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“FORMULATION AND EVALUATION OF SORAFENIB TABLETS”
M. Pharm. Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Bangalore
Karnataka
By
Mr. BHAGATH REDDY SEELAM, B. Pharm.
Under the Guidance of
Mr. RAJASHEKHAR VALLURU
(Assistant Professor)
``
DEPARTMENT OF PHARMACEUTICS
EAST WEST COLLEGE OF PHARMACY
BANGALORE -560091.
2011-2013.
1
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1
Name of candidate and address
(In Block Letters)
Mr.BHAGATH REDDY SEELAM,
H.NO: 2-112,
KALAMALACHERUVU (V),
GARIDEPALLY (M),
NALGONDA (D)-508201,
ANDHRA PRADESH.
2
Name of the Institute
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560091.
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Course of study and subject:
M.PHARM (PHARMACEUTICS)
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Date of admission of course:
30-04-2011
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Title of the topic:
“FORMULATON AND EVALUATION OF SORAFENIB
TABLETS”
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Brief Resume of this intended work:
6.1 Need for the study
6.2 Review of Literature
6.3 Objectives of study
Enclosure-I
Enclosure-II
Enclosure-III
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Materials and Methods:
7.1 Source of data
Enclosure-IV
7.2 Method of collection of data (Including sampling procedure, if any)
Enclosure-V
7.3 Does the study require any investigation or interventions to be conducted on
patients of humans or animals? If so, please describe briefly.
---------NO---------7.4 Has ethical clearance been obtained from your institution in case of 7.3?
-------NOT APPLICABLE-------
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List of References
Enclosure-VI
2
9
Signature of the candidate
( BHAGATH REDDY SEELAM )
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Remarks of the Guide
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Name and designation of
(in block letters)
11.1 Guide
The proposed research work will be carried out in the
Academic Laboratory and is recommended for
approval and registration
Mr. RAJASHEKHAR VALLURU
ASSISTANT PROFESSOR,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091.
11.2 Signature
11.3 Co-Guide (if any)
------NA------
11.4 Signature
------------
11.5 Head of Department
DR. JAGADEESH G. HIREMATH
PROFESSOR & DIRECTOR,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091.
11.6 Signature
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12.1 Remarks of the
Chairman/Principal
The proposed research work will be carried out in
the Academic Laboratory and is recommended for
approval and registration
12.2 Signature
PROF. K. A. SRIDHAR
PRINCIPAL,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091.
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ENCLOSURE-I
6) Brief resume of the intended work:
6.1) Need for the study:
The modern-day approach to cancer management is a multidisciplinary one, consisting primarily
of surgery, radiation and chemotherapy. Chemotherapy is a major therapeutic approach for the
treatment of a wide range of cancers. Conventional-release tablets are expected to achieve fast
tablet disintegration which would dissolve rapidly in the gastrointestinal tract for absorption into
the blood stream.
Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenic activity and
has demonstrated potent anti-tumour activity in advanced hepatocellular carcinoma, renal cell
carcinoma, breast cancer, lung cancer, and colorectal cancer, all of which are known to exhibit a
dysregulated raf pathway and upregulated angiogenesis.1 Chemically it is 4-(4-{3-[4-Chloro-3(trifluoromethyl)
phenyl]
ureido}
phenoxy)-N2-methylpyridine-2-carboxamide
4-
methylbenzenesulfonate. Sorafenib is insoluble in aqueos media, practically insoluble in ethanol
and soluble in PEG 400, dimethylsulfoxide, and dimethylformamide. The mean relative
bioavailability is 38-49% when compared to an oral solution. It exhibits oral absorption with rapid,
uniform and absolute bioavailability nearly 28-39%. Its mean elimination half life is about 25-48
h.2
The rate and extent of dissolution of the drug from any solid dosage form determines the rate and
extent of absorption of the drug, in case of poorly water soluble drugs, dissolution rate is limiting
step in the process of drug absorption, potential bioavailability problem a relevant with extremely
hydrophobic drug due to erratic and incomplete absorption from GIT. A number of drugs have
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been successfully applied to improve the solubility, dissolution rate and consequently the bio
availability of poorly water soluble drugs, when converted to solid dispersion (SD), complexation,
crystallisation or by using various surfactants. Because of poorly aqueous solubility of sorafenib
may possess dissolution related absorption problem, hence an attempt is made to improve the
solubility and dissolution of sorafenib.
The current aim is to enhance the solubility of sorafenib by suitable techniques like solid
dispersion or, using surfactants or by any suitable method and to carry out their in-vitro
characterization.
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ENCLOSURE-II
6.2) Review of literature:
Extensive literature review was made for understanding the study and there has been for various
drugs like diclofenac sodium, paracetamol, sorafenib, etc. Literature review made by referring to
various national and international Journals, Databases such as International Pharmaceutical
Abstracts, SciFinder and various other web resources along with general books for pharmaceutical
scientists.
Richly et al., have developed sorafenib, an oral multikinase inhibitor, shows efficacy in renal cell
carcinoma (RCC) and hepatocellular carcinoma (HCC) and is well tolerated when combined with
doxorubicin in other solid tumours. Eighteen patients with inoperable HCC received doxorubicin
60 mg/m2 IV for up to six 3-week cycles. Sorafenib 400 mg bid was administered continuously
starting day 4. Patients discontinuing doxorubicin were eligible for sorafenib monotherapy. The
most frequent grade 3-4 drug-related adverse events were neutropaenia (61%), leukopaenia (45%)
and diarrhoea (17%, grade 3). Seven of eight patients who completed six cycles of doxorubicin
continued treatment with sorafenib for at least 3 months. Doxorubicin moderately increased AUC
(21%) and Cmax (33%) when administered with sorafenib. The disease control rate were
evaluated on 16 patients found to be 69%. Sorafenib plus doxorubicin appears to be well tolerated
and more effective in the treatment of HCC than doxorubicin. Follow-up with single-agent
sorafenib in these patients also appears to be well tolerated.1
Arranz et al., have studied about sorafenib in renal cell carcinoma. Metastatic renal cell
carcinoma is resistant to conventional treatment with chemotherapy. Recently the use of
molecular-targeted therapies with multikinase inhibitors has been recommended as first choice
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therapy because they inhibit cell proliferation and tumour angiogenesis. Sorafenib is a well
tolerated tyrosine kinase inhibitor that initially demonstrated efficacy in the treatment of patients
with metastatic RCC who progressed after immunotherapy. Expanded-access studies in europe and
north america showed the safety and efficacy of sorafenib in special populations such as elderly,
renal failure and cerebral metastases, as well as patients with no prior therapy. No cross-resistance
has been suggested in non-randomized trials when used in second line treatment after other
targeted therapies. Ongoing clinical trials will better define the role of sorafenib in first and second
line either as monotherapy or in combination, as well as the best strategies for the sequential use of
this drug.3
Mousa et al., studied the sorafenib a multikinase inhibitor, tested and found effective in other solid
tumours recently found to be significantly improved the survival of the patients with advanced
HCC. Sorafenib exerts its action through inhibition of several kinases involved in both tumour cell
proliferation and angiogenesis. It was well tolerated at a dose of 400 mg twice daily and permanent
discontinuation of the drug was rarely required.4
Liu et al., have prepared sorafenib self-micro emulsifying drug delivery system and its relative
bioavailability in rats. Sorafenib is a novel antitumor drug, which is poorly absorbed in the
gastrointestinal tract due to its low solubility in water. To improve the bioavailability of sorafenib,
they prepared a self-micro emulsifying drug delivery system (SMEDDS) formulation of sorafenib
and its relative bioavailability in rats was evaluated. They concluded that SMEDDS is a promising
vesicle for the oral delivery of the poorly soluble antitumor drug sorafenib.5
Choi et al., have prepared felodipine solid dispersions in the presence of various carriers.
Dichloromethane is not needed when HPMC solid dispersions were produced using the solvent
wetting method. The amount of ethanol used to prepare solid dispersions did not have a significant
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effect on the dissolution rate of felodipine. The results of X-ray diffraction and thermal analysis
indicated that the drug was in the amorphous state when PVP, HPMC, and poloxamer were used
as carriers. The dissolution rates of felodipine in PVP, HPMC, or poloxamer solid dispersions
were much faster than those for the corresponding physical mixtures. However, dissolution
profiles were found to depend on the carrier used; the dissolution rate of felodipine increased
slowly for solid dispersions prepared using HPMC, whereas rapid initial dissolution rates were
observed for solid dispersions prepared using PVP or poloxamer. Increased the dissolution rate
was partly dependent on the ratios of felodipine to carrier. No significant changes in crystal form
was observed by X-ray diffraction or thermal analysis, and no significant changes in dissolution
rate was observed when sorbitol and mannitol were used as carriers.6
Prasad et al., have formulated solid dispersion tablet of terbinafine hydrochloride by using carriers
polyethylene glycol 6000 (by melting method) and polyvinyl pyrrolidone K 30 (by solvent
method) in the drug carrier ratio of 1:1, 1:2 and 1:3. Prepared solid dispersions were characterized
for their drug content, thermal studies, infrared spectral studies, differential scanning calorimetric
studies, aqueous solubility studies and in-vitro release studies. From their results, it was clear that
solid dispersion formulation showed improved dissolution rate than pure drug and physical
mixture. The solid dispersion showed better release profile was chosen to formulate into a tablet
dosage form of weight 600 mg. The tablets compressed were evaluated for its physical parameters
like thickness, hardness, weight variation, friability, drug content and disintegration tests. They
performed dissolution profile of formulated tablet, compared with the marketed product. The
formulated tablet showed better release profile than the marketed product.7
Akiladevi et al., have developed solid dispersion of paracetamol by physical triturating method,
and fusion method using 1:1, 1:4 and 1:5 ratios of drug and polymers (PEG 4000, PEG 6000 and
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urea). The solid dispersion (SD) was characterized for physical appearance, solubility, IR, and invitro dissolution studies. FTIR study revealed that drug was stable in SDs. They found drug
content was high and uniformly distributed in the all formulation. In-vitro dissolution studies were
carried using USP type XXVII (paddle) type dissolution apparatus. They prepared dispersion
showed marked increase in the dissolution rate of paracetamol than that of pure drug. The
dispersion with PEG 6000 (1:5) by fusion method showed faster dissolution rate (107.26%) as
compared to other dispersions with PEG 4000 and urea (1:4 and 1:5) whichever prepared by
physical mixture (PM) and fusion method. Of the three carriers used, dissolution of the drug was
more in PEG 6000 based SDs. They concluded that dissolution of the Paracetamol can be
improved by the solid dispersion and PEG 6000 based solid dispersions were more effective in
enhancing the dissolution.8
Paradkar et al., developed solid dispersions (SDs) of glibenclamide (GBM); a poorly watersoluble drug and polyglycolized glycerides (Gelucire®) with the aid of silicon dioxide (Aerosil®
200); as an adsorbent, prepared by spray drying technique. They compared SDs and spray dried
GBM with pure GBM and corresponding physical mixtures. Initial characterization of SDs and
spray dried GBM by DSC and XRPD showed that GBM was present in its amorphous form
(AGBM). They observed improvement in the solubility and dissolution rate for all samples.
DRIFT spectroscopy revealed presence of hydrogen bonding in SDs. During their study, almost no
decrease in the in-vitro drug dissolution was observed, over the period of 3 months as compared
with freshly prepared SDs. They observed slight crystallinity in SDs in the DSC and XRPD studies
during ageing. Their study demonstrated the high potential of spray drying technique for obtaining
stable free flowing SDs of poorly water-soluble drugs using polyglycolized glycerides carriers
with the aid of silicon dioxide as an adsorbent.9
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Moneghini et al., have developed gas anti solvent crystallisation technique (GAS), using
supercritical carbon dioxide as processing medium, for preparation of enhanced release dosage
form for poorly soluble carbamazepine, employing PEG 4000 as a hydrophilic carrier. They
performed physical characterisation of the systems using laser granulometer, powder X-ray
diffraction, thermal analyses, and scanning electron microscopy in order to understand the
influence of this technological process on the physical status of the drug. Results of the physical
characterisation attested a substantial correspondence of the solid state of the drug before and after
treatment with GAS technique, whereas a pronounced change in size and morphology of the drug
crystals was noticed. The dramatic reduction of the dimensions and the better crystal shape,
together with the presence of the hydrophilic polymer determined a remarkable enhancement of
the in-vitro drug dissolution rate.10
Xie et al., have prepared solid dispersions of esomeprazole zinc (SDEZ) in polyethylene glycol
4000 (PEG 4000) with different EZ to PEG 4000 ratios by solvent method. Their studies showed
that dissolution rate of EZ were distinctively increased in the solid dispersion system compared to
that in pure EZ or physical mixtures. The increase of dissolution rate was obviously related to the
ratio of EZ to PEG 4000. Their result suggests that SDEZ-EC has a lower absorption rate than
nexium (an enteric-coated tablet of esomeprazole magnesium which is commercially available in
market) and corresponds with the in-vitro dissolution.11
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ENCLOSURE-III
6.3) Objective of the study:
The present study is planned with the following objectives:
 To increase the solubility (S) by solid dispersion technique.
 To prepare conventional Sorafenib tablets by suitable method.
 To carry out the pre compression studies of granules if necessary.
 To carry out the post compression studies for the formulated tablets.
 To carry out in-vitro drug release studies for the prepared formulations.
 The prepared tablet is compared with marketed product.
 Fitting the data to various kinetic equations and to find the release parameters.
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ENCLOSURE-IV
7) Materials and Methods:
Materials:
Drug
: Sorafenib
Polymers: Natural/synthetic polymers like micro crystalline cellulose, croscarmellose sodium,
hypromellose, sodium lauryl sulphate, or any other suitable polymers.
Methods:
Development of sorafenib tablet will be carried out using different polymers with different
techniques like solid dispersion or, by using various surfactants or any suitable methods and invitro evaluation tests will be carried out for the prepared tablets.
7.1) Source of data:
Data is collected from:

RGUHS Library.

Science direct & other internet facilites.

National and international research and review publications.

Poster presentations.

Textbooks and reference books.
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ENCLOSURE-V
7.2) Method of collection of data:
 Standardization, selection, process development, stabilization of polymer and preparation of
sorafenib conventional tablets.
 Evaluation of precompression and postcompression parameters for developed formulations
are as follows:
Pre compression parameters:
 Angle of repose
 Bulk density
 Tapped density
 Porosity
 Tapped porosity
 Compressibility index
Post compression parameters:
 Weight variation
 Hardness
 Thickness
 Friability
 Disintegration
 Estimation of drug content in the developed formulation.
 To carry out in-vitro drug release studies for the prepared formulations.
 Fitting the data to various kinetic equations and to find the release parameters.
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ENCLOSURE- VI
8) List of References:
1. Richly H, Schultheis B, Adamietz IA, Kupsch P, Grubert M, Hilger RA et al.,
Combination of sorafenib and doxorubicin in patients with advanced hepatocellular
carcinoma. Results from a phase I extension trial. Eur J Cancer 2009;45:579-87.
2. http://dailymed.nlm.nih.gov.
3. Arranz JA, Climent MA, Gonzalez-Larriba JL, Leon L, Maroto JP. Sorafenib in renal cell
carcinoma. Cr Rev Oncol Hem 2011;80:314-22.
4. Mousa AB. Sorafenib in the treatment of advanced hepatocellular carcinoma. Saudi J
Gastroenterol 2008;14(1):40-2.
5. Wang XQ, Liu YO, Fan JM, Zhang Q. Preparation of sorafenib selfmicroemulsifying drug
delivery system and its relative bioavailability in rats. J Chin Pharm Sci 2011;20:164-70.
6. Choi HK, Kim EJ, Chun MK, Jang JS, Lee IH, Lee KR. Preparation of a solid dispersion
of felodipine using a solvent wetting method. Eur J Pharm Biopharm. 2006;64:200-05.
7. Prasad KA, Narayanan N, Rajalakshmi G. Preparation and evaluation of solid dispersion of
terbinafine hydrochloride. Int J Pharm Sci Rev Res 2010;3:130-34.
8. Akiladevi D, Shanmugapandiyan P, Jebasingh D, Basak S. Preparation and evaluation of
paracetamol by solid dispersion technique. Int J Pharm Pharm Sci 2011;3:188-91.
9. Paradkar A, Shimpi S, Chauhan B. Preparation and evaluation of glibenclamide
polyglycolized glycerides solid dispersions with silicon dioxide by spray drying technique.
Eur J Pharm Sci 2005;26:219-30.
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10. Moneghini M, Kikic I, Voinovich D, Perissutti B, Grcic JF. Processing of carbamazepine–
PEG
4000
solid
dispersions
with
supercritical
carbon
dioxide.
Preparation,
characterisation, and in-vitro dissolution. Int J Pharm 2001;222:129-38.
11. Song H, Xie Y, Xie P, Song X, Tang X. Preparation of esomeprazole zinc solid dispersion
and study on its pharmacokinetics. Int J Pharm 2008;360:53-57.
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