1.0Brief resume of intended work:
1.1Need for study:
The rate and extent of dissolution of the activeingredient from any solid dosage form determinesthe bioavailability of the drug. Inthe case of poorly water soluble drugs, dissolutionis the rate limiting step in the process of drugabsorption. Poorly soluble drugs have been shownto be unpredictably and slowly absorbed as comparedto drugs with higher solubility. Several methods have been employed like solid dispersion, eutectic mixture formation, salt formation, complexation, and many othersto improvethe solubility of poorly water soluble drugs(1).Solubility enhancement of these drugsremains one of the most challenging aspects of pharmaceutical technology.
The solid dispersion method is one of the effective approaches to achieve the goal ofsolubility enhancement of poorly soluble drugs (2).Theterm solid dispersion refers to the dispersion of one ormore active ingredients in an inert carrier or matrix at solidstate prepared by the melting (fusion), solvent evaporation or the melting-solvent method (3).Inert hydrophilliccarrierslike poloxamer, crospovidone, polyethylene glycol,poly vinyl pyrrolidone,and several hydrophilic polymers have been widely investigated as carrier substances for solid dispersionfor enhancement of solubility and dissolution rate.
Norfloxacin,a fluroquinolone, is selected as model drug. It is active on both actively dividing as well as dormantbacteria by inhibiting bacterial DNA gyrase. Itis approved for urinary and genital tract infection. It isalso good for bacterial diarrhoea and gonorrhoea. However, the bioavailability of norfloxacin is only 35-45%, owing to its poor solubility.In order to enhance the extent of absorption, it is necessary to improveits solubility (4).
1.2 Review of literature:
A comparative bioavailability study was carried out in rabbits on pure powder of norfloxacin, its aqueous solutions, polyethylene glycol- 6000 solid dispersions,and β-cyclodextrin complexes by Fawaz et al (5). Bioavailabilty was improved significantly with cyclodextrincomplexes than with the powder and other formulations.
Guyotet al (6)studied the water solubility and dissolution rate of norfloxacinby using two systems: solid dispersion with polyethylene glycol-6000 prepared by using fusion method and inclusion complexes with cyclodextrins (β-cyclodextrin and HP-β-cyclodextrin) obtained by freeze drying.The solubility and dissolution rate of norfloxacin were significantly increased with polyethylene glycol solid dispersion in comparision to cyclodextrin complexes and norfloxacin cyclodextrin physical mixture.
The effect of EDTAand sodium caprate on oral bioavailability of norfloxacin was investigated earlier(7). The result of the study indicated that the solubilizing property of EDTA and sodium caprate did not have any prominent effect on absorptionrate of norfloxacin.
Vyas et al (8) observed dissolution behaviour of a poorly soluble drug, tadalafil, from its solid dispersion systems with poloxamer-407. Solid dispersion systems of tadalafil were prepared with poloxamer- 407 in 1:0.5,1:1.5 and 1:2.5 ratios using the melting method. It was observed that, higher proportions of poloxamer- 407 (1:1.5 and 1:2.5) offered no advantagetowards dissolution enhancement of the drug, indicatingaltered rheological characteristics of the polymer at itshigher concentration, which might have retarded the releaserate of tadalafil.
Solid dispersionof indomethacin with crospovidone was prepared using mechanical mixing followed by heating to temperatures below the melting point in another study (9). Indomethacin and crospovidone interacted to produce indomethacinin an amorphous state when its concentration was 40%. The solubility of indomethacinwas improved about fourfold compared to indomethacincrystal. The solid dispersion tablets were prepared by direct compression. The dissolution of indomethacinfrom tablets was similar to that of solid dispersion powder because crospovidone, a disintegrating agent, caused the tablets to break up rapidly.
1.3 Objective of the study:
The objectives of the proposed study are:
(a)Prefomulation study of norfloxacin and hydrophilic carriers.
(b)Investigation of the effect of carriersand other excipients concentration on solubility and dissolution rate.
(c)Solid state characterization of the dispersed drug using DSC, XRD and FTIR.
(a)Stability studies of the selected solid dispersion as per ICH guidelines.
2.0Materials and methods:
2.1 Source of data:
Preliminary data required for the experimental study would be obtained from scientific journals and books.
2.2 Method of collection of data:
Data on drug and excipients will be collected from the drug information center, standard books, catalogs etc. On the basis of extensive preformulation trials on the drug and excipients, the final formulation will be developed.
i. Materials:
The materials required for the study like norfloxacin, hydrophilic carriers (Poloxamer, crospovidone, etc) will be procured from commercial suppliers.
ii. Methodology:
Solvent evaporation technique will be used as a primary methodology for preparation of solid dispersion of norfloxacin. Here, the drug is dispersed or dissolved in solution of selected hydrophilic carrier in a suitable solvent system. The solvent used in the preparation is removed by evaporation. The dried product obtained will be stored in an air tight container until further use.For a comparative evaluation a set of formulations will be prepared by different methodologies to evaluate enhancement in dissolution rates.
iii. Evaluation of prepared solid dispersions
The prepared solid dispersion will be evaluated for solubility, drug content and dissolution by using standard procedures. Drug-carrier interactions and crystallinity will be investigatedusing differential scanning calorimetry (DSC), fourier transform infrared spectroscopy (FTIR) and powder x-ray diffraction (PXRD).
2.3 Does this study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please describe briefly.
No studies are intended to be performed on humans or animals.
2.4Has ethical clearance been obtained from you in case of 2.3.
Not applicable.
3. References:
1.BetageriGV, Makarla KR.Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques.Int J Pharm.1995;126:155-60.
2.SharmaDK, Joshi SB.Solubility enhancement strategies for poorly water-solubledrugs in solid dispersions: a review. Asian J Pharm. 2007;1:9-19.
3.KumarN, JainAK, Akhilesh, SinghC, Agarwal K, NemaRK. A Development, characterization and solubility study ofsolid dispersion of terbinafine hydrochloride.Int J PharmNanotech.2008;1:171-6.
4.Dua K, Ramana MV, Singh Sara UV, HimajaM, Agrawal A, GargV, Pabreja K.Investigation of enhancement of solubility of norfloxacin β-cyclodextrin in presence of acidic solubilizing additives. CurrDrugDel.2007;4:21-5.
5. Fawaz F, Bonini F,GuyotM,BildetJ, MauryM, Lagueny AM. Bioavailability of norfloxacin from PEG-6000 solid dispersion and cyclodextrin inclusion complex in rabbits.Int J Pharm.1996;132:271-5.
6.Guyot M,Fawaz F,Bildet J,Bonini F, Lagueny AM. Physicochemical characterization and dissolution of norfloxacin-cyclodextrin inclusion compounds and PEG solid dispersion. Int J Pharm.1995;123:53-63.
7.Santos DI,Fawaz F,Laguency AM,BoniniF.Improvement of norfloxacin oral bioavailability by EDTA and Sodium caprate.Int J Pharm. 2003;260:1-4.
8.VyasV,Sancheti P, Karekar P, Shah M, Pore Y.Physicochemical characterization of solid dispersion systems of tadalafil with poloxamer 407.Acta Pharm.2009;59:453–61.
9.Fujii M,OkadaH,ShibataY,Teramachi H,Kondoh M,Watanabe Y.Preparation, characterization, and tableting of a solid dispersion of indomethacin with crospovidone.Int J Pharm.2005;293:145-53.
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