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INVITED REVIEW
Year : 2010  |  Volume : 2  |  Issue : 2  |  Page : 72-79 Table of Contents     

Cyclodextrins in delivery systems: Applications


1 Jaipur National University, Jagatpura, Jaipur, Rajasthan, India
2 Department of pharmaceutics, Pranveer Singh Institute of Technology, Kalpi Road, Bhauti, Kanpur 208020, Uttar Pradesh, India

Date of Submission20-Mar-2010
Date of Decision26-Mar-2010
Date of Acceptance13-Apr-2010
Date of Web Publication2-Aug-2010

Correspondence Address:
Gaurav Tiwari
Jaipur National University, Jagatpura, Jaipur, Rajasthan
India
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DOI: 10.4103/0975-7406.67003

PMID: 21814436

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   Abstract 

Cyclodextrins (CDs) are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. CD molecules are relatively large with a number of hydrogen donors and acceptors and, thus in general, they do not permeate lipophilic membranes. In the pharmaceutical industry, CDs have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs and to increase their bioavailability and stability. CDs are used in pharmaceutical applications for numerous purposes, including improving the bioavailability of drugs. Current CD-based therapeutics is described and possible future applications are discussed. CD-containing polymers are reviewed and their use in drug delivery is presented. Of specific interest is the use of CD-containing polymers to provide unique capabilities for the delivery of nucleic acids. Studies in both humans and animals have shown that CDs can be used to improve drug delivery from almost any type of drug formulation. Currently, there are approximately 30 different pharmaceutical products worldwide containing drug/CD complexes in the market.

Keywords: Complexation, transdermal, targeted drug delivery, colon, rectal


How to cite this article:
Tiwari G, Tiwari R, Rai AK. Cyclodextrins in delivery systems: Applications. J Pharm Bioall Sci 2010;2:72-9

How to cite this URL:
Tiwari G, Tiwari R, Rai AK. Cyclodextrins in delivery systems: Applications. J Pharm Bioall Sci [serial online] 2010 [cited 2014 Dec 18];2:72-9. Available from: http://www.jpbsonline.org/text.asp?2010/2/2/72/67003

A drug delivery system is expected to deliver the required amount of drug to the targeted site for the necessary period of time, both efficiently and precisely. Different carrier materials are being constantly developed to overcome the undesirable properties of drug molecules. [1] Amongst them, cyclodextrins (CDs) have been found as potential candidates because of their ability to alter physical, chemical and biological properties of guest molecules through the formation of inclusion complexes. CDs were discovered approximately 100 years ago and the first patent o要 CDs and their complexes was registered in 1953. [2] However, their large-scale commercial utilization was prevented mainly due to their high cost and concerns regarding their safety. Recent advancements have resulted in dramatic improvements in CD production, which have lowered their production costs. This has led to the availability of highly purified CDs and CD derivatives which are well suited as pharmaceutical excipients. A lot of work has also been done regarding the safety-assessment of CDs and CD derivatives, which has allayed the fears that were initially raised regarding their safety.


   Cyclodextrins and Complexation Phenomenon Top


CDs are cyclic oligosaccharides of a glucopyranose, containing a relatively hydrophobic central cavity and hydrophilic outer surface. Owing to the lack of free rotation around the bonds connecting the glucopyranose units, the CDs are not perfectly cylindrical molecules but are toroidal or cone shaped. [3] As a result of their molecular structure and shape, they possess a unique ability to act as molecular containers by entrapping guest molecules in their internal cavity. No covalent bonds are formed or broken during drug CD complex formation, and in aqueous solution, the complexes readily dissociate and free drug molecules remain in equilibrium with the molecules bound within the CD cavity. The parent or natural CDs consist of 6, 7 or 8 glucopyranose units and are referred to as alpha, beta and gamma CD, respectively. CDs containing 9, 10, 11, 12 and 13 glucopyranose units have also been reported. Hundreds of modified CDs have been prepared and shown to have research applications, but o要ly a few of these derivatives, those containing the hydroxypropyl (HP), methyl (M) and sulfobutylether (SBE) substituents have been commercially used as new pharmaceutical excipients.


   Advantages of Cyclodextrin Inclusion Complexation Top


CDs have mainly been used as complexing agents to increase the aqueous solubility of poorly water-soluble drugs and to increase their bioavailability and stability. In addition, CDs have been used to reduce or prevent gastrointestinal or ocular irritation, reduce or eliminate unpleasant smells or tastes, prevent drugdrug or drugadditive interactions, or even to convert oils and liquid drugs into microcrystalline or amorphous powders.

  1. Enhancement of solubility: CDs increase the aqueous solubility of many poorly soluble drugs by forming inclusion complexes with their apolar molecules or functional groups. The resulting complex hides most of the hydrophobic functionality in the interior cavity of the CD while the hydrophilic hydroxyl groups o要 the external surface remain exposed to the environment. The net effect is that a water-soluble CD drug complex is formed. [4]
  2. Enhancement of bioavailability: When poor bioavailability is due to low solubility, CDs are of extreme value. Preconditions for the absorption of an orally administered drug are its release from the formulation in dissolved form. When drug is complexed with CD, dissolution rate and, consequently, absorptionare enhanced. Reducing the hydrophobicity of drugs by CD complexation also improves their percutaneous or rectal absorption. In addition to improving solubility, CDs also prevent crystallization of active ingredients by complexing individual drug molecules so that they can no longer self-assemble into a crystal lattice. [5]
  3. Improvement of stability: CD complexation is of immense application in improving the chemical, physical and thermal stability of drugs. For an active molecule to degrade upon exposure to oxygen, water, radiation or heat, chemical reactions must take place. When a molecule is entrapped within the CD cavity, it is difficult for the reactants to diffuse into the cavity and react with the protected guest. [6]
  4. Reduction of irritation: Drug substances that irritate the stomach, skin or eye can be encapsulated within a CD cavity to reduce their irritancy. Inclusion complexation with CDs reduces the local concentration of the free drug, below the irritancy threshold. As the complex gradually dissociates and the free drug is released, it gets absorbed into the body and its local free concentration always remains below the levels that might be irritating to the mucosa.
  5. Prevention of incompatibility: Drugs are often incompatible with each other or with other inactive ingredients present in a formulation. Encapsulating o要e of the incompatible ingredients within a CD molecule stabilizes the formulation by physically separating the components in order to prevent drugdrug or drugadditive interaction. [7]
  6. Odor and taste masking: Unpleasant odor and bitter taste of drugs can be masked by complexation with CDs. Molecules or functional groups that cause unpleasant tastes or odors can be hidden from the sensory receptors by encapsulating them within the CD cavity. The resulting complexes have no or little taste or odor and are much more acceptable to the patient.
  7. Material handling benefits: Substances that are oils/liquids at room temperature can be difficult to handle and formulate into stable solid dosage forms. Complexation with CDs may convert such substances into microcrystalline or amorphous powders which can be conveniently handled and formulated into solid dosage forms by conventional production processes and equipment. [8]



   Applications of Cyclodextrins in Drug Delivery Systems Top


The multifunctional characteristics of CDs have enabled them to be used in almost every drug delivery system, be it oral drug delivery or transdermal drug delivery or ocular drug delivery. The commercial viability of CD-based oral formulations has been established with the marketing of more than 20 products worldwide. [9]

A number of excellent reviews have appeared in the literature in the last few years describing the applications of CDs in various drug delivery systems [Table 1]. We present below an update o要 the recent work done in the different fields.

Oral drug delivery system

Since time immemorial, out of all the sites available for delivering drugs, oral route has been the most popular route for designing a drug delivery system. In the oral delivery system, the release of the drug is either dissolution controlled, diffusion controlled, osmotically controlled, density controlled or pH controlled. [10] CDs have been used as an excipient to transport the drugs through an aqueous medium to the lipophillic absorption surface in the gastrointestinal tract, i.e., complexation with CDs has been used to enhance the dissolution rate of poorly water-soluble drugs. Hydrophilic CDs have been particularly useful in this regard. Rapid dissolving complexes with CDs have also been formulated for buccal and sublingual administration. In this type of drug delivery system, a rapid increase in the systemic drug concentration takes place along with the avoidance of systemic and hepatic first-pass metabolism. [11]

Rectal dug delivery system

Recent studies have shown that rectal mucosa can be used as a potential site for delivering drugs which have a bitter and nauseous taste, have a high first-pass metabolism and degrade in the gastrointestinal pH. It is an ideal route to deliver drugs to the unconscious patients, children and infants. However, rectal mucosa offers a very limited area for drug absorption resulting in an erratic release of drugs. To overcome these problems, a number of excipients have been used, and amongst them CDs have been found to be quite useful. [12] [Table 2] shows CDs in rectal drug delivery system. To be used as excipients in rectal drug delivery system, CDs should have the following characteristics:

  1. They should be non-irritating to the rectal mucosa
  2. They should inhibit the reverse diffusion of drugs into the vehicle
  3. They should have a low affinity for the suppository base.


Nasal drug delivery system

The use of nasal mucosa for transporting drugs is a novel approach for the systemic delivery of high potency drugs with a low oral bioavailability, due to extensive gastrointestinal breakdown and high hepatic first-pass effect. CDs have the ability to enhance drug delivery through biological barriers without affecting their barrier function, a property which makes CDs ideal penetration enhancers for intranasal drug delivery [Table 3]. To be used as excipients in nasal drug delivery system, CDs should have the following characteristics:

  1. They should not have any local or systemic effect;
  2. They should not interfere with the nasal muco-ciliary functions;
  3. They should not show ciliostatic effect;
  4. They should be non-irritating and non-allergenic and
  5. They should enhance the permeation of drugs across nasal epithelium in a reversible manner. [13]


Transdermal drug delivery system

Transdermal drug delivery system is a sophisticated and more reliable means of administering the drug through skin, for local and systemic action. [Table 4] shows CDs in transdermal drug delivery system. To be used as excipients in transdermal drug delivery system, CDs should possess the following characteristics:

  1. They should be therapeutically inert;
  2. They should not interfere with the normal functions of the skin such as protection from heat, humidity, radiation and other potential insults;
  3. They should not alter the pH of the skin;
  4. They should not interact with any component of the skin and
  5. They should not cause skin irritation. [14]


Ocular drug delivery system

In an ocular drug delivery system, the most preferred dosage form is the eye drop due to easy instillation in the eye. But the major disadvantage of this dosage form is its inability to sustain high local concentration of drug. CDs have been used to increase the solubility and/ or stability of drugs and to prevent side effects of drugs such as irritation and discomfort.

[Table 5] shows CDs in occular drug delivery system. To be used as excipients in ocular drug delivery system, CDs should possess the following characteristics:

  1. They should be non-irritating to the ocular surface, as irritation can cause reflex tearing and blinking resulting in fast washout of instilled drug
  2. They should be non-toxic and well tolerated
  3. They should be inert in nature and
  4. They should enhance the permeability of the drug through the corneal mucosa.
Numerous studies have shown that CDs are useful additives in ophthalmic formulations for increasing the aqueous solubility, stability and bioavailability of ophthalmic drugs and to decrease drug irritation. [15]

Controlled and targeted drug delivery system

Whereas most of the earlier work done o要 CDs concentrated o要 their property to enhance the release rate of drugs from dosage forms, some recent work has also been done to evaluate CDs as carriers in controlled release drug delivery systems. Of the various CD derivatives, hydrophobic CDs such as alkylated and acylated derivatives have been used to prolong the release rate of drugs while hydrophilic derivatives have been used to enhance the release rate. Recently, Kumar et al. (2003)prepared a bilayered tablet of melatonin whereby the release rate of drug was increased in the fast-release portion by the use of CDs while it was retarded in the slow-release portion by the use of cellulosic polymers. [Table 6] enlists the drugs formulated as controlled and targeted delivery systems using different CDs. [16],[17]

Peptide and protein delivery

Various problems associated with the practical use of therapeutic peptides and proteins are their chemical and enzymatic instability, poor absorption through biological membranes, rapid plasma clearance, peculiar dose response curves and immunogenicity. [18],[19],[20] CDs, because of their bioadaptability in pharmaceutical use and ability to interact with cellular membranes, can act as potential carriers for the delivery of proteins, peptides, and oligonucleotide drugs. Therapeutic use of peptides across the blood brain barrier (BBB) is greatly hindered by their very low penetration and it was reported that P-gp substrates, such as synthetic hydrophobic peptides, can stimulate the transport of drugs across the BBB. An apically polarized verapamil-sensitive efflux system for small hydrophobic peptides has been found in the BBB of rats. [21]

Gene and oligonucleotide delivery

The toxicity and immunogenicity associated with viral vectors led to the development of nonviral vectors for gene delivery. Besides the plasmid or virusbased vector systems, "naked" nucleotide derivatives have also been investigated for possible use as therapeutic agents through several routes of administration. Gene delivery technologists are now testing CD molecules in the hope of finding an optimal carrier for the delivery of therapeutic nucleic acidsHowever, the limitations of CDs such as CD-associated toxicity (e.g., DM-β-CD) have to be considered before their clinical use. [22]

Dermal and transdermal delivery


CDs have been used to optimize local and systemic dermal drug delivery. Applications of CDs in transdermal drug delivery include enhancement of drug release and/or permeation, drug stabilization in formulation or at absorptive site, alleviation of drug-induced local irritation, sustaining of drug release from vehicle and alteration of drug bioconversion in the viable skin. Parent CDs (α, β, and γCDs) and various chemically modified CD derivatives with extended physicochemical properties and inclusion capacity have been used in transdermal drug delivery. [23]

Brain drug delivery or brain targetting

The concept of Bodor's chemical delivery system (CDS) (i.e., covalent coupling of drugs to 1-methyl-1,4dihydronicotinic acid through an enzymatically labile linkage, which increases drug lipophilicity) was applied for targeting drugs such as steroids, antitumor agents and calcium channel antagonists to brain. However, presence of the lipophilic moiety makes prodrugs of CDS poorly water soluble. HP-β-CD, due to its ability to solubilize drugs and also to enhance the chemical stability of dihydronicotinic acid in aqueous solution solved the solubility problems of CDs. [24],[25],[26],[27]


   CD Applications in the Design of Some Novel Delivery Systems Top


Liposomes

In drug delivery, the concept of entrapping CD-drug complexes into liposomes combines the advantages of both CDs (such as increasing the solubility of drugs) and liposomes (such as targeting of drugs) into a single system and thus circumvents the problems associated with each system. Liposomes entrap hydrophilic drugs in the aqueous phase and hydrophobic drugs in the lipid bilayers and retain drugs en route to their destination. [28] The fact that some lipophilic drugs may interfere with bilayer formation and stability limits the range and amount of valuable drugs that can be associated with liposomes. By forming water-soluble complexes, CDs would allow insoluble drugs to accommodate in the aqueous phase of vesicles and thus potentially increase drug-to-lipid mass ratio levels, enlarge the range of insoluble drugs amenable for encapsulation (i.e., membrane-destabilizing agents), allow drug targeting and reduce drug toxicity. Problems associated with intravenous administration of CD complexes such as their rapid removal into urine and toxicity to kidneys, especially after chronic use, can be circumvented by their entrapment in liposomes [29] .When the concept of entrapping CD complexes into liposomes was applied to HP-β-CD complexes of dexamethasone, dehydroepiandrosterone, retinal and retinoic acid, the obtained dehydration-rehydration vesicles (DRV liposomes) retained their stability in the presence of blood plasma [30] . Liposomal entrapment can also alter the pharmacokinetics of inclusion complexes. Liposomal entrapment drastically reduced the urinary loss of HP-βCD/drug complexes but augmented the uptake of the complexes by liver and spleen, where after liposomal disintegration in tissues, drugs were metabolized at rates dependent on the stability of the complexes.

Microspheres

In the presence of a high percentage of highly soluble hydrophilic excipients, complexation may not improve the drug dissolution rate from microspheres. Nifedipine release from chitosan microspheres was slowed down on complexation with HP-β-CD in spite of the improved drug-loading efficiency. Since it is highly unlikely for CD molecules to diffuse out of the microspheres, even with a low stability constant, the complex must first release the free drug that can permeate out of the microspheres. Hence, the observed slow nifedipine release from the microspheres was reported to be due to lesser drug availability from the complex and also due to formation of hydrophilic chitosan/CD matrix layer around the lipophilic drug that further decreases the drug matrix permeability. [31],[32],[33],[34] Sustained hydrocortisone release with no enhancement of its dissolution rate was observed from chitosan microspheres containing its HP-β-CD complex. The sustained hydrocortisone release was reported to be due to formation of a layer adjacent to the interface by the slowly dissolving drug during the dissolution process that makes the microsphere surface increasingly hydrophobic. [35]

Microcapsules

It was suggested that cross-linked βCD microcapsules, because of their ability to retard the release of watersoluble drugs through semipermeable membranes, can act as release modulators to provide efficiently controlled release of drugs. Terephthaloyl chloride (TC) cross-linked β-CD microcapsules were found to complex pnitrophenol rapidly and the amount complexed increased as the size of the microcapsules decreased. TC cross-linked βCD microcapsules retarded the diffusion of propranolol hydrochloride through dialysis membrane. Double microcapsules, prepared by encapsulating methylene blue with different amounts of β-CD microcapsules inside a cross-linked human serum albumin (HSA), showed decreasing release rate of methylene blue with increasing amount of β-CD microcapsules. [36],[37],[38],[39]

Nanoparticles

Nanoparticles are stable systems suitable to provide targeted drug delivery and to enhance the efficacy and bioavailability of poorly soluble drugs. However, the safety and efficacy of nanoparticles are limited by their very low drug loading and limited entrapment efficiency (with classical water emulsion polymerization procedures) that may lead to excessive administration of polymeric material. Two applications of CDs have been found very promising in the design of nanoparticles: one is increasing the loading capacity of nanoparticles and the other is spontaneous formation of either nanocapsules or nanospheres by nanoprecipitation of amphiphilic CDs diesters. Both the new techniques have been reported to be useful due to great interest of nanoparticles in oral and parenteral drug administration. [40],[41],[42]

Porphyrin−cyclodextrin conjugates as a nanosystem for versatile drug delivery and multimodal cancer therapy

The porphyrin−CD conjugates were prepared and tested for selective and effective multifunctional drug delivery and therapy. The porphyrin receptor system combines efficient binding of the selected drug to the CD cavity and photosensitizing properties of the porphyrin moiety with high accumulation of the whole complex in cancer tissue. [43] Many therapeutic methods such as chemotherapy, radiotherapy, photodynamic therapy and immunotherapy are used for treatment of cancer. [44] These methods can be used as a single therapy or in combination with other therapeutic approaches; the latter strategy is called combined therapy. The advantage of the combined therapies is their higher therapeutic effect compared to the single therapy approach. The most favorable results are achieved when two or more different modes of treatment are applied simultaneously. For instance, Ladewig et al. have published a clinical study [45] on the successful combination of therapies utilizing parallel action of two drugs employing principles of photodynamic therapy (drug verteporfin) and chemotherapy [bevacizumab, mAb against vascular endothelial growth factor-A (VEGF-A)] for the treatment of neovasculature-related macular degeneration. Recently, several synergic photosensitizers integrating photodynamic therapy (PDT) and chemotherapy capabilities in one specifically designed agent have been developed.

Cyclodextrin use as excipients in drug formulation

As excipients, CDs have been finding different applications in the formulation and processing of drugs. βCD, due to its excellent compactability (varied with source) and minimal lubrication requirements, showed considerable promise as a filler binder in tablet manufacturing but its fluidity was insufficient for routine direct compression. βCD was also found to be useful as a solubility enhancer in tablets. The ability of β-CD to complex progesterone by wet granulation was found to be dependent on both binder solution and mixture type. [46] Complexation can cause changes in the tabletting properties of drugs or CDs that can substantially affect the stability and tabletting performance of tablet formulations containing drug/CD complexes. Complexation of tolbutamide with HP-β-CD (freezedried or spraydried) altered the water sorption-desorption and tabletting properties of the CD, and the resultant complex showed worse compactability than the pure CD or the drug/CD physical mixture. [47] CDs also affect the tabletting properties of other excipients, e.g., microcrystalline cellulose codried with β-CD showed improved flowability, compactability and disintegration properties suitable for direct compression. [48] Avicel/β-CD codried product showed improved flowability and disintegration properties but its rounder particles, because of their sensitivity to lubrication, gave weaker tablets than those with avicel. But on addition of magnesium stearate, the codried excipient with improved powder flowability served as a better excipient in wet granulation. [49] CDs can be used to mask the taste of drugs in solutions, e.g., suppression of bitter taste of 4 mm oxyphenonium bromide by CDs. Carbomers, owing to their ionic nature and large number of acidic groups, tend to interact with cationic substances and hydrophilic polymers with alcoholic groups. CDs were found to inhibit carbomerdrug interactions in hydrogel. Large differences were observed in the powder and particle characteristics of β, α-, γ-, and HP-β-CDs. With these CDs, the order of sphericity was βCD < αCD < γCD < HPβCD and that of shape uniformity was αCD < βCD < γCD < HPβCD.


   Cyclodextrin Effects on Important Drug Properties in Formulation Top


Effect on drug solubility and dissolution

CDs have been playing a very important role in formulation of poorly water-soluble drugs by improving apparent drug solubility and/or dissolution through inclusion complexation or solid dispersion, by acting as hydrophilic carriers for drugs with inadequate molecular characteristics for complexation, or as tablet dissolution enhancers for drugs with high dose, with which use of a drug/CD complex is difficult, e.g., paracetamol. [50] CD applications as solubilizing agents are summarized in [Table 7].

Effect on drug bioavailability

CDs enhance the bioavailability of insoluble drugs by increasing the drug solubility, dissolution and/or drug permeability. CDs increase the permeability of insoluble, hydrophobic drugs by making the drug available at the surface of the biological barrier, e.g., skin, mucosa or the eye cornea, from where it partitions into the membrane without disrupting the lipid layers of the barrier. In such cases it is important to use just enough CD to solubilize the drug in the aqueous vehicle since excess may decrease the drug availability. In the case of water-soluble drugs, CDs increase drug permeability by direct action on mucosal membranes and enhance drug absorption and/or bioavailability. [51]

Effect on drug safety

CDs have been used to ameliorate the irritation caused by drugs.The increased drug efficacy and potency (i.e., reduction of the dose required for optimum therapeutic activity), caused by CD-increased drug solubility, may reduce drug toxicity by making the drug effective at lower doses. β-CD enhanced the antiviral activity of ganciclovir on human cytomegalovirus clinical strains and the resultant increase in the drug potency reduced the drug toxicity. [52],[53],[54] The toxicities associated with crystallization of poorly water-soluble drugs in parenteral formulations can often be reduced by the formation of soluble drug:CD complexes.

Effect on drug stability

CDs can improve the stability of several labile drugs against dehydration, hydrolysis, oxidation and photodecomposition and thus increase the shelf life of drugs. It was reported that CD-induced enhancement of drug stability may be a result of inhibition of drug interaction with vehicles and/or inhibition of drug bioconversion at the absorption site. [55] By providing a molecular shield, CD complexation encapsulates labile drug molecules at the molecular level and thus insulates them against various degradation processes.

Future prospects of cyclodextrins

The future prospects of CD and its derivatives are quite bright since they possess remarkably unique properties of forming inclusion complexes with drugs. An increasing number of drugs being developed today have problem of poor solubility, bioavailability and permeability. CDs can serve as useful tools in the hands of pharmaceutical scientists for optimizing the drug delivery of such problematic drugs and also for drugs having other undesirable properties such as poor stability, objectionable taste and odor, and irritation potential. [56],[57],[58],[59],[60],[61],[62] Although presently, o要ly conventional formulations such as tablets, capsules, solutions and ointments have been commercialized using CDs, they are also extensively being studied for their utilization in novel formulations such as nanoparticles, liposomes, nasal, ophthalmic and rectal formulations, transdermal products and targeted drug delivery systems, and the time is not far when such products will become commercially available. CDs, as a result of their complexation ability and other versatile characteristics, are continuing to have different applications in different areas of drug delivery and pharmaceutical industry. However, it is necessary to find out any possible interaction between these agents and other formulation additives because the interaction can adversely affect the performance of both. It is also important to have knowledge of different factors that can influence complex formation in order to prepare drug/CD complexes economically with desirable properties. [62],[63],[64],[65],[66],[67],[68]


   Conclusion Top


CDs, as a result of their complexation ability and other versatile characteristics, are continuing to have different applications in different areas of drug delivery and pharmaceutical industry. However, it is necessary to find out any possible interaction between these agents and other formulation additives because the interaction can adversely affect the performance of both. It is also important to have knowledge of different factors that can influence complex formation in order to prepare economically drug/CD complexes with desirable properties.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]


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