Cyclodextrins in Pharmaceuticals: An Overview

O.M.Aleem aleemomair

The objective of this review article
is to explore the use of cyclodextrins as pharmaceutical excipients for various
applications such as solubility, bioavailability and stability enhancement of
various drugs.

The article highlights the chemistry
of cyclodextrins and summarizes the issue of mechanism of drug release from
cyclodextrin complexes and its application in the different drug delivery systems
such as nasal, ophthalmic, transdermal and rectal drug delivery etc. The studies
on cyclodextrins have revealed that, cyclodextrins are versatile excipients
in different routes of drug administration because of increased aqueous solubility,
stability and bioavailability with reduction in drug irritation.

Introduction

Cyclodextrin, first
described by Villiers in 1981 as “Cellulosin”. After that, Schardinger identify
the three naturally occurring cyclodextrins named as α, β and γ cyclodextrin and
referred them as “Schardinger Sugars”. Later on, between 1911 to 1935,
Pringsheim in Germany was the leading researcher in this area, showed that
cyclodextrins formed stable aqueous complexes with many other chemicals
(Drugs).  In the mid 1970 each of the natural cyclodextrins had been
structurally and chemically characterized and many more complexes had been
studied. In the 1953, first patent on cyclodextrin and there complexes was
registered. Till 1970 only small amount of relatively pure cyclodextrin was
generated and high production cost prevented their industrial uses
^1,2.

“Dextrin” is the enzymatic
degradation of starch, generally results in the production of glucose and maltose that is long series of liner and branched chain of malto-oligomers.
Dextrin is heterogenous, amorphous, hygroscopic substance
².

“Cyclodextrins” are cyclic
oligosaccharides consisting of multiple (α, D1-4) linked glucopyranose units that display amophoteric properties of a lipophilic central cavity and
hydrophilic outer surface. Cyclodextrins are crystalline, homogenous and non-hygroscopic substance, which are tours-like macro ring shape
^2,3,5.

Fig: 1 Chemical structure
of α, β, and γ cyclodextrin.

The hydrophilic exterior
surface of the cyclodextrin molecules makes them water soluble, but the hydrophobic cavity provides a microenvironment for appropriately sized non-polar molecules ⁴.

Fig: 2 Schematic representations of hydrophobic cavity and hydrophilic
outer surface of cyclodextrin

Synthesis and production

The production of
cyclodextrins involves treatment of starch with
cyclodextrin-glycosyltransferase (CGTase) and α-amylase.  Starch is liquefied by two processes by heat treatment
or using α-amylase then, for enzymatic conversion CGTase is added. This conversion product gives three main types of cyclic molecules mixture, α, β and
γ cyclic molecule, which depend on CGTase enzyme used. Each CGTase has its own characteristic α, β, and γ synthesis ratio. For purification of the three types
of cyclodextrin, techniques used like chromatography, crystallization, and use of organic solvents like toluene, ethanol etc. as a complex forming agent with
cyclodextrin forming precipitate. This results in formation of precipitated cyclodextrins from the starch, which is collected by centrifugation
².

Physicochemical properties of natural cyclodextrins

Physical properties ²

Table 1. Some physical properties of natural cyclodextrins.

Chemical properties

1. Chemical reactivity:
Cyclodextrin has no reducing end groups. No formic acid or formaldehyde is
formed in the periodate oxidation of α β and γ cyclodextrin, providing that
these molecules do not contain free end groups.

2. Radiolysis: On γ
irradiation, cleavage of β and γ cyclodextrin occurs mainly at the 1-4
glycosidic bonds. The mechanism is different from that of acid hydrolysis. No
glucose is formed. The main products being malto-hexose, malondialdehyde and
gluconic acid, also hydrogen, carbon monoxide and carbon dioxide.

3. Acid hydrolysis: Partial
acid hydrolysis yields glucose and series of acyclic maltosaccharides. In the
hydrolysis of oligopolysaccharides, the glyosidic bond of terminal glucose unit
is cleaved faster than bond between non-terminal members
².

Cyclodextrin complexation

Inclusion complexation with
cyclodextrin is like a “host-guest interaction”. In this interaction
cyclodextrin act as host molecule and the drug molecule to be entrapped in host
cavity act as guest molecule. Comparing to other encapsulation methods, which
involve entrapment of more than one guest, cyclodextrin complexation involve
entrapment of one molecule of guest in cyclodextrin cavity. For formation of
complex with cyclodextrin, variety of non-covalent forces like Vander wall
forces, hydrophobic interaction, and dipole movement are responsible. In
majority of cases only a single guest molecules is entrapped in the cavity. For
High molecular weight molecules, more than one molecule of cyclodextrins can
bind to the guest.

For the preparation of
complex, many solvents are used, but generally water is preferred as a solvent
for complexation. The cavity of cyclodextrin in non-polar and it favours
non-polar area of guest molecule. Water gives driving force for formation of
complexation. Not all guests are sufficiently soluble in water. It is not
necessary that complete solubilization of guest should be done. Small amount of
guest must be soluble to form a complex. Some times water miscible solvents in
small quantities are helpful for dissolution of guest, which enhances
complexation reaction. After addition of the dissolved guest to the solution of
cyclodextrin, either guest may be dissolved or suspended in the form of high
precipitate. Excess quantity of solvent if added, results in decrease in driving
force for complexation reaction by reducing the difference in polarity between
the bulk solution and cyclodextrin cavity which ultimately leads to little or no
complexation but good solubilization of guest. Heat can destabilized the
inclusion complex. Complexation stability depends on the temperature of guest
and it must be optimized for every guest ^2,3,6,7.

Fig: 3 Schematic representation of host-guest interaction.

Methods of complex Preparation

Several methods were
reported for host-guest complex preparation. Some have advantageous to other.
The methods generally preferred are

1. Kneading

The method involves the
formation of paste of cyclodextrin with guest molecules by using small
quantity of either water or ethanol to form kneaded mass. Kneaded mass can be
dried at 45°C and pulverized ^8-18.

2. Melting

Excess quantity of guest
melted, mixed with powdered cyclodextrin, after cooling excess quantity of
quest is removed by washing with weak complex forming solvent. The method
restricted to sublimable guest like menthol ¹⁹.

3. SEDS (Super critical fluids)

SEDS is novel, single
step method, which can produce solid drug-cyclodextrin complexes.  The
optimization of processing conditions is essential in order to achieve the
optimum complexation efficiency and to compare with drug-cyclodextrin
complexation methods described earlier in the literature (e.g. kneading,
freeze drying, spray drying etc). Advantages over other methods are (a)
preparation of solid-cyclodextrin complexes in single step process, (b)
achievement of high complexation efficiency (avoidance of excess cyclodextrin
in powder). (c) possibility to minimize the contact of drug with cyclodextrin
during the process. (d) achievement of enhanced dissolution rate of the drug
(which is comparable to the dissolution behavior of micronized
drug-cyclodextrin complex) ²⁰.

4. Co-evaporation

To the alcoholic solution
of guest, aqueous solution of host is added and stirred for sometimes and
evaporated at room temp until dried mass obtained, pulverized and sieved and
fraction is collected  ^{9, 11-13}.

5. Microwave irradiation  

This method is developed
for rapid organic synthesis and reactions, which require shorter reaction time
and higher aim product ²¹.

6. Freeze Drying:

The required
stoichiometric quantity of host and guest were added to aqueous solution of
cyclodextrin and this suspension stirred magnetically for 24 hours, and
resulting mixture is freeze dried at –60°C for 24 hours ^12-15,
23.

7. Spray drying

In this method, host
solution prepared generally in ethanol: water 50% v/v. To this guest is added
and resulting mixture is stirred for 24 hr. at room temperature and solution
is spray dried by observing following conditions-air flow rate, atomizing air
pressure, inlet temperature, outlet temperature, flow rate of solution etc.
Product obtained by passing through 63-160 micrometer granulometric sieve
^15,16,18,24.

Benefits after complexation

• Bioavailability enhancement: Drugs
  having limited oral bioavailability due to poor dissolution rate and
  solubility can be complexed with cyclodextrins to improve their absorption.
  Complexation reduces active recrystalization of drugs, which may help to
  increase their aqueous solubility
  ²⁵.                            

• Reduction in drug irritation: Drugs,
  which are irritant to mucus membrane of GIT and skin, are complexed with
  cyclodextrins to minimize the irritation ²⁵.
  
• Stability of active ingredients:
  Cyclodextrins can prevent the deterioration of active pharmaceutical
  ingredients due to light, temperature and atmospheric oxidation
  ^26,27.
  
• Prevent drug-drug and drug
  additive-interaction ⁶
  
• Improve patient compliance by taste
  masking of bitter drugs ⁶.

Mechansim of Drug release

It is important to
understand the intrinsic drug solubility, the magnitude of binding constant for
the inclusion complex. Most pharmaceutical agent forms 1:1 Complexes with
cyclodextrin as shown in figure ^{2, 29}

Fig: 4 1:1 Drug-cyclodextrin complex formation.

On the basis of structure
and properties of drug as well as cyclodextrin, higher order complexes are also
possible like 1:2,2:1.

The magnitude of binding
constant K_{1: 1} can be calculated by equation,

                   
[drug] _complex

K_1:1 
= 
_____________________

            
[drug] _free [cyclodextrin] _free

K _1:1 is
generally in the range of 100 to 1000 M^-1

[drug] _complex
=Concentration of drug in complex form

[drug] _free=
Free drug concentration

[Cyclodextrin]
_free= Concentration of free cyclodextrin

For illustration of the
relationship between drug solubility, magnitude of binding constant, dilution,
hypothetical drug (Mol. Wt. 400) with an intrinsic solubility of 10 mcg/ml and
K_1:1 of 100000 M^-1 for its interaction with cyclodextrin
of unlimited solubility was examined in presence of cyclodextrin. The drug
solubility is defined by following equation ^28,30

                  
  K _1:1[drug] _intrinsic [cyclodextrin]
_total

      __________________________

                         
[Drug] _total  =    [drug] _intrinsic
+K_1:1 [drug]_intrinsic + 1

Some Pharmaceutical applications of Cyclodextrins

Improvement of solubility and dissolution rate of poorly soluble drugs by
cyclodextrin-

Complexation

Cyclodextrins are the novel
excipients for improving the aqueous solubility of poorly soluble drugs.
Cyclodextrins have hydrophobic cavity and hydrophilic external surface. Poorly
soluble drug accommodates in hydrophobic cavity. This molecular entrapment
improves drug solubility. The cyclodextrin complexes of hydrophobic drugs
dissolve faster, better than pure drug. Crystalline drug is dispersed over a
hydrophilic matrix. This particular drug will be passively carried in to
dissolution and this may increase dissolution rate.  Therefore solubility
and dissolution rate of poorly soluble drugs were improved via a complexation
with various both natural and modified cyclodextrins
^{10,11,13,15,22,23}.

Table 2. Effect of cyclodextrin on solubility, stability and dissolution
rate of various poorly soluble drugs ^31-38.    ↑ = Increase   

Improvement of absorption / bioavailability

Bioavailability means the
rate and extent of absorption of drug in systemic circulation. Poor solubility
of drugs is major criteria for low bioavailability of drugs. By formation of
cyclodextrin inclusion complexes of poorly soluble drugs, it helps in improving
the aqueous solubility and ultimately bioavailability of drug. The oral
absorption and or bioavailability of drugs were improved via complexation with
various both natural and modified cyclodextrin ¹¹.

Table 3. List of drugs showing bioavailability enhancement ^{16,17,19,33,34,36}

Cyclodextrin in liposome

Mc Coremark and Gregoriadis
have proposed this new concept in drug delivery. Its main purpose to combine
some advantages of cyclodextrins such as increasing the drug solubility with the
some advantages of liposome such as targeting of drug to the active site. In
fact, liposome can direct drugs to organs or tissues and it properly deliver
them to active site with a pre-determined rate of clearance and
distribution²⁶. Entrapment of photo-labile drugs with α or γ
cyclodextrin inclusion in liposome containing light absorber increases their
stability ³⁹.

Cyclodextrins in micro particles

Loftsson et al; first
studied the role of cyclodextrins in micro particle preparation, prepared ethyl
cellulose micro particles containing hydrocortisone with
hydroxypropyl-β-cyclodextrin by simple alcohol-in oil emulsion and solvent
evaporation method.  The release rate of hydrocortisone from micro
particles significantly increases. The dimension of PVA and γ-cyclodextrin
microsphere is much higher compared to PVA/α and β cyclodextrin. The cross
linking of microsphere were estimated by iodine retained in the polymer matrix
^39-41.

Cyclodextrins in release control /sustain release

Y. Horiuchi showed that
hybridizing its hydrophilic, hydrophobic and ionizable cyclodextrin complexes
performed the release control of theophylline from tablet. The rate of release
of theophylline from tablet is accelerated by β-cyclodextrin while that form
diethyl-β-Cyclodextrin complex was decelerated, both showing pH independent
release⁴². K Uekma designs the slow release dosage form of pertained
by using cyclodextrin or other cellulose derivative combination. J S Smith
develops the sustained release beads by using SBE7-β-cyclodextrin together with
some hydrophilic polymer such as HPMC, PVP and prepared sustained release beads
for Carbamazepine (a poorly soluble drug).  These ternary and binary
approaches were considered suitable technique to improve release rate and
bioavailability of poorly soluble drugs ⁴³.

Cyclodextrins in osmotic pump tablet

In a controlled porosity
osmotic pump system for poorly water soluble drugs have been developed using
sulfobutylether-β cyclodextrin, sodium salt (SBE) 7M-β cyclodextrin.
Testosterone release from the device was significantly faster with (SBE) 7M-β
cyclodextrin than with hydroxypropyl-β-cyclodextrin or sugar mixture
^44,45

Cyclodextrins for peptide administration

Cyclodextrins have many
advantages as novel tools for the delivery of peptide, protein and
oligonucleotide. Cyclodextrins have been investigated for their potential use as
excipients for the oral delivery of peptides. A modified calcitonin and the
somatostatin analog octapeptide octeroide were chosen as model drug. It shows
that cyclodextrins have protective and absorption enhancing effects on peptides
by preparing simple physical mixtures of the two components.  However, the
extent of protection and absorption enhancement seems to depend strongly on the
nature of the peptide used as well as the chosen cyclodextrins. Cyclodextrins
(hydrophilic) can be used as stabilizers, artificial chaperones, absorption
enhancers, and sustained release carrier where as cyclodextrins (sulphated) used
as heparinoids. It also be used as oligonucleotide carrier and for lipoprotein
measurements ⁴⁶ .

Cyclodextrins in Buccal drug delivery

The buccal mucosa that is
easily and convenient site for drug delivery and routinely exposed to food and
other foreign substance and thus it is robust.  This makes tablet for
sublingual/buccal drug delivery widely acceptable. For the drug to be effective
by buccal route the drug must dissolve in saliva and able to pass through the
mucosal barrier in to the blood circulation. The drug having hydrophobic nature
difficult to penetrate in the mucosal barrier. By using cyclodextrins drug can
be solubilized in the saliva and able to reach in blood circulation
⁴⁷.

Cyclodextrins in Nasal drug delivery

It is reported that
cyclodextrin is ideal penetration enhancer as it enhances drug penetration
without affecting biological barrier and solubilized lipophilic water insoluble
drugs enabling for formulation of such drugs in aqueous nasal spray formulation.
It also decreases the irritation of drugs, and drugs, which are unstable in
aqueous solution, stabilize it ²⁹.

Cyclodextrins in ophthalmic drug delivery

It is reported that
2-hydroxy propyl β cyclodextrin are nontoxic and well tolerated in formulation
containing aqueous eye drops ²⁹. It is reported that corneal
permeability could not be modified by the cyclodextrins, but it was advantageous
in improving availability of ophthalmic drugs such as acetazolamide, which is
administered with HP-β-cyclodextrin in eye drops
⁴⁸.

Cyclodextrins as permeation enhancers

Passive diffusion mostly
occurs for lipophilic molecules and the major driving force for this is higher
concentration of drug and its high activity in aqueous fluid at the absorption
site. Drug-cyclodextrin inclusion complex increases the aqueous solubility,
increases driving force for diffusion across the biological membrane for
lipophilic drugs. Cyclodextrins acts as permeation enhancers through biological
membrane by increasing availability of drug at the absorption site but the major
barrier for cyclodextrins to act as permeation enhancers is its large size and
highly hydrophilic surface. Excess amount of cyclodextrin can lead to decrease
drug absorption through the skin, eye cornea and intestine. Generally, for
in-vitro drug permeation study, a silicone membrane preferred, because of their
lipophilic nature as like biological membranes. Silicone membrane used for
evaluation of true drug thermodynamic activity in presence of the complexing
agent and optimization of cyclodextrin formulations ^50-53. Caco-2
monolayer in vitro model used for transcellular permeation of flutamide from the
complex ³⁴. Diclofenac, diffusion through silicone membrane was
higher for saturated diclofenac solution than the freeze-dried inclusion
complexes with β-cyclodextrin ⁴⁹.

Cyclodextrins in nanocapsules and nanoparticles

Nanoparticles have various
advantages comparing to liposomes, like greater stability, larger surface area
than microparticle and better contact with biological membranes, which results
in greater bioavailability. Cyclodextrins when used, loading capacity of
nanoparticles are greatly enhanced ²⁶. A variety of amphiphilic
cyclodextrins useful for various targeting of drugs when it is given in the
amphiphilic cyclodextrin nanospheres shows greater approach towards targeting
system. Erem M et al; have synthesized and characterized amphiphilic
β-cyclodextrin, modified on primary face with substitutes of varying chain
length (C6 and C14) and bond types (ester or amide) ⁵⁴.

Cyclodextrins in rectal and transdermal drug delivery

The main criteria for local
action through rectal and transdermal delivery are the drug stability and drug
solubility. Cyclodextrins play an important role in drug solubility and
stability. Hydrophilic cyclodextrin are applicable for rectal, transdermal drug
delivery. Vollmer et al; suggest the mechanism for lirazole delivery with
hydroxypropyl-β-cyclodextrin and DM-β-cyclodextrin through the dermal route by
enhancing the transdermal absorption, partitioning and absorption through
changing the structure of stratum cornium ⁵⁶. Watanable et al; report
the rectal absorption of insulin in rabbit from hollow type suppositories with
different cyclodextrin, increase the rectal absorption of insulin
⁵⁷.

Cyclodextrins in anesthesia

Cyclodextrin generally used
in anesthesia as a good anesthetic induction agent and act as reversal agent for
neuromuscular blocker rocuronium. Now days, cyclodextrins containing polymer
used for nucleic acid delivery and as protein therapeutic agents
⁵⁵.

Cyclodextrins in cryopreservation of bull sperms

Emoce et al; developed the novel application of cyclodextrin for cryopreservation
of bull sperm by using the cholesterol loaded cyclodextrin, which maintain the
motility of sperm cell ⁵⁸.

Cyclodextrins in HIV infection

Witvrouw M et al; reported
the use of cyclodextrin in HIV infection. Cyclodextrin blocks the virus
attachment, especially at a particular viral receptor protein in entry of human
immunodeficiency virus ⁵⁹. 

Summary

The present article explores various applications of cyclodextrins in pharmaceutical
formulations. Cyclodextrins are able to form inclusion complexes with drugs,
which can improve solubility and bioavailability. Poor dissolution is a major
problem of almost all BCS class II drugs, which leads to poor bioavailability. 
Cyclodextrins can be used extensively as a polymer in novel drug delivery systems
like liposomes, nanoparticles and microspheres that can be expected to improve
the therapeutic efficacy of drug and patient compliance.

References

1. href="http://www.wikipedia.com/"
target=_blank>http://www.wikipedia.com/

2. Jozsef Szejtli,
Cyclodextrin Technology, Klunwer Academic Publishers, 1988.

3. Jozsef Szejtli; Past,
present, and future of cyclodextrin research, Pure Appl Chem, 2004, 76
(10), 1825-1845.

4. href="http://www.lsbu.ac.uk/water/cyclodextrin.htm"
target=_blank>http://www.lsbu.ac.uk/water/cyclodextrin.htm

5. Sham S, Bhaskar C,
Prjakta S; Cyclodextrin application in different route of administration,
Acta pharma, 2005, 55, 139-156. 

6. S. Baboota, R. Khanna,
S. P. Agarwal et al; Cyclodextrin in drug delivery systems: An update, href="http://www.pharmainfo.net/" target=_blank>http://www.pharmainfo.net/,
2003, (05).

7.
Larrucea E, Arellano A, Santoyo S,
Ygartua P; Study of the complexation behavior of tenoxicam with cyclodextrins in
solution: improved solubility and percutaneous permeability. Drug Dev Ind
Pharm, 2000, 27, 245-252.

8. H O Ammar, H A salma, M
Ghorab, Formulation and biological evaluation of
glimepiride-cyclodextrin-polymer systems, Int J Pharm, 2006, 309,
129-138.

9. M Cirri, F Maestrelli, G
Corti, et al; Simultaneous effect of cyclodextrin complexation, pH, and
hydrophilic polymers on naproxen solubilization, Jr Pharm Biomed Anal,
2006, 42, 126-131.

10. Belgamwar V S, Nakhat P
D, Indurwade N H et al; Studies on occlusion complexes of furazolidone with
cyclodextrins and their hydroxy propyl derivatives, Indian Drugs, 2001,
38(9), 479-482.

11. Alka Pravin and MS
Nagarsenker; Triamterene-β-cyclodextrin system: prepartion, characterization and
in vivo evaluation, AAPS PharmSciTech, 2004, 5(1), 19, 1-8.

12. L Ribeiro, T Loftsson,
D Ferreira, Invvestigation and physicochemical characterization of vinpocetine
sulfobutyl ether β-cyclodextrin binary and ternary complexes, Chem Pharm
Bull, 2003, 51(80), 914-922.

13. M Narender Reddy,
Tasneem R, Ramkarishna K et al; β-cyclodextrin complexes of celecoxib: Molecular
modeling, characterization and dissolution studies, AAPS Pharm Sci, 2004,
6(1) 7, 1-9.

14. J. S. Smith, R.J.
MacRae, M.J. Snowden; Effect of SBE7-β-cyclodextrin complexation on carbamzepine
release from sustain release beads, Eur J Pharm Biopharm, 2005, 60,
73-80.

15. J R Moyano, J M Gines M
J Arias,A M Rabasco; Study of dissolution characteristics of oxazepam via
complexation with β-cyclodextrin; Int J Pharm, 1995, 114,
95-102.

16. Carlos V, Jacqueline S,
Mario R, et al; Inclusion complex of antiviral drug acyclovir with cyclodextrin
in aqueous solution and in solid phase; Quimica nova, 2000, 23(6),
749-752.

17.  P T Tayade and P
R Vavia; Inclusion complexes of ketoprofen with β-cyclodextrins: Oral
pharmacokinetic of ketoprofen in human, Indian J Pharm Sci, 2006, 68(2),
164-169.

18.  Catarina M,
Fernandes and Francisco; Effect of the hydrophobic nature of
triacetyl-β-cyclodextrin on the complexation with nicardipine hydrochloride:
Physicochemical and dissolution properties of the kneaded and spray-dried
complexes, Chem Pharm Bull, 2002, 50(12), 1597-1602.

19. Marie W, Maggie A,
Solid state studies of drug-cyclodextrin inclusion complexes in PEG-6000
prepared by new method, Eur J Pharm Sci, 1999, 8, 269-281.

20. T Toropainen, S Velaga,
T Heikkila,et al.; Preparation of budesonide/γ-cyclodextrin complexes in
supercritical fluids with a novel SEDS method, J Pharml Sci, 2006,
95(10), 2235-2245.

21. Xianu H W, Fei T,
Zhijun J; Preparation and study of the 1:2 inclusion complex of carvedilol with
β-cyclodextrin, J Pharm Biomed Anal, 2004, 34, 517-523.

22. David C. Bibby, Nigel
M. Davies,Ian G. Tucker; Improvement of water solubility and in vitro
dissolution rate of gliclazide by complexation with β-cyclodextrin,
Pharmaceutical Acta Helvetiae 2000, 74, 365-370.

23. M L Manca, M Zaru, G
Ennas; Diclofenac-β-cyclodextrin binary systems: Physicochemical
characterization and in-vitro dissolution and diffusion studies, AAPS
PharmSciTech, 2005, 6(3) 58.

24. Sanjula B, Mona D,
Kanchan K; Physicochemical characterization, in-vitro dissolution behavior, and
pharmacodynamic studies of roficoxib-cyclodextrin inclusion compounds.
prepartion and properites of roficoxib hydroxypropyl β-cyclodextrin inclusion
complex:A techanical note, AAPS PharmSciTech, 2005, 6(1), 14,
E-83-90.

25. B N Nalluri, K P R
Chowdary and K V Ramana; Cyclodextrins-The novel excipients: A review on
pharmaceutical applications, Int J Pharm Excip, 2002, 79.

26. D Duchene, G Ponchel, D
Wouessidjewe; Cyclodextrin in targeting application to nanoparticles, Adv
drug delivery reviews, 1999, 36, 29-40.

27. B S Kuchekar;
Cyclodextrin inclusion complexes: characterizations and application, Chemical
weekly, 1993, 28.

28. Valentino J S,
Venkatramana M R, Erika A Z, et al; Mechanism of drug release from cyclodextrin
complexes, Adv drug Delivery review, 1999, 36, 3-16.

29.V J Stella and Roger A
R, Cyclodextrins: Their future in drug formulation and delivery, J Pharm
Res, 1997, 14(5), 556-567.

30.D Hall, D Bloor, K
Tawarah, et al; Kinetic and equilibrium studies associated with the formation of
inclusion compounds involving n-butanol and n-pentanol in aqueous cyclodextrin
solution, J Chem Soc Faraday Trans, 1986, 82, 2111-2121.

31. Giridhar S, Tirucherai
and Ashim K; Effect of hydroxypropyl-β cyclodextrin complexation on aqueous
solubility, stability, and corneal permeation of acyl ester prodrugs of
gancyclovir, AAPS PharmSciTech, 2003, 4(3), 45, 1-12. 

32. Rao B P, Suresh S;
Preparation and evaluation of γ-cyclodextrin complexes of rifampicin, Indian
Drugs, 2004, 41(11), 650-654.

33. Zhong Z, Y K Tam, J
Diakur et al; Hydroxypropyl-β-cyclodextrin-flutamide inclusion complex.
II.oral and intravenous pharmacokinetics of flutamide in the rat, J Pharm
Sci, 2002, 5(3), 292-298

34. Zhong Z, Glen K, Bruce
S, Flutamide-hydroxypropyl-β-cyclodextrin complex: formulation, physical
characterization, and absorption studies using the caco-2 in vitro model; J
Pharm Sci, 2000, 3(2), 220-227.

35. Parya R N, Robert R,
Piroska S R; Physicochemical characterization of meloxicam-mannitol binary
systems, J Pharm Biomed Anal, 2006, 41, 1191-1197.

36. Jun L, Liyan Q Jianqing
G et al; Preparation, characterization and in-vivo evaluation formulation of
baicalein with hydroxypropyl-β-cyclodextrin; Int J Pharm, 2006,
312, 137-143.

37. Sarasija Suresh, H.N.
Shin-vkumar and G.kiran kumar; Effect of β-cyclodextrin complexation on the
solubility and dissolution rate of carbamazepine from tablets, Indian J Pharm
Sci, 2006, 301-307.

38. B N Nalluri, K P R
Chowdary, K V R Murthy et al.; Physicochemical characterization and dissolution
properties of nimesulide-cyclodextrin binary systems, AAPS PharmSciTech,
2003, 4(1) 2 1-12.

39. Y L Louks, V Vraka, G
Grgoriadis, Entrapment of sodium ascorbate-α-cyclodextrin inclusion complex in
multilamellar liposome containing light absorber, greatly increase the stability
of the vitamin against photochemical oxidation, J Pharm Sci, 1996, 2,
523-527.

40. David C B, Nigel M D
Ian G T; Poly (acrylic acid) microsphere containing β-cyclodextrin: loading and
in vitro release of two dyes, Int J Pharm, 1999, 187, 243-250

41. David C B, Nigel M D
Ian G T; Investigation into the structure and composition of β-cyclodextrin/poly
(acrylic acid) microspheres, Int J Pharm, 1999, 180, 161-168.

42.Y Horiuchi, K Abe, F
Hirayama and K Uekama: Release control of theophylline by β-cyclodextrin
derivative: hybridizing effect of hydrophilic, hydrophobic and ionizable
β-cyclodextrin complexes, Journal of control release, 1991, 15,
177-183.

43. K Uekama, K Matsubara,
K Abe; Design and in-vitro evaluation of slow-release dosage form of pertained:
utility of β-cyclodextrin/ cellulose derivative combination as a
modified-release drug carrier J. Pharm Sci.  1990, 79,
244-248.

44. K Okimoto, Roger A,
Rajewski, Valentino J; Release of testosterone from an osmotic pump tablet
utilizing (SBE) 7M- β -cyclodextrin as both a solubilizing and an osmotic pump
agent, Journal of Control release, 1999, 58, 28-38.

45. K Okimoto, R A
Rajewski, K Uekama; The interaction of charged and uncharged drugs with neutral
(hydroxypropyl-β-cyclodextrin) and anionically charged (SBE7-β-cylodextrin)
cyclodextrin, Pharm Res, 1996, 13, 256-263.

46. Tetsumi I, K Uekama;
Cyclodextrins in peptide and protein delivery; Adv drug delivery reviews,
1999, 36, 101-123.

47. Francois M, Snoedx E,
Putteman P et al; A mucoadhesive, cyclodextrin-based vaginal cream formulation
of itraconazole, AAPS PharmSci, 2003, 5(1), 5 1-7.

48. Pate D w, Jarvinen K,
Urtti A et al; Curr Eye Res, 1995, 14, 791.

49. Attama A A, Ndibe O N
and Nnamani P O, Studies on diclofenac-β-cyclodextrin inclusion complexes, J
Pharm Res, 2004, (3), 47-49.

50. Bruce J Aungst;
Intestinal permeation enhancers- mini-review, J Pharm Sci, 2000, 89(4),
429-441.

51. Gian C C, Paolo C M,
Simone L B, et al; Skin permeation study of dehydroepiandrosterone (DHEA)
compared with its α-cyclodextrin complex form, J Pharm Sci, 2002, 91(11),
2399-2405.

52. Mar M, Thorsteinn L,
Gisli M; Cyclodextrins as permeation enhancers: some theoretical evaluation and
in-vitro testing, J controlled release, 1999, 59, 107-118.

53. T Lftsson, N Bodor, E
Smith et al; Percutaneous penetration enhancers, CRC Press. Boca Raton, 1995,
335-342.

54. Erem M, Amelie B, Murat
S et al; Amphiphilic β-cyclodextrins modified on the primary face: synthesis,
characterization, evaluation of their potential a novel excipients in the
preparation on nanocapsules, J Pharm Sci, 2002, 91(5),
1214-1224.

55. Current opinion in
Anesthesiology- Abstract volume, 2005, 18(4), 392-395.

56.E Moce and J K Granham;
Cholesterol-loaded cyclodextrins added to fresh bull ejaculates improve sperm
cryosurvival, J Anim Sci, 2006, 84 826-833.

57.Witvrouw M, Fikkert V,
Pluymers W et al; Polyanionic (i.e. polysulfonate) dendrimers can inhibit the
replication of human immunodeficiency virus by interfering with both virus
adsorption and later steps (reverse transcriptase / integrase) in the virus
replicative cycle. Mol Pharmacol, 2000, 58, 1100-8.

58. Watannabe Y, Matsumoto
Y, Seki M et al; Chem Pharm Bull, 1992, 40, 3042.

59. Vollmer U, Mueller B W, Peeter J, et al; J Pharm Phamacol, 1994,
46, 19.

About Authors:

O.M. Aleem aleemomair

O.M. Aleem, Department of Pharmaceutical Chemistry, Government College of Pharmacy,
Karad, Maharashtra, 415124, India, Tel: +91-09822597037; +91-02164-271196; Fax:
+91-02164-271196, Email: aleem12323@rediffmail.com.

A.L. Patil abhijitpatil

Y.V. Pore yogeshvpore

B.S. Kuchekar bskuchekar

Department of Pharmaceutical Chemistry,
Government College of Pharmacy, Karad, Maharashtra, India, 415124.