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Effect of carriers on etodolac dissolution from binary and ternary based formulations: in-vitro characterization


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EFFECT OF CARRIERS ON ETODOLAC DISSOLUTION FROM BINARY AND TERNARY BASED FORMULATIONS: IN-VITRO CHARACTERIZATION”

M. Pharm. Dissertation Protocol Submitted to


Rajiv Gandhi University of Health Sciences, Bangalore

Karnataka

By
Mr . SRAVAN KUMAR .MANDALAPU B.Pharm.

Under the Guidance of

Mr .AMARJIT GIRI

Assistant Professor
ewcp- logo

DEPARTMENT OF PHARMACEUTICS

EAST WEST COLLEGE OF PHARMACY

BANGALORE – 560 091
2010-2012


ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION


1


Name of candidate and address (In Block Letters)




SRAVAN KUMAR .MANDALAPU

H.NO. 16B-1-99, TILAK NAGAR,

TANGELLAMUDI, ELURU,

ANDHRA PRADESH. 534007



2


Name of the Institute




EAST WEST COLLEGE OF PHARMACY, BANGALORE-560 091


3

Course of study and subject:



M.PHARM. PHARMACEUTICS.

4

Date of admission of course:


19-08-2010


5



Title of the topic:

EFFECT OF CARRIERS ON ETODOLAC DISSOLUTION FROM BINARY AND TERNARY BASED FORMULATIONS: IN-VITRO CHARACTERIZATION”



6



Brief Resume of this intended work:

6.1 Need for the study Enclosure-I

6.2 Review of Literature Enclosure-II

6.3 Objectives of study Enclosure-III



7



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-------



8

List of References Enclosure-VI


9


Signature of the candidate




(SRAVAN KUMAR .MANDALAPU)



10


Remarks of the Guide




The proposed research work is recommended for registration and approval



11

Name and designation of (in block letters)

11.1 Guide

11.2 Signature



Mr. AMARJIT GIRI,

ASSIANT.PROFESSOR,

DEPT. OF PHARMACEUTICS,

EAST WEST COLLEGE OF PHARMACY,

BANGALORE-560 091.




11.3 Co-Guide (if any)

11.4 Signature



Mrs. SRI LATHA. KS




11.5 Head of Department


11.6 Signature



Dr. JAGADEESH G. HIREMATH

PROFESSOR & HOD,

DEPT. OF PHARMACEUTICS,

EAST WEST COLLEGE OF PHARMACY,

BANGALORE-560 091

12


12.1 Remarks of the Chairman / Principal


12.2 Signature




Prof. K. A. SRIDHAR

PRINCIPAL,

EAST WEST COLLEGE OF PHARMACY,

BANGALORE-560 091



ENCLOSURE-I



6) Brief resume of the intended work:

6.1) Need for the study:

Nearly 40% of the new chemical entities currently being discovered are poorly water soluble drugs. The improvement of pharmaceutical and biological availability of poor water soluble hydrophobic drugs is still a major technological problem for formulation scientist. Plenty of reports demonstrating the several approaches attempted in order to overcome this drawback. Among the strategies investigated for enhancing the dissolution properties of poorly water-soluble drugs, the solid dispersion technique in carriers has often been successfully applied.1,2 However, despite the many number of the studies on this topic, the mechanisms by which dissolution enhancement occurs are still not fully understood. Recent investigations demonstrated that formulation of ternary and binary solid dispersion systems became very useful in enhancement of drug dissolution properties using suitable combinations of carriers.3-5

In this present study, etodolac is a member of the pyranocarboxylic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs) is chosen as a drug candidate.6 Inspite of well absorption and 100% systemic bioavailability of drug, it is insoluble in water, which makes the drug itself as a suitable drug candidate for preparation of solid dispersions.7,8

Hence, our present objective of the study is to prepare binary and ternary based formulations using various drug carriers and to study their in-vitro characterization.








ENCLOSURE-II


6.2) Review of literature:

Cirri M et al., have discussed the possibility of increasing the dissolution properties of ibuproxam (a poorly water-soluble anti-inflammatory drug) using hydrophilic carriers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), or urea, alone or in combination. They have carried out the Phase-solubility studies and found that the carrier solubilizing power was in the order PEG>PVP>urea and reported that a synergistic effect is seen in drug solubility by using carrier combinations. Binary and ternary systems, at 20:80or 20:40:40 (w/w) drug/carrier(s) ratios, were prepared by co-evaporation of their ethanolic solutions or by cogrinding physical mixtures in a high-energy vibrational micromill and they have characterized with differential scanning calorimetry (DSC), hot stage microscopy (HSM), and scanning electron microscopy (SEM) analyses. They have reported the dissolution tests (USP paddle method), in terms of dissolution efficiency, indicated that ternary systems were up to 35% more effective than the corresponding binary preparations and coevaporated products were up to 45% more efficacious than the corresponding coground ones. They found that the best performance of this system was attributed to a joined effect of the strong amorphizing power of PVP, with the high solubilizing efficacy of PEG. They have reported that the drug dissolution rate from solid dispersions remained practically unchanged after one-year storage at room temperature in closed containers.1

Nagasamy VD et al., have reported the preparation of roxythromycin/ β-cyclodextrin (Roxy/ β-CD) dispersions with a view to study the influence of β-CD on the solubility and dissolution rate of this poorly soluble drug. Phase-solubility profile indicated that the solubility of roxythromycin was significantly increased in the presence of β-cyclodextrin and was classified as AL-type, indicating the 1:1 stoichiometric inclusion complexes. They carried out physical characterization of the prepared systems by differential scanning calorimetry (DSC), X-ray diffraction studies (XRD) and IR studies. The results of solid state characterization of the drug β-CD binary system using XRD, FTIR and DSC revealed that distinct loss of drug crystallinity in the formulation, ostensibly accounting for enhancement of dissolution rate.2

Ibrahim MM et al., have prepared the etodolac (ET) chewable tablets by three carriers of known potential to improve solubility and hence dissolution rate of this poorly soluble drugs through coevaporation technique. It has shown dissolution rate-dependent bioavailability. They have seen the dissolution rate of ET at pH 1.2 and 6.8 results in improved dissolution rate in all of the solid dispersion systems compared to that of the pure drug and physical mixtures. They found the dissolution rate was enhanced by loss of ET crystallinity which was further confirmed by X-ray diffraction. Chewable tablets were prepared which shows 86% of dissolved amount within 15 min & it was compared with in vivo absorption study with pure ET-filled hard gelatin capsules. The results showed significantly higher mean Cmax and shorter mean Tmax.6

Barakat NS has prepared the solid dispersion of etodolac by carrier fusion method with Gelucire 44/14 and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as carriers. He determined the physical characteristics by differential scanning calorimetry (DSC) and dissolution by USP Paddle II method .He has prepared the dispersion in the ratio of 2:8 (drug:carrier) and found that the dissolution rate of etodolac was increased in all the dispersion systems compared to that of pure drug. He has carried out the stability studies according to ICH guide lines & found that etodolac was chemically stable against the effects of temperature and humidity9.

Hisham AO and Graham B have prepared the solid dispersions of griseofulvin and hydroxypropyl methylcellulose acetate succinate (HPMCAS) by using the spray drying method. They have studied the stability and dissolution properties of griseofulvin in binary and ternary solid dispersions and reported that when a third polymer, poly[N-(2-hydroxypropyl)methacrylate] (PHPMA), was incorporated into the griseofulvin along with HPMCAS it form H bonds with griseofulvin directly & the addition of PHPMA to the solid dispersion enhanced the stability of the amorphous griseofulvin due to greater interaction with griseofulvin. They have reported that by carrying out X-ray powder diffraction, that griseofulvin (binary and ternary solid dispersions) remained amorphous for more than 19 months when stored at 85% RH and compared them with the spraydried griseofulvin which was crystallized totally with in 24 h at ambient conditions. By Fourier transform infrared scan they have studied that griseofulvin carbonyl group formed hydrogen bonds with the hydroxyl group in the HPMCAS, which results in the extended stability of the drug. Further broadening in the peak was observed when they have added PHPMA to the solid dispersion. They have reported that dissolution rate of the drug in the solid dispersion (both binary and ternary) has significantly increased when compared with the dissolution profile of the spray-dried griseofulvin.10

Sucheta DB has prepared the ternary solid dispersion of poorly water soluble drug fenofibrate using a novel surfactant and was to improve the solubility and bioavailability of the drug. He has followed different methods like melt method, solvent evaporation, and spray drying for the preparation of solid dispersions and characterized the prepared solid dispersion by FT-IR, XRPD and DSC. He has performed the solubility and dissolution studies of pure drug and solid dispersions in various media and reported that solubility & bioavailability of fenofibrate was increased with poloxamer 188 & TPGS significantly. The solid dispersion prepared by spray drying resulted in maximum dissolution rate. He has carried out the dissolution of fenofibrate solid dispersions in poloxamer 188 along with TPGS, reached a satisfactory level (above 90%) within 100 min in water, 0.1N HCl and 0.1M SLS.11

Chul SY et al., have prepared the ibuprofen–poloxamer 188 (P 188) binary solid dispersions (SD) with different drug loadings, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and fourier transform infrared spectroscopy (FTIR), and evaluated for solubility, in-vitro release, and oral bioavailability of ibuprofen in rats. They have studied the loss of their individual surface properties during melting and solidification by SEM micrographs & absence or shifting towards the lower melting temperature of the drug peak in SDs and physical mixtures in DSC & reported the possibilities of its interactions with P 188. However, no such interactions in the solid state were confirmed by FTIR spectra which showed the presence of drug crystalline in SDs. They have observed that the immediate and complete release of ibuprofen from SDs might be because of the reduction in the drug crystalline due to eutectic formation, and reported their dose in fasted rats resulted in a significant increase in the area under curve (AUC) of the plasma concentration versus time curve.12

Liu L and Wang X have prepared the binary solid dispersions consisting of oleanolic acid(OA) and polyvinylpyrrolidone as a drug & polymeric carrier. They prepared the ternary solid dispersions by incorporating polysorbate 80, a nonionic surfactant into binary solid dispersions as a third component. They have characterized the solid dispersions by differential scanning calorimetry, fourier transform infrared spectroscopy, and dissolution tests and they have reported crystallization of OA was prohibited in solid dispersions. The dissolution of OA was enhanced by both the binary and ternary solid dispersions & moreover, the dissolution of ternary solid dispersion was faster compared with that of binary solid dispersion.13
ENCLOSURE-III

6.3) Objective of the study:

The present study is planned with the following objectives:



  • To prepare binary and ternary solid dispersions of etodolac using various drug carriers .

  • To increase the solubility of etodolac.

  • To estimate the drug content in the prepared formulation.

  • To perform the in-vitro release studies for prepared solid dispersions.

















ENCLOSURE-IV


7) Materials and Methods:

Materials:

Drug :Etodolac

Polymers: Povidone/plasdonek29/32/syloid244/avicel/β-cyclodextrins/polyethelyne

glycol/gelucire50/13 or any other appropriate polymers, which will be used



for the preparation of formulation during the course of study.

Methods: Etodolac solid dispersion is prepared by solvent evaporation / solvent deposition / spray drying method / fusion method / lyophilization technique / kneading method.
7.1) Source of data:

Data is collected from:

  1. Science Direct & other internet facilities.

  2. Research publications.

  3. International and Indian journals.

  4. Textbooks and reference books.

  5. RGUHS Library.



ENCLOSURE-V

7.2) Method of collection of data
  1. Identification of drug by UV spectroscopy:


  • Etodolac drug solution is prepared by using a suitable appropriate analytical buffer & analyse the drug solution for identification.

  1. Solid dispersions are prepared by using any one/two of the following methods:

  • Solvent evaporation.

  • Solvent deposition.

  • Spray drying method.

  • Fusion method.

  • Lyophilization technique.

  • Kneading method.

  1. The drug content of the prepared solid dispersions will be evaluated by using appropriate analytical tool.

  2. In-vitro drug release studies.


ENCLOSURE- VI


8) List of references:

  1. Cirri M, Mura P, Rabasco AM, Gine´s JM, Moyano JR, Gonzalez ML, et al. Characterization of ibuproxam binary and ternary dispersions with hydrophilic carriers. J Drug Dev Ind Pharmacy 2004;30(1):65-74.

  2. Nagasamy VD, Karthick S, Umesh M, Vivek G, Valliappan RM, Ramesh N, et al. Studies on the preparation, characterization and solubility of β-cyclodextrin-roxythromycin inclusion complexes. Int J Pharm and Nano Tech 2009;2(2):523-30.

  3. Mura P, Faucci MT, Manderioli A, Bramanti G, Parrini P. Thermal behavior and dissolution properties of naproxen from binary and ternary solid dispersions. Drug Dev Ind Pharm 1999;25(3):257-64.

  4. Jachowicz R, Nurnberg E, Pieszczek B, Kluczykowska B, Maciejewska A. Solid dispersion of ketoprofen in pellets. Int J Pharm 2000;206:13-21.

  5. Vippagunta SR, Maul KA, Tallavajhala S, Grant DJW. Solid-state characterization of nifedipine solid dispersions. Int J Pharm 2002;236:111-23.

  6. Ibrahim MM, Nabarawi Mohamed EL, Setouh, Doaa Ahmed El, Fadlalla Montasir A. Polymeric surfactant based etodolac chewable tablets: Formulation and in-vitro evaluation. AAPS Pharm Sci Tech 2010;11(4): 1730-37

  7. British Pharmacopoeis 2009;Vol.I&II:2396.

  8. The Merck Index, Merck Research Laboratories, 14 th ed, NJ, USA, 2004: 3871.

  9. Barakat NS. Etodolac-liquid-filled dispersion into hard gelatin capsules: An approach to improve dissolution and stability of etodolac formulation. Lett Drug Des Discov 2009;32:865-76.

  10. Hisham AO and Graham B. Evaluation of griseofulvin binary and ternary solid dispersions with HPMCAS. AAPS Pharm Sci Tech 2009;10(4):1172-77.

  11. Sucheta DB. Ternary solid dispersions of fenofibrate with poloxamer 188 and TPGS for enhancement of solubility and bioavailability. Int J Res Pharm Biomed Sci 2011;2(2):583-95.

  12. Chul SY, Han GC, Madhuri N, Krishna HB, Dong XL, Kwon TH, et al. Preparation, characterization and in-vivo evaluation of ibuprofen binary solid dispersions with poloxamer 188. Int J Pharma 2007;343:228-37.

  13. Liu LX and Wang X. Improved dissolution of oleanolic acid with ternary solid dispersions. AAPS Pharm Sci Tech 2007;8(4):E1-E5.




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