betadex and hydroxypropyl-gamma-cyclodextrin

The current cyclodextrin (CD) literature is reviewed concerning synthesis, characterization, and pharmaceutical relevant applications of CD derivatives. Although natural CDs have been used extensively to improve pharmaceutical properties, the effects of chemically modified CDs on the solubility, dissolution rate, and stability of drugs are overproportional. Concerning the parenteral application, the major interest is focussed on highly water-soluble, randomly substituted hydroxyalkyl derivatives of beta- and gamma-CD such as 2-hydroxypropyl-beta-cyclodextrin (2-HP-beta-CD). Although the heptakis-(2,6-di-O-methyl)-beta-cyclodextrin is applied in the pharmaceutical field, 2-HP-beta-CD is predestined as a parenteral drug carrier owing to its weak hemolytic activity and intrinsically amorphous character. A minimal average degree of substitution is especially preferred when 2-HP-beta-CD is used as solubilizer of pharmaceuticals for the use in parenteral applications. The influence of the type, degree, and pattern of substitution of the CDs, as well as substituent effects of the guest molecule is elucidated.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Chemistry, Pharmaceutical; Cyclodextrins; Drug Carriers; Drug Stability; gamma-Cyclodextrins; Humans; Infusions, Parenteral; Pharmaceutical Preparations

The development of novel nanomaterials that provide an efficient encapsulation and protection for the active food additives is one of the main focuses of current research efforts at food application areas. From this point of view, in this study, nanofibrous webs from inclusion complexes (IC) of modified cyclodextrins (hydroxypropyl-β-cyclodextrin (HPβCD), hydroxypropyl-γ-cyclodextrin (HPγCD) and methyl-β-cyclodextrin (MβCD)) and essential oils compound (i.e. thymol) was produced through electrospinning technique. While pure thymol has a highly volatile nature, the volatility of thymol was effectively suppressed by the inclusion complexation and ~88-100% (w/w) of thymol was preserved in electrospun thymol/cyclodextrin inclusion complex nanofibers (Thymol/CD-IC NF). The aqueous solubility enhancement for hydrophobic thymol was demonstrated by phase solubility diagram which also suggested the 1:1M inclusion complexation between thymol and CD molecules. Besides, Thymol/CD-IC NF displayed quite fast disintegration in water compared to poorly water soluble thymol. By inclusion complexation, high temperature stability for volatile thymol was achieved for Thymol/CD-IC NF samples. The loading of thymol in Thymol/CD-IC NF conferred DPPH radical scavenging ability to these nanofibrous webs. So, the Thymol/CD-IC NF have shown antioxidant activity along with enhanced water solubility and high thermal stability of thymol. In brief, encapsulation of essential oil compounds such as thymol in electrospun CD-IC nanofibers can promote its potential application in food and oral-care products by associating the large surface area of nanofibrous webs along with CD inclusion complexation which provides enhanced water solubility and antioxidant property, and high temperature stability for thymol.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antioxidants; beta-Cyclodextrins; Cyclodextrins; Drug Carriers; Drug Stability; gamma-Cyclodextrins; Hot Temperature; Nanofibers; Solubility; Thymol; Volatilization; Water

Niemann-Pick type C (NPC) disease is a fatal hereditary neurodegenerative disorder characterized by a massive accumulation of cholesterol in lysosomes and late endosomes due to a defect in intracellular cholesterol trafficking. Dysfunction in intracellular cholesterol trafficking is responsible for about 50 rare inherited lysosomal storage disorders including NPC. The lysosomal proteins NPC1 and NPC2 play a crucial role in trafficking of cholesterol from late endosomes and lysosomes to other cellular compartments. However, the detailed mechanisms of cholesterol trafficking at the late endosomes/lysosomes (LE/LY) are poorly understood. Studies showed that 2-hydroxypropyl-β-cyclodextrin (HPβCD) alleviates the cholesterol accumulation defect in animal model and has been approved for a phase 2b/3 clinical trial for NPC. HPβCD is known to bind cholesterol; however, the mechanisms how HPβCD mediates the exit of cholesterol from the LE/LY compartments are still unknown. Further, another cyclodextrin (CD) derivative, 2-hydroxypropyl-γ-cyclodextrin (HPγCD), was shown to reduce intracellular cholesterol accumulation in NPC patient cells and NPC mice model. Herein, we identified a number of candidate proteins differentially expressed in NPC patient-derived cells compared to cells derived from a healthy donor using a proteomic approach. Interestingly, both HPβCD and HPγCD treatments modulated the expression of most of these NPC-specific proteins. Data showed that treatment with both CDs induces the expression of the lysosome-associated membrane protein 1 (LAMP-1) in NPC patient-derived cells. Remarkably, LAMP-1 overexpression in HeLa cells rescued U18666A-induced cholesterol accumulation suggesting a role of LAMP-1 in cholesterol trafficking. We propose that HPβCD and HPγCD facilitate cholesterol export from the LE/LY compartments via the LAMP-1 protein, which may play a crucial role in cholesterol trafficking at the LE/LY compartments when there is no functional NPC1 protein. Together, this study uncovers new cellular mechanisms for cholesterol trafficking, which will contribute to development of novel therapeutic approaches for lysosomal storage diseases.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Cell Line; Cell Line, Tumor; Cholesterol; Endosomes; gamma-Cyclodextrins; HEK293 Cells; HeLa Cells; Humans; Lysosomal Membrane Proteins; Lysosomes; Niemann-Pick Disease, Type C; Protein Transport; Proteins; Proteomics

Curcumin (Cur) is known to bind to human serum albumin (HSA) which may lead to a reduced phototoxic effect of the compound in the presence of serum or saliva. The influence of excipients on the Cur-HSA binding was studied by HSA florescence quenching and Cur absorption and emission spectroscopy in the presence and absence of the selected excipients. Photostabilty of Cur in the presence of HSA was evaluated, as well as the effect of excipients on HSA bound Cur photodegradation. Cyclodextrins (CDs) (2-hydroxypropyl-β-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin) and polymers (polyethylene glycol 400, PEG 400 and Pluronic F-127, PF-127) were selected for the study. CDs and PF-127 seem to decrease Cur binding to HSA, probably through competitive binding. Cur was still bound to HSA in polyethylene glycol (PEG) solutions at the highest investigated concentration (5% w/v). However, high PEG concentration appears to have effect on the protein conformation, as shown by the fluorescence quenching study. Low Cur photostability in the presence of HSA could be improved by the addition of hydroxylpropyl-γ-cyclodextrin (HPγCD) to the samples, whereas PEG and PF-127 showed no effect.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antineoplastic Agents; beta-Cyclodextrins; Coloring Agents; Curcumin; Excipients; gamma-Cyclodextrins; Humans; Photolysis; Poloxamer; Polyethylene Glycols; Protein Binding; Serum Albumin

In this paper, we reported the molecular entrapment performance of hydroxypropyl-beta-cyclodextrin (HPβCD) and hydroxypropyl-gamma-cyclodextrin (HPγCD) electrospun nanofibers (NF) for two common volatile organic compounds (VOCs); aniline and benzene. The encapsulation efficiency of CD samples were investigated depending on the various factors such as; CD form (NF and powder), electrospinning solvent (DMF and water), CD (HPβCD and HPγCD) and VOCs (aniline and benzene) types. BET analysis indicated that, electrospun CD NF have higher surface area compared to their powder form. In addition DMA measurement provided information about the mechanical properties of CD NF. The encapsulation capability of CD NF and CD powder was investigated by (1)H-NMR and HPLC techniques. The observed results suggested that, CD NF can entrap higher amount of VOCs from surroundings compared to their powder forms. Besides, molecular entrapment efficiency of CD NF also depends on CD, solvent and VOCs types. The inclusion complexation between CD and VOCs was determined by using TGA technique, from the higher decomposition temperature of VOCs. Finally, our results were fortified by the modeling studies which indicated the complexation efficiency variations between CD and VOC types. Here, the inclusion complexation ability of CD molecules was combined with very high surface area and versatile features of CD NF. So these findings revealed that, electrospun CD NF can serve as useful filtering material for air filtration purposes due to their molecular entrapment capability of VOCs.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Air Pollutants; Aniline Compounds; Benzene; beta-Cyclodextrins; Electricity; gamma-Cyclodextrins; Nanofibers

Ursolic and oleanolic acids have been brought into the spotlight of research due to their chemopreventive, anti-inflammatory and immunomodulatory properties. The most important disadvantage of ursolic and oleanolic acids is their weak water solubility which limits their bioavailability. Pentacyclic triterpenes can form inclusion complexes with different types of cyclodextrins which provide the hydrophilic matrix requested for the molecular dispersion of drugs in order to become more water soluble. The aim of the current study is the complexation of ursolic and oleanolic acids with hydrophilic cyclodextrins in order to achieve an improvement of their pharmacological effect. After the virtual screening of the binding affinities between ursolic and oleanolic acids and various cyclodextrins, 2-hydroxypropyl-β-cyclodextrin and 2-hydroxypropil-γ-cyclodextrin were selected as host-molecules for the inclusion complexation. Using the scanning electron microscopy, differential scanning calorimetry and X-ray diffraction the formation of real inclusion complexes between ursolic and oleanolic acids and the two cyclodextrins was confirmed. The anti-proliferative potential of the complexes was tested in vitro on several melanoma cell lines, using the pure compounds as reference. The complexes exhibited higher in vitro anti-proliferative activity as compared to the pure compounds; this improvement was significant for ursolic acid complexes, the highest activity being reported for the 2-hydroxypropil-γ-cyclodextrin complex. Weaker results were recorded for the oleanolic acid complexes where 2-hydroxypropyl-β-cyclodextrin proved to be the most fitted inclusion partner. The entrapment of the two active compounds inside ramified hydrophilic cyclodextrins proved to be a suitable option to increase their anti-proliferative activity.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antineoplastic Agents; beta-Cyclodextrins; Calorimetry, Differential Scanning; Cell Line, Tumor; Cell Proliferation; Drug Evaluation, Preclinical; gamma-Cyclodextrins; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Mice; Molecular Docking Simulation; Oleanolic Acid; Triterpenes; Ursolic Acid; X-Ray Diffraction

Niemann-Pick disease type C (NPC) is a lysosomal storage disease characterized by abnormal accumulation of free cholesterol and glycolipids. Here, we established induced pluripotent stem cell (iPSC) lines from NPC patients. Hepatocyte-like cells (HLCs) and neural progenitors derived from the iPSC lines accumulated cholesterol and displayed impaired autophagy and ATP production. A molecular signature related to lipid metabolism was also impaired in the NPC-iPSC-derived HLCs. These findings indicate that iPSC-derived cells can phenocopy human NPC. We also newly found that 2-hydroxypropyl-γ-cyclodextrin (HPGCD) could reduce the cholesterol accumulation and restore the functional and molecular abnormalities in the NPC patient-derived cells, and do so more effectively than 2-hydroxypropyl-β-cyclodextrin treatment. In addition, NPC model mice showed an improved liver status and prolonged survival with HPGCDs. Thus, iPSC lines derived from patient cells are powerful tools to study cellular models of NPC, and HPGCD is a potential new drug candidate for future treatment of this disease.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Coculture Techniques; Fibroblasts; gamma-Cyclodextrins; Humans; Induced Pluripotent Stem Cells; Mice; Niemann-Pick Disease, Type C; Treatment Outcome

Curcumin (CURC) was incorporated in liposomes as free drug or after formation of hydropropyl-β- or hydroxypropyl-γ-cyclodextrin (HPβCD or HPγCD) complexes prepared by coprecipitation and characterized by X-ray diffractometry. Liposomes encapsulating CURC as free drug or CD-complexes (hybrid formulations) were prepared by the dehydration-rehydration vesicle (DRV) method followed by extrusion, and characterized for size, zeta-potential and CURC loading. CURC stability (at 0.01 and 0.05 mg/mL) in 80% (v/v) fetal bovine serum (FBS) was evaluated at 37 °C. Results demonstrate that HPβCD stabilizes CURC more than HPγCD, but liposome encapsulation provides substantially more protection, than CDs. CURC stabilization is similar, when encapsulated as free compound or CD-complex. However, the last method increases CURC loading by 23 times (depending on the lipid composition of liposomes and the CD used), resulting in higher solubility. The stability profile of CURC in serum depends on the composition of liposomes and CURC concentration, since at lower concentrations larger CURC fractions are protected due to protein binding. Compared to the corresponding CD complexes, hybrid formulations provide intermediate CURC solubility (comparable to HPβCD) but profoundly higher stabilization.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antioxidants; beta-Cyclodextrins; Chemical Precipitation; Chemistry, Pharmaceutical; Curcumin; Drug Stability; gamma-Cyclodextrins; Lipids; Liposomes; Particle Size; Solubility; X-Ray Diffraction

Sustained release aqueous eye drops of dexamethasone, based on cyclodextrin (CD) nanogels, were designed and tested in vivo. γCD units were cross-linked in the form of nanogels by means of an emulsification/solvent evaporation process. The composition of the nanogels was optimized with regard to drug loading and release rate. The eye drops consisted of an aqueous solution of dexamethasone in 2-hydroxypropyl-γ-cyclodextrin (HPγCD) medium containing γCD nanogels. The nanogel eye drops (containing 25 mg dexamethasone per ml) were tested in rabbits and compared to the commercially available product Maxidex(®) (suspension with 1 mg dexamethasone per ml). One drop administration of the nanogel eye drops resulted in nearly constant dexamethasone concentration for at least 6h in the tear fluid (mean concentration±SD=295±59 μg/ml) whereas the concentration after administration of Maxidex(®) fell rapidly from 9.72±3.45 μg/ml 1 h after application to 3.76±3.26 μg/ml 3 h after application. The maximum dexamethasone concentration in the aqueous humor (2 h after application) was 136±24 mg/ml after application of the nanogel eye drops, and only 44.4±7.8 μg/ml after application of Maxidex(®). The dexamethasone nanogel eye drops were well tolerated with no macroscopic signs of irritation, redness or other toxic effects.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Anti-Inflammatory Agents; Aqueous Humor; beta-Cyclodextrins; Delayed-Action Preparations; Dexamethasone; Drug Delivery Systems; Emulsions; gamma-Cyclodextrins; Gels; Ophthalmic Solutions; Rabbits; Solubility; Time Factors

LPSF/AC04 (5Z)-[5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione] is an acridine-based derivative, part of a series of new anticancer agents synthesized for the purpose of developing more effective and less toxic anticancer drugs. However, the use of LPSF/AC04 is limited due to its low solubility in aqueous solutions. To overcome this problem, we investigated the interaction of LPSF/AC04 with hydroxypropyl-β-cyclodextrin (HP-β-CyD) and hydroxypropyl-γ-cyclodextrin (HP-γ-CyD) in inclusion complexes and determine which of the complexes formed presents the most significant interactions. In this paper, we report the physical characterization of the LPSF/AC04-HP-CyD inclusion complexes by thermogravimetric analysis, differential scanning calorimetry, infrared spectroscopy absorption, Raman spectroscopy, (1)HNMR, scanning electron microscopy, and by molecular modeling approaches. In addition, we verified that HP-β-CyD complexation enhances the aqueous solubility of LPSF/AC04, and a significant increase in the antiproliferative activity of LPSF/AC04 against cell lines can be achieved by the encapsulation into liposomes. These findings showed that the nanoencapsulation of LPSF/AC04 and LPSF/AC04-HP-CyD inclusion complexes in liposomes leads to improved drug penetration into the cells and, as a result, an enhancement of cytotoxic activity. Further in vivo studies comparing free and encapsulated LPSF/AC04 will be undertaken to support this investigation.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Absorption; Acridines; Antineoplastic Agents; beta-Cyclodextrins; Cell Line, Tumor; Cell Proliferation; Drug Stability; Excipients; gamma-Cyclodextrins; Humans; Liposomes; Solubility; Thiazolidinediones; Water

In vitro studies of α-amylase degradation of α-, β- and γ-cyclodextrins and 2-hydroxypropyl-β- and -γ-cyclodextrins were investigated spectrophotometrically by measuring the formation of reducing sugars, the reaction products of α-amylase degradation. This was done to evaluate potential degradation and thereby biological conversion of the cyclodextrins if dosed orally, as the intestinal tract contains α-amylase for digestive purposes. The results demonstrated that only γ- and 2-hydroxypropyl-γ-cyclodextrins can be degraded by α-amylase to a relevant extent, that is, γ- and 2-hydroxypropyl-γ-cyclodextrins have different biopharmaceutical behaviours than the other evaluated cyclodextrins. The rate of degradation was affected by the addition of the inclusion complex forming additives flurbiprofen, ibuprofen and benzo[a]pyrene. This effect between the degradation dynamics and the included additives was caused by a correlation between solubility of the additives and the stability of the complex.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Amylases; alpha-Cyclodextrins; Animals; Benzo(a)pyrene; beta-Cyclodextrins; Drug Stability; Flurbiprofen; gamma-Cyclodextrins; Hydrolysis; Ibuprofen; Kinetics; Pancreas; Solubility; Solutions; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Substrate Specificity; Swine

The aim of the present study was to incorporate a model water-insoluble photosensitizer, curcumin, in novel alginate foams, further to evaluate the suitability of the curcumin loaded foams in antimicrobial photodynamic therapy of infected wounds. Six foam formulations were prepared and characterized with respect to physical characteristics, in vitro release and storage- and photo-stability of curcumin. One formulation was sterilized (gamma-sterilization). The foams contained hydroxypropyl-beta-cyclodextrins or hydroxypropyl-gamma-cyclodextrins as solubilizers of curcumin. A reference foam without cyclodextrins was prepared with PEG 400 as the solubilizer. At a curcumin load of 0.153% (w/w), the water insoluble photosensitizer was uniformly distributed in the hydrophilic foams matrix. All foams were easy to handle, flexible and hydrated rapidly in a model physiological fluid. Release of curcumin in its monomeric form was demonstrated in vitro and found to be dependent on the type and amount of cyclodextrins in the formulation. Curcumin was stable during storage, but susceptible to photodegradation in the foams, especially when the formulations contain PEG 400 or hydroxypropyl-gamma-cyclodextrins. Curcumin did not degrade after gamma-sterilization, however a decrease in the in vitro release rate of curcumin and changes in the foams physical characteristics were detected.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Absorption; Alginates; Anti-Infective Agents; beta-Cyclodextrins; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Color; Curcumin; Delayed-Action Preparations; Drug Delivery Systems; Drug Stability; Excipients; gamma-Cyclodextrins; Kinetics; Light; Photochemotherapy; Sterilization; Wound Infection

Complexation in solution between methylprednisolone and three different cyclodextrins [2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), gamma-cyclodextrin (gamma-CD), and 2-hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD)] was studied using phase solubility analysis, one and two-dimensional (1)H-NMR and molecular modeling. Estimates of the complex formation constant (K(1:1)) show that the tendency of methylprednisolone to complex with CDs follows the order: gamma-CD > HP-gamma-CD > HP-beta-CD. The large variation of chemical shifts from protons located around the interior of the hydrophobic cavity (H-3', H-5', and H-6') coupled with minimal variation of shifts from protons located on the outer sphere of gamma-CD (H-1', H-2', and H-4') provided clear evidence of inclusion complexation. The molecular modeling study, indicated inclusion complexation between methylprednisolone and gamma-CD and HP-gamma-CD by entrance of the A and B rings of methylprednisolone into the CD cavity from its bigger rim. For the methylprednisolone: HP-beta-CD complex, the molecular modeling study could not be carried out; hence, two possibilities of complex formation are proposed: (1) methylprednisolone enters HP-beta-CD from the wider rim by its D and C ring, (2) the A and B ring of methylprednisolone enters deeper in to the CD cavity so that a part of the A ring of steroidal structure is outside of the cavity.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Anti-Inflammatory Agents; beta-Cyclodextrins; gamma-Cyclodextrins; Magnetic Resonance Spectroscopy; Methylprednisolone; Models, Molecular; Solubility

The effect of pharmaceutical excipients like alcoholic co-solvents and water-soluble polymers on the inclusion complexation of curcumin in hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin was investigated with a UV-VIS titration method. The association constants and the stoichiometries of the inclusion complexes in buffered media containing various amounts dl of alcoholic co-solvents and alginates were determined. The results showed a 1 : 1 stoichiometry between curcumin and both the cyclodextrins investigated in buffered media containing 10% (v/v) alcoholic co-solvents, although some 1 : 2 (host:guest) complexation was suspected between curcumin and hydroxypropyl-beta-cyclodextrin. The presence of 0.1% (w/v) sodium alginate or propylene glycol alginate did apparently not change the stoichiometry of the complexes formed. Curcumin was found to have a more than 30-fold higher association constant with hydroxypropyl-gamma-cyclodextrin compared to hydroxypropyl-beta-cyclodextrin in buffer containing 0.5% ethanol. Large variation in the association constants between curcumin and the cyclodextrins as a result of different co-solvents in the aqueous complexing media were found. A decrease in the association constant was seen as the chain lenght of the added co-solvent increased. Further, a decrease in the association constants was observed by addition of alginates in the case of hydroxypropyl-gamma-cyclodextrin at 0.5 or 5% (v/v) ethanol. The trend was opposite in the case of hydroxypropyl-beta-cyclodextrin, where a 30-90% increase in the association constant was observed in the presence of alginates. The results in the current study showed the large variations in the complexation between curcumin and hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin, resepctively, as a result of various alcoholic co-solvents and alginates in the complexing media. The results also illustrated the importance of optimizing the solvent systems when utilizing cyclodextrins as drug carriers.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Alcohols; Alginates; beta-Cyclodextrins; Curcumin; Cyclodextrins; Excipients; gamma-Cyclodextrins; Glycerol; Pharmaceutical Solutions; Polyethylene Glycols; Solvents; Spectrophotometry, Ultraviolet; Thermodynamics

The aggregation status of chlorophyll a (Chl a) and the ability of four cyclodextrins, hydroxypropyl-beta-cyclodextrin (HP-beta-CD), hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB), and heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TRIMEB), to solubilize the pigment in the complete cellular medium RPMI 1640 was estimated by means of UV-Vis absorption and static resonance light scattering (RLS) measurements. The results indicate that the pigment interacts with cyclodextrins in the cellular medium differently to that observed in water. The cytotoxic and phototoxic activity of these complexes towards human leukemia T-lymphocytes (Jurkat cells) was tested by means of experiments aimed to discriminate between the intrinsic toxicity and the toxicity induced by light. The overall data indicate that the HP-beta-CD is the cyclodextrins having the best characteristics to form with Chl a a potential supramolecular system for the photodynamic therapy.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Cell Death; Chlorophyll; Cyclodextrins; Dermatitis, Phototoxic; gamma-Cyclodextrins; Humans; Jurkat Cells; Macromolecular Substances; Photochemotherapy

Liposome stability during incubation in presence of cyclodextrins (CDs) is studied. Dried-rehydrated vesicle (DRV), multilamellar vesicle (MLV) and small unilamellar vesicle (SUV) calcein-encapsulating liposomes, composed of different lipids are formulated, and retention of calcein is followed during vesicle incubation in hydroxypropyl-beta-CD (HP beta-CD), HP gamma-CD or methyl-beta-CD (Me beta-CD), for 24h. Results demonstrate that liposome integrity in cyclodextrins is affected by lipid composition and type. For the same lipid composition calcein release from vesicles is faster in the order: MLV > DRV > SUV. Me beta-CD influences liposome stability most, compared to the other CD's studied. Vesicles composed of saturated phospholipids were found more stable compared to phosphatidyl-choline (PC) liposomes, suggesting that phospholipid saturation and membrane rigidity influences the interaction between liposomal-lipids and CD molecules. Chol (cholesterol) addition in lipid membrane improves PC-liposome integrity, but has opposite or no effect on liposomes consisting of saturated lipids. Decrease of vesicle dispersion turbidity and size distribution in presence of CD, implies that Me beta-CD induces vesicle disruption and solubilization (to micelles). Turbidity measurements confirm that DRV liposomes are affected more than SUV.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Chemistry, Pharmaceutical; Cholesterol; Cyclodextrins; Drug Compounding; Excipients; Fluoresceins; Fluorescent Dyes; gamma-Cyclodextrins; Lipids; Liposomes; Membrane Fluidity; Nanotechnology; Nephelometry and Turbidimetry; Particle Size; Phosphatidylcholines; Solubility; Technology, Pharmaceutical; Time Factors

A potential novel therapy for phenylketonuria involves oral administration of microencapsulated phenylalanine ammonia lyase (PAL), an enzyme that converts phenylalanine to transcinnamic acid. A drawback of this potential therapy is that encapsulated PAL retains only 23% of its activity. Microcapsules are prepared by emulsifying PAL in 10% hemoglobin solution with water-saturated ether (WSE) and subsequent addition of cellulose nitrate dissolved in ether:ethanol (E:E) mixture. The objective of this paper was to determine the contribution of emulsification to the overall loss in activity of encapsulated PAL, and to devise strategies to protect PAL against such loss in activity. Emulsification was simulated by stirring the aqueous phase containing PAL with the organic phase. The mixture was then centrifuged, and the protein content and catalytic activity of PAL in the aqueous phase was measured. Emulsification of PAL solution with WSE caused no loss in activity but resulted in a loss in protein content of aqueous phase. Size exclusion chromatography and gel electrophoresis studies showed that the loss was primarily due to the specific loss of impurities in the PAL sample. Emulsification of PAL solution with E:E resulted in a 50% decrease in its activity. Among the additives, hydroxypropyl-gamma-cyclodextrin and hydroxy propyl-beta-cyclodextrin protected PAL against emulsion mediated loss in activity.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adsorption; beta-Cyclodextrins; Capsules; Chromatography, Gel; Drug Stability; Electrophoresis, Polyacrylamide Gel; Emulsions; Ethanol; Ether; Excipients; gamma-Cyclodextrins; Glass; Hemoglobins; Phenylalanine Ammonia-Lyase; Solvents; Tromethamine; Water

The aim of this study was the development of eye drops with 1 mg/mL sirolimus and the evaluation of the drug's ability to permeate the freshly isolated pig cornea. Cyclodextrin solutions, liposomes, hydrotrope mixtures, poloxamer gels, and a microemulsion were tested for their suitability to dissolve the extremely hydrophobic drug sirolimus (solubility in water 2.6 microg/mL). The drug content in the formulations was determined by high-performance liquid chromatography, whereas this method is not sensitive enough for the quantification of therapeutic concentrations (7-12 ng/mL). Thus, the acceptor samples of the permeation tests were examined by microparticle enzyme immunoassay. A microemulsion is a suitable vehicle to prepare eye drops with sufficient sirolimus concentrations of 1 mg/mL in a formulation with acceptable tolerance and satisfactory stability over 12 months. However, the drug cannot permeate the intact cornea. After removal of the corneal epithelium, drug concentrations in the acceptor sample reach the lower limit of therapeutical levels. Conclusively, the present sirolimus eye drops might be promising therapeutic tools for the immunomodulatory treatment of ocular surface disorders, such as keratoconjunctivitis sicca, vernal conjunctivitis, or atopical blepharitis. They are not suitable to achieve therapeutic concentrations in the aqueous humour of patients with intact cornea.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Chromatography, High Pressure Liquid; Cornea; Drug Stability; Drug Storage; Emulsions; Excipients; gamma-Cyclodextrins; Gels; Hydrophobic and Hydrophilic Interactions; Immunoenzyme Techniques; Immunosuppressive Agents; In Vitro Techniques; Liposomes; Ophthalmic Solutions; Permeability; Poloxamer; Sirolimus; Solubility; Swine

Lipid rafts play critical roles in many aspects of the influenza A virus life cycle. Cholesterol is a critical structural component of lipid rafts, and depletion of cholesterol leads to disorganization of lipid raft microdomains. In this study, we have investigated the effect of cholesterol depletion by methyl-beta-cyclodextrin (MbetaCD) treatment on influenza virus budding. When virus-infected Madin-Darby canine kidney cells were treated with MbetaCD at the late phase of infection for a short duration, budding of virus particles, as determined by protein analysis and electron microscopy, increased with increasing concentrations and lengths of treatment. However, infectious virus yield varied, depending on the concentration and duration of MbetaCD treatment. Low concentrations of MbetaCD increased infectious virus yield throughout the treatment period, but higher concentrations caused an initial increase of infectious virus titer followed by a decrease with a longer duration. Relative infectivity of the released virus particles, on the other hand, decreased with increasing concentrations and durations of MbetaCD treatment. Loss of infectivity of virus particles is due to multiple effects of MbetaCD-mediated cholesterol depletion causing disruption of lipid rafts, changes in structural integrity of the viral membrane, leakage of viral proteins, a nick or hole on the viral envelope, and disruption of the virus structure. Exogenous cholesterol increased lipid raft integrity, inhibited particle release, and partially restored the infectivity of the released virus particles. These data show that disruption of lipid rafts by cholesterol depletion caused an enhancement of virus particle release from infected cells and a decrease in the infectivity of virus particles.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Cholesterol; Dogs; gamma-Cyclodextrins; Influenza A virus; Membrane Microdomains; Microscopy, Electron; Virion; Virus Replication

Cyclodextrin is a water-soluble circular oligosaccharide with a cylinder shape characterized by exterior hydrophilic rims and an interior hydrophobic cavity, which makes it an ideal additive to prevent proteins from aggregating during refolding. In this research, three hydroxypropyl cyclodextrins (HPCDs), HP-alpha-, beta-, and gamma-CD, were used to investigate the molecular mechanism of their effects on assisting aminoacylase refolding. The aggregation and reactivation experiments suggested that at moderate concentrations, HPCDs could suppress aggregation and assist aminoacylase refolding in a concentration-dependent manner, and HP-beta-CD was the most efficient of the three HPCDs. Low concentrations of HP-alpha-CD and high concentrations of HP-gamma-CD promoted off-pathway aggregation. Spectroscopic studies indicated that the hydrophobic exposure of the unstructured species in the refolded solutions was gradually reduced by the three HPCDs with the efficiency HP-beta-CD > HP-gamma-CD > HP-alpha-CD. Furthermore, the fast phase of aminoacylase reactivation was slowed down by the addition of 75 mM HP-beta- and gamma-CD, but no significant effect was observed for HP-alpha-CD. The dissimilarity in the effects of the three HPCDs suggested that the internal cavity size played a crucial role in their antiaggregation ability. Further analysis suggested that the observations might be much more complicated than expected because of the various types of interactions between cyclodextrins and proteins in addition to their ability to bind to protein aromatic residues.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; Amidohydrolases; beta-Cyclodextrins; Enzyme Activation; Enzyme Reactivators; gamma-Cyclodextrins; Guanidine; Hydrophobic and Hydrophilic Interactions; Protein Denaturation; Protein Folding; Spectrometry, Fluorescence

We studied the influence of hydroxypropylcyclodextrins (HPCDs) on the toxicity of some mixtures. Using the Photobacterium phosphoreum toxicity test, the joint toxicological effect for Mixture I (containing p-nitrobenzaldehyde and 1-nitronaphthalene) and Mixture II (containing p-nitrobenzaldehyde and malononitrile) were determined in water and in aqueous solutions of HPCDs. The results indicate that, although the toxicological joint effect for Mixture I (simple addition) differs from that of Mixture II (synergism), alpha- and beta-HPCD can significantly reduce the toxicity of the test compounds, whereas gamma-HPCD has only a slight effect. Explanations for these observations are given that invoke the molecular structure of the individual chemicals as well as the structures of HPCDs. This provides information to assist the application of HPCDs in remediation of environmental pollution.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; Benzaldehydes; beta-Cyclodextrins; Drug Combinations; Drug Interactions; Environmental Pollution; gamma-Cyclodextrins; Inhibitory Concentration 50; Molecular Structure; Naphthalenes; Nitriles; Photobacterium; Toxicity Tests; Water Pollutants, Chemical

Reported here is an analytical method enabling the stereochemical resolution of a new antianginal compound possessing two stereogenic centers, leading to four stereoisomers. Only one of these isomers is currently under development as a novel antianginal agent and consequently, the other three isomers are considered as unwanted chiral impurities. Therefore, an enantioselective method is required in order to check its enantiomeric purity. This paper presents a method exploiting the high efficiency of capillary electrophoresis and the complexing properties of cyclodextrins to achieve the separation of the four stereoisomers of this weakly basic compound (pKa = 7.4). For this purpose, the combination of a neutral cyclodextrin, hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), and an anionic cyclodextrin, carboxymethyl-beta-cyclodextrin (CM-beta-CD), was added to the separation buffer running in an uncoated silica capillary. After selection of the suitable cyclodextrin system, satisfactorily separation conditions were as follows: 30 mM phosphate buffer (pH 6.4) containing 10 mM of HP-gamma-CD and 10 mM of CM-beta-CD, running voltage +30 kV. The resulting run time and resolutions were respectively about 17 min and between 1.95 and 2.84. Linearity curves (0.993 < r2 < 0.998) are also shown.

Topics: Angina Pectoris; beta-Cyclodextrins; Cardiovascular Agents; Electrophoresis, Capillary; gamma-Cyclodextrins; Humans; Molecular Structure; Reproducibility of Results; Stereoisomerism

The development of a parenteral lorazepam formulation, using cyclodextrins (CDs) as inclusion complexation agents, was investigated. CDs suitable for parenteral injection, i.e., hydroxypropyl-beta-cyclodextrin (HP-beta-CD), hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), sulfobutylether-7-beta-cyclodextrin (SBE-7-beta-CD), and maltosyl-beta-cyclodextrin (malt-beta-CD) were studied for the possibility to increase the solubility of lorazepam. Lorazepam interacted with all tested CD derivatives and 1:1 complexes are formed. HP-beta-CD exerts the highest solubility improvement, reaching about 6 mg/ml lorazepam in 30% (w/v) CD solution. When using SBE-7-beta-CD or malt-beta-CD only half of that concentration can be dissolved. HP-gamma-CD interacts much less with lorazepam. Parenteral solutions with 4 mg/ml in 30% (w/v) HP-beta-CD solution, with 2 mg/ml in 30% (w/v) SBE-7-beta-CD, and with 2 mg/ml lorazepam in 15% (w/v) HP-beta-CD, were prepared. Sterile filtration of the formulation needs to be applied because of massive degradation of lorazepam during autoclaving. No precipitation is observed after dilution of the different formulations with (physiological) water or with 5% dextrose in water, which proves their suitability for administration with perfusions. The stability of the preparations was investigated in aqueous medium. During the first month, in all solutions more than 90% of lorazepam remained; after 3 months, less than 60% of lorazepam remained in the solutions with 15% (w/v) HP-beta-CD and around 65-70% in the solutions with 30% (w/v) of CDs. Because of this short stability time, the preparations need to be lyophilized.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Cyclodextrins; Delayed-Action Preparations; Drug Packaging; Drug Stability; Excipients; gamma-Cyclodextrins; Humans; Hydrogen-Ion Concentration; Injections, Intraperitoneal; Isotonic Solutions; Lorazepam; Maltose; Reproducibility of Results; Solubility; Sterilization

The stability constants for the inclusion of butylbenzenes (BBs) with 2-hydroxypropyl-cyclodextrins (2HP-CDs) in aqueous solution have been determined using the static head-space method. The 1:1 stability constants were obtained by this method. For the complexation of BBs by 2HP-alpha-CD, the order of stability constants was n-BB > isoBB > tert-BB. In contrast, the order for complexation of BBs by 2HP-beta-CD was the opposite: tert-BB > isoBB > n-BB. The order of the stability constants by 2HP-gamma-CD was similar to that of 2HP-beta-CD, but the values of the stability constants were not significantly different in the BB types. In addition, the binding effects are discussed in relation to the different alkyl groups of BBs.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; Benzene Derivatives; beta-Cyclodextrins; Cyclodextrins; Environmental Pollutants; gamma-Cyclodextrins; Models, Chemical; Volatilization

gamma-Aminobutyric acid (GABA), glutamate (Glu), and L-aspartate (L-Asp) are three major amino acid neurotransmitters in the central nervous system. In this work, a method for the separation of these three neurotransmitters in brain microdialysis samples using a commercially available capillary electrophoresis (CE) system has been developed. Molecules were tagged on their primary amine function with the fluorogene agent naphthalene-2,3-dicarboxaldehyde (NDA), and, after separation by micellar electrokinetic chromatography, were detected by laser-induced fluorescence using a 442 nm helium-cadmium laser. The separation conditions for the analysis of derivatized neurotransmitters in standard solutions and microdialysates have been optimized, and this method has been validated on both pharmacological and analytical basis. The separation of GABA, Glu, and L-Asp takes less than 10 min by using a 75 mmol/L borate buffer, pH 9.2, containing 70 mmol/L SDS and 10 mmol/L hydroxypropyl-beta-cyclodextrin and + 25 kV voltage. The detection limits were 3, 15 nmol/L and, 5 nmol/L for GABA, Glu, and L-Asp, respectively. Moreover, submicroliter samples can be analyzed. This method allows a simple, rapid and accurate measurement of the three amino acid neurotransmitters for the in vivo brain monitoring using microdialysis sampling.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Aspartic Acid; beta-Cyclodextrins; Brain Chemistry; Buffers; Chromatography, Micellar Electrokinetic Capillary; Cyclodextrins; Dialysis Solutions; Electrophoresis, Capillary; Fluorescence; gamma-Aminobutyric Acid; gamma-Cyclodextrins; Glutamic Acid; Hydrogen-Ion Concentration; Lasers; Microdialysis; Naphthalenes; Neurotransmitter Agents; Rats; Rats, Sprague-Dawley; Sodium Dodecyl Sulfate; Time Factors

To explore the use of cyclodextrins (CD) to form inclusion complexes with beta-lapachone (beta-lap) to overcome solubility and bioavailability problems previously noted with this drug.. Inclusion complexes between beta-lap and four cyclodextrins (alpha-, beta-, gamma-, and HPbeta-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and 1H-NMR spectroscopy. Biologic activity and bioavailability of beta-lap inclusion complexes were investigated by in vitro cytotoxicity studies with MCF-7 cells and by in vivo lethality studies with C57Blk/6 mice (18-20 g).. Phase solubility studies showed that beta-lap solubility increased in a linear fashion as a function of alpha-, beta-, or HPbeta-CD concentrations but not gamma-CD. Maximum solubility of beta-lap was achieved at 16.0 mg/ml or 66.0 mM with HPbeta-CD. Fluorescence and 1H-NMR spectroscopy proved the formation of 1:1 inclusion complexes between beta-CD and HPbeta-CD with beta-lap. Cytotoxicity assays with MCF-7 cells showed similar biologic activities of beta-lap in beta-CD or HPbeta-CD inclusion complexes (TD50 = 2.1 microM). Animal studies in mice showed that the LD50 value of beta-lap in an HPbeta-CD inclusion complex is between 50 and 60 mg/kg.. Complexation of beta-lap with HPbeta-CD offers a major improvement in drug solubility and bioavailability.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adjuvants, Pharmaceutic; alpha-Cyclodextrins; Animals; beta-Cyclodextrins; Biological Availability; Cyclodextrins; gamma-Cyclodextrins; Humans; Injections, Intraperitoneal; Lethal Dose 50; Mice; Mice, Inbred C57BL; Naphthoquinones; Solubility; Tumor Cells, Cultured

Effects of the addition of various additives in the working electrolyte on the selectivity of capillary electrophoretic separation of naphthalenesulphonic acids used as intermediates in the production of synthetic dyes were investigated. Cyclodextrins form inclusion complexes with various compounds and are not only excellent chiral selectors, but have been also successfully applied for separations of positional isomers. In this work, methyl-beta-cyclodextrin, heptakis(2,6-di-O-methyl)-beta-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin, (2-hydroxypropyl)-beta-cyclodextrin and (2-hydroxypropyl)-gamma-cyclodextrin were studied as isomeric selector additives and compared with unsubstituted beta-cyclodextrin. In addition to the size of the cyclodextrin cavity, the number and type of the substituents in the cyclodextrin molecules strongly affect the separation of isomeric naphthalenesulphonic acids, but the effect of the substituted cyclodextrins on the separation selectivity is different for various types of sulphonic acids. Best separations of non-substituted naphthalenesulphonic acids were achieved in a borate buffer with methyl-beta-cyclodextrin, whereas the running buffer with non-substituted beta-cyclodextrin provides superior separation of amino and hydroxynaphthalenesulphonic acids.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Algorithms; beta-Cyclodextrins; Cyclodextrins; Electrochemistry; Electrophoresis, Capillary; gamma-Cyclodextrins; Indicators and Reagents; Osmosis; Reference Standards; Sulfonic Acids

Chiral separation of moderately to highly hydrophobic polychlorinated biphenyls (PCBs) using a conventional chiral micelle or a polymeric chiral surfactant, as the single chiral selector is very difficult since the hydrophobic interactions between the chiral PCB and the monomeric or polymeric surfactant is very strong. Combined use of a polymeric chiral surfactant, polysodium N-undecanoyl-D-valinate (poly-D-SUV) with hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) was successful in cyclodextrin modified electrokinetic chromatography (CD-EKC) enantioseparation of PCB congeners. Addition of HP-gamma-CD to the background electrolyte containing poly-D-SUV functioned to improved chiral resolution for the PCBs and reduce the analysis time for these congeners. In addition, concentration of methanol, concentration of 2-(N-cyclohexylamino) ethanesulfonic acid (CHES) buffer and separation voltage was also varied to optimize multicomponent separation of five chiral PCBs. Simultaneous separation and enantioseparation of all five PCBs was possible in less than 50 min under optimized conditions that requires a 5 mM CHES solution buffered at about pH 10 with 1.5% w/v (ca. 60 mM) poly-D-SUV and 16 mM HP-gamma-CD. In addition, 1 M urea and 20% v/v methanol should be added as organic modifier and the capillary temperature maintained at 45 degrees C. As expected the polymeric surfactant showed improved chiral resolution of PCBs over conventional micelles of SUV. Under optimized conditions, when CD-EKC of chiral PCBs using poly-D-SUV was compared to sodium dodecyl sulfate (SDS), better resolution, higher efficiency and shorter analysis time was achieved with poly-D-SUV.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Biopolymers; Chromatography, Micellar Electrokinetic Capillary; Cyclodextrins; Dose-Response Relationship, Drug; gamma-Cyclodextrins; Methanol; Peptides; Polychlorinated Biphenyls; Proteins; Stereoisomerism; Surface-Active Agents; Taurine

A high-performance size exclusion chromatographic method with analyte enhanced fluorescence detection is described for the analysis of 2-hydroxypropyl-gamma-cyclodextrin (HPGCD) in different biological fluids. The principle of detection was the in situ complexation of 8-anilinonaphthalene-1-sulfonic acid (ANS) by HPGCD. When HPGCD eluted from the column the increased fluorescence was measured at excitation and emission wavelengths of 270 and 512 nm, respectively. Solid-phase extraction cleanup and concentration of samples resulted in higher than 78% recovery of HPGCD for each of the studied biological fluids. Some important details of the method development as well as the validation of the method for rabbit plasma, rabbit aqueous humour, monkey plasma and monkey urine are given. The limits of quantification varied between 1 and 10 nmol/ml (correspond to 1.5-15 microg/ml) depending on the biological matrix used. The method was successfully adapted in another laboratory proving that HPGCD had not absorbed into aqueous humour and plasma after topical application of HPGCD containing eye drop in rabbits.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Body Fluids; Chromatography, High Pressure Liquid; Cyclodextrins; gamma-Cyclodextrins; Rabbits; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Fluorescence

Bropirimine (ABPP) is an orally active immunomodulator that increases endogenous alpha-interferon and other cytokines used clinically against carcinoma in situ of the bladder. The oral absorption of ABPP is poor because its low solubility in water. The purpose of this study is to develop a technological procedure useful to increase the water solubility of ABPP. To this end, the interaction of ABPP with several cyclodextrin derivatives-alpha-, beta-, gamma- and hydroxypropyl-beta-cyclodextrin with a degree of substitution 2.7 (HPbetaCD) was studied and the effect of the complexation process on the water solubility of the drug was evaluated. The best results were obtained with the hydroxypropyl derivative, HPbetaCD, that interacts in a 1:1 drug:cyclodextrin molar ratio. The inclusion complex ABPP-HPbetaCD was characterized in solution by nuclear magnetic resonance (1H-NMR). The solid inclusion complex was obtained by freeze-drying and characterized by differential scanning calorimetry (DSC), X-ray diffractometry and mass spectrometry. The dissolution rate of ABPP from the HPbetaCD solid inclusion complex was increased compared to the powdered drug but not differences were found between the complex and a physical mixture with a similar molar ratio. The increase of the dissolution rate of the drug can be attributed to the breakdown in solution of the drug dimers in the presence of the cyclodextrin and to the complex formation.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; beta-Cyclodextrins; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Cyclodextrins; Cytosine; gamma-Cyclodextrins; Interferon Inducers; Nuclear Magnetic Resonance, Biomolecular; Solubility; X-Ray Diffraction

The simultaneous interaction of 15 steroidal drugs with tau-cyclodextrin (tauCD) and hydroxypropyl-beta-CD (HPbetaCD) was determined by charge transfer chromatography and the relative strength of interaction was calculated for each drug-tauCD-HPbetaCD ternary complex. The mixture of CDs interacted with each steroidal drugs decreasing the lipophilicity of the guest molecules. The chemical structure of steroidal drugs markedly influenced their capacity to interact with the mixture of CDs, the more lipophilic compounds formed stronger complexes with CDs. In the overwhelming majority of cases the stability of drug-tauCD-HPbetaCD system was higher than those of binary (drug-tauCD and drug-HPbetaCD) system indicating the probability of ternary complex formation. The data indicated that the ternary complex formation has to be taken into consideration in pharmaceutical formulations containing more than one type of CD or CD derivatives.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Chromatography, Thin Layer; Cyclodextrins; gamma-Cyclodextrins; Methanol; Regression Analysis; Solvents; Spectrophotometry, Ultraviolet; Steroids

Tolbutamide-hydroxypropyl-gamma-cyclodextrin (TBM-HPGCD) interaction has been investigated in an aqueous environment and in the solid state. The solubility of TBM was increased in accord with the amount of HPGCD added to the aqueous medium forming a soluble inclusion compound. The phase solubility diagram obtained was of A(L) type. Physical mixtures and kneaded systems of the drug and cyclodextrin derivative were prepared in 1:1 and 1:2 drug/cyclodextrin mol/mol ratio. All solid binary systems were characterised by hot-stage microscopy (HSM), differential scanning calorimetry (DSC), thermogravimetry (TG) and X-ray powder diffractometry (XRD). An inclusion complex was formed in both of the kneaded systems. In the 1:2 kneaded system, the entire drug was included in the cyclodextrin cavity, while, in the 1:1 kneaded system only a part of the drug formed an inclusion complex with the cyclodextrin. A significant improvement in the dissolution of the drug was obtained from the kneaded systems in comparison with that of the pure TBM and physical mixtures. However, there was no significant difference between the dissolution profiles of the two kneaded systems. The study suggests that an inclusion complex was obtained both in aqueous solution and in solid state.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Calorimetry, Differential Scanning; Cyclodextrins; gamma-Cyclodextrins; Solubility; Solutions; Thermogravimetry; Tolbutamide; X-Ray Diffraction

An enantiomeric assay for the flavonoids vestitone and medicarpin from transgenic plant extracts was developed using capillary electrophoresis. It was found that no single cyclodextrin proved capable of resolving the enantiomers of both medicarpin and vestitone. Instead, hydroxypropyl-beta-cyclodextrin provided the best selectivity for the vestitones while hydroxypropyl-gamma-cyclodextrin was best for the medicarpins. The addition of organic modifiers improved the resolution of both enantiomers. Acetonitrile proved best for the vestitones and only methanol improved the resolution of the medicarpins. An optimization study of mixed hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin containing electrolytes revealed that the separation of the medicarpin enantiomers was intolerant to the presence of hydroxypropyl-beta-cyclodextrin. Our optimized running electrolyte was composed of 2 mM hydroxypropyl-beta-cyclodextrin, 20 mM hydroxypropyl-gamma-cyclodextrin, and 25 mM borate at pH 10.0 with 10% v/v methanol. This system provided a resolution of 1.47 and 1.80 for the medicarpin and vestitone enantiomers, respectively. This analysis was completed in 12 min. This separation provided a rapid screen to determine the enantiomeric purity of key flavonoids biosynthesized by transgenic legumes.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Benzopyrans; beta-Cyclodextrins; Chromones; Cyclodextrins; Electrophoresis, Capillary; gamma-Cyclodextrins; Hydrogen-Ion Concentration; Indicators and Reagents; Isoflavones; Molecular Structure; Pterocarpans; Stereoisomerism

The object of this study was to enhance the solubility, dissolution rate, and oral bioavailability of rutin by complexation with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The interaction of rutin with cyclodextrins (CyDs) was evaluated by the solubility, and ultraviolet (UV) and circular dichroism (CD) spectrophotometries. The chemical and enzymatic stability of rutin was examined in an alkaline buffer solution and in rat small intestinal homogenates, respectively. Dissolution rates of rutin and its CyD complexes were measured by the dispersed amount method. In vivo absorption studies of rutin after oral administration via conventional tablet containing rutin alone or its beta-CyD complexes was performed on beagle dogs. The stability constants calculated from the phase solubility method increased in the order of HP-gamma-CyD < G2-beta-CyD < beta-CyD < HP-beta-CyD. Spectroscopic studies also revealed that HP-beta-CyD and beta-CyD formed a relatively more stable inclusion complex with rutin. The dissolution rates of rutin increased by the complexation with CyDs in the order of rutin alone < HP-beta-CyD < or = beta-CyD. HP-beta-CyD inhibited the hydrolysis of rutin in the alkaline buffer solution and the small intestinal homogenates of rats, suggesting that HP-beta-CyD may stabilize rutin in a gastrointestinal tract after oral administration. When the tablet containing rutin or its beta-CyD complexes was administered to beagle dogs, the plasma levels of homovanillic acid (HVA) (a major stable metabolite of rutin) after oral administration of HP-beta-CyD complex were much higher than in either that of rutin alone or in its beta-CyD complex. The in vivo absorption study suggests that HP-beta-CyD increased the oral bioavailability of rutin from the gastrointestinal tracts of beagle dogs because of the increase in solubility, faster dissolution rate, and gastrointestinal stability. HP-beta-CyD has a significant advantage with respect to providing high aqueous solubility while maintaining a lack of toxicity in oral pharmaceutical preparations of rutin.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Absorption; Administration, Oral; Animals; beta-Cyclodextrins; Biological Availability; Cyclodextrins; Drug Stability; gamma-Cyclodextrins; Male; Rats; Rats, Wistar; Rutin; Solubility

The effects of native cyclodextrins (alpha, beta or gamma), hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin solubilized in urea, soluble starch and glucose in water solution on the fluorescence behaviour of melatonin (N-acetyl-5-methoxytryptamine) (M) and 5-methoxytryptamine [5-methoxy-3-(2-aminoethyl)indole] (5M) were determined. In addition, the effect of methanol and propanol with and without beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin was assessed. From the fluorescence changes with pH, the values of the pKa for the ground (9.9 +/- 0.2) and the excited state (7.7 +/- 0.2) for 5M were determined. From the fluorescence changes with beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin, the association constants of M, 5MH [5-methoxy-3-(2-ammoniumethyl)indole] and 5M with the two hosts were determined. The values with beta-cyclodextrin were KAssoc5MH = (1.4 +/- 0.4) x 10(2) mol-1 dm3, KAssoc5M = (1.6 +/- 0.1) x 10(2) mol-1 dm3 and KAssocM = (1.1 +/- 0.2) x 10(2) mol-1 dm3, and with hydroxypropyl-beta-cyclodextrin KAssoc5MH = (1.1 +/- 0.3) x 10(2) mol-1 dm3, KAssoc5M = (2.5 +/- 0.1) x 10(2) mol-1 dm3 and KAssocM = (1.51 +/- 0.07) x 10(2) mol-1 dm3. The ratios of the fluorescence quantum yields for the bound and free substrate (phi b/phi f) were in the range 1.15-1.48. The detection limits under the optimum conditions were 0.381 +/- 0.001 ng cm-3 for the complex 5MH-hydroxypropyl-beta-cyclodextrin in water and 0.290 +/- 0.001 ng cm-3 for the complex M-hydroxypropyl-beta-cyclodextrin in water with 5% of methanol. The recovery of melatonin from pharmaceutical preparations was 98-103% with an RSD of 2%. The recovery from rat pineals was also good. The method is direct, simple and accurate.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; 5-Methoxytryptamine; alpha-Cyclodextrins; Animals; beta-Cyclodextrins; Cyclodextrins; Fluorometry; gamma-Cyclodextrins; Melatonin; Pineal Gland; Rats

The effect of some chemically modified cyclodextrins [namely, 2-hydroxypropyl-beta-, methyl-beta-, and 2-hydroxypropyl-gamma-cyclodextrin (HP-beta-CD, Me-beta-CD, and HP-gamma-CD, respectively)] on the aqueous solubility and dissolution rate of the hypnotic agent Zolpidem (ZP) was investigated. Solid complexes were prepared by freeze drying and characterized by infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. The solubility and dissolution rate of the drug were significantly improved by complexation with HP-beta-CD or Me-beta-CD. The structure of the inclusion complex ZP-HP-beta-CD in CH(3)COOD/D(2)O was investigated by (1)H and (13)C NMR spectroscopy, including NOE measurements. These measurements revealing a weak interaction between the tolyl moiety of the guest molecule and the HP-beta-CD cavity. The ataxic activity in rat was also investigated and it was found that ZP-HP-beta-CD and ZP-Me-beta-CD complexes showed almost 2-fold longer ataxic induction times than controls.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Ataxia; beta-Cyclodextrins; Cyclodextrins; gamma-Cyclodextrins; Hypnotics and Sedatives; Male; Pyridines; Rats; Rats, Sprague-Dawley; Solubility; Zolpidem

Using capillary zone electrophoresis (CZE) with a 75 mM phosphate buffer at pH 8.5 containing 5 mM hydroxypropyl-gamma-cyclodextrin (OHP-gamma-CD) as chiral selector, the separation of the enantiomers of thiopental and its oxybarbiturate metabolite, pentobarbital, is reported. Enantiomer assignment was performed via preparation of enantiomerically enriched fractions using chiral recycling isotachophoresis (rITP) processing of racemic barbiturates and analysis of rITP fractions by chiral CZE and circular dichroism spectroscopy. Thiopental and pentobarbital enantiomers in plasma were extracted at low pH using dichloromethane and extracts were reconstituted in acetonitrile or 10-fold diluted, achiral running buffer. The stereoselectivity of the thiopental and pentobarbital metabolism was assessed via analysis of 12 plasma samples that stemmed from patients undergoing prolonged or having completed long-term racemic thiopental infusion. The data obtained revealed a modest stereoselectivity with R-(+)-thiopental/S-(-)-thiopental and R-(+)-pentobarbital/S-(-)-pentobarbital plasma ratios being < 1 (P < 0.05 compared to data obtained with racemic controls) and > 1 (P < 0.001), respectively. The total S-(-)-thiopental plasma concentration was found to be on average about 24% higher compared to the concentration of R-(+)-thiopental, whereas the total R-(+)-pentobarbital plasma level was observed to be on average 29% higher compared to the S-(-)-pentobarbital concentration.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Buffers; Circular Dichroism; Cyclodextrins; Electrophoresis, Capillary; gamma-Cyclodextrins; Humans; Hydrogen-Ion Concentration; Methylene Chloride; Pentobarbital; Phosphates; Stereoisomerism; Thiopental

The interaction between the UV filter, 2-ethylhexyl-p-dimethylaminobenzoate, and unmodified and modified alpha-, beta- or gamma-cyclodextrins was studied in water by phase-solubility analysis. Of the cyclodextrins available, only hydroxypropyl-beta-cyclodextrin caused a marked increase in the aqueous solubility of 2-ethylhexyl-p-dimethylaminobenzoate. The data from the solubility study indicated the formation of a 1:1 (sunscreen-cyclodextrin) complex. The inclusion of the sunscreen agent into the hydroxypropyl-beta-cyclodextrin cavity was confirmed by thermal analysis and by nuclear magnetic resonance spectroscopy. Irradiation-induced degradation of 2-ethylhexyl-p-dimethylaminobenzoate was reduced by complexation with hydroxypropyl-beta-cyclodextrin, this effect being more pronounced in solution (the extent of degradation was 25.5% for the complex compared with 54.6% for free 2-ethylhexyl-p-dimethylaminobenzoate) than in the emulsion vehicle (the extent of degradation was 25.1% for the complex compared with 33.4% for free 2-ethylhexyl-p-dimethylaminobenzoate). Although photodegradation of the sunscreen agent is significantly reduced by formation of the inclusion complex it is important to design a suitable vehicle. Inclusion of 2-ethylhexyl-p-dimethylaminobenzoate-DMAB into the hydroxypropyl-beta-cyclodextrin cavity limits interaction of the UV filter with the skin reducing the side-effects of the formulation.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; 4-Aminobenzoic Acid; alpha-Cyclodextrins; beta-Cyclodextrins; Cyclodextrins; Differential Thermal Analysis; Drug Stability; gamma-Cyclodextrins; Gas Chromatography-Mass Spectrometry; Magnetic Resonance Spectroscopy; para-Aminobenzoates; Sunscreening Agents; Ultraviolet Rays

The interaction of cyclodextrins (CDs) with dipalmitoylphosphatidylcholine (DPPC) liposomes has been studied using differential scanning calorimetry (DSC). The phase transition temperature and the enthalpy change due to the gel-to-liquid crystalline phase transition of the liposomes were measured in the presence of alpha-CD, beta-CD, gamma-CD, heptakis (2,6-di-O-methyl)-beta-CD (DOM-beta-CD), heptakis (2,3,6-tri-O-methyl)-beta-CD (TOM-beta-CD) and 2-hydroxylpropyl beta-CD, respectively. The effects on the change of enthalpy of the transition temperature were remarkable in the order of DOM-beta-CD > alpha-CD > TOM-beta-CD. The residual CDs caused scarcely detectable changes in the enthalpy changes and the transition temperatures. In order to clarify the DSC curves in the presence of the CDs mentioned above, the type of interactions which occurred between CDs and DPPC liposomes were studied. Consequently, it was found that DOM-beta-CD forms a soluble complex and alpha-CD forms an insoluble complex with DPPC liposomes, whereas only a slight amount of TOM-beta-CD was suggested to penetrate the matrix of the liposomes.

Topics: 1,2-Dipalmitoylphosphatidylcholine; 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; beta-Cyclodextrins; Calorimetry, Differential Scanning; Cyclodextrins; gamma-Cyclodextrins; Liposomes; Thermodynamics

This report describes a specific and highly sensitive gas chromatography-mass spectrometry (GC-MS) assay for the analysis of industrially produced 2-hydroxypropyl-gamma-cyclodextrin, a heterogeneous mixture of homologues and isomers, in plasma of cynomolgus monkeys. Instead of analyzing the polysaccharide mixture as a whole, in a first step the HP-gamma-cyclodextrin mixture, together with the internal standard (2,6-di-O-methyl-beta-cyclodextrin), was deuteromethylated, and in a second step hydrolyzed with hydrochloric acid to the respective monosaccharides. The resulting reaction mixture was trimethylsilylated to 1,4-bis(O-trimethylsilyl)-2,3-bis-O-deuteromethyl-6-O-2'-deuter omethoxypropylglucose (representative for HP-gamma-CD) and 1,4-bis-(O-trimethylsilyl)-bis-2,6-O-methyl-3-O-deuteromethylglucose+ ++ (representative for the internal standard), respectively, and analyzed by GC-MS. The limit of quantification of this assay was 20 nmol/l.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Administration, Oral; Animals; beta-Cyclodextrins; Calibration; Cyclodextrins; gamma-Cyclodextrins; Gas Chromatography-Mass Spectrometry; Macaca fascicularis; Reference Standards; Reproducibility of Results

Differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy and transmission electron microscopy (TEM) have been used to determine the influence of beta-cyclodextrin (beta-CyD), hydroxypropyl-beta-CyD (HP-beta-CyD) and gamma-CyD on the structural properties of the stratum corneum from the hairless mouse. Some modest changes in the stratum corneum lipid transition temperature were induced by HP-beta-CyD and blue shifts were observed in the FTIR spectra of the C-H asymmetric and symmetric stretching of the lipids from the stratum corneum. Results from TEM studies indicated that HP-beta-CyD caused removal and possible disorganization of the lipid matrix that envelopes the corneocytes of the stratum corneum, whereas no effect was seen after treatment of the samples with beta-CyD and gamma-CyD. These results suggest that HP-beta-CyD can increase the permeability of the stratum corneum possibly as a result of extraction of lipids, and might thus enhance drug permeation through the skin.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Calorimetry, Differential Scanning; Cyclodextrins; Epidermis; gamma-Cyclodextrins; Lipid Metabolism; Male; Mice; Mice, Hairless; Microscopy, Electron; Permeability; Skin; Spectroscopy, Fourier Transform Infrared

Poor oral bioavailability of three experimental compounds, 1-III, observed in animals has been attributed to the low intrinsic solubility. To enhance their GI absorption, we attempted to increase the solubility of these compounds with hydroxypropyl beta-cyclodextrin (HPB)4 and gamma-cyclodextrin (HPG). Compound I showed an increase in solubility over 1,000-fold with 25% HPB at 25 degrees C. The association constant of the 1:1 complex between I and HPB was determined by phase-solubility analysis. Thermodynamic parameters involved were all favorable for the complexation. The large positive delta S degrees observed suggests that the complex formation is driven by a hydrophobic interaction. Apical-to-basal transport of I across the Madin Darby canine kidney (MDCK) cell monolayer was studied at 37 degrees C in the presence of HPB with or without agitation. The complex itself did not pass through the cell layer. Diffusion of the unbound I as well as the complex through the aqueous boundary layer in the apical side is rate-limiting. Regardless of hydrodynamics, decreasing HPB concentration at a given drug concentration increased the transport rate. The findings indicate that the transepithelial transport is attributed to the passive diffusion of available free drug molecules rather than the collision complex transfer at the cell surface.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Biological Transport; Cell Line; Cyclodextrins; Dogs; Epithelium; gamma-Cyclodextrins; Solubility; Thermodynamics

The potential use of three 2-hydroxypropyl ether derivatives of cyclodextrins (HP-alpha-, HP-beta- and HP-gamma-CyDs) as biocompatible solubilizers and stabilizers for oleic acid, a lipophilic absorption enhancer, was assessed in the nasal absorption of buserelin, an agonist of luteinizing hormone-releasing hormone, in rats. HP-CyDs increased the aqueous solubility of oleic acid and protected it against oxidation through the formation of inclusion complexes with the efficacy increasing in the order: HP-gamma-CyD << HP-alpha-CyD < HP-beta- CyD. The bend structure due to a cis-double bond halfway along the acyl chain of oleic acid provided a better fit into the cavity of HP-beta-CyD, in which the double bond appears to be buried, and hence becomes less susceptible to oxidation. The rate and extent of nasal bioavailability of buserelin were remarkably increased by coadministration of oleic acid and HP-beta-CyD, compared with the sole use of the enhancer. This enhancement was ascribable to the lowering of both the enzymatic and physical barriers of the nasal epithelium to the peptide, probably through the facilitated transmucosal penetration of oleic acid solubilized in HP-beta-CyD.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Absorption; Administration, Intranasal; alpha-Cyclodextrins; Animals; beta-Cyclodextrins; Biological Availability; Buserelin; Cyclodextrins; Drug Stability; gamma-Cyclodextrins; Gonadotropin-Releasing Hormone; Magnetic Resonance Spectroscopy; Male; Nasal Mucosa; Oleic Acids; Oxidation-Reduction; Rats; Rats, Wistar

In the first part of this work, the use of capillary electrophoresis (CE) for the separation of two groups of pharmaceuticals, namely a metabolite of tamoxifen and a basic drug substance, DS1 was investigated. The effects of pH and types of modifiers, e.g. surfactant, bile salt, gamma-cyclodextrin and hydroxypropyl-beta-cyclodextrin on selectivity, separation and peak shape were studied. Besides achieving complete separation of the compounds, the CE system was capable of providing separation with significant improvements in overall peak shape of the compounds compared with HPLC. In the case of the basic drug substance DS1, validation of the CE system developed in terms of linearity, selectivity, sensitivity and reproducibility was satisfactorily performed. At the same time, a study of the sample solvent matrix effects on the separation of this group of compounds was examined. The system was successfully applied to the analysis of laboratory-synthesized samples. Good correlation was observed between CE and HPLC, although higher efficiency and faster speed of separation were obtained using the CE system developed. For the tamoxifen metabolite, special emphasis was placed on the use of CE for the separation of the pair of isomers. This was readily achieved through the introduction of gamma-cyclodextrin in the electrolyte. Resolution of at least 1.5 was obtained for the isomers using the CE method.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Alkenes; beta-Cyclodextrins; Capillary Action; Chromatography, High Pressure Liquid; Cyclodextrins; Drug Contamination; Electrophoresis; gamma-Cyclodextrins; Hydrogen-Ion Concentration; Micelles; Ondansetron; Phenols; Reproducibility of Results; Sensitivity and Specificity; Tamoxifen; Technology, Pharmaceutical

Derivatives of beta-cyclodextrin differing in the length of a hydroxyalkyl substituent (CH2CH2OH, CH2CHOHCH3, CH2CHOHCH2CH2CH2CH3) or in the electrical charge of the substituents (SO4-, CH2CHOHCH2N(CH3)3+) and hydroxypropyl derivatives (CH2CHOHCH3) of alpha-, beta-, and gamma-cyclodextrin were compared, individually and in mixtures, as solubilizers of cholesterol. The most effective solubilizer proved to be hydroxypropyl derivatives of beta-cyclodextrin; beta-cyclodextrin sulfate (SO4-) was practically devoid of solubilizing activity. Oral administration of these cyclodextrin derivatives, some of which are both nondegradable and effective complexation agents for cholesterol and bile acids, nevertheless did not affect the conversion of [14C]acetic acid to [14C]-cholesterol in rat under the same conditions when another bile acid complexation agent, cholestyramine, increased that conversion. Thus, complexation of cholesterol and of bile acids by cyclodextrin derivatives, which is a significant and well-defined phenomenon in vitro, seems to have limited importance in terms of excretion of cholesterol from the gastrointestinal tract. It is proposed that various untoward effects observed after chronic large oral doses of hydroxypropyl beta-cyclodextrin are administered are not caused by an increased excretion of some vital lipophile or enzyme but are probably caused by solubilization and increased absorption of toxic contaminants of the ingested food.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; Animals; Aorta; beta-Cyclodextrins; Bile Acids and Salts; Cholesterol; Cyclodextrins; gamma-Cyclodextrins; Liver; Male; Rats; Rats, Sprague-Dawley; Steroids

Hydroxypropyl ethers of cyclodextrins form water-soluble inclusion complexes with lipids. Of the three hydroxypropylcyclodextrins examined, hydroxypropyl-alpha-cyclodextrin had limited specificity for phospholipids, and hydroxypropyl-beta-cyclodextrin had limited specificity for cholesterol, and hydroxypropyl-gamma-cyclodextrin was nonspecific. The formation of inclusion complexes was found to be a fast and reversible process in which complexation of cholesterol did not inhibit its oxidation by cholesterol oxidase, and cholesterol of the erythrocyte membrane could be exchanged within a minute for cholesteryl methyl ether which was in the inclusion complex. Thus, hydroxypropylcyclodextrin in the circulation may catalyze the transport of lipids in the direction of equilibrium distribution.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; beta-Cyclodextrins; Chemical Phenomena; Chemistry, Physical; Cholesterol; Cyclodextrins; Erythrocyte Membrane; gamma-Cyclodextrins; Humans; In Vitro Techniques; Lipids; Solubility

Hydroxypropyl ethers of cyclodextrins, after parenteral administration, come into contact with lipids in tissues and in circulation and form water-soluble inclusion complexes with these lipids. A single intravenous administration of hydroxypropyl-beta-cyclodextrin to a hereditary hyperlipidemic Watanabe rabbit slightly and temporarily decreased the level of total cholesterol in serum. Single injections of hydroxypropyl-alpha-cyclodextrin and of the corresponding gamma-homologue, both of which are less potent solubilizers of cholesterol, had lesser effects. Repeated administration of hydroxypropyl-beta-cyclodextrin to rabbits led to a gradual increase in total cholesterol in circulation and eventually to a slight relief of atherosclerotic lesions in the thoracic aorta. The only untoward effects of repeated treatments (total doses of up to 40 g/kg) were vacuoles in cells of proximal convoluted tubules in the kidneys. Repeated administration also strongly increased cholesterol in urine, probably because of excretion of the soluble cholesterol-hydroxypropyl-beta-cyclodextrin complex. Proteins in urine increased significantly, whereas triglycerides increased only moderately after repeated administrations. Intravenous infusion of hydroxypropyl-beta-cyclodextrin into a patient with hypervitaminosis A led to a release of liver-stored retinoids into serum in quantities much higher than those that could be directly solubilized by hydroxypropyl-beta-cyclodextrin. Levels of total cholesterol in the circulation of this patient decreased during the infusion. Thus, hydroxypropylcyclodextrins may serve as artificial lipid carriers in the circulation, and because the exchanges that involve inclusion complexation occur very quickly, the presence of hydroxypropylcyclodextrins in organisms may catalytically augment the establishment of equilibria in lipid distribution.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; Animals; beta-Cyclodextrins; Cyclodextrins; gamma-Cyclodextrins; Humans; Hypervitaminosis A; Hypolipidemic Agents; Injections, Intravenous; Lipids; Lipoproteins; Rabbits; Retinoids

The substituted glucopyranose ring structure 2-hydroxypropyl-beta-cyclodextrin (CDEX) increases the solubility of molecules by inclusion of the agent in the lipophilic interior of the ring. This property is of particular use for the administration of molecules by the intracerebral (ICV) or intrathecal (IT) routes. In concentrations up to 40% w/v (isotonic), this agent (10 microliters) effect upon nociceptive or motor function after IT injection or on EEG and general behavior after ICV injection in rats. Using 20% CDEX, there is no change in the ED50 as compared to saline on the hot plate (HP) after IT injection of morphine, D-Ala2-D-Leu5 enkephalin or Tyr-Aib-Gly-gPhe-mAib-NH2, (Aib: alpha-aminoisobutyric acid) although there is an increase in their respective durations of effect. Cyclic peptide opioids: Tyr-c[D-A2bu-Gly-D-beta Nal(1)-D-Leu] (A2bu: alpha, gamma-diaminobutyric acid; beta-Nal(1): beta-naphthylalanine(1)) or Tyr-c[DA2bu-Gly-beta Nal(1)-D-Leu] are insoluble in saline but are readily dissolved in CDEX, and display a naloxone-sensitive antinociception following spinal administration. In other studies, saline insoluble capsaicin is administered in 25% dimethylsulfoxide (DMSO) or 20% CDEX (15 microliters; 5 mg/ml) which result in a significant reduction in the spinal levels of substance P and calcitonin gene related peptide and an increase in the HP latency. DMSO alone, but not CDEX alone, reduces the levels of the two peptides. These data emphasize the utility of complexation with CDEX for intracerebral drug delivery and compatibility with brain and spinal tissue.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; Analgesia; Animals; beta-Cyclodextrins; Calcitonin Gene-Related Peptide; Capsaicin; Cerebral Ventricles; Cyclodextrins; Dimethyl Sulfoxide; Electroencephalography; Enkephalin, Leucine-2-Alanine; gamma-Cyclodextrins; Injections, Intraventricular; Injections, Spinal; Male; Morphine; Motor Activity; Naloxone; Narcotics; Pain; Pharmaceutical Vehicles; Rats; Rats, Inbred Strains; Solubility; Substance P; Time Factors