PRESENTED BY:DIVYA MISHRA

M.PHARM(I YEAR)QUALITY ASSURANCE

Preparation, characteristic and pharmacology study on inclusion complex

of sulfobutylether-b-cyclodextrin witH glaucocalyxin-A

INTRODUCTION The objective of this study was to improve the

water solubility and solubility of glaucocalyxin-A by producing its complex with SBE-B-CD.

Solubility of GLA and its complex were 2.4 x 10² and 1.82x10⁴ug/ml, respectively, and the value of incusion complex was improved by 76 fold compared with solubility of free GLA.

WHY SOLUBILITY ENHANCEMENTSolubility the phenomenon of dissolution of solute in

solvent to give a homogeneous system

Important to achieve desired conc. Of drug to show pharmacological response in systemic circulation.

Insufficient disso rate of the drug is limiting factor in oral availability of poorly water soluble drug.

Any drug to be absorbed must be prsent in aqueous form at the site of absorption.

COMPLEXATION

Hydrophobic molecules are incorporated in cavity of CD by displacing water . The reaction is followed by repulsion of the molecule by water.

Effective encapsulation of molecule occur.

CYCLODEXTRIN

They are cycloamyloses family of compounds made up of sugar molecule bound together in a ring.

they are hydrophobic inside and hydrophilic outside.

hydrophilic to

impart CD water solubility.

less hydrophilic than aq. Solvent.

cyclodextrin were called cellulosine in 1891.Schardinger identified naturallyn occuring α,β,γ cyclodextrins-SCHARDINGER SUGAR.

WHY β-CD USED?α-CD-6 glucopyranose units. Small cavities not capable of

accepting many molecule.γ-CD-8 glucopyranose units. larger cavities than many

molecules to be incorporated and CD hydrophobic charges cannot effectively interact to facilitate complexation.

β-CD- 7 glucopyranose units. cavity diameter most appropriate site for hormones,vitamins, other compound frequently used.

Β,α,γ-CD ARE GENERALLY REGARDED AS SAFE.

SYNTHESIS OF CD STARCH enzymatic conversion

LIQUID PRODUCTCGTase synthesise all form of CD,product of

conversion result in mix. of 3 main type of cyclic molecule in ratio strictly dependent on enzyme used.

β-CD has v.poor water solubilty,can be retrieved through crystallisation while α and γ purified by chromatography.

CHEMICALLY MODIFIED CDDifferent chemical moieties introduced into CD

molecule by reaction with OH group lining upper and lower ridge of toroid. Ex.

Hydroxypropyl-β-CD:CH₂CHOHCH₃Diethyl-β-CD:CH₃CH₃Sulfobutylether-β-CD:(CH₂)₄SO₃Na

CD-3n substituents, n=no.of glucopyranose units.Randomness of position and type of subs. cause

resultant CD pdk to be amorphous i.e. AQUEOUS

SOLUBILITY.Maximum degree of substitution-21-for β-CD.

RELEASE OF DRUG MOIETYMECHANISM of controlled degradation of

such complex based on ph, change of water solution leading to loss of hydrogen or ionic bond between host and guest molecule.

Alternative means-1. by heating2. enzymatic cleavage of α-1,4 linkage

between glucose monomer .

ADVANTAGES OF COMPLEXATION WITH CDa) Imp. Comp like vitamins & hormones having low

solubility get solubilised.b) Used as carriercaaaaaaaaaaaaaaaaaaaa carrier.c) α & γ- food-

soluble dietary fibre –can be found as a-CD on list of ing.of commercial pdks.

d) β-CD-complex with caretenoid food colorant –intensify color by increasing water solubility and improving light stability

e) Inclusion compd CD penetrate body tissues,f) Aq.solubility enhancement by CD diff than co-

solvent and surfectant.Surfectant-toxicity. Co solvent-enhance solubility

nonlinearly

SULFOBUTYLETHER-β-CDCAPTISOLPolyanionic variably substituted

sulfobutylether of β-CD as non nephrotoxic.

Interact v.well with neutral drug to facilitate solu and stability .

Polyanionic interact well with cationic drug.

Complex disso rapidly after parentral administration to have no tissue-irritating effect,no advrse effect on kidney,or other organs following i.v.

Provide protective effect against drug induced cytotoxicity.

GLAUCOCALYXIN-ABIO-ACTIVE ent-kauranoid

diterpenoid.Have v.poor water solubilityUSES:Inhibit tumour cell proliferationInhibit platelet aggregationImmunosuppressionAntioxidativeDNA-protective activity.Earlier complex of GLA with

HP-β-CD lead to increase in solubilty by only 13 fold.

Rabdosia japonicaGLA isolated from

leaves of Rabdosia japonica,chinese herb

o Family-lamiaceae,Rabdosia.

o Perennial herb

Leaves contain GLA,sitosterol,ursolic acid.

• USES:• Gastric &abdominal

swelling pain• Bites by insects &snakes• jaundice

FORMATION OF COMPLEX1:1 molar ratio GLA-SBE-B-CD inclusion complex was prepared using CO-EVAORATED METHOD.Weighed amount of SBE-B-CD was dissolved in waterSolution of GLA in ethanol was added slowly to SBE-B-CD SolutionSuspension stirred at RT for 24h.Fitered through 0.22um filter Dried under reduced pressure for 12h in vacuum dessicator.

SOLID COMPLEXMethod is simple & economical on lab and large scale.

ANALYSIS OF COMPLEXChromatographySolubility studyPhase solubility UVThermal analysisFourier transform infrared spectroscopyPowder X-ray diffraction Proton nuclear magnetic resonance

spectroscopyPharmocokinetic study

Solubility studyExcess GLA

added10 ml of

water in vials

Mixture agitated at

25˚C for 24 h.

Filtered through 0.22um

membrane

Drug conc determind by

HPLC

PHASE SOLUBILITY STUDYPurified water

+various conc of captisol(0-10mM)

Excess GLA

Mixture stirred at 35˚C for 24h.

Cooled to RT& filtered through 0.45um filter.

GLA conc measured using

HPLC

DISSOLUTION STUDYRotation -50 rpmTemperature 25±0.5˚CConc-1mg GLA

RESULTSa) PHASE SOLU.LINEAR PORTION-A1 TYPE C

complex.Kc of complexes 134.9/M

b)DISSOLUTION

ULTRAVIOLET -VISIBLE

COMPLEX

GLA

CAPTISOL

DSC

ENDOTHERMIC PEAK OF GLA -

225˚C

DISSAPPEARANCE OF PEAK OF CAPTISOL

PEAK OF CAPTISOL

POWDER X-RAY DIFFRACTIONGLA-CRYSTALLINE-

MANY SHARP PEAKS

CAPTISOL-AMORPHOU

S-WEAK PEAK

FTIR SPECTRA

1727-GLA-CO

PROTON NMR SPECTRO

CAPTISOL GLA

SIGNALS OF GLA

DISSAPPEAREDIN

COMPLEX

PHARMACOKINETIC STUDY24 male sprague rats takenAll rats assigned in 2 groups (n=12/group)Single iv dose givenBlood samples at 5,10,15,30,45,60,90 min

withdrawnPlasma separated by centrifugationPlasma conc with respect to time was

plottedMaximum plasma drug conc,time to reach

it,elimination half life,mean residence time,systemic clearance was measured.

Plasma AUC₀₋∞ of complex was 3 fold greater than free GLA.

HALF LIFE of complex was significantly prolonged than free GLA.

THUS FORMULATION OF GLA-SBE-B-CD COMPLEX WAS RETAINED FOR A LONGER PERIOD COMPARED WITH FREE GLA INJECTION SOLUTION.

USFDA APPROVED DRUGS CAPTISOL & HP-B-CD –CLEARED safety studies & used in 6 product approved by FDA.

Vfend (iv voriconazole; captisol)Geodon (im ziprazidone)Abilify (im aripiprazole)Ceremia (sc maropitant)

Sporanpox (iv & liq itraconazole ; HP-B-CD)

HP-B-CD-approved for administration in brain-OMMAYA RESERVOIR-to treat NEIMAN-PICK-TYPE-DISEASE

CONCLUSIONCYCLODEXTRINS are gaining popularity day by day & many researchers pay great emphasis on this approach.The solubility & disso behaviour of complex was improved.Sustain delivery of drug observed

Thermal methods are best method to characterise complexes & CD

Not much compounds have been complexed with captisol

Research can be done for inclusion complex of any other bioactive drug having solubility problem with captisol.Analyse the complex to check the enhancement in solubility of the guest molecule and hence its action.This inclusion complex aids strategies to produce more effective and marketable drugs.

THANK YOU