Download annexure – ii

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
BANGALORE
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1.
Name of the Candidate
and Address:
AZMI SULTANA
#7, 14th Cross, 5th main, Wilson Garden
Bangalore – 560 030
2.
Name of the Institution:
Al-Ameen College of Pharmacy,
Hosur Road, Bangalore – 560 027.
3.
Course of Study and Subject:
M. Pharm – Pharmaceutics
4.
Date of Admission:
6th July 2010
5.
Title of the Topic:
“Formulation and Evaluation of solid lipid microparticles of curcuminsoya lecithin complex”
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6.0
Brief resume of the intended work:
6.1 – Need for the study:
Curcumin, a hydrophobic polyphenolic compound present in the rhizomes of turmeric
(Curcuma longa Linn.), has a wide biological and pharmacological profile.
Curcumin an orange yellow powder has a molecular weight of 368.38 Daltons and a
melting point of 183ºC. It is practically insoluble in water, but it is soluble in ethanol,
acetone and glacial acetic acid. Curcumin is unstable at neutral and basic pH values. It
undergoes photo degradation when exposed to light.
Chemically, curcumin is a bis-α, β- unsaturated β di ketone (commonly called
diferuloylmethane), which exhibits keto-enol tautomerism having a predominant keto form
in acidic and neutral solutions. In basic pH enolate form of curcumin predominates and acts
as a powerful electron donor a mechanism typical for antioxidants.
Many clinical study reports have revealed that curcumin has many beneficial properties; for
example-
anticarcinogenic,
antioxidant,
anti-inflammatory,
hypocholestrolomeic,
antibacterial, hepatoprotective etc. It is also known that process of inflammation has been
shown to play a major role in most chronic illnesses, including neurodegenerative,
cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases thus curcumin
is also used in the treatment of these diseases. Phase 1 clinical trials have shown that
curcumin is extremely safe at very high doses in humans but exhibit poor bioavailability. 3
Despite the promising safety and biological effects of curcumin, its poor oral bioavailability
has restricted its use in the management of human ailments. Poor oral absorption due to its
extremely low aqueous solubility or extensive pre systemic metabolism may be responsible
for the unfavourable pharmacokinetics of this molecule. 3
2
Keeping in view, the promise of curcumin as a therapeutically active agent and its poor oral
absorption, it is pertinent to develop a formulation of curcumin which can increase
its solubility and stability in GI and thus enhance its bioavailability.
In this case, improved bioavailability can be achieved by the use of delivery systems, which
can enhance the rate and/or the extent of drug solubilizing into aqueous intestinal fluids.
Phospholipids play a major role in drug delivery technology. There are numerous
advantages of phospholipids in addition to solubilizing property while considering them for
a carrier system. In the present experiment curcumin–phospholipid complex will be
prepared by a simple and reproducible method. The prepared complex possesses enhanced
aqueous solubility and stability. 1,2
Solid lipid Microparticles (SLM) represents an alternative carrier system to the traditional
carriers such as emulsions, liposomes, polymeric micro and nanoparticles. SLMs consist of
a biocompatible lipid core and an amphiphilic surfactant as an outer shell. SLM are
composed of 0.1% (w/w) to 30% (w/w) solid lipid dispersed in an aqueous medium and if
necessary stabilized with preferably 0.5% (w/w) to 5% (w/w) surfactant. SLMs have
attracted increasing attention as a potential drug delivery carrier owing to their advantages
such as increased drug stability, low toxicity and possibility of simple and large scale
production.
Thus when the above formed curcumin soya lecithin complex is incorporated into solid
lipid microparticles (SLM) by hot melt method or microemulsion method the
pharmacokinetic parameters and the stability of curcumin can further be enhanced. 11
In the present study an attempt will be made to design, develop and evaluate the Solid lipid
microparticles containing curcumin soya lecithin complex in order to improve the solubility
and thus bioavailability.
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6.2 REVIEW OF LITERATURE

Bharat B. Aggarwal, et al. showed that curcumin regulates numerous transcription
factors, cytokines, protein kinases, adhesion molecules, redox status and enzymes
that have been linked to inflammation. The process of inflammation has been
shown to play a major role in most chronic illnesses, including neurodegenerative,
cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. In the
current review, we provide evidence for the potential role of curcumin in the
prevention and treatment of various proinflammatory chronic diseases.1

Ying-Jan Wang, et al. studied the stability of curcumin in buffer solutions and
characterised the degradation products. When curcumin was incubated in 0.1M
phosphate buffer and serum free medium, pH 7.2 at 37ºC, about 90% decomposed
within 30 min. A series of pH conditions varying from 3 to 10 were tested and
results showed decomposition was pH dependent and occurred faster at neutral pH
conditions. It is more stable in cell culture medium containing 10% fatal calf serum
and in human blood; less than 20% of curcumin decomposed in 1 hr. and after
incubation for 8 hrs. 50% of curcumin is still remained.4

Akira Asai, et al investigated the absorption and metabolism of orally administered
curcuminoids in rats. After enzymatic hydrolyses the predominant metabolites in
plasma following administration were glucuronides and glucuronide/sulfates of
curcuminoids. The plasma concentrations of conjugated curcuminoids reached a
maximum one hour after administration. The conjugative enzyme activities for
glucuronidation and sulfation of curcumin were found in liver, kidney and intestinal
mucosa. These results indicate that orally administered curcuminoids are absorbed
from the alimentary tract and present in the general blood circulation after largely
being metabolized to form glucuronide and glucuronide/sulfate conjugates.6

Shaiju K. Vareed, et al. examined the pharmacokinetics of a curcumin preparation
in healthy human volunteers 0.25 to 72 h after a single oral dose. Curcumin was
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administered at doses of 10 g (n = 6) and 12 g (n = 6). Serum samples were assayed
for free curcumin, for its glucuronide, and for its sulfate conjugate by HPLC
technique. The data were fit to a one compartment absorption and elimination
model. only one subject had detectable free curcumin at any of the 14 time points
assayed, but curcumin glucuronides and sulfates were detected in all subjects. The
curcumin conjugates were present as either glucuronide or sulfate, not mixed
conjugates.7

Lee, et al. studied antiallergic property of curcumin and showed that Curcumin
inhibits Syk kinase–dependent signalling events in mast cells and might thus
contribute to its antiallergic activity. Therefore curcumin might be useful for the
treatment of mast cell–related immediate and delayed allergic diseases. In this
respect curcumin has similar potential for topical therapy of various allergic
diseases, including allergic rhinitis, especially in view of its low toxicity in human
subjects. Curcumin is a potent inhibitor of antigen-stimulated degranulation and
cytokine secretion in mast cells and of mast cell–mediated PCA in mice. A key
action appears to be its ability to inhibit Syk kinase activation and downstream
signals in mast cells. These and the known anti-inflammatory properties of
curcumin suggest that further evaluation of its utility in the treatment of immediate
and delayed allergic diseases is warranted.8

Kurd, et al. stated that, although in vitro curcumin has been shown to block
pathways necessary to develop psoriasis, it is possible that oral administration will
not produce a desired clinical effect because of low bioavailability. Animal
experiments suggest that concentration of the drug absorbed is independent of dose,
40% to 90% of orally administered curcumin is excreted in stool. It is possible that
combining oral curcumin with agents that may enhance its absorption may result in
better efficacy. Furthermore, new liposomal formulations of curcumin may enhance
oral bioavailability and should be considered for future trials. 9

P. Anand et al. has detailed in this review, curcumin can modulate multiple cellular
signaling pathways and interact with numerous molecular targets. Thus, it may have
the potential to act against a large number of cancers. In vitro, in vivo, and human
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clinical studies have all established curcumin’s promise and revealed its therapeutic
value. More extensive randomized clinical trials are now needed. The safety, low
cost, and already proven efficacy of this ‘‘age old” natural medicine makes it a
promising agent for the treatment of an ‘‘old-age” disease like cancer.10

Kumar et al stated that the purpose of present study was to prepare and characterize
the complex between curcumin and soya lecithin, and to evaluate its
hepatoprotective activity. The prepared complex provided a 3-fold increase in
solubility of curcumin. On evaluation of in vitro intestinal permeability of curcumin
across the everted sheep gut sac, the complex was found to provide the higher
intestinal permeation of curcumin. On in vivo evaluation of curcumin-soya lecithin
complex in paracetamol-induced hepatotoxicity in mice, it was observed that the
complexed curcumin afforded a significantly higher protection against paracetamolinduced rise in serum aspartate aminotransferase and alanine aminotransferase
levels as compared to pure curcumin.1

K. Maiti et al. has stated that a novel formulation of curcumin in combination with
the phospholipids was developed to overcome the limitation of absorption and to
investigate the protective effect of curcumin–phospholipid complex on carbon
tetrachloride induced acute liver damage in rats. The antioxidant activity was
evaluated by measuring various enzymes in oxidative stress condition. Curcumin–
phospholipid complex significantly protected the liver by restoring the enzyme
levels of liver glutathione system and that of superoxide dismutase catalase. The
complex provided better protection to rat liver than free curcumin at same doses.
Serum concentration of curcumin obtained from the complex was higher than pure
curcumin and the complex maintained effective concentration of curcumin for a
longer period of time in rat serum. The result proved that curcumin phospholipid
complex has better hepatoprotective activity, than free curcumin at the same dose
level.2
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
V R Yadav, et al. stated curcumin-loaded SLMs were prepared by a micro emulsion
technique. The process parameters, such as the amount of lipid and surfactant, were
crucial factors for the resulting mean particle size and the efficacy of drug
incorporation. At optimal conditions, the mean particle size of curcumin loaded
SLMs was 108 mm and incorporation efficacy of curcumin was 79.24% (w/w). The
release kinetics of curcumin from a lipid base could be fitted with Higuchi’s squareroot model and showed that approximately 79.24% of curcumin was released within
12 h with a 24.1% burst release within the first hour, suggesting that most of the
curcumin was still incorporated in the SLMs.
Formulation F4 exhibited anti-
angiogenic properties, which was found to be greater than those of the pure drug. In
in-vivo studies using a rat colitis model, the SLM formulation-treated group showed
a faster weight gain than the DSS control. This study has demonstrated that the
degree of colitis caused by administration of DSS was significantly attenuated by
the SLM formulation of curcumin.
6.3 OBJECTIVE OF STUDY
To formulate solid lipid microparticles of curcumin-soya lecithin complex and evaluate its
stability and bioavailability.
SPECIFIC OBJECTIVES
1. Preparation of curcumin- soya lecithin complex.
2. Evaluation of the complex.
3. Evaluation of novel lipids for preparation of SLM.
4. Preparation of SLM.
5. To evaluate the permeability of the formulation topically using rat abdominal skin
6. To evaluate the oral bioavailability of curcumin using sheep intestine.
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7.0 Materials and Methods
7.1 Source of Data:
I. Review of Literature from
a. Journals - such as

Science Direct.

Scopus.

J-Gate@HELINET

PubMed.

Journal of Pharmaceutical and Biomedical Analysis.

International Journal of Biochemistry & Cell Biology.

International Journal of Pharmaceutical Sciences.
b. Internet Browsing.
www.google.com
7.2 - Method of collection of data:

From Literature

Laboratory based studies including:
1. Preformulation studies
a) Standardization of method of estimation of curcumin.
b) Phase solubility studies, profile, IR of pure drug.
c) Evaluation of drug excipient interaction by IR
2. Preparation of curcumin soya lecithin complex.
3. Evaluation of prepared complex for solubility studies, drug content.
Characterization of complex by IR, NMR and DSC.
4. Preparation of solid lipid microparticles of curcumin-soya lecithin complex.
5. Evaluation of SLM- Drug content, particle size distribution, drug entrapment
efficiency, SEM, DSC, x ray diffraction study, In vitro release study.
7.3 - Does the study require any investigations or interventions to be conducted on patients
or other humans or animals? If so, Please describe briefly.
Permeability of the SLM containing curcumin-soya lecithin complex is studied using rat
abdominal skin
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7.3 – Has ethical clearance been obtained from your Institution in case of 7.3?
Yes
8.0
Bibliography
1. Kumar M, Ahuja M, Sharma SK. Hepatoprotective Study of Curcumin-Soya
Lecithin Complex. Sci Pharm. 2008; 76: 761-74
2. Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK. Curcumin phospholipid
complex: Preparation, therapeutic evaluation and pharmacokinetic study in rats. Int
J Pharm 2007; 155–63
3. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of
Curcumin: Problems and Promises. Mol Pharm 2007 September 27; 4 (6):807–18
4. Wang YJ, Pan MJ, Cheng AL, Linn LI, Ho YS, Hseih CY et al. Stability of
curcumin buffer solutions and characterization of its degradation products.
J.
Pharm. Biomed. Anal. 15 1997: p. 1867-76.
5. Asai A, Miyazawa T. Occurrence of orally administered curcuminoid as
glucuronide and glucuronide/sulphate conjugates in rat plasma. Life Sci. 2000;
2785–93
6. Vareed SK, Kakarala M, Ruffin MT, Crowell JA, Normolle DP, Djuric Z et al.
Pharmacokinetics of Curcumin Conjugate Metabolites in Healthy Human Subjects.
Cancer Epidemiol Biomarkers Prev 2008 June; 1411-17
7. Lee JH, Kim JW, Ko NY, Mun SH, Her ME, Kim PBK et al. Curcumin, a
constituent of curry, suppresses IgE-mediated allergic response and mast cell
activation at the level of Syk. J Allergy Clin Immunol 2008 may; 121:1225-31
8. Kurd SK, N Smith, Voorhees AV, Troxel AB, Badmaev V, Seykora JT et al. Oral
curcumin in the treatment of moderate to severe psoriasis vulgaris: A prospective
clinical trial. J AM ACAD DERMATOL 2008 April;58:625-31
9. Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB. Curcumin and
cancer: An ‘‘old-age” disease with an ‘‘age-old” solution. Cancer Letters 2008;
133–64.
10. Yadav VR, Suresh S, Devi K and Yadav S. Novel formulation of solid lipid
microparticles of curcumin for anti-angiogenic and anti-inflammatory activity for
optimization of therapy of inflammatory bowel disease. J Pharm Pharmacol 2009;
61: 311–21
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Signature of the candidate:
(AZMI SULTANA)
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Remarks of the Guide:
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Name and Designation of:
11.1 Institutional Guide:
Recommended for Approval
Dr. (Mrs.) ROOPA S. PAI
Professor, Department of Pharmaceutics,
Al-Ameen College of Pharmacy,
Bangalore- 560027
11.2 Signature:
11.3 Head of the Department:
Dr. (Mrs.) V. KUSUM DEVI
Professor and Head,
Department of Pharmaceutics,
Al-Ameen College of Pharmacy,
11.4 Signature:
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12.1 Remarks of the Chairman and
Principal:
12.2 Signature:
Forwarded to the University for scrutiny
Prof. B. G. SHIVANANDA
Principal
Al-Ameen College of Pharmacy,
Hosur Road, Bangalore – 560 027.
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