drug-CD Complexes Research Articles

Auxiliary Substances for Enhancement of Complexation Efficiency and Dissolution Rate of Drug-Cyclodextrin Complexes

Background: Enzymatic starch breakdown yields 1, 4-linked D-glucopyranoside subunits, which are the building blocks of the cyclodextrin (CD) family of macromolecules. β-Cyclodetrins (β-CDs) have the capability to improve the solubility of partially soluble drugs, as well as their permeability across biological membranes and stability. However, factors like limited solubility, high cost of derivatives and their toxicity at high concentrations has directed the researchers toward multicomponent inclusion complexes (MCIC). Introduction: Incorporating auxiliary substances (AS) leads to MCIC formation during complexation. The auxiliary agent interacts at the molecular level with the CDs, enhances the complexation competence of β-CD or its derivatives, and minimizes the amount required for solubilization of poorly soluble drugs. They also enhance stability of drug-CD complex. Due to these advantages, the popularity of MCIC has increased amongst formulation scientists. Conclusion: This review describes various AS that could be used to prepare MCIC to expand solubility and other properties of drugs and minimize cost of related formulation.

CYCLODEXTRIN IN NOVEL FORMULATIONS AND SOLUBILITY ENHANCEMENT TECHNIQUES: A REVIEW

Using cyclodextrin helps make different dosage forms more soluble. The oligosaccharide class known as cyclodextrins (CDs) is made up of glucose units bound together in a ring. CDs have the promising ability to assemble into complexes with drug molecules and improve their physicochemical properties without the need for molecular modifications. Generally, drug-CD complexes have a stoichiometry of 1:1. However, natural CDs have a tendency to self-assemble and form aggregates in aqueous media, which can reduce the solubility of the CDs by aggregating. One can increase their complexation capacity and solubility through derivative formation, but the final outcome depends on the kind and extent of substitution. Drug penetration through biological membranes can be improved by the formation of water-soluble drug-CD complexes. Solubility is the property of a solid dissolving into a liquid phase to form a homogenous system. Solubility is a crucial component in obtaining the right drug concentration in the systemic circulation for the optimal pharmacological response. Orally administered poorly soluble drugs often require high dosages to reach therapeutic plasma concentrations. Their low solubility in water is one of the primary problems with creating new chemical entities through formulation. The BCS classification system places these medications in class II, which is characterized by high permeability and poor solubility. To greatly improve these medications, it is possible to make them more bioavailable and soluble.

Cyclodextrins and Their Polymers Affect Human Serum Albumin's Interaction with Drugs Used in the Treatment of Pulmonary Infections.

Respiratory infectious diseases have challenged medical communities and researchers. Ceftriaxone, meropenem and levofloxacin are widely used for bacterial infection treatment, although they possess severe side effects. To overcome this, we propose cyclodextrin (CD) and CD-based polymers as a drug delivery system for the drugs under consideration. CD polymers demonstrate higher binding affinity for levofloxacin (Ka ≈ 105 M) compared to drug-CD complexes. CDs slightly alter the drugs' affinity for human serum albumin (HSA), whereas CD polymers increase the drugs' binding affinity up to 100 times. The most significant effect was observed for more the hydrophilic drugs ceftriaxone and meropenem. The drug's encapsulation in CD carriers leads to a decrease in the degree of change in the protein's secondary structure. The drug-CD carrier-HSA complexes demonstrate satisfying antibacterial activity in vitro, and even a high binding affinity does not decrease the drug's microbiological properties after 24 h. The proposed carriers are promising for a drug form with a prolonged drug release.

Hot liquid extrusion assisted drug-cyclodextrin complexation: a novel continuous manufacturing method for solubility and bioavailability enhancement of drugs

In this study, drug-cyclodextrin (CD) complexes were prepared using hot liquid extrusion (HLE) process with an aim to improve solubility and bioavailability of carbamazepine. Saturation solubility studies of CBZ in water and different pH media showed a pH-independent solubility. Phase solubility studies of CBZ at different molar concentrations of beta-cyclodextrin (β-CD) and hydroxypropyl beta-cyclodextrin (HP-β-CD) indicated AL-type solubility profile with stability constants of 574 M−1 and 899 M−1 for β-CD and HP-β-CD. Drug-β-CD and drug-HP-β-CD complexes were prepared using HLE process and conventional methods (such as physical mixture, kneading method, and solvent evaporation) as well. Optimized complexes prepared using HLE viz. CBP-4 and CHP-2 showed a solubility of 4.27 ± 0.09 mg/mL and 6.39 ± 0.09 mg/mL as compared to plain CBZ (0.140 ± 0.007 mg/mL). Formation of drug-CD inclusion complexes was confirmed using DSC, FTIR, and XRD studies. Drug release studies indicated highest release of CBZ from CHP-2 (98.69 ± 2.96%) compared to CBP-4 (82.64 ± 2.45%) and plain drug (13.47 ± 0.54%). Complexes prepared using kneading showed significantly lesser drug release (KMB 75.52 ± 2.68% and KMH 85.59 ± 2.80%) as that of CHP-2 and CBP-4. Pre-clinical pharmacokinetic studies in Wistar rats indicated a significant increase in Cmax, Tmax, AUC, and mean residence time for CHP-2 compared to KMH and plain CBZ. All these results suggest that HLE is an effective method to increase the solubility of poorly water-soluble drugs.Graphical

Experimental characterization and molecular dynamic simulation of ketoprofen-cyclodextrin complexes

Traditional experimental methods have their own limitations to obtain a deep understanding about the molecular mechanism of drug-cyclodextrin (CD) complexes. Thus, present research investigated the molecular interactions between poorly water-soluble drug Ketoprofen (KTP) and six commonly used CDs by combined experimental and modeling methods. Experimental characterizations of prepared KTP-CD complexes observed the crystalline changes and hydrogen bonding formations of KTP. The molecular dynamic simulations at revealed that three β-CD derivatives had higher binding affinity with KTP. Thus, this research present that the combination of experimental and modelling methods could clearly reveal the molecular mechanism of drug-CD complexes.

Water-soluble Complex of Curcumin with Cyclodextrins: Enhanced Physical Properties For Ocular Drug Delivery.

Curcumin, a natural hydrophobic polyphenol, has been reported to have diverse pharmacological activities. Previous studies have evaluated its efficacy using both oral and transdermal dosage forms. However, two major obstacles-poor aqueous solubility and low stability-severely limited its pharmaceutical use. The main objective of this study was to prepare curcumin eye drops that provided sustained release to allow for once daily application in retinitis pigmentosa. To achieve our goal, curcumin was complexed with β -cyclodextrin and hydroxypropyl-β- cyclodextrin in two molar ratios (1:1 and 1:2) using co-solvent, co-solvent with sonication and freezedrying filtration methods. A total of 12 complexes were prepared, then characterized using differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, solubility assessment and in vitro release studies. An improvement in curcumin aqueous solubility relative to pure curcumin was achieved for all 12 complexes. However, the freeze-drying filtration method was superior to all other methods because it produced highly water-soluble drug-CD complexes. Based on our stability analyses, pH 6.8 phosphate buffer containing 1% Tween 80 was selected as the release medium for in vitro release studies because curcumin exhibited high stability in this medium. Our F11 formulation provided sustained release of the drug for more than 96 h with a maximum amount released of drug (21.77±0.26 μg/ml). Our in vitro release data also showed that release of drug from curcumin-CDs inclusion complexes followed a Higuchi non-Fickian diffusion mechanism. Based on these results, F11 was formulated as eye drops, which provide a promising once daily novel topical delivery of this naturally derived phytochemical.

Host-guest kinetic interactions between HP-β-cyclodextrin and drugs for prediction of bitter taste masking

Cyclodextrins (CD) are widely used bitter taste masking agents, for which the binding equilibrium constant (K) for the drug-CD complex is a conventional parameter for quantitating the taste masking effects. However, some exceptions have been reported to the expected relationship between K and bitterness reduction and the relationship between kinetic parameters of a drug-CD interaction, including association rate constant (Ka) and disassociation rate constant (Kd), and taste masking remains unexplored. In this study, based upon a database of kinetic parameters of drugs-HP-β-CD generated by Surface Plasmon Resonance Imaging for 485 drugs, the host-guest kinetic interactions between drugs and HP-β-CD for prediction of taste masking effects have been investigated. The taste masking effects of HP-β-CD for 13 bitter drugs were quantitatively determined using an electronic gustatory system (α-Astree e-Tongue). Statistical software was used to establish a model based on Euclidean distance measurements, Ka and Kd of the bitter drugs/HP-β-CD-complexes (R2=0.96 and P<0.05). Optimized parameters, Ka3, Kd, KaKd, Kd3, Ka2 and Ka/Kd with notable influence, were obtained by stepwise regression from 12 parameters derived from Ka, Kd and K (Ka/Kd). 10-fold cross-validation was used to verify the reliability of the model (correlation coefficient of 0.84, P<0.05). The established model indicated a relationship between Ka, Kd, K and taste masking by HP-β-CD and was successful in predicting the extent of taste masking by HP-β-CD of 44 bitter drugs, which was in accordance with the literature reported. In conclusion, the relationship between kinetics of drug-CD interactions and taste masking was established and providing a new strategy for predicting the cyclodextrin mediated bitter taste masking.

Modified Release and Improved Stability of Unstable BCS II Drug by Using Cyclodextrin Complex as Carrier To Remotely Load Drug into Niosomes.

In answering to the challenge of enzymatic unstability of Biopharmaceutics Classification System (BCS) class II drugs, an effective remote loading strategy was developed to successfully incorporate the drug-cyclodextrin (CD) complex into niosomes to modify the release and stability of a drug candidate, pseudolaric acid B (PAB). Judged by binding constants, and combined solubilization effects of pH and CD complexation on PAB at different pH, the complex internalization driven by a transmembrane pH gradient (from 2.0 to 7.4) and the dynamic shifting of PAB-CD complexation equilibrium at this gradient were introduced. The transfer of PAB-CD complex into the internal aqueous phase of niosomes at 60 °C was primarily verified by synchrotron radiation Fourier transform infrared spectroscopy. The remote loading samples behaved as retarded release at pH 5.8, 6.8, and 7.4, for which the stability of PAB in rat plasma was significantly enhanced (about 8.1-fold), in comparison with niosomes prepared by the passive and lipid bilayer loading of PAB. The drug-carrier interaction based release modeling was further fitted, and the convection rate constant (ks) and free energy difference between free and bound states (ΔG) indicated the strongest PAB-carrier interactions in remote loading niosomes. The remote loading strategy also reduced the CD-cholesterol interaction and provided better physical stability of the system. In conclusion, the remote loading of drug-CD complex into niosomes provides advantages to modify the release and enhance the stability of unstable BCS class II drug.

Photostability of Loratadine Inclusion Complexes with Natural Cyclodextrins

The purpose of this study was to evaluate the photostability of inclusion complexes of the histamine antagonist loratadine (LORA) withα-,β-, andγ-cyclodextrins (CDs). Accordingly, binary drug-CD complexes were prepared using the coevaporation method at 1 : 1, 1 : 2, and 1 : 3 stoichiometric ratios, which were characterized by thermal analysis. Subsequently, solutions of the complexes at 500 μg mL−1in HCl 0.1 M were subjected to irradiation in a photostability chamber for 12 hours, and the content of the remaining active ingredient was quantified by means of high-performance liquid chromatography. It is possible to observe the presence of two products originating from photodegradation (P1 and P2), which were identified in solutions of loratadine withα- andβ-CD. By means of statistical analysis, we conclude that the drug:α-CD and drug:γ-CD (1 : 1) complexes proved to be more efficient in the photostability assay, obtaining a nonsignificant level of degradation and full recovery of LORA.

Spectral and molecular modeling investigations of supramolecular complexes of mefenamic acid and aceclofenac with α- and β-cyclodextrin

Inclusion complexes of mefenamic acid (MFA) and aceclofenac (ALF) with α- and β-cyclodextrins (CDs) in aqueous medium were investigated by absorption, fluorescence, time-resolved fluorescence methods. The solid inclusion complexes between drugs and CDs were characterized by SEM, TEM, FT-IR, 1H NMR, DSC and powder XRD techniques. Spectral studies indicated that both CDs form 1:1 inclusion complex with MFA and ALF. The experimental results revealed that the inclusion process is a spontaneous process. Time-resolved fluorescence studies suggested that ALF exhibited biexponential decay in aqueous and triexponential decay in CD whereas significant enhancement of lifetime of decay components of MFA was observed. Morphologies of drug-CD complexes observed by TEM demonstrate that self-aggregates of MFA/α-CD, ALF/α-CD and ALF/β-CD were nano-sized particles while vesicles were observed for MFA/β-CD. A spatial arrangement of inclusion complex is proposed based on 1H NMR and PM3 results. Investigations of thermodynamic and electronic properties confirmed the stability of the inclusion complex.

Excimer emission in norepinephrine and epinephrine drugs with α- and β-cyclodextrins: spectral and molecular modeling studies.

The inclusion complexation behavior of norepinephrine (NORE) and epinephrine (EPIN) with native cyclodextrins (α-CD and β-CD) were investigated by UV-visible, fluorimetry, time-resolved fluorescence, SEM, TEM, FT-IR, (1)H NMR, DSC, powder XRD and PM3 methods. Single emission was observed in aqueous solution where as dual emission (excimer) noticed in the CD solutions. Both drugs form 1:1 drug-CD complexes in lower CD concentrations and 1:2 CD-drug2 complexes in the higher CD concentrations. Time-resolved fluorescence studies indicated that both drugs showed single exponential decay in water and biexponential decay in CD. Nano-sized self-aggregated particles of drug-CD were found by TEM studies. Molecular modeling studies indicated that aliphatic chain part of the drug was entrapped in the CD cavity. Thermodynamic parameters and binding affinity of complex formation of the CD were determined according to PM3 method. The PM3 results were in good agreement with the experimental results.

2D Solid-State NMR Analysis of Inclusion in Drug–Cyclodextrin Complexes

The solubility of drug molecules can often be improved through preparation and delivery of cyclodextrin (CD) inclusion complexes. These drug-oligosaccharide complexes can be prepared in solution and converted to the solid state via methods such as lyophilization and spray-drying, or they can be prepared directly from solids by a variety of methods. The development of drug-CD complexes as solids allows for potential advantages in dosage form design, such as the preparation of layered formulations, and it also can yield improvements in chemical and physical stability. 2D solid-state NMR (SSNMR) methods provide a direct way to probe drug-CD interactions in solid complexes through dipolar interactions between nuclei within the drug and CD molecules. In this study, 2D heteronuclear and homonuclear correlation SSNMR experiments involving (1)H, (13)C, (19)F, and (31)P nuclei are used to demonstrate the inclusion of drug within the CD cavity in a variety of powder samples. To illustrate the general applicability of the SSNMR approach presented, examples are shown for the drugs diflunisal, adefovir dipivoxil, voriconazole, dexamethasone, and prednisolone in complexes with α-CD, β-CD, and sulfobutylether-substituted β-CD. The quantitative analysis of included and free drug fractions in a solid drug-CD complex using SSNMR is also demonstrated. On the basis of these results, general approaches to the characterization of these materials using SSNMR are proposed.

Molecular Cycloencapsulation Augments Solubility and Improves Therapeutic Index of Brominated Noscapine in Prostate Cancer Cells

We have previously shown that a novel microtubule-modulating noscapinoid, EM011 (9-Br-Nos), displays potent anticancer activity by inhibition of cellular proliferation and induction of apoptosis in prostate cancer cells and preclinical mice models. However, physicochemical and cellular barriers encumber the development of viable formulations for future clinical translation. To circumvent these limitations, we have synthesized EM011-cyclodextrin inclusion complexes to improve solubility and enhance therapeutic index of EM011. Phase solubility analysis indicated that EM011 formed a 1:1 stoichiometric complex with β-CD and methyl-β-CD, with a stability constant (K(c)) of 2.42 × 10(-3) M and 4.85 × 10(-3) M, respectively. Fourier transform infrared spectroscopy suggested the penetrance of either a O-CH(2) or OCH(3)-C(6)H(4)-OCH(3) moiety of EM011 in the β-CD or methyl-β-CD cavity. In addition, multifarious techniques, namely, differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, NMR spectroscopy, and computational studies validated the cage complex of EM011 with β-CD and methyl-β-CD. Moreover, rotating frame overhauser enhancement spectroscopy showed that the H(a) proton of the OCH(3)-C(6)H(4)-OCH(3) moiety was in close proximity with H3 proton of the β-CD or methyl-β-CD cavity. Furthermore, we found that the solubility of EM011 in phosphate buffer saline (pH 7.4) was enhanced by ~11 fold and ~21 fold upon complexation with β-CD and methyl-β-CD, respectively. The enhanced dissolution of the drug CD-complexes in aqueous phase remarkably decreased their IC(50) to 28.5 μM (9-Br-Nos-β-CD) and 12.5 μM (9-Br-Nos-methyl-β-CD) in PC-3 cells compared to free EM011 (~200 μM). This is the first report to demonstrate the novel construction of cylcodextrin-based nanosupramolecular vehicles for enhanced delivery of EM011 that warrants in vivo evaluation for the superior management of prostate cancer.

Drug-cyclodextrin-vesicles dual carrier approach for skin targeting of anti-acne agent.

In the present study attempt was made for preparation of isotretinoin-hydroxypropyl beta cyclodextrin (HP-beta-CD) inclusion complex and encapsulate this complex in elastic liposomes to study the effect of dual carrier approach on skin targeting of isotretinoin. The isotretinoin HP-beta-CD complex was prepared by freeze-drying method and characterized by IR spectroscopy. The drug and drug-CD complex loaded elastic liposomal formulation were prepared and characterized in vitro, ex-vivo and in vivo for shape, size, entrapment efficiency, no. of vesicles per cubic mm, in vitro skin permeation and deposition study, photodegradation and skin toxicity assay. The transdermal flux for different vesicular formulations was observed between 10.5 +/- 0.5 to 13.9 +/- 1.6 microg/cm(2)/h. This is about 15-21 folds higher than that obtained from drug solution (0.7 +/- 0.1 microg/cm(2)/h) and 4-5 folds higher than obtained with drug-CD complex solution (2.7 +/- 0.1 microg/cm(2)/h). The amount of drug deposit was found to increase significantly (p < 0.05) by cyclodextrin complexation (30.1 +/- 0.1 microg). The encapsulation of this complex in elastic liposomal formulation further increases its skin deposition (262.2 +/- 21 microg). The results of skin irritation study using Draize test also showed the significant reduction in skin irritation potential of isotretinoin elastic liposomal formulation in comparison to free drug. The results of the present study demonstrated that isotretinoin elastic liposomal formulation possesses great potential for skin targeting, prolonging drug release, reduction of photodegradation, reducing skin irritation and improving topical delivery of isotretinoin.

Development of a new delivery system consisting in ‘drug–in cyclodextrin–in PLGA nanoparticles’

A combined approach based on drug cyclodextrin (CD) complexation and loading into PLGA nanoparticles (NP) has been developed to improve oxaprozin therapeutic efficiency. This strategy exploits the solubilizing and stabilizing properties of CDs and the prolonged-release and targeting properties of PLGA NPs. Drug-loaded NPs, prepared by double-emulsion, were examined for dimensions, zeta-potential and entrapment efficiency. Solid-state studies demonstrated the absence of drug–polymer interactions and assessed the amorphous state of the drug-CD complex loaded into NPs. Drug release rate from NPs was strongly influenced by the presence and kind of CD used. The percentage released at 24 h varied from 16% (plain drug-loaded NPs) to 50% (drug-βCD-loaded NPs) up to 100% (drug-methylβCD-loaded NPs). This result suggests the possibility of using CD complexation not only to promote, but also to regulate drug release rate from NPs, by selecting the proper type of CD or CD combination.

Prolonged absorption of antimony(V) by the oral route from non‐inclusion meglumine antimoniate–β‐cyclodextrin conjugates

The orally active composition comprising meglumine antimoniate (MA) and beta-cyclodextrin (beta-CD) differs markedly from conventional drug-CD complexes, since it combines a water-soluble drug and a hydrophilic CD. In order to obtain insights into the mechanism(s) responsible for the improved oral delivery of the drug, physicochemical and pharmacokinetic studies were carried out. The composition investigated here was prepared at a 7:1 antimony(Sb)/beta-CD molar ratio, a condition that improves its solubility in water and allows the oral administration of a high dose of Sb in large animals. It was characterized by circular dichroism, (1)H-NMR, ESI-MS and photon correlation spectroscopy. Pharmacokinetic data were obtained in Beagle dogs after oral administration of the composition at 100 mg Sb/kg. (1)H-NMR and ESI-MS data supported the formation of non-inclusion complexes between MA and beta-CD. Sub-micron assemblies were also evidenced that slowly dissociate and presumably release the MA drug, upon reconstitution of the composition in water. Pharmacokinetic studies of MA and MA/beta-CD in dogs showed a prolongation of the serum mean residence time of Sb from 4.1 to 6.8 h, upon complexation of MA with beta-CD. Evidence was also obtained that Sb remains essentially under the form of pentavalent Sb-meglumine complex, following gastro-intestinal absorption from the MA/beta-CD composition. In conclusion, the present data support the model that the sustained drug release property of 7:1 MA/beta-CD composition resulted in the prolongation of MA absorption by the oral route and, consequently, in the increase of the drug mean residence time in serum.

Preparation of Hydrophobic Drugs Cyclodextrin Complex by Lyophilization Monophase Solution

ABSTRACTA novel method was evaluated for preparation of hydrophobic drugs cyclodextrin (CD) complex in this study. To obtain sterilized drug-CD complex lyophilized powder for injection or other purpose, the CD solution in water and the hydrophobic drug in tertiary butyl alcohol (TBA) were mixed in a suitable volume ratio, filtered through 0.22 μm millpores, and subsequently freeze-dried. A high drug concentration was obtained in the co-solvent due to the good solvency of TBA, which is miscible with water in any proportion, for hydrophobic drugs. Moreover, TBA could be removed rapidly and completely by freeze-drying because of its high vapor pressure and high melting point. The chemical stability of some labile active compounds was also improved in TBA-water co-solvent. Based on the data from differential scanning calormetry (DSC) and X-ray diffractometry (XRD), drug was amorphous in freeze-dried complex. The fourier transform infrared spectra indicated drug-CD interaction was present in drug-CD complex. An enhanced dissolution rate was also obtained in drug-CD complex. These results proved drug-CD complex had been formed after this technique. Thus, this report provided a simple, efficient, and economic technique for preparation of hydrophobic drugs CD complex, which may be useful practically in modifying hydrophobic drugs physicochemical properties and improving their absorption and pharmacodynamics.

Absorption, distribution and excretion of beta-cyclodextrin and glucosyl-beta-cyclodextrin in rats.

The absorption, distribution and excretion of intravenously and orally administered beta-cyclodextrin (beta-CD) and glucosyl (G)-beta-CD in rats were studied using HPLC with pulsed amperometric detection. Within 10 h after intravenous administration, unchanged beta-CD and G-beta-CD recovered in urine were about 90% of each dose. The nephritic accumulation of G-beta-CD after the intravenous administration of G-beta-CD was slightly lower than that of beta-CD using the same treatment. The maximum plasma concentrations of beta-CD and G-beta-CD after the oral administration of CDs (500 mg/kg) were observed within 40 min. After oral administration, 0.6% of beta-CD and 0.3% of G-beta-CD were excreted in urine. The pharmacokinetic behaviour of both CDs after the intravenous administration of CDs (50 mg/kg) was almost the same. Furthermore, the inclusion complexes of estriol and betamethasone with CDs were prepared, and their absorption was evaluated after oral administration in rats. The plasma concentrations of CDs after oral administration of drug-CD complexes were significantly decreased in comparison with those after the oral administration of CDs alone. On the other hand, the plasma concentrations of drugs after the oral administration of drug-CD complexes were higher than those after the administration of drugs alone.