research article on inclusion complex of GLAUCOCALYXIN-A with CAPTISOL.

1. Preparation, characteristic and pharmacology study on inclusion
complex of sulfobutylether-b-cyclodextrin witH glaucocalyxin-A

2. 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.

3. WHY SOLUBILITY ENHANCEMENT
Solubility 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.

4. 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.

5. 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.

6.  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.

7. SYNTHESIS OF CD
STARCH
enzymatic conversion
LIQUID PRODUCT
 CGTase 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.

8. CHEMICALLY MODIFIED CD
 Different chemical moieties introduced into CD
molecule by reaction with OH group lining upper and
lower ridge of toroid. Ex.
 Hydroxypropyl-β-CD:CH₂CHOHCH₃
 Diethyl-β-CD:CH₃CH₃
 Sulfobutylether-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.

9. RELEASE OF DRUG MOIETY
 MECHANISM 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 heating
2. enzymatic cleavage of α-1,4 linkage between glucose
monomer .

10. ADVANTAGES OF COMPLEXATION WITH CD
a) 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

11. SULFOBUTYLETHER-β-CD
 CAPTISOL
 Polyanionic 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.

12. GLAUCOCALYXIN-A
BIO-ACTIVE ent-kauranoid
diterpenoid.
Have v.poor water solubility
USES:
Inhibit tumour cell proliferation
Inhibit platelet aggregation
Immunosuppression
Antioxidative
DNA-protective activity.
Earlier complex of GLA with HP-β-
CD lead to increase in solubilty by
only 13 fold.

13. Rabdosia japonica
GLA 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

14. 1:1 molar ratio GLA-SBE-B-CD inclusion complex was
prepared using CO-EVAORATED METHOD.
Weighed amount of SBE-B-CD was dissolved in water
Solution of GLA in ethanol was added slowly to SBE-B-
CD Solution
Suspension stirred at RT for 24h.
Fitered through 0.22um filter
Dried under reduced pressure for 12h in vacuum
dessicator.
SOLID COMPLEX
Method is simple & economical on lab and large scale.

15. ANALYSIS OF COMPLEX
Chromatography
Solubility study
Phase solubility
UV
Thermal analysis
Fourier transform infrared spectroscopy
Powder X-ray diffraction
Proton nuclear magnetic resonance spectroscopy
Pharmocokinetic study

16. Solubility study
Excess GLA
added
10 ml of
water in
vials
Mixture
agitated at
25˚C for 24 h.
Filtered
through
0.22um
membrane
Drug conc
determind
by HPLC

17. PHASE SOLUBILITY STUDY
Purified 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

18. DISSOLUTION STUDY
 Rotation -50 rpm
 Temperature 25±0.5˚C
 Conc-1mg GLA
RESULTS
a) PHASE SOLU.
 LINEAR PORTION-A1 TYPE C
complex.
Kc of complexes
134.9/M

19. b)DISSOLUTION

20. ULTRAVIOLET -VISIBLE
COMP
LEX
GLA
CAPTISOL

21. DSC
ENDOTHERMIC
PEAK OF GLA -225˚C
DISSAPPEARANCE OF
PEAK OF CAPTISOL
PEAK OF
CAPTISOL

22. POWDER X-RAY DIFFRACTION
GLA-CRYSTALLINE-
MANY SHARP PEAKS
CAPTISOL-
AMORPHOUS-
WEAK PEAK

23. FTIR SPECTRA
1727-GLA-
CO

24. PROTON NMR SPECTRO
CAPTIS
OL
GLA
SIGNALS OF
GLA
DISSAPPEARED
IN COMPLEX

25. PHARMACOKINETIC STUDY
 24 male sprague rats taken
 All rats assigned in 2 groups (n=12/group)
 Single iv dose given
 Blood samples at 5,10,15,30,45,60,90 min
withdrawn
 Plasma separated by centrifugation
 Plasma conc with respect to time was plotted
 Maximum plasma drug conc,time to reach
it,elimination half life,mean residence
time,systemic clearance was measured.

27. 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.

28. 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

29. CYCLODEXTRINS 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.