Development and Characterization of the Neuroregenerative Xanthohumol C/Hydroxypropyl-β-cyclodextrin Complex Suitable for Parenteral Administration

Planta Medica ◽  
2019 ◽  
Vol 85 (16) ◽  
pp. 1233-1241
Author(s):  
Michael Kirchinger ◽  
Lara Bieler ◽  
Julia Tevini ◽  
Michael Vogl ◽  
Elisabeth Haschke-Becher ◽  
...  
Keyword(s):  
Water Solubility ◽  
Pharmaceutical Research ◽  
Water Soluble ◽  
Complexing Agents ◽  
Cyclodextrin Complex ◽  
Scanning Calorimetry ◽  
In Vivo Experiments ◽  
Strong Candidate

AbstractThe chroman-like chalcone Xanthohumol C, originally found in hops, was demonstrated to be a potent neuroregenerative and neuroprotective natural product and therefore constitutes a strong candidate for further pharmaceutical research. The bottleneck for in vivo experiments is the low water solubility of this chalcone. Consequently, we developed and validated a suitable formulation enabling in vivo administration. Cyclodextrins were used as water-soluble and nontoxic complexing agents, and the complex of Xanthohumol C and 2-hydroxypropyl-β-cyclodextrin was characterized using HPLC, HPLC-MS, NMR, and differential scanning calorimetry. The water solubility of Xanthohumol C increases with increasing concentrations of cyclodextrin. Using 50 mM 2-hydroxypropyl-β-cyclodextrin, solubility was increased 650-fold. Furthermore, in vitro bioactivity of Xanthohumol C in free and complexed form did not significantly differ, suggesting the release of Xanthohumol C from 2-hydroxypropyl-β-cyclodextrin. Finally, a small-scaled in vivo experiment in a rat model showed that after i. p. administration of the complex, Xanthohumol C can be detected in serum, the brain, and the cerebrospinal fluid at 1 and 6 h post-administration. Mean (± SD) Xanthohumol C serum concentrations after 1, 6, and 12 h were determined as 463.5 (± 120.9), 61.9 (± 13.4), and 9.3 (± 0.8) ng/mL upon i. v., and 294.3 (± 22.4), 45.5 (± 0.7), and 13 (± 1.0) ng/mL after i. p. application, respectively. Accordingly, the formulation of Xanthohumol C/2-hydroxypropyl-β-cyclodextrin is suitable for further in vivo experiments and further pharmaceutical research aiming for the determination of its neuroregenerative potential in animal disease models.

Fenofibrate Solid Dispersion for Improving Oral Bioavailability: Preparation, and Characterization and in vivo Evaluation

2020 ◽  
Vol 13 (5) ◽  
pp. 5102-5109
Author(s):  
Venu Madhav K ◽  
Somnath De ◽  
Chandra Shekar Bonagiri ◽  
Sridhar Babu Gummadi
Keyword(s):  
Oral Bioavailability ◽  
Oral Delivery ◽  
Solid Dispersions ◽  
In Vitro Release ◽  
Aqueous Solubility ◽  
Water Soluble ◽  
Scanning Calorimetry ◽  
In Vivo Evaluation

Fenofibrate (FN) is used in the treatment of hypercholesterolemia. It shows poor dissolution and poor oral bioavailability after oral administration due to high liphophilicity and low aqueous solubility. Hence, solid dispersions (SDs) of FN (FN-SDs) were develop that might enhance the dissolution and subsequently oral bioavailability. FN-SDs were prepared by solvent casting method using different carriers (PEG 4000, PEG 6000, β cyclodextrin and HP β cyclodextrin) in different proportions (0.25%, 0.5%, 0.75% and 1% w/v). FN-SDs were evaluated solubility, assay and in vitro release studies for the optimization of SD formulation. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) analysis was performed for crystalline and morphology analysis, respectively. Further, optimized FN-SD formulation evaluated for pharmacokinetic performance in Wistar rats, in vivo in comparison with FN suspension.  From the results, FN-SD3 and FN-SD6 have showed 102.9 ±1.3% and 105.5±3.1% drug release, respectively in 2 h. DSC and PXRD studies revealed that conversion of crystalline to amorphous nature of FN from FT-SD formulation. SEM studies revealed the change in the orientation of FN when incorporated in SDs. The oral bioavailability FN-SD3 and FN-SD6 formulations exhibited 2.5-folds and 3.1-folds improvement when compared to FN suspension as control. Overall, SD of FN could be considered as an alternative dosage form for the enhancement of oral delivery of poorly water-soluble FN.

scholarly journals Activity of Indenoisoquinolines against African Trypanosomes

2008 ◽  
Vol 53 (1) ◽  
pp. 123-128 ◽  
Author(s):  
Rahul P. Bakshi ◽  
Dongpei Sang ◽  
Andrew Morrell ◽  
Mark Cushman ◽  
Theresa A. Shapiro
Keyword(s):  
Anticancer Agents ◽  
Mammalian Cells ◽  
Sleeping Sickness ◽  
Water Soluble ◽  
African Trypanosomes ◽  
In Vivo Experiments ◽  
Topoisomerase Ib ◽  
Topoisomerase Poisons

ABSTRACT African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill T. brucei. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.

Formulation and Evaluation of Benidipine Nanosuspension

2021 ◽  
pp. 4111-4116
Author(s):  
Sejal Patel ◽  
Anita P. Patel
Keyword(s):  
Particle Size ◽  
Water Solubility ◽  
Polymer Concentration ◽  
Oral Route ◽  
Water Soluble ◽  
In Vitro Dissolution ◽  
Scanning Calorimetry ◽  
23 Factorial Design ◽  
Selection Of

In the interest of administration of dosage form oral route is most desirable and preferred method. After oral administration to get maximum therapeutic effect, major challenge is their water solubility. Water insoluble drug indicate insufficient bioavailability as well dissolution resulting in fluctuating plasma level. Benidipine (BND) is poorly water soluble antihypertensive drug has lower bioavailability. To improve bioavailability of Benidipine HCL, BND nanosuspension was formulated using media milling technique. HPMC E5 was used to stabilize nanosuspension. The effect of different important process parameters e.g. selection of polymer concentration X1(1.25 mg), stirring time X2 (800 rpm), selection of zirconium beads size X3 (0.4mm) were investigated by 23 factorial design to accomplish desired particle size and saturation solubility. The optimized batch had 408 nm particle size Y1, and showed in-vitro dissolution Y2 95±0.26 % in 30 mins and Zeta potential was -19.6. Differential scanning calorimetry (DSC) and FT-IR analysis was done to confirm there was no interaction between drug and polymer.

scholarly journals Considerable Improvement of Ursolic Acid Water Solubility by Its Encapsulation in Dendrimer Nanoparticles: Design, Synthesis and Physicochemical Characterization

Nanomaterials ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2196 ◽  
Author(s):  
Silvana Alfei ◽  
Anna Maria Schito ◽  
Guendalina Zuccari
Keyword(s):  
Ursolic Acid ◽  
Water Solubility ◽  
Drug Loading ◽  
Physicochemical Characterization ◽  
Systemic Toxicity ◽  
Water Soluble ◽  
Design Synthesis ◽  
Pentacyclic Triterpenoid

Ursolic acid (UA) is a pentacyclic triterpenoid found in many medicinal plants and aromas endowed with numerous in vitro pharmacological activities, including antibacterial effects. Unfortunately, UA is poorly administered in vivo, due to its water insolubility, low bioavailability, and residual systemic toxicity, thus making urgent the development of water-soluble UA formulations. Dendrimers are nonpareil macromolecules possessing highly controlled size, shape, and architecture. In dendrimers with cationic surface, the contemporary presence of inner cavities and of hydrophilic peripheral functions, allows to encapsulate hydrophobic non-water-soluble drugs as UA, to enhance their water-solubility and stability, and to promote their protracted release, thus decreasing their systemic toxicity. In this paper, aiming at developing a new UA-based antibacterial agent administrable in vivo, we reported the physical entrapment of UA in a biodegradable not cytotoxic cationic dendrimer (G4K). UA-loaded dendrimer nanoparticles (UA-G4K) were obtained, which showed a drug loading (DL%) much higher than those previously reported, a protracted release profile governed by diffusion mechanisms, and no cytotoxicity. Also, UA-G4K was characterized by principal components analysis (PCA)-processed FTIR spectroscopy, by NMR and elemental analyses, and by dynamic light scattering experiments (DLS). The water solubility of UA-G4K was found to be 1868-fold times higher than that of pristine UA, thus making its clinical application feasible.

scholarly journals Formulation Development of Mucoadhesive Microparticle-Laden Gels for Oral Mucositis: An In Vitro and In Vivo Study

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 603
Author(s):  
Hiroomi Sakurai ◽  
Yuri Ikeuchi-Takahashi ◽  
Ayaka Kobayashi ◽  
Nobuyoshi Yoshimura ◽  
Chizuko Ishihara ◽  
...  
Keyword(s):  
Oral Mucosa ◽  
Oral Mucositis ◽  
Formulation Development ◽  
Scanning Calorimetry ◽  
In Vivo Experiments ◽  
Drug Retention ◽  
Drug Concentrations ◽  
Diffraction Patterns

In order to relieve pain due to oral mucositis, we attempted to develop mucoadhesive microparticles containing indomethacin (IM) and gel preparations with IM microparticles that can be applied to the oral cavity. The mucoadhesive microparticles were prepared with a simple composition consisting of IM and polyvinyl alcohol (PVA). Two kinds of PVA with different block properties were used, and microparticles were prepared by heating-filtration and mixing-drying. From the X-ray powder diffraction patterns, differential scanning calorimetry thermograms, and morphological features of the IM microparticles, IM should exist as polymorphic forms in the microparticles. Rapid drug release properties were observed in the IM microparticles. Increased drug retention was observed in IM microparticles containing PVA, and the IM-NK(50) gel, using a common block character PVA and heating-filtration, showed good long-term drug retention properties. In vivo experiments showing significantly higher drug concentrations in the oral mucosa were observed with IM microparticles prepared by heating-filtration, and the IM-NK(50) gel maintained significantly higher drug concentrations in the oral mucosa. From these results, the IM-NK(50) gel may be useful as a preparation for relieving oral mucositis pain.

Exploration on the adsorption mechanism of aminopyrimidines and quinazoline compounds on graphene oxide: Hydrophobicity and structure-controlled release process

2019 ◽  
Vol 9 (5) ◽  
pp. 419-428
Author(s):  
Li Li ◽  
Chunjiao Pan ◽  
Zhongqiu Guo ◽  
Bingmi Liu ◽  
Hao Pan ◽  
...  
Keyword(s):  
Graphene Oxide ◽  
Computer Simulations ◽  
Water Solubility ◽  
High Water ◽  
Water Soluble ◽  
Release Process ◽  
Adsorption Mechanisms ◽  
Mechanical Stirring

In this study, graphene oxide was synthesized using the Hummers method, and stable and homogeneous graphene oxide aqueous solutions were obtained through mechanical stirring and ultrasonic stripping. In conjunction with our previous studies, graphene oxide-loaded insoluble compound delivery systems were prepared to verify the in vivo release profiles of the graphene oxide delivery system. Several insoluble compounds including imatinib, nilotinib, erlotinib, gefitinib, and afatinib were selected for loading and in vitro graphene oxide release assays to study the non-covalent adsorption mechanisms. Computer simulations were employed for validation processes. For in vivo release assays, the T1/2 values of the poorly water soluble groups were 1.104 ± 0.18 h and the Cmax was 2.600 ± 2.06 mg/L. In previous assays, compounds with high water solubility supported by graphene oxide were released and detected in vivo. The solubility of the compound and its binding force with the carrier played a crucial role in release. The results of graphene oxide loading experiments showed that the maximum loading and entrapment efficiencies of the insoluble model compounds with similar aromatic rings were comparable. Under basic conditions, the in vitro release rates and maximum release levels of amino pyrimidine were elevated. In contrast, quinazoline release declined. Combined with computer simulations, π–π stacking was identified as the dominant mechanism for adsorption onto graphene oxide. Both hydrogen bonding and cation-π bonds played an auxiliary reinforcing role, and the two were regarded as antagonistic.

scholarly journals Improved water solubility of quercetin by preparing complexation with cyclodextrins in binary solvent

2021 ◽  
Vol 18 (4) ◽  
pp. 701-708
Author(s):  
Pham Thi Lan ◽  
Pham Long Khanh ◽  
Nguyen Thi Ngoan ◽  
Le Hai Khoa ◽  
Vu Xuan Minh ◽  
...  
Keyword(s):  
Water Solubility ◽  
Biological Effects ◽  
Pure Water ◽  
Phase Solubility ◽  
Binary Solvent ◽  
Complexation Reaction ◽  
Cyclodextrin Complex ◽  
Pharmaceutical Industries

The antioxidant capacity of polyphenols have been widely used in food and pharmaceutical industries. Quercetin (Quer) is a polyphenolic flavonoid that shows several biological effects such as antioxidant, antitumor, antibacterial and antiproliferative effects both in-vitro and in-vivo. However, the solubility of quercetin in water is poor. Thus, it is essential to improve solubility of quercetin in pharmaceuticals by making its complexation with other compounds. In this study, the synthesis of the 2-hydroxypropyl-β-cyclodextrin complex with quercetin (Quer-HPβCD) in the form of nanoparticles in water-ethanol solvents has been carried out. The results showed that the obtained yield of (Quer-HPβCD) complexation in binary solvent was greater than that in pure water. The highest Y value was 80% in a binary solvent with 20% v/v of ethanol. The composition, morphology, structural and thermodynamic properties of the nanoparticles Quer-HPβCD have been determined. This study demonstrated that using mixed water- ethanol solvent and lyophilization technique was able to produce quercetin nanoparticles with significantly smaller particle size. The nanoparticles have a spherical shape with an average size of about 40-60 nm. The results of the phase solubility diagram showed that in water the solubility of quercetin increased and linearly depended on the concentration of host’s molecule while Quer and HP-βCD obtained a 1:1 stoichiometric complex. The stability constant of (Quer-HPβCD) complex was found to be logK = 2.56. The Gibbs energy change of the complexation reaction was found to be -14.60 kJ/mol.

scholarly journals Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2560 ◽  
Author(s):  
Gökçe Şeker Karatoprak ◽  
Esra Küpeli Akkol ◽  
Yasin Genç ◽  
Hilal Bardakcı ◽  
Çiğdem Yücel ◽  
...  
Keyword(s):  
South African ◽  
Water Solubility ◽  
The Body ◽  
Water Soluble ◽  
In Vivo Studies ◽  
Lead Compounds ◽  
Combretastatin A4 ◽  
Potential Applications

Combretastatins are a class of closely related stilbenes (combretastatins A), dihydrostilbenes (combretastatins B), phenanthrenes (combretastatins C) and macrocyclic lactones (combretastatins D) found in the bark of Combretum caffrum (Eckl. & Zeyh.) Kuntze, commonly known as the South African bush willow. Some of the compounds in this series have been shown to be among the most potent antitubulin agents known. Due to their structural simplicity many analogs have also been synthesized. Combretastatin A4 phosphate is the most frequently tested compounds in preclinical and clinical trials. It is a water-soluble prodrug that the body can rapidly metabolize to combretastatin A4, which exhibits anti-tumor properties. In addition, in vitro and in vivo studies on combretastatins have determined that these compounds also have antioxidant, anti-inflammatory and antimicrobial effects. Nano-based formulations of natural or synthetic active agents such as combretastatin A4 phosphate exhibit several clear advantages, including improved low water solubility, prolonged circulation, drug targeting properties, enhanced efficiency, as well as fewer side effects. In this review, a synopsis of the recent literature exploring the combretastatins, their potential effects and nanoformulations as lead compounds in clinical applications is provided.

scholarly journals Efficacious Treatment of Experimental Leishmaniasis with Amphotericin B-Arabinogalactan Water-Soluble Derivatives

1999 ◽  
Vol 43 (9) ◽  
pp. 2209-2214 ◽  
Author(s):  
Jacob Golenser ◽  
Shoshana Frankenburg ◽  
Tirtsa Ehrenfreund ◽  
Abraham J. Domb
Keyword(s):  
Amphotericin B ◽  
Leishmania Major ◽  
Water Soluble ◽  
In Vivo Experiments ◽  
Drug Concentrations ◽  
Efficacious Treatment ◽  
Lipid Formulations ◽  
Established Infection

ABSTRACT In this study, we tested the efficacy of amphotericin B (AmB)-arabinogalactan (AmB-AG) conjugates for the treatment of experimental leishmaniasis. Chemical conjugation of AmB to a water-soluble, biodegradable, and biocompatible polymer could present many advantages over presently available AmB formulations. Two conjugates were tested, a reduced (rAmB-AG) form and an unreduced (uAmB-AG) form. In vitro, the drug concentrations which lower the values of parasites (for promastigotes) or infected macrophages (for amastigotes) to 50% of the untreated values (ED50s) of uAmB-AG and rAmB-AG were 0.19 and 0.34 μg/ml, respectively, forLeishmania major promastigotes and 0.17 and 0.31 μg/ml, respectively, for amastigotes. The effect on Leishmania infantum-infected macrophages was more marked, with ED50s of 0.035 μg/ml for rAmB-AG and 0.027 μg/ml for uAmB-AG. In in vivo experiments, BALB/c mice injected with L. major were treated from day 2 onwards on alternate days for 2 weeks. Both conjugates, as well as liposomal AmB (all at 6 mg/kg of body weight) and Fungizone (1 mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugates, but not liposomal AmB, were significantly more effective than Fungizone. Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. When an established infection was treated, uAmB-AG was somewhat more effective than liposomal AmB. In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial infections. The conjugates, which are stable and can be produced relatively cheaply (compared to lipid formulations), can be used in the future for the treatment of leishmaniasis infections.

scholarly journals Synthesis of New Water Soluble β-Cyclodextrin@Curcumin Conjugates and In Vitro Safety Evaluation in Primary Cultures of Rat Cortical Neurons

2021 ◽  
Vol 22 (6) ◽  
pp. 3255
Author(s):  
Amina Ben Mihoub ◽  
Samir Acherar ◽  
Céline Frochot ◽  
Catherine Malaplate ◽  
Frances T. Yen ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Cortical Neurons ◽  
Water Solubility ◽  
Photophysical Properties ◽  
Primary Cultures ◽  
Average Diameter ◽  
Water Soluble ◽  
Cell Toxicity

Self-aggregation of Curcumin (Cur) in aqueous biological environment decreases its bioavailability and in vivo therapeutic efficacy, which hampers its clinical use as candidate for reducing risk of neurodegenerative diseases. Here, we focused on the design of new Cur- β-Cyclodextrin nanoconjugates to improve the solubility and reduce cell toxicity of Cur. In this study, we described the synthesis, structural characterization, photophysical properties and neuron cell toxicity of two new water soluble β-CD/Cur nanoconjugates as new strategy for reducing risks of neurodegenerative diseases. Cur was coupled to one or two β-CD molecules via triazole rings using CuAAC click chemistry strategy to yield β-CD@Cur and (β-CD)2@Cur nanoconjugates, respectively. The synthesized nanoconjugates were found to be able to self-assemble in aqueous condition and form nano-aggregates of an average diameter size of around 35 and 120 nm for β-CD@Cur and (β-CD)2@Cur, respectively. The photophysical properties, water solubility and cell toxicity on rat embryonic cortical neurons of the designed nanoconjugates were investigated and compared to that of Cur alone. The findings revealed that both new nanoconjugates displayed better water solubility and in vitro biocompatibility than Cur alone, thus making it possible to envisage their use as future nano-systems for the prevention or risk reduction of neurodegenerative diseases.

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