticles as drug delivery System. Int J Pharm Bio Sci 2010; 1(3):1-9.

9 / Signature of the Candidate
10 / Remarks of the Guide / The above information and literature has been reviewed, verified and was found to be correct. present study will be carried out under my guidance
11 / Name and Designation of

11.1 Institutional Guide / Ms.JAYANTHI
Asst. Professor
Acharya & B.M. Reddy College of Pharmacy,
Bangalore-560 090.
11.2 Signature
11.3 Co-Guide / NIL
11.4 Signature / _
11.5 Head of the Department /
Dr.SHIVANAND KALYANAPPA.
Professor and H.O.D
Dept. of Pharmaceutics.
Acharya & B.M. Reddy College of Pharmacy,
Bangalore-560 090.
11.6 Signature
12 / 12.1 Remarks of the Principal
/ 12.2 Signature /
Dr. DIVAKAR GOLI M.Pharm,Ph.D
Principal
Acharya & B.M. Reddy College Of Pharmacy,
Bangalore-560 090.

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