Co-Solvent Evaporation Method for Anti-HIV Drug to Enhance Solubility and Dissolution Rate
Synopsis for
M.PHARM DISSERTATION
Submitted To
Rajiv Gandhi University of Health Sciences
Karnataka, Bangalore
Submitted By
SIRISHA G.
Department Of Pharmaceutics
Under The Guidance Of
Mrs. A.GEETHA LAKSHMI
Asst. Professor
Department of Pharmaceutics
The Oxford College of Pharmacy
Hongasandra, Bangalore-68
Karnataka
Rajiv Gandhi University of Health Sciences
Bangalore, Karnataka
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1 / Name of the Candidate and Address / SIRISHA G.Postal Address:
No-1,18th A cross, Sir M V Nagar,
T C Palya Main Road, Ramamurthy nagar
Bangalore
Karnataka 560016
2 / Name of the Institute / The oxford College of Pharmacy
6/9 1st cross,
Begur main road, Hongasandra,
Bangalore – 560068
Karnataka.
3 / Course of Study and subject / Master of Pharmacy (Pharmaceutics)
4 / Date of Admission to the Course / 05-07 -2012
5 / Title of the Project:
“Co-Solvent Evaporation Method for Anti-HIV Drug to Enhance Solubility and Dissolution Rate ”
6
/ Brief Resume of the Intended work:
6.1 Need for the Study:
Ø Human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDS) is a retro virus, which causes irreversible destruction of the immune system leading to the occurance of AIDS. This virus mainly targets the T cells of the immune system there by reduces the immunity in the body. In infected individuals, the virus is mainly present in the monocytes, dendritic cells of brain, lungs, spleen, liver, kidney, lymph nodes and bone marrow1.
Ø It is mainly transmitted by sexual intercourse (including anal and even oral sex), contaminated blood transfusions and hypodermic needles, and from mother to child during pregnancy, delivery, or breastfeeding. It is not transmitted by body fluids like tears and saliva2. It can be prevented by safe sex and needle-exchange programs2.
Ø Now a days it became a leading disease which may cause severe death.3 The World Health Organization (WHO) estimates that around 34 million people in the world and 2.4 million of people were affected in India3.
Ø Research work has been carried out to formulate the anti-retro viral drugs which can cure the disease. Drugs have been marketed to protect the immune system to prolong their life span. Drugs such as nevirapine, efavirenz, ritonavir, telaprevir, boceprevir are used for the treatment of the diseases4.
Ø Though the drugs are used for the treatment they are less soluble and the absorption is low to produce better therapeutic activity. So, in order to enchance the therapeutic activity the absorption rate should be improved by increasing the solubility nature and dissolution rate of the drug.
Ø To improve the solubility and dissolution rate, the methods such as Micronisation, Complexation, solid dispersion co-solvent evaporation technique, etc. have been employed. Solid dispersion co solvent evaporation technique has been selected for the formulation of anti HIV drug to enhance the solubility and dissolution rate to produce better therapeutic activity5.
6.2 Review of Literature:
1) Solid dispersions were formulated using naturally obtained polysaccharide carrageenan in the molecular ratio of 1:1, 1:3, 1:5 using trituration method (TM), solvent evaporation method (SE) and kneading method (KM). The formulated solid dispersions were manually filled in hard gelatin capsules (size 1) and evaluated for the physicochemical properties. This solid dispersion enhances solubility of Efavirenz6.
2) Solid dispersion as an approach for bioavailability enhancement of poorly water-soluble drug ritonavir was studied by using Gelucire as carrier in 1:4 ratios by different methods7.
3) Solid dispersion was prepared by physical mixing, solvent evaporation and kneading method. The interaction of the Nevirapine with PVP K 30 enhances the solubility of nevirapine. Fourier transform infrared (FTIR) spectroscopy; Differential scanning Calorimetry (DSC), X-ray diffraction patterns (XRD).The results from the FTIR and XRD analyses showed that Solid dispersion might exist in the amorphous form8.
4) Role of various hydrophilic binders for enhancement of dissolution of a poorly soluble drug, raloxifene hydrochloride (RLX-HCL), Using solid oral dosage form was studied. Hydrophilic binders viz poly vinyl pyrrolidone, hydroxyl propyl methyl cellulose, hydroxyl propyl cellulose were investigated for the purpose to improve the solubility in the formulation Dissolution behavior of different formulation and pure drug was studied in different relevant media, which reveals significant improvement in dissolution behavior of drug was observed using hydrophilic binder.9
5) Solubility and dissolution of poorly aqueous soluble drug Simvastatin (sim) was enhanced using hydrophilic, low viscosity grade polymer (HPMC K3LV). The co-solvent evaporation method was developed for efficient encapsulated of hydrophobic drug in polymer of HPMC K3LV spray drying and Rota evaporation were applied for solvent evaporation .In-vitro, in-vivo studies were performed on co solvent evaporation mixture and compare with SIM. The co-solvent evaporation method provides good encapsulation efficiency and produces amorphous form of SIM gave better solubility and dissolution than the crystalline SIM5.
6) Improvement of the solubility and oral absorption of the drug in gastric fluid and to enhance its dissolution rate solid dispersions and Lyophilization of dispersion is designed and evaluated. Solid dispersions containing Fenofibrate /Poloxamer 407, 1: 8, showed a 14-fold increase in dissolution after 60 min (D60) and another dispersion containing Fenofibrate /PEG 6000, 1:10, showed an 8-fold increase in the 0.1 N HCl systems. The dispersion containing six parts of the PEG 6000: Poloxamer 407 mixture (PEG 4000/PEG 6000, 1:1 mixture) showed a 12-fold increase in dissolution at 60 min as compared with pure drug. When multi carrier solid dispersion containing six parts of mixture was prepared by the solvent method, dissolution at 60 min value was about 2-fold that of the same dispersion prepared by the melt method10.
7) Water insoluble polymers are used as encapsulation matrix using microencapsulation by solvent evaporation. The hydrophobic drugs such as cisplatin, lidocaine, naltrexone and progesterone; and hydrophilic drugs such as insulin, proteins, peptide and vaccine are coated with biodegradable polymers. The choice of encapsulation materials and the testing of the release of drug have been intensively investigated11.
8) Solubility is the phenomenon of dissolution of solid in liquid phase to gives a homogeneous system. There are many techniques which are used to enhance the aqueous solubility. The ability to increase aqueous solubility can thus be a valuable aid to increase efficiency and/or reducing side effects for certain drugs. This is true for parenterally, topically and orally administered solutions. Hence various techniques are used for the improvement of the solubility of poorly water soluble drugs including hydro trophy, Use of salt form, Use of precipitation inhibitors, alteration of pH of the drug microenvironment, Precipitation pH adjustment, Nanonisation, Co-solvency , Solid Dispersion, Complexation , Micro Emulsion, Solid Solution ,Eutectic Mixture, Selective Adsorption on Insoluble Carriers, Evaporative precipitation into aqueous solution, Use of surfactants, Use of amorphs, anhydrates, solvates and metastable polymorphs. By use of these techniques there is improvement of effective absorption and bioavailability12.
9) Complexation of UC781 with either hydroxypropyl -beta-Cyclodextrin (HP-beta-CD) or methyl-beta-cyclodextrin (M-beta-CD) was optimized by evaluation of four processing methods (autoclave, lyophilization, shaking, and kneading), incorporation of four water-soluble polymers (HPMC, HEC, PVA, and PVP K30), and utilization of three buffering systems (pH 7.0, 9.0 and 11.0). Finally, three formulations methylcellulose (MC) gel, hydroxy ethylcellulose (HEC) gel, and polyvinyl alcohol (PVA) film were developed for UC781. The physical properties, toxicity, and anti-HIV activity of UC781 containing formulations were evaluated with in vitro and ex vivo models. Results: Complexation of UC781 with beta-CDs was confirmed and characterized with UV, FTIR, DSC, and NMR. UC781¡¦s complexation was found to be an enthalpy driven process. The solubility of UC781 was increased13.
10) Solid dispersion formulations made up of d-alpha-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) and polyvinyl pyrrolidone co-vinyl acetate 64 (PVPVA 64) or hydroxy propyl methyl cellulose 2910 (HPMC 2910) were developed in order to improve the dissolution of UC 781. UC 781 dissolution rate was markedly improved as compared to the physical mixtures and the pure drug, attaining maximum drug releases of up to 100% after only 5 min in the case of TPGS 1000-UC 781-PVPVA 64 solid dispersions and 30 min in TPGS 1000-UC 781-HPMC 291014.
11) Solid dispersion have been prepared by the hot-melt or solvent method by using a mixture of Eudragit® EPO and poly vinyl pyrrolidone/ vinyl acetate copolymer (PVP/VA) (Kollidon VA64) as carriers, a Nimodipine solid dispersion (NM-SD) was prepared by hot-melt extrusion (HME) to achieve high dissolution15.
6.3 Objective of the Study:
Ø To enhance the solubility and dissolution rate of the anti HIV viral drug using Co-solvent evaporation technique by using Rota evaporator.
Ø The selected category of drug has poor solubility when given orally. So a new approach co-solvent evaporation method is helpful to increase the bioavailability.
Ø The class of drugs that have poor intestinal absorption, dissolution, solubility and so the performance of these is dissolution rate limited and which can be improved by reducing particle size or by co-solvent method.
7 / 7.1 Materials And Methods:
Ø DRUG : Anti - HIV drug
Ø Polymer : Methyl cellulose, hydroxyl propyl methyl cellulose., etc
Ø Method : Co-solvent evaporation method.
7.2 Source Of Data:
The data has been collected from different books, journals and articles available in the library of the Oxford college of pharmacy, journals available in internet source, The Rajiv Gandhi university of Health sciences website and through various internet sources.
7.3 Method of collection of data:
Ø Co-solvent evaporation method:
Ø Formulation:
The tablets can prepared by any of following method:
· Wet granulation technique
· Dry granulation technique
Ø Evalution Methods:
· Pre formulation parameters:
1. Solubility study
2. Bulk density
3. Tap density
4. Angle of repose
5. Differential scanning colorimetry
6. Powder X-ray diffraction studies
7. Scanning electron microscopy
8. FTIR/IR Studies
· Post formulation studies :
1. Weight variation
2. Hard ness
3. Friability
4. Drug content
5. In-vitro dissolution studies
6. Short term stability studies
7.4 Does the study require any investigations of interventions to be conducted on patients or other human or animals? If so please describe briefly?
NO
7.5 Has ethical clearance been obtained from your institute in case of as above?
NA
8 / List of references:
1. Dandagi PM, Patel PD, Gadad AP, Aravapalli AK. RES and brain targeting stavudine-loaded solid lipid nanoparticles for AIDS therapy. Asian J Pharm 2012;6:116-23
2. Markowitz, edited by William N. Rom; associate editor, Steven B. (2007). Environmental and occupational medicine (4th ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. p. 745. ISBN 978-0-7817-6299-1
3. http://www.avert.org/aidsindia.htm
4. Essentials of medical pharmacology by KD Tripathi, Jaypee publications 6th edition.pg no 772.
5. Priyanka Pandya, Surendra Gattan, Co-solvent Evaporation Method for Enhancement of Solubility and Dissolution Rate of Poorly Aqueous Soluble Drug Simvastatin:In vitro–In vivoEvaluation, AAPS PharmSciTech.2008 Dec;9(4):1247–1252
6. Vedha Hari B.N., Yasmin Begum A., Ramya Devi D, Solid State Modification For The Enhancement Of Solubility Of Poorly Soluble Drug: Carrageenan As Carrier, International Journal Of Pharmaceutical Investigation.2011 Jan-Mar;1(1):29–34.
7. Shilpi Sinha,Mushir Ali,Sanjula Baboota,Alka Ahuja, Solid Dispersion as an Approach for Bioavailability Enhancement of Poorly Water-Soluble Drug Ritonavir, AAPS PharmSciTech.2010 June;11(2):518–527.
8. Ahire B. R., Rane B. R., Bakliwal S. R., Pawar S. P Solubility Enhancement of Poorly Water Soluble Drug by Solid Dispersion Techniques, IJPRIF 2010 July-Sept(2)3:2007-2015.
9. Rai VK, Brajendra SR, Manoj S, Ashish A, Anil G, Narendra S. Solubility enhancement of poorly water-soluble drug (raloxifene hydrochloride) by using different hydrophilic binders in solid dosage form. Pharmacie Globale Int. J.
Comprehensive Pharmacy 2010;1(2).
10. Tejas Patel, Patel LD, Timir P, Sunil M, Tushar P. Enhancement of dissolution of Fenofibrate by solid dispersion technique. Int. J. Res. Pharm.Sci 2010;1(2):132
11. Ming L, Olivier R, Denis P. Microencapsulation by solvent evaporation: state of the art for process engineering approaches, Int. J. Pharm. 2008;26–39.
12. Varun RV, Venkateshwarlu L, Srikanth L. Solubility enhancement techniques.
Int. J. Pharm. Sci. Review & Research 2010:(5);41-51
13. Yang, Haitao, Beta-Cyclodextrin Complexation And Formulation As An Anti-Hiv Microbicide. Doctoral Dissertation, University of Pittsburgh.
14. Formulation of fast disintegrating tablets of ternary solid dispersions consisting of TPGS 1000 and HPMC 2910 or PVPVA 64 to improve the dissolution of the anti-HIV drug UC 781, Eur jol pharm sci, 2008 Aug;34(4-5):293-302.
15. Fu Jijun, Xu Lishuang, Wang Xiaoli, Nimodipine (NM) tablets with high dissolution containing NM Solid dispersions prepared by hot-melt extrusion, Drug Development and Industrial Pharmacy, 2011;37(8): 934–944.
9 / Signature of the Candidate / (SIRISHA G.)
10 / Remarks of the Guide:
11 / 11.1 Name and Designation of Guide / MRS. A. GEETHA LAKSHMI
ASST. PROFESSOR
DEPT. OF PHARMACEUTICS
11.2 Signature of Guide
11.3 Co-Guide if any / -NA-
11.4 Signature of Co-Guide / -NA-
11.5 Head of Department / Mrs. SURINDER KAUR
ASSO.PROFESSOR AND HOD
DEPT. OF PHARMACEUTICS
11.6 Signature of HOD
12 / 12.1 Remarks of the Principal
12.2 Signature of Principal / DR. PADMAA M. PAARAKH
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