Synthesis and Characterization of Linear Water-soluble γ-Cyclodextrin based Polymers as Drug Carrier Systems

A series of new linear water-soluble homo and copolymers of γ-cyclodextrin are reported. These water-soluble polymers were synthesized from γ-cyclodextrin (γ-CD) and triazine through a single pot condensation polymerization procedure and the synthetic parameters optimized. Lactose and maltose based γ-cyclodextrin copolymers were also prepared. The physicochemical properties of these synthesized polymers were characterized by FT-IR spectroscopy, XRD analysis, thermogravimetry analysis (TGA) and aqueous solubility determination. The formation of a 1:1 efavirenz (an anti HIV drug)/γ-CD polymer inclusion complex was confirmed from FT-IR and UV–VIS spectroscopy and phase solubility studies. The release performance of efavirenz was investigated through phase solubility and dissolution studies. It was found that these copolymers showed improved drug dissolution abilities.     

Effect of self-aggregation of γ-cyclodextrin on drug solubilization

The purpose of this study was to investigate the physicochemical properties of drug-saturated aqueous cyclodextrin (CD) solutions. Phase solubility profiles of different drugs were determined in aqueous solutions containing γ-cyclodextrin (γCD) and/or hydroxypropyl-γ-cyclodextrin (HPγCD) in absence or presence of water-soluble polymers. ¹H-NMR and turbidity analysis were performed as well as permeation studies. Phase solubility diagrams showed that the observed γCD content (1–20% w/v) was only slightly different from the theoretical values for aqueous solutions that had been saturated with indomethacin, diclofenac sodium or amphotericin B, all displayed A-type profiles, while it was less than the theoretical value in solutions that had been saturated with corticosteroids (hydrocortisone and dexamethasone) that displayed B_S-type profiles. In the latter case self-assemble of drug/CD complexes decreased the overall CD solubility. Water-soluble polymers enhanced aqueous solubility of the drugs tested by stabilizing the drug/CD complexes, i.e. enhancing their stability constants, without affecting the observed aqueous γCD solubility. When the drug solubility leveled off (the B_S-type profiles) the amount of dissolved γCD increased and approached the theoretical values. Hydrocortisone formed partial inclusion complex with γCD and HPγCD and no non-inclusion or aggregates could be detected in diluted solutions by ¹H-NMR. Both permeation and turbidity studies showed that formation of dexamethasone/γCD complex promoted CD aggregation. All these observations indicate that CD aggregate formations play a role in CD solubilization of lipophilic and poorly water-soluble drugs and that the water-soluble polymers enhance the complexation efficiency of γCD and HPγCD by stabilizing the self-assembled drug/CD nanoparticles and promote non-inclusion complex formation.     

The Effect of Molecular Architecture of Sulfobutyl Ether β-Cyclodextrin Nanoparticles on Physicochemical Properties of Complexes with Moxifloxacin

A method has been developed for nanoparticles synthesis based on oligomers of sulfobutyl ether β-cyclodextrin (SBE-β-CD) and their structure has been studied by FTIR spectroscopy. The physicochemical properties of “guest?host” inclusion complexes formed by SBE-β-CD and its oligomers with moxifloxacin have been investigated. It has been shown that, as compared with SBE-β-CD, the synthesized oligomers have an increased affinity for moxifloxacin: the dissociation constants for the complexes of monomeric and oligomeric SBE-β-CD are (1.0 ± 0.3) × 10^?4 and nearly 5 × 10^?6 M, respectively. The binding efficiency increases due to the multy-point interaction of a moxifloxacin molecule with functional groups of the oligomeric carrier. SBE-β-CD oligomers are promising carriers for drugs, in particular, fluoroquinolone-based antibacterial agents, and may be used for the development of new compositions with improved solubility, bioavailability, and prolonged drug release.     

Binary and ternary inclusion complexes of dapsone in cyclodextrins and polymers: preparation, characterization and evaluation

Dapsone (DAP) is a synthetic sulfone drug with bacteriostatic activity, mainly against Mycobacterium leprae. In this study we have investigated the interactions of DAP with cyclodextrins, 2-hydroxypropyl-β-cyclodextrin (HPβCD) and β-cyclodextrin (βCD), in the presence and absence of water-soluble polymers, in order to improve its solubility and bioavailability. Solid systems DAP/HPβCD and DAP/βCD, in the presence or absence of polyvinylpyrrolidone (PVP K30) or hydroxypropyl methylcellulose (HPMC), were prepared. The binary and ternary systems were evaluated and characterized by SEM, DSC, XRD and NMR analysis as well as phase solubility assays, in order to investigate the interactions between DAP and the excipients in aqueous solution. This study revealed that inclusion complexes of DAP and cyclodextrins (HPβCD and βCD) can be produced in order to improve DAP solubility and bioavailability in the presence or absence of polymers (PVP K30 and HPMC). The more stable inclusion complex was obtained with HPβCD, and consequently HPβCD was more efficient in improving DAP solubility than βCD, and the addition of polymers had no influence on DAP solubility or on the stability of the DAP/CDs complexes.     

Inclusion Compound of Efavirenz and γ-Cyclodextrin: Solid State Studies and Effect on Solubility

Efavirenz is an antiretroviral drug of widespread use in the management of infections with human immunodeficiency virus type 1 (HIV-1). Efavirenz is also used in paediatrics, but due to its very poor aqueous solubility the liquid formulations available resort to oil-based excipients. In this report we describe the interaction of γ-cyclodextrin with efavirenz in solution and in the solid state. In aqueous solution, the preferential host–guest stoichiometry was determined by the continuous variation method using ¹H NMR, which indicated a 3:2 host-to-guest proportion. Following, the solid inclusion compound was prepared at different stoichiometries by co-dissolution and freeze-drying. Solid-state characterisation of the products using FT-IR, ¹³C{¹H} CP-MAS NMR, thermogravimetry, and X-ray powder diffraction has confirmed that the 3:2 stoichiometry is the adequate starting condition to isolate a solid inclusion compound in the pure form. The effect of γ-cyclodextrin on the solubility of efavirenz is studied by the isotherm method.     

STUDIES ON THE POLYMERIZATION OF β-CYCLODEXTRIN WITH EPICHLOROHYDRIN*

Different proportions of β-cydodextrin and epichlorohydrin were used to prepare a group of β-cyclodextrin polymers. The relationship between the reaction extent and the molar ratios of reactants was discussed according to the results of ~1H-NMR, ~(13) C-NMR spectra and elemental analysis. Especially, high resolution ~1H-NMR spectra were usd for studying the reaction active sites and the extent of reaction. The solubility of oil soluble drugs in water was largely improved in the presence of water-soluble β-cyclodextrin polymer.     

Threading of cyclodextrins onto a polyester of octanedicarboxylic acid and polyethylene glycol

A water-soluble polyester was synthesized from dimethyl octane-1,8-dicarboxylate and polyethylene glycol (M̄_n = 900). This polymer forms water-soluble inclusion compounds with α-, β- and hydroxypropyl-α-cyclodextrin as proven by surface tension measurements, ¹H NMR spectroscopy and titration microcalorimetry. Mainly the octamethylene segments were covered by the cyclodextrins. This inclusion can be used to increase the solubility and the critical micelle concentration of the polyester in water.     

Solubility and dissolution enhancement of saquinavir mesylate by inclusion complexation technique

The objective of the present study was to formulate inclusion complex of saquinavir mesylate to improve the aqueous solubility and dissolution rate. Saquinavir mesylate is a BCS class II drug having low aqueous solubility and therefore low oral bioavailability. In the present study, inclusion complex of saquinavir mesylate with hydroxypropyl-β-cyclodextrin were prepared by kneading method. Inclusion complex were characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), ¹H NMR studies, and Fourier transform infrared spectroscopy and evaluated for in vitro dissolution, and phase solubility studies. DSC and XRD study demonstrated that there was a significant decrease in crystallinity of pure drug present in inclusion complex, which resulted in an increased dissolution rate of saquinavir mesylate and ¹H NMR studies strongly, confirmed that the inclusion complex has formed. Inclusion complexation results in improvement in solubility and dissolution rate. The inclusion complexation would be suitable method for dissolution and bioavailability enhancement of saquinavir mesylate.     

Effect of β-cyclodextrin complexation on physicochemical properties of zaleplon

The physicochemical properties and dissolution profile of zaleplon (ZPN) β-cyclodextrin (βCD) inclusion complex were investigated. The phase solubility profile of ZPN with β-cyclodextrin was classified as A_L-type. Stability constant with 1:1 molar ratio was calculated from the phase solubility diagram and the aqueous solubility of ZPN was found to be enhanced by 714% (p < 0.001) for β-cyclodextrin. Binary systems of ZPN with βCD were prepared by kneading method. The solid-state properties of complex were characterized by differential scanning calorimetry, Fourier transformation-infrared spectroscopy and powder X-ray diffractometry. It could be concluded that ZPN could form inclusion complex with β-cyclodextrin. The dissolution profile of inclusion complex was determined and compared with those of ZPN alone and its physical mixture. The dissolution rate of ZPN was significantly increased by complexation with βCD, as compared with pure drug and physical mixture.     

Influence of Cyclodextrin Complexation on the Physicochemical and Biopharmaceutical Properties of Ketoconazole

The effects of hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin on the solubility of ketoconazole were studied. Products were prepared by physical mixing, kneading and spray-drying methods in four molecular ratios. Kneaded products in a ratio of drug: cyclodextrin (1:2) and spray-dried products showed the highest dissolution rate. Phase solubility diagrams of ketoconazole with these cyclodextrins at 25,°C in water and simulated intestinal medium were constructed. A solubility diagram of A_L type was obtained with hydroxypropyl-β-cyclodextrin, and A_P type with methyl-β-cyclodextrin. The complexes were characterized by thermal methods (DSC, TG, DTG and DTA). Multicomponent systems were prepared with tartaric acid. The effects of water-soluble polymers, e.g., polyvinylpyrrolidone, on the aqueous solubility of ketoconazole were investigated. The particle size of ketoconazole (70 ～ μm) is reduced to 12 μm by the preparation of spray-dried products. As the solubilty in water increased, the partition coefficient, surface tension and wetting angle values decreased. Ketoconazole needed more energy for dissolution compared to the products. In order to examine complex formation thermal methods were used.     

Supramolecular polymers based on cyclodextrins

Two types of supramolecular polymers based on cyclodextrins were prepared. One was a host–guest type, and the other was a polyrotaxane type. When a guest part was covalently attached to cyclodextrin, they formed supramolecular dimers, a cyclic daisy chain, supramolecular oligomers, and polymers. t-Boc-cinnamamide-α-cyclodextrin was found to form chiral supramolecular polymers in aqueous solutions. Supramolecular poly[2]rotaxane polymers and supramolecular α,β-cyclodextrin copolymers were obtained. Polyrotaxanes containing β-cyclodextrin or γ-cyclodextrin were prepared. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 5113–5119, 2006     

Effect of β-cyclodextrins based nanosponges on the solubility of lipophilic pharmacological active substances (repaglinide)

Cyclodextrin based nanosponges (CD-NS) are nanostructured cross-linked polymers, usually obtained by reacting cyclodextrin with a cross-linker such as carbonyldiimidazole, organic carbonates or (±) epichlorohydrin. They have been used to increase the solubility and stability of poorly soluble pharmacological active substances, as they combine the complex forming properties of CDs and properties of polymers (such as the high molecular weight). The affinity of CDs for certain lipophilic molecules is characteristic to the polymeric nano-structured system and allows the development of specific drug delivery systems. Knowing that cyclodextrin capacity to form inclusion complexes is maintained and enhanced when the CD molecules form aggregates, cross-link together or copolymerize with other compounds, we have synthesized cyclodextrin based nanosponges (from β-cyclodextrin and sulfobutylether-β-cyclodextrin). The complexing properties of the polymers were investigated against repaglinide (a hypoglycemic agent, practically insoluble in water). Solubility studies were performed according to the method reported by Higuchi and Connors and the phase solubility diagrams were plotted. The repaglinide-nanosponges complexes were prepared, lyophilized and the resulted inclusion complexes were characterized by FT-IR and NMR. The solubility profile and the loading capacity of the cyclodextrin based polymers were also determined.     

Complexation of ebastine with β-cyclodextrin derivatives

Complexation of ebastine (EB) with hydroxypropyl and methyl-β-cyclodextrin (HP-β-CD and Me-β-CD) was studied in aqueous solutions and in the solid state. The formation of inclusion complexes in aqueous solutions was analysed by the solubility method. The assays were designed using low CD concentrations compared with the solubility of these derivatives in order to avoid non-inclusion phenomena and to obtain a linear increase in EB solubility as a function of CD concentration. The values of complexation efficiency for HP-β-CD and Me-β-CD were 1.9 × 10^?2 and 2.1 × 10^?2, respectively. It seems that the non polar character of the methyl moiety slightly favoured complexation. In relation to solid state complexation, 1:1 EB:CD systems were prepared by kneading, and by heating a drug-CD mixture at 90 ºC. They were analysed using X ray diffraction analysis by comparison with their respective physical mixtures. A complex with a characteristic diffraction pattern similar to that of the channel structure of β-CD was formed with Me-β-CD in 1:1 melted and 1:2 EB:CD kneaded systems. Complexation with HP-β-CD was not clearly evidenced because only a slight reduction of drug crystallinity was detected. Finally, the loading of EB in two β-CD polymers cross-linked with epichlorohydrin yielded 7.3 and 7.7 mg of EB/g polymer respectively.     

Inclusion complexes of fluconazole with β-cyclodextrin: physicochemical characterization and in vitro evaluation of its formulation

Fluconazole (FZ) is a triazole antifungal drug administered orally or intravenously. It is employed for the treatment of mycotic infections. However, the efficacy of FZ is limited with its poor aqueous solubility and low dissolution rate. One of the important pharmaceutical advantages of cyclodextrins is to improve pharmacological efficacy of drugs due to increasing their aqueous solubility. The aim of present study was to prepare an inclusion complex of FZ and β-cyclodextrin (β-CD) to improve the physicochemical and biopharmaceutical properties of FZ. The effects of β-CD on the solubility of FZ were investigated according to the phase solubility technique. Complexes were prepared with 1:1 M ratio by different methods namely, freeze-drying, spray-drying, co-evaporation and kneading. For the characterization of FZ/β-CD complex, FZ amount, practical yield %, thermal, aqueous solubility, XRD, FT-IR and NMR (¹H and ¹³C) analysis were performed. In vitro dissolution from hard cellulose capsules containing FZ/β-CD complexes was compared to pure FZ and its commercial capsules and evaluated by f₁ (difference) and f₂ (similarity) factors. Paddle method defined in USP 31 together with high pressure liquid chromatographic method were used in in vitro dissolution experiments. It was found that solubility enhancement by FZ/β-CD complexes depends on the type of the preparation method. High release of active agent from hard cellulose capsules prepared with β-CD complexes compared to commercial capsules was attributed to the interactions between β-CD and active agent, high energetic amorphous state and inclusion complex formation.     

Supramolecular self-assembly and nanoencapsulation of [60]fullerene by bis-β-cyclodextrin

Bis-β-cyclodextrin connected via ethylene diamine on the primary side of the β-cyclodextrin was synthesized and used for the supramolecular non-covalent inclusion complex with C₆₀ in a mixed solvent system at room temperature. The apparent association constant of the 2:2 inclusion complex determined by combination of UV–Vis absorbance and Benesi–Hildebrand equation was found to be 1.78 × 10⁶ M^?1. The product obtained was highly water-soluble and superior in stability in aqueous medium as compared to previously known β-cyclodextrin/C₆₀ complex. The non-covalent self-assembly of bis-β-cyclodextrin and C₆₀ was characterized and confirmed from FT-IR, UV–Vis, XRD and TGA. The supramolecular aggregation behavior and particle size of the inclusion complex was found from transmission electron microscope and static light scattering measurements. The size of the inclusion complex was found to be ~30 ± 5 nm.     

Thermo-reversible flurbiprofen liquid suppository with HP-β-CD as a solubility enhancer: improvement of rectal bioavailability

The purpose of this work was to develop a thermo-reversible flurbiprofen liquid suppository base composed of poloxamer and sodium alginate for the improvement of rectal bioavailability of flurbiprofen. Cyclodextrin derivatives such as α-, β-, γ-cyclodextrin and hydroxypropyl-β-cyclodextrin (HP-β-CD) were used to enhance the aqueous solubility of flurbiprofen. The effects of HP-β-CD and flurbiprofen on the physicochemical properties of liquid suppository were then investigated. Pharmacokinetic studies were performed after rectal administration of flurbiprofen liquid suppositories with and without HP-β-CD or after intravenous administration of commercial Lipfen^® (flurbiprofen axetil-loaded emulsion) to rats, and their pharmcokinetic parameters were compared. HP-β-CD decreased the gelation temperature and reinforced the gel strength and bioadhesive force of liquid suppository, while flurbiprofen was opposed to HP-β-CD. Thermo-reversible flurbiprofen liquid suppository showed the physicochemical properties suitable for rectal administration. The flurbiprofen liquid suppository with HP-β-CD showed significantly higher plasma levels, AUC and C_max of flurbiprofen than those of the liquid suppository without HP-β-CD, indicating that flurbiprofen could be well absorbed due to the enhanced solubility by formation of inclusion complex. Moreover, the flurbiprofen liquid suppository with HP-β-CD showed an excellent bioavailability in that the AUC of flurbiprofen after its rectal administration was not significantly different from that after intravenous administration of commercial Lipfen^®. It is concluded that HP-β-CD could be a preferable solubility enhancer for the development of liquid suppository containing poorly water-soluble drugs.     

Innovative Cross-Linked Polyurethane Networks Based on Cyclodextrins and Polyethylene Glycols: Inclusion Capacity and Potential Use as Controlled Release Carrier for Nifedipine

Summary: Polymers derived from cyclodextrins show several biomedical applications. In this paper, six cross-linked polyurethane networks based on β-cyclodextrin (βCD) or hydroxypropyl-β-cyclodextrin (HPβCD) and polyethylene glycols (PEG 400, PEG 1500 or PEG 4000) were synthesized by the usual two-step polymerization method. The polymers were characterized by Fourier-transformed infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA) and X-ray diffraction (XRD). The inclusion capacity was evaluated by the discoloration method of a phenolphthalein solution. In order to explore their potential use as controlled drug delivery systems, dissolution profiles and release behavior of inclusion complexes between PUR/TDI/βCD/PEG4000 or PUR/TDI/HPβCD/PEG1500 and nifedipine (NIF) were investigated. FTIR assignments confirmed the formation of urethane linkages. XRD patterns revealed that the crystallinity decreased mainly due to the crosslinking process. TGA showed three stages of mass loss attributed to water loss, cleavage of urethane bonds and volatilization of decomposition products. The inclusion capacity of cyclodextrins cross-linked with polyurethane was suitably maintained. Dissolution profiles demonstrated that the inclusion complexes PUR/TDI/βCD/PEG4000-NIF and PUR/TDI/HPβCD/PEG1500-NIF are feasible systems for controlling drug release, showing a biexponential release behavior.     

Thermosensitive mucoadhesive gel formulation loaded with 5-Fu: cyclodextrin complex for HPV-induced cervical cancer

Human Papilloma Virus (HPV) infections are the major cause of cervical cancers. To achieve a better therapeutic efficacy and patient compliance in the treatment for HPV-induced cervical cancers, anticancer agent 5-fluorouracil has been formulated in a vaginal gel using the thermosensitive polymer Pluronic^® F127 together with alternative mucoadhesive polymers e.g., hyaluronic acid, Carbopol 934 and hydroxypropylmethylcellulose. To increase its aqueous solubility and to achieve the complete release of 5-FU from the gel, the drug was incorporated as its inclusion complex with 1:1 molar ratio with either β-cyclodextrin or hydroxypropyl-β-cyclodextrin. Following the characterization of drug:CD complexes, thermosensitive gel formulations containing different mucoadhesive polymers and the drug in free or complexed form were characterized in vitro by determining the gelation temperature and the rheological behavior of different formulations along with the in vitro release profiles of these formulations in pH 5.5 citrate buffer. It was observed that complexation with cyclodextrin accelerated the release of 5-FU with the exception of formulation containing Carbopol 934 as mucoadhesive polymer. As far as rheological properties are concerned, favorable thermosensitive in situ gelling properties were obtained with formulations containing HPMC as mucoadhesive polymer. Complete release of 5-FU from gels were obtained with both complexes of β-CD and HP-β-CD and cytotoxicity studies against HeLa human cervical carcinoma cells demonstrated that 1% 5-FU:CD complexes were equally effective as 1% free 5-FU indicating better therapeutic efficacy with lower dose.     

Solubility and Kinetic Release Studies of Naproxen and Ibuprofen in Soluble Epichlorohydrin-β-cyclodextrin Polymer

Naproxen (NAP) and ibuprofen (IBU) are poor water soluble anti-inflammatory drugs. A water-soluble epichlorohydrin-β-cyclodextrin polymer (β-CDEPI) was synthesized in a highly basic aqueous solution and at a molar ratio β-CD/EPI of 1:12. Drug solubility and kinetic release of NAP and IBU from the inclusion complexes they form with β-CDEPI as host was studied. Water solubility for both drugs in the presence of this polymer increased (NAP 0.28 mmol and IBU 0.40 mmol per gram of β-CDEPI). The apparent inclusion constants for both drugs in β-CDEPI were calculated from the solubility-phase diagrams with K_incl values of 4300 ± 100 L.mol^? 1 for NAP and 5100 ± 300 L.mol^? 1 for IBU. Kinetic release of Ibuprofen gave a pure Fick trend (t^1/2) behavior. However, for Naproxen a zero order was obtained (t). These results indicate that the nature and bulkiness of the drugs are ruling these kinetic behaviors in the environment of a highly branched polymer.     

Effect of external factors on the curcumin/2-hydroxypropyl-β-cyclodextrin: in vitro and in vivo study

The effect of 2-hydroxypropyl-β-cyclodextrin (HPβCD) on solubility, stability and oral bioavailability of curcumin by external factors adjustment, was investigated with an aim of a simple, stable and effective formulation. The phase solubility studies showed the solubility of curcumin increased slightly with increasing pH. However, the apparent stability constant (K _S) were found to decrease with increasing pH from 1.29?×?10⁴?M^?1 at pH 3.0 to 5.22?×?10³?M^?1 at pH 7.0. The thermodynamic parameters were calculated for inclusion complex formation in aqueous solution. Interestingly, it could be concluded that the degrees of curcumin stability improved by HPβCD grew with increasing drug–cyclodextrin binding ability. Furthermore, in vivo study not only revealed that the bioavailability of curcumin after oral administration to rats was significantly improved by curcumin/HPβCD inclusion complex, but also showed more dramatic changes in the plasma concentration–time curve (1752.76–866.70?ng?mL^?1?h) and the peak plasma concentration (370.10–178.11?ng?mL^?1) of drug by formation of complexes in pH 3–7 solution.