Download annexure – ii

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1.
NAME OF THE CANDIDATE SUSHANTH.M.S
S/O Siddarudha Swamy.M.N
AND ADDRESS:
#967/1,7th cross Sunadakeri
K.R.Mohalla
Mysore- 570024
Karnataka.
2.
NAME OF THE INSTITUTE:
3.
COURSE OF THE STUDY & Master of Pharmacy
SUBJECT:
(Pharmaceutics)
4.
DATE OF ADMISSION TO 07/07/2010
THE COURSE:
5.
TITLE OF THE TOPIC:
Krupanidhi College of Pharmacy,
Chikka Bellandur,
Carmelaram Post,
Varthur Hobli,
Bangalore – 560035.
“ENHANCING THE SOLUBILITY OF A MODEL ANTIRETROVIRAL
DRUG COMPLEXED WITH CYCLODEXTRINS”.
OF SELENO-QUIANAZOLONE AND EVALUA
IA
6. BRIEF STUDY OF THE INTENDED WORK:
6.1 Need of Study:
Acquired
immunodeficiency
syndrome
(AIDS),
caused
by
Human
immunodeficiency virus (HIV), is an immunosuppressive disease that results in life-threatening
opportunistic infections and malignancies. HIV infection is one of the major threats to human
health due to the lack of relevant vaccine and drugs to cure AIDS.
Highly active anti-retroviral therapy (HAART) strategy involves the use of
combination anti-retroviral agents for synergistic therapeutic outcomes. With the adoption of
HAART, the average survival of HIV/AIDS patients has increased from less than 1 year to over
10 years. Despite the success of HAART in the clinics, HIV/AIDS therapy is far from optimal.
One of the major problems in the chronic treatment is the fact that the viral particles are able to
reside in cellular and anatomical sites in the body following replication and remain viable even
when there are adequate drug concentrations in the blood1.
Although anti retro viral drug therapy has contributed significantly to
improve patient/disease management, its current use is associated with several disadvantages
and inconveniences to the HIV/AIDS patient. Many anti retro viral drugs suffer with drawbacks
like poor solubility, extensive first pass metabolism and gastrointestinal degradation leading to
low and erratic bioavailability18.
Solubility plays an important role in drug disposition, since the maximum rate of passive drug
transport across a biological membrane, is the product of permeability and solubility.
According to the biopharmaceutics classification system (BCS), aqueous solubility and
permeability are the most important parameters affecting drug bioavailability. Retrospective
studies show that greater than 40% of drug failures in development can be traced to poor
biopharmaceutical properties, mainly due to poor dissolution or poor permeability. Thus
improvement of aqueous solubility in such case is valuable goal to effectively formulate them
into bioavailable dosage forms. Hence, great efforts have been made to improve oral
bioavailability of poorly water soluble drugs by increasing their dissolution rate through various
techniques, such as the formulation of amorphous solid form, nanoparticles, microemulsions,
solid dispersions, melt extrusion, salt formation and formation of water‐soluble complexes etc.
Among them, the complexation with cyclodextrins is most frequently used2.
Cyclodextrins are cyclic oligosaccharides derived from starch, and contain α-1,4-linked α-Dglucopyranose units, the CD’s take the shape of a truncated cone or torus, rather than a perfect
cylinder. The primary hydroxyl group is oriented to the narrow edge of the cone at the exterior
and the secondary group to the wider edge. The central cavity of the CD molecule is lined with
skeletal carbons and ethereal oxygens of the glucose residue, which gives a relatively
lipophillic character. This cavity enables cyclodextrins to complex the ‘guest’ drug molecules
and in so doing alters the physicochemical properties of the drug3.
Some examples of marketed products containing cyclodextrin are4;
Cyclodextrin
type
Administration
route
Brand name
Market
OP-1206
(Oral) Tablet
Opalmon
Ono (Japan)
Alprostadil
i.v.
Caverject Dual
Pfizer (Europe)
Cefotiam-hexetil
HCl
PGE1
(Oral) Tablet
Pansporin T
Takeda (Japan)
Parenteral
solutions
Prostavastin
Schwarz (Europe)
Benexate HCl
Oral
Ulgut, Lonmiel
Japan
Dexamethasone
Dermal
Glymesason
Japan
Cephalosporin
Oral (Tablet)
Meiact
Seika(Japan)
Cetirzine
Chewing
tablet
Cetrizin
Losan Pharma
(Germany)
Chlordiazepoxide
Tablet
Transillium
Gador (Argentina)
Iodine
Solution
MenaGargle
Kyushin (Japan)
α -cyclodextrin
β -cyclodextrin
Piroxicam
Tablet,
suppository
Brexin,
Flogene,
Cicladon
Chiesi (Europe);
Aché (Brazil)
2Hydroxypropylβ-cyclodextrin
Cisapride
Rectal
Propulsid
Europe
Hydrocortisone
Buccal
Dexocort
Europe
Indomethacin
Eye
Indocid
Chauvin (Europe)
Mitomycin
Oral and i.v
MitoExtra,
Mitozytrex
Ovartis(Europe)
Itraconazole
Oral and i.v
Sporanox
Janssen (Europe,
USA)
17β-Estradiol
Nasal spray
Aerodiol
Europe
Chloramphenicol
Eye drops
Clorocil
Europe
Eye drop
Voltaren
Novartis (Europe)
i.v.
CardioTec
Bracco (USA)
Randomely
methylated
β cyclodextrin
2Hydroxypropylγ-cyclodextrin
(HPγCD)
Diclofenac
sodium salt
Tc-99
Teoboroxime
Sulfobutylether
β-cyclodextrin
sodium
salt
(SBEβCD)
Aripiprazole
im
Abilify
Maropitant
Parenteral
solution
Cerenia
Bristol-Myers
Squibb (USA);
Otsuka
Pharm. (USA)
Pfizer Animal
Health (USA)
The proposed project is aiming to improve the solubility, dissolution characters and
bioavailability of a poorly soluble antiretroviral drug by complexation with cyclodextrins.
6.2 Objective of Study:
The primary goal of this investigation would be to formulate and evaluate Antiretroviral
drug–cyclodextrin complexes.
The individual objectives to be achieved include:
1. Conducting preformulation studies of drug and cyclodextrins.
2. Conducting phase solubility studies according to method reported by Higuchi and
Connors.
2. Formulation of Antiretroviral drug-cyclodextrin complexes using various methods
like kneading, solvent evaporation, physical mixtures and heat treated method etc.
3. Characterization of formulated complexes using Infrared spectroscopy (IR),
Differential scanning Calorimetry (DSC), X-Ray Diffraction studies (XRD).
4. Conducting dissolution studies for the formulated complexes.
5. Conducting stability studies of the optimized formulation.
6.3 Review of Literature:
Lokamath K.M et al., studied the aqueous solubility and dissolution rate of Nevirapine(NVP),
a poorly soluble drug via complexation with β‐cyclodextrin (β‐CD). The complexation of NVP
with β‐CD was investigated by phase solubility studies in the presence and absence of PVP in
pH 1.2 and pH 6.8 as the NVP exhibited pH dependent solubility. Ternary complexes were
prepared by kneading method with addition of PVP (5%, 10% and 20% w/w of the solid
complex) to NVP: β‐CD (1:1M) systems. All solid complexes were characterized by
performing dissolution studies in 0.1N HCl and pH 6.8 and by analytical techniques such as
DSC, FT‐IR, P‐XRD and SEM. Both binary and ternary systems exhibited higher dissolution
rates in 0.1N HCl and pH 6.8 than their corresponding physical mixtures and pure drug2.
Rajashree Hirlekar et al., has done study on inclusion complexes of Valsartan with βcyclodextrin and hydroxypropyl β-cyclodextrin, Valsartan is a potent, highly selective
antagonist of angiotensin-2 AT1 receptor and lowers blood pressure in hypertensive patients.
And their study showed that improvement in solubility and dissolution rate of Valsartan using
β-cyclodextrin and hydroxypropyl β-cyclodextrin. Formation and characterization of solid
inclusion complexes were investigated by DSC, FTIR, Scanning electron microscopy (SEM),
Proton Nuclear Magnetic Resonance (HNMR) and in-vitro dissolution studies and inclusion
complexes obtained by co-evaporation method showed higher in-vitro drug dissolution rates5.
Shrikant P Beloshe et al., studied the inclusion complexes of pioglitazone with β CD were
prepared using the methods of kneading and co-precipitation. The formation of inclusion
complexes with β-CD in the solid state, were confirmed by infrared spectroscopy, partition
coefficient, and thin layer chromatography, and their dissolution rates were determined using
the USP basket method. The present invention relates to the study effect of the preparation
method on the dissolution profiles of pioglitazone HCL-β-cyclodextrin inclusion complexes3.
Gordon Becket et al., studied the in vitro dissolution of Praziquantel which is used for the
treatment of schistosomiasis. The aqueous solubility of Praziquantel was improved by forming
inclusion complexes with α-β-and-γ-cyclodextrins (CDs). These complexes were assessed and
confirmed by solubility analysis, FTIR, elemental analysis, Differential scanning calorimetry
and mass spectrometry. Dissolution of Praziquantel from α-β-and-γ-cyclodextrins complexes
was 2.6-, 5- and 8-fold greater respectively, than that of the pure drug. However, only the βcomplex had a stability constant in the optimum range for pharmaceutical use, suggesting that
the preferred complex for further development would be a water-soluble β-CD derivative6.
Nicolas Grancher et al., interesting study done by in vitro antiviral effects of complexes of
Ribavirin with α-β-and-γ-cyclodextrins against two clade. A laboratory strains of Measles virus
(MEV) grown on Vero cells. Complexation of ribavirin with α-β-and-γ-cyclodextrins lead to a
five-fold or two-fold decrease in the 50% inhibitory concentration respectively, against both
MEV strains7.
Alix Dubes et al., studied the synthesis and characterization of sulfated amphiphilic α-, β-, and
γ- cyclodextrins, cyclodextrins are cyclic oligosaccharides composed of D-glucopyranose
residues, linked into a macro cycle by α (1, 4) glycosidic bonds. The Cyclodextrins are well
known for their ability to interact with lipophilic molecules to form non-covalent inclusion (or
host-guest) complexes. Cyclodextrin complexes are currently used in the pharmaceutical
industry to improve aqueous stability, and bioavailability of drugs. Cyclodextrins are
chemically modified by introduction of sulfate groups onto the hydroxyl groups confers higher
aqueous solubility and a wide range of biological activities such as anti-inflammatory, antilipemic, anti-angiogenic, and antiviral properties. The antiviral activity of acyclovir with
sulfated Cyclodextrins has been studied for improvement of bioavailability8.
Mario jug et al., prepared solid piroxicam complexes with β- cyclodextrin and randomly
methylated β-cyclodextrin by freeze drying and characterized using Differential scanning
calorimetry, X-ray powder diffractometry. Piroxicam, a non-steroidal anti-inflammatory agent
is having poor water solubility. According to this study, molecular complexation of piroxicam
with β-cyclodextrin improved drug solubility, and therefore hastened piroxicam absorption,
resulting in a faster onset of action9.
Beatriz Pose-Vilarnovo et al., has done interesting study on Modulating drug release with
cyclodextrins in hydroxypropyl methylcellulose gels and tablets. Cyclodextrins have been
reported to modify transdermal drug penetration of many compounds by complexation. If the
drug is loaded in the vehicle in a concentration above saturation, Cyclodextrins can accelerate
its release by enhancing the proportion of diffusible species10.
H. Boudad et al., has studied the Combined hydroxypropyl-β-cyclodextrin and poly
(alkylcyanoacrylate) nanoparticles intended for oral administration of saquinavir Saquinavirloaded nanoparticles were prepared in the presence of drug-cyclodextrin complex. This study
found that large amounts of Cyclodextrins remained associated with the particles, resulting in a
20-fold increase in saquinavir loading compared to nanoparticles prepared in absence of
Cyclodextrins11.
Marcela Linares et al., studied the effects of the hydroxypropyl- β -cyclodextrin
on the solubility of 2-hydroxy-N-(5-methyl-3-isoxazolyl)- 1,4-naphthoquinone4-imine were investigated with I as an experimental drug for treatment of
cancer. Also the influence of the pH on the solubility- Increasing effect of the
CD was considered12.
Maria Veiga D et al., done interesting study regarding displacement of drug from its
cyclodextrin-based inclusion complex by a third substance such a surfactant. The dissolution
behaviors of tolbutamide- β cyclodextrin inclusion complex in demineralised water and in
aqueous solution of different surfactants were studied. Results suggested that simultaneous
presence of β cyclodextrin and surfactants of proper molecular structure in a pharmaceutical
formulation can give rise to unexpected dissolution of the drug13.
Beatriz Pose Vilarnovo et al., prepared Sulfamethizole solid inclusion complexes with βcyclodextrin and hydroxypropyl-β-cyclodextrin (HPBCD), characterized by freeze - drying.
Their drug dissolution characteristics were compared with those of
uncomplexed drug. The dissolution rates of Sulfamethizole was improved by the
complexation of β cyclodextrin and hydroxypropyl- β- cyclodextrin14.
Bencini M et al., has done interesting study on Preparation and in vitro evaluation of the
antiviral activity of the acyclovir complex of a β-cyclodextrin/ poly (amidoamine) copolymer.
Acyclovir, an acyclic guanine derivative inhibits herpes virus DNA polymerase which is used
in treatment of infections caused by herpes simplex virus (HSV-1 & HSV-2). Since acyclovir is
having poor water solubility it was complexed with poly (amidoamine) copolymer & β
cyclodextrin and the complexation was confirmed by DSC and FTIR analysis. The acyclovir- β
cyclodextrin/ poly (amidoamine) complex exhibited a higher solubility than free drug15.
Echezarreta Lopez M et al., prepared solid inclusion complexes of an orally active
immunomodulator like bropirimine with hydroxypropyl β cyclodextrin. The complexed
formulation showed greater dissolution rates compared to that of pure drug dissolution16.
Jennifer LH et al., prepared complexes of new hepatitis C drugs like Interferon and Ribavarin
which is insoluble and unstable in water, dissolved in glacial acetic acid. The acetic acid was
removed by rotoevaporation such that the drug exists primarily in the complexed form. The
stability of formulation was determined upon dry storage and after reconstitution in simulated
intestinal fluid (SIF), simulated gastric fluid (SGF), and water. Formulation was found to be
stable upon storage. The unique use of acetic acid and HPβCD results in a solid dosage form of
that is both soluble and stable in water17.
7.
Materials & Methods:
Drug: Antiretroviral drug.
Cyclodextrin: βCD, HPβCD etc.
Methods: Suitable methods for the preparation like Physical mixture, Kneading method,
Co-precipitation etc.
7.1 Source of Data:
Data will be obtained from the literature search and experimental work, which includes
preformulation studies, formulation, product evaluation, optimization and subjecting the
formulation to accelerated stability studies.
Data on drugs will be collected from drug information centre, physicochemical database and
literature search.
7.2 Method of Collection of Data (including sampling procedure, if any):
The physicochemical properties, of the drug will be collected from drug information
center, various standard Books, journals, websites and other sources like research literature
bases data such as Medline, Science Direct etc.
The experimental data will be collected from study of the drug; its formulation, through
investigation of the process and product variables in the laboratory of Krupanidhi College of
Pharmacy, Bangalore-35.
The steps involved in the methodology are:
1. Screening of a suitable antiretroviral drug.
2. Selection of suitable cyclodextrin’s like βCD, HPβCD etc.
3. Pre-formulation studies of the drug and cyclodextrins.
4. Conducting phase solubility studies according to the method reported by Higuchi
and Connors.
5. Formulation of antiretroviral drug-cyclodextrin complexes by methods like solvent
evaporation, kneading method, physical mixtures and heat treated method etc.
6. Evaluation of the complexes by Infra Red spectrophotometer (IR) and Differential
Scanning Calorimetry (DSC), X-Ray Diffraction studies (XRD).
7. Carrying out in vitro drug release studies.
8. Comparison of dissolution profiles with the pure drug.
9. Conducting stability studies of the optimized formulation.
7.3 Does the study require any investigations or interventions to be conducted on patients
or other human or animals? If so please describe briefly:
No.
7.4 Has the Ethical Clearance been obtained from your Institution in case of 7.3?
Not applicable.
8.
LIST OF REFERENCES:
1. Sharma A, Jain S, Modi M, Vashisht V, Singh H. Recent Advances in NDDS (Novel drug
delivery systems) for delivery of Anti-HIV drugs. Res J Pharm Biol Chem Sci 2010 Jul-
Sep;1(3):78-88.
2. Lokamatha K M, Bharathi A, Shantha Kumar S M, Rama Rao N. Effect of pvpk30 on
complexation and dissolution rate of nevirapine-β-cyclodextrin complexes. Int J Pharm Pharm
Sci 2010 Jun 26;2(4):170-176.
3. Beloshe SP, Chougule DD, Shah RR, Ghodke DS, Pawar ND, Ghaste RP. Effect of method
of preparation of pioglitazone HCL-β-cyclodextrin inclusion complexes. Asian j Pharm 2010
Apr-Jun:168-172.
4. Brewster ME, Loftsson T. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv
Rev 2007 Jul 30;59(7):645-666.
5. Nalawade P, Kadam V, Hirlekar R. Study of inclusion complexes of valsartan with βcyclodextrin and hydroxypropyl β-cyclodextrin. J Sci Ind Res 2010 Apr;69:295-299.
6. Becket G, Schep LJ, Tan MY. Improvement of the in vitro dissolution of praziquantel by
complexation with α-, β- and γ-cyclodextrins. Int J Pharm1999:65-71.
7. Grancher N, Venard V, Kedzierrewicz F, Ammerlaan W, Finance C, Faou AL et al.
Improved antiviral activity in vitro of ribavirin against measles virus after complexation with
cyclodextrins. Antiviral Res 2004;62(3):135-137.
8. Dubes A, Degobert G, Fessi H, Lopez HP. Synthesis and characterization of sulfated
amphiphilic α-, β-, and γ- cyclodextrins: application to the complexation of acyclovir.
Carbohydr Res 2003;338:2185-93.
9. Mario Jug, Lacan MB, Kwokal A, Cizmek BC. Influence of cyclodextrin complexation on
piroxicam gel formulations. Acta pharm 2005;55:223-36.
10. Pose-Vilarnovo B, Rodriguez-Tenreiro C, Rosa dos Santos J, Vazquez-Doval J, Concheiro
A, Alvarez-Lorenzo C et al. Modulating the drug release with cyclodextrins in hydroxypropyl
methycellulose gels and tablets. J Control Release 2004;94:351-63.
11. Boudad H, Legrand P, Lebas G, Cheron M, Duchene D, Ponchel G. combined
hydroxypropyl-β-cyclodextrin and poly (alkylcyanoacrylate) nanoparticles intended for oral
administration of saquinavir. Int J Pharm 2001;218:113-24.
12. Linares M, Bertorello MM, Longhi M. Solubilization of naphthaquinones by complexation
with hydroxypropyl-β-cyclodextrin. Int J Pharm 1997;159:13-8.
13. Veiga MD, Ahsan F. Influence of surfactants (present in the dissolutiuon media) on the
release behavior of tolbutamide from its inclusion complex with β-cyclodextrin. Eur J Pharm
Sci 2000;9:291-9.
14. Pose-Vilarnovo B, Perdomo Lopez I, Echezarreta Lopez M, Schroth Pardo P, Estrada E,
Torres-Labandeira JJ et al. Improvement of water solubility of sulfamethizole through its
complexation with β- and hydroxypropyl-β-cyclodextrin characterization of the interaction in
solution and in the solid state. Eur J Pharm Sci 2001;13:325-31.
15. Bencini M, Ranucci E, Ferruti P, Trotta F, Cornaglia M et al. Preparation and in vitro
evaluation of the antiviral activity of the acyclovir complex of a β-cyclodextrin/ poly
(amidoamine) copolymer. J Control Release 2008;126:17-25.
16. Echezarreta-Lopez M, Torres-Labandeira JJ, Castineiras-Seijo L, Vila-Jato JL.
Complexation of the interferon inducer, bropirimine with hydroxypropyl-β-cyclodextrin. Eur J
Pharm Sci 2000;9:381-6.
17. Johnson JL, He Y, Jain A, Yalkowsky SH. Improving cyclodextrin complexation of a New
Antihepatitis Drug With Glacial Acetic acid. AAPS Pharm Sci Tech 2006;7(1):E18.
18. Ojewole E, Mackraj I, Naidoo P, Govender T. Exploring the use of novel drug delivery
systems for antiretroviral drugs. Eup J Pharm BioPharm 2008;70:697-710.
9.
Signature of the candidate:
(Sushanth.M.S)
(((Rajesh
10.
Remarks of the Guide:
Cyclodextrins are having wide pharmaceutical applications. Nearly 30 pharmaceutical products
of cyclodextrins are available in the market globally. The present investigation would be
providing an insight into improving solubility of poorly soluble anti retro viral drug, and is
having great potential for introduction into market. Therefore, it is recommended for necessary
clearance.
11.
Name & Designation (in BLOCK LETTERS)
11.1 Guide
Mrs. BHARANI S SOGALI,
ASSISTANT PROFESSOR,
Department of Pharmaceutics,
Krupanidhi College of Pharmacy,
Bangalore – 560035.
11.2 Signature of guide
11.3 Head of the Department
Prof. Dr.R.S THAKUR
PROFESSOR AND HEAD
Department of Pharmaceutics
Krupanidhi College of Pharmacy
Bangalore – 560035.
11.4 Signature of HOD:
12.
12.1 Remarks of the Principal:
The program and the that Mr. Rajesh
12.2 Signature of the Principal
Prof. Dr. PREMKUMAR N
Principal
Krupanidhi College of Pharmacy
Chikka Bellandur,
Carmelaram Post,
Varthur Hobli,
Bangalore – 560035.