Design and characterisation of nanoparticulate drug delivery system of an anticancer drug



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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BENGALURU, KARNATAKA



S J M COLLEGE OF PHARMACY

CHITRADURGA-577502



A PROTOCOL FOR THE PROJECT WORK ENTITLED

DESIGN AND CHARACTERISATION OF



NANOPARTICULATE DRUG DELIVERY SYSTEM OF AN

ANTICANCER DRUG”

By,

MALLAMMA.T.

M. Pharm Part–I

Department of Pharmaceutics

S J M College of Pharmacy

Chitradurga–577 502
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE

KARNATAKA
ANNEXURE-II
PROFAMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION



1

Name of the candidate and address (in block letters)




MALLAMMA.T. S J M College Of Pharmacy

Chitradurga -577502

PERMANENT ADDRESS:

T.mallamma D/o T.Thippeswamy.

N.Devarahalli. Mahadevapura(post)

Challakere..


2.

Name of the institute



S J M  College Of Pharmacy

S J M I T Campus

Chitradurga-577502

3.

Course of study and subject



Master Of Pharmacy In Pharmaceutics.

4.

Date of admission to course

17-10-2011



5.




Title of the project:

DESIGN AND CHARACTERISATION OF NANOPARTICULATE



DRUG DELIVERY SYSTEM OF AN ANTICANCER DRUG”





6

7

8



9

BRIEF RESUME OF THE INTENDED WORK

NEED FOR THE STUDY:

The effectiveness of anticancer agents may be hindered by low solubility in water, poor permeability & high efflux from cells. Nanomaterial have been used to enable drug delivery with lower toxicity to healthy cells & enhanced drug delivery to tumour cells.1

Treatment of cancer includes chemotherapy, radiation therapy, gene therapy, photodynamic therapy, biologic therapy, surgical removal of tumour cells, etc. Cancer treatment vary according to the type of cancer and the extent of the tumour.2

Biodegradable polymeric nanoparticles have shown great therapeutic potential as a drug delivery nano carrier. Biodegradable polymers such as poly (D, L-lactic-co-glycolic acid) (PLGA) and poly (caprolactone) (PCL) have been used in several FDA-approved therapeutic products. Their co-polymers with PEG are commonly used to form core shell structured nanoparticles to encapsulate a variety of therapeutic agents.3

Nanoparticles- particle in the size range 1-1000 nm emerging as a class of therapeutic for cancer .The nanoparticle therapeutics can show enhanced efficacy, while Simultaneously reducing side effects, owing to properties such as more targeted localization in tumour and active cellular uptake. The use of nanoparticles has a number of advantages: targeting, decreasing the doses, availability for parenteral administration, maintaining the therapeutic concentration & limiting the toxic effects.4

Tremendous opportunities exist for using nanoparticles as controlled drug delivery systems for cancer treatment. Natural and synthetic polymers including albumin, fibrinogen, alginate, chitosan and collagen have been used for the fabrication of nanoparticles.5

In comparison to other class of drugs, cytotoxic anticancer drugs present unique problems that come primarily from the relative lack of specificity of their systemic bio distribution and the subsequent side effects provoked by the drug attacking both healthy and target cells.

In addition, their unfavourable pharmacokinetics implies the administration of high drug doses and imposes on patients a rigorous schedule for reaching the desired therapeutic effect.6


These unwanted properties exhibited by free drugs can be summarized in the following points:

  1. The hydrophobic character of many drugs promotes their precipitation in aqueous media;

  2. They suffer of poor selectivity for target tissues;

  3. They undergo bio distribution in a large body volume with severe side effects in

sensitive non target tissues;

  1. Their inadvertent extravasation can produce damage in healthy tissues;

  2. Molecular drugs suffer rapid clearance;

  3. Their in vivo degradation implies the necessity of high dose administration;

  4. Susceptibility to induce drug resistance.6,7

Chemotherapy is the most convenient and less-expensive when compared to other modes of treatment. Varieties of anticancer drugs are available in the market and some of them are under clinical trials. The main problem with anti-cancer drugs is that they not only affect the tumour cells but also affect the normal cells. These happen due to non-specific targeting to tumour cells and hence other normal cells get affected.

Recently, drug targeting especially targeting by nanoparticles have been getting much attention by the researchers for treating cancer. A critical advantage in treating cancer with nanoparticles is the inherent leaky vasculature present serving cancerous tissues. The defective vascular architecture, created due to rapid vascularization necessary to serve fast-growing cancers, coupled with poor lymphatic drainage allows an enhanced permeation and retention effect. Targeting the tumour vasculature is a strategy that can allow targeted delivery to a wide range of tumour types.8

Hence considering the importance of treating cancer, an attempt will be made to target and deliver an anti-cancer drug to these cancerous cells so as to minimize adverse effects, dose and dosing frequency, improved therapeutic index, potentially overcoming resistance associated with anticancer drugs in the form of nanoparticles.

Nanoparticles can be prepared from a variety of materials such as proteins, polysaccharides and synthetic polymers. The selection of matrix materials is dependent on many factors including :

(a) Size of nanoparticles required;

(b) Inherent properties of the drug, e.g., aqueous solubility and stability;


(c) Surface characteristics such as charge and permeability;

(d) Degree of biodegradability, biocompatibility and toxicity;

(e) Drug release profile desired; and

(f) Antigenicity of the final product.9

Nano systems with different compositions and biological properties have been extensively investigated for drug and gene delivery applications. Several anticancer drugs, including paclitaxel, doxorubicin, 5-fluorouracil, vinblastine, chlorambucil, flutamide, methotrexate, 6-mercaptopurine, boswellic acid, cisplatin, etoposide etc… have been successfully formulated using nano materials.

REVIEW OF THE STUDY:

Tamizhrasi S et al.,10 have reviewed on the preparation and evaluation of the polymethacrylic acid nanoparticles containing lamivudine in different drug to polymer ratio by Nano-precipitation method and evaluation by SEM and FT-IR has revealed that average particle size was found to be 121-403nm and there was no chemical interaction

between drug and polymer and stability of drug. The in vitro release behaviour from all the drug loaded batches was found to be zero order and provided sustained release over a period of 24 h.



Potnuru S et al.,11 developed formulation and characterization of novel biodegradable nanoparticles of Stavudine by using solvent evaporation method, in-situ Nano emulsion polymer cross linking method. Drug containing nanoparticles were prepared with different drug polymer ratio at ambient temperature and freeze drying of nanoparticles formulation for long term stability, comparatively based upon the method of preparation the in- situ method has produced a good results like drug loading efficiency, in-vitro release.

Umasanker. K et al.,12 formulated and evaluated Cytarabine nanoparticles.

Cytarabine nanoparticles were formulated by ionic gelation method using polymer chitosan in different ratios. Nanoparticle were characterised by determining its particle size, drug entrapment efficiency, drug release and stability studies.



Sivabalan M. et al.,13 formulated and evaluated nanoparticles of 5-fluorouracil by using polymers like chitosan and eudarit for cancer therapy in different concentrations. The physical characteristics, drug loading & drug release patterns were studied.
Erem Bilensoya et al.,14 Intravesical cationic nanoparticles of chitosan and Polycaprolactone for the delivery of Mitomycin C to bladder tumours. Elation For chitosan nanoparticle ionic gelation and nanoprecipitation method is used and characterisation is for various parameters like particle size distribution, zeta potential, DSC and SEM are performed.

Sompur c.k et al.,15 A novel approach for development and characterisation of Etoposide loaded solid lipid nanoparticles by solvent displacement method by using various concentration of SLNS & evaluated for percentage yield, drug loading, percentage entrapment efficiency, particle size, surface morphology, in vitro release rate studies.

Nilesh M. Mahazan et al.,16 Design and development of mesalamine loaded PLGA nanoparticles. Nanoparticles were prepared using spontaneous emulsification solvent diffusion method. NPS were characterised in terms of surface morphology, particle size and distribution, zeta potential, encapsulation efficiency and drug release profile. X-ray diffraction and differential scanning colorimetry were employed to determine any interaction between drug and polymer.

Vinod Ramani et al.,17 Formulation and evaluation of nanoparticles of HMG-CoA reductase inhibitor. The formulations were done by emulsion- solvent evaporation method followed by freeze drying. The formulated nanoparticle were subjected to characterisation studies like particle size analysis, X-ray diffraction studies, differential scanning colorimetry,SEM and UV analysis.

Rajat Sharma et al.,18 Formulated and evaluated Paclitaxel loaded PSA-PEG nanoparticles by nanoprecipitation method The influence of different experimental parameters on the particles size, entrapment efficiency, percent drug released etc. was evaluated.

Saji Uthaman et al.,19 Novel Boswellic acids Nanoparticles induces cell death in

Prostate cancer cells. The nanoparticle prepared by controlled nanoprecipitation method

and were characterised by dynamic light scattering, scanning electron microscopy etc.

and it’s in vitro cytotoxicity is assisted by different human cell lines.



Adlin jino nesalin J et al.,20 formulated and evaluated nanoparticles containing Flutamide, which were formulated using chitosan polymer by ionic gelation technique. Nanoparticles of different core: coat ratio were formulated and were subjected for total drug Content, loading efficiency, particle size and in vitro drug release studies.

Objective of the study:

The objective of the study is to develop nanoparticles for anticancer drug:



  • To design suitable formulation of nanoparticles for anticancer drug.

  • Characterization of formulated nanoparticle.

  • Evaluation of developed nanoparticles.

8.1 MATERIALS AND METHODS:

Source of data



  • National and International journals.

  • Official Pharmacopoeia

  • Internet browsing

  • Helinet

  • From available literature

  • From library based books.

8.2. Materials:

Anticancer drug and polymers will be procured from suitable Pharma grade Manufacturer. Other Reagents are of Analytical grade.



Polymers: hydrophilic polymers such as bovine serum albumin, chitosan, and gelatin. Lecitin, legumin and vicillin. Polysaccharides are alginate, dextran, chitosan and pollulan. Collagen, poly methacrylic acid, eudragit, polyvinyl alcohol, etc. From the above mentioned list and any other suitable polymers will be used.

    1. Method of collection of data.

1) Formulation of nanoparticles for an selected anticancer drug by any one of suitable following method.

  1. Solvent emulsification method.

  2. Solvent evaporation method.

  3. Nano/co precipitation method.

  4. Nano encapsulation method

  5. Ionic gelation method, etc.

2) Selection of suitable drug and polymer for the preparation of nanoparticles.



  • Preformulation studies.

  • Evaluation of formulated nanoparticles include:

    • Drug polymer interaction studies.

    • Drug loading efficiency.

    • In vitro drug release studies

    • Release kinetics

    • Stability studies for selected batches as per ICH guidelines.

3) Physical Characterization

a. Particle size and surface morphology determination



  • Scanning electron microscopy.




    1. Does the study require any investigation or inventions to be conducted on

Patients or other human or animals? If so, please describe briefly.

No

8.5 Has ethical clearance been obtained from your institution in case of 7.3?



Not applicable.

LIST OF REFERENCES:

  1. Dinarvand R. Polylactide-co-glycoside nanoparticles for controlled delivery of

Anticancer agents. Int. J. of Nanomedicine 2011; 6:877-95.

  1. http://womenhealth.about.com/cs/cancer/a/diagtreatcancer_3.htm.Accessed on 09/11/2010.

  2. Li Zhang & Liangfang Zhang, lipid –polymer hybrid nanoparticle: synthesis,

Characterisation and applications. 2010;1(1&2):163-173.

  1. Mark E. Davis, Zhuo (Georgia) Chen & Dong M. Shin Nanoparticle therapeutics: an

Emerging treatment modality for cancer. Nature Reviews Drug Discovery 7,2008;

771-82.


5) Davaran S, Rashidi MR, Pourabbas B, dadashzadeh M, and Haghshenas NM.

Adriamycin release from poly(lactide-co-glycolide)- polyethylene glycol

Nanoparticles: synthesis and in vitro characterisation. Int. J. nanomedicine

2006;1(4):535-39.


6) Wong HL, Benda an R, Ruth AM, Li Y, Wu XY. Chemotherapy with anticancer

drugs encapsulated in solid lipid nanoparticles. Adv. Drug Delivery Review

2007;59(6):491-504

7) Duran JDG, Arias JL, Gallardo V, Delgado AV. Magnetic colloids as drug vehicles.

J.Pharm Sic 2008; 97(8):2948-83.

8) Pappas LB and Blanchet JO. Nanoparticle and targeted systems for cancer Therapy.Adv. Drug Delivery Rev.2004; 56:1649-59.

9) Mohsen Jahanshah and Zahra Babaei. Protein nanoparticle: A unique system as

drug delivery vehicles.Afr. J. of Biotech 2008;7 (25):4926- 934.

10) Tamizhrasi S, Shukla A, Shivkumar T, Rathi T, Rathi JC. Formulation and

Evaluation of Lamivudine loaded Polymethacrylic acid nanoparticles. Int. J. of

Pharm Tech 2009; 1(3): 411-5.

11) Potnuru S, Sundaramoorthy.K and Vetrichel Van T. Design of biodegradable

polymer nanoparticles for oral drug delivery of stavudine: in vitro dissolution

Studies and characterization, Int. J. Pharm Tech 2011; 3(1):1360-72.

12) Umasankar.K and Maheswara Reddy.C2. Formulation and evaluation of Cytarabine

Nanoparticles. Int. J. of Innovative Pharm Res, 2010; 1(2):48-52.

13) M.Sivabalan, Anto shering, Phaneendhar Reddy, vasudevaiah, Anup Jose and

G Nigila. Formulation and evaluation of nanoparticles of 5-fluorouracil loaded

Chitosan and eudarit for cancer therapy. Int. J. comprehensive pharmacy, 2011;

1(07):1-4.

14) Erem Bilensoy, Can Sarisozen, Gunes Esendagli, A.Lale Dogan, Yesim Aktas,

Murat Sen, N.Aydin Mungan. Intravesical cationic nanoparticles of chitosan and

Polycaprolactone for the delivery of Mitomycin C to bladder tumour. Int J of

Pharm 2009; 371: 170–76.

15) Sompur C.K, Doijad R.C, Goje Arjun. A novel approach for development and

Characterisation of Etoposide Loaded solid lipid nanoparticles. Int. J. of pharm

and Biosci 2011; 2(3): 298-306.


  1. Nilesh M. Mahazan, Dr. Dinesh M.Sakarkar, Amit S. Manmode. Design and

Development of mesalamine loaded PLGA nanoparticles. J of Pharm Res, 2011;

4(4): 1263-66.





  1. Vinod Ramani, Sachin Chauhan, Jibin Joshi, Tejas Ghelani, Gajanan Deshmukh.

Formulation and evaluation of nanoparticles of HMG-CoA reductase inhibitor. Pharm

Sic Monitor an Int J of Pharm Scie.2011; 2(4):42-58.



  1. Rajat Sharma, Mohd Yasir, Sanjay Bhaskar and Mohd Asif :Formulation and

evaluation of Paclitaxel loaded PSA-PEG nanoparticles by nanoprecipitation

method. J of Applied Pharm Sic 2011; 01 (05): 96-98.



  1. Saji Uthaman, Snima K.S, Annapoorna M, Ravindranath K.C, Shanti V, Nair, Vinoth-

Kumar Lakshmanan .Novel Boswellic acids Nanoparticles induces cell death in

Prostate cancer cells.J. Of Natural Products, 2O12; 5:100-08.



  1. Adlin jino nesalin j, Gowthamarajan K and Somashekhara C.N. Formulation and

Evaluation of nanoparticles containing Flutamide. Int. J. of ChemTech Res, 2OO9;

1(4):1331-34.







10


SIGNATURE OF CANDIDATE


(T.MALLAMMA)

11

REMARK OF THE GUIDE:

The proposed work of the candidate is original and has not been submitted to this University / any other University for the award of Degree. It is intended to train the candidate for gaining basic knowledge of planning, organization and experimentation to present this research work in form of dissertation systematically.



12.

NAME AND DESIGNATION OF








12.1 GUIDE

Mrs.SNEHALATHA M.pharma(Ph.D)

Assistant professor.

Dept. Of Pharmaceutics

S J M College Of Pharmacy

Chitradurga.





12.2 SIGNATURE







12.3 CO-GUIDE

R.YOGANANDA M.Pharm(ph.D)




12.4 SIGNATURE







12.5 HEAD OF THE DEPARTMENT

Mr.T.S.NAGARAJA M.Pharm(ph.D)

H O D., Asst. Professor.

Dept. Of Pharmaceutics

S J M College Of Pharmacy

Chitradurga.





12.6 SIGNATURE




13.

13.1 REMARK OF THE CHAIRMAN AND PRINCIPAL

The above mentioned information is correct and I recommend the same for approval.





13.2 principal

Dr.BHARATHI D.R. M. Pharm.PhD.

Professor and Principal

S J M College Of Pharmacy

Chitradurga.






13.3 SIGNATURE OF PRINCIPAL


(Dr. BHARATHI.D.R.)

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