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1.
J Pharm Biomed Anal ; 207: 114420, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34662781

RESUMO

Retention behavior of two structural isomeric pentacyclic triterpenic acids, maslinic acid and corosolic acid, was investigated by reverse phase high performance liquid chromatography (HPLC) with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) as mobile phase additive. Inclusion complexation of maslinic acid, corosolic acid with hydroxypropyl-ß-cyclodextrin was evaluated under different concentration of hydroxypropyl-ß-cyclodextrin. Apparent formation constant (Km) between methanol and hydroxypropyl-ß-cyclodextrin was determined to be 13.82 L mol-1 under 25 °C using UV-spectrophotometry. Two retention models were employed individually for evaluation of inclusion complexation between the two pentacyclic triterpenic acids and hydroxypropyl-ß-cyclodextrin. It was found that a higher apparent formation constant (Kf) for corosolic acid and hydroxypropyl-ß-cyclodextrin was obtained, 19115 L mol-1, indicating that a greater affinity of hydroxypropyl-ß-cyclodextrin with corosolic acid was produced compared with that of maslinic acid, 11775 L mol-1, in the selected mobile phase, and stoichiometric ratio for both of inclusion complex was found to be 1:1. Thermodynamic analysis showed that a negative standard enthalpy change (ΔH) and an entropy change (ΔS*) for analyte transfer were obtained, where ΔH of maslinic acid and corosolic acid was found to be -10.188 kJ mol-1 and -10.650 kJ mol-1, ΔS* of two compounds was -2.092 and -2.180, respectively, indicating that transfer of structural isomers from mobile phase to stationary phase was enthalpically driven. Meanwhile, positive values were obtained for standard enthalpy change and standard entropy change, 136 kJ mol-1 and 274 kJ mol-1 and 536 J mol-1 K-1and 1004 J mol-1 K-1, for inclusion complexation between maslinic acid, corosolic acid and hydroxypropyl-ß-cyclodextrin, while negative values were obtained for Gibbs free energy during formation of inclusion complex, -160 kJ mol-1 and -299 kJ mol-1, indicating a spontaneous inclusion reaction happened.


Assuntos
beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Cromatografia Líquida , Cromatografia de Fase Reversa , Triterpenos Pentacíclicos , Termodinâmica
2.
Food Chem ; 375: 131874, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34942499

RESUMO

This study aimed to evaluate the effect of inclusion complexes (ICs) on the oxidative stability of myofibrillar proteins (MPs) and microstructures in lamb during frozen storage. The inclusion process between apple polyphenols (APs) and hydroxypropyl-ß-cyclodextrin (HP-ß-CD) was verified using Fourier transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy, and the antioxidant activity of APs. Results showed that the sensitivity of MPs to oxidation improved after 40 weeks. The ICs (0.2-1.6 mg/mL) significantly reduced the carbonyl content, particle size aggregation, protein degradation, fluorescence quenching effect, and decreased the α-helix contents loss of MPs. Additionally, the changes in protein oxidation showed a correlation with the microstructure of muscles, and the addition of 1.6 mg/mL IC remarkably improved the structure of muscle tissues while that of 3.2 mg/mL IC was detrimental to the structural properties. Overall, the exertion of antioxidant activity significantly influenced the cryoprotective effect of ICs on frozen lamb meat.


Assuntos
Polifenóis , Carne Vermelha , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Antioxidantes , Oxirredução , Ovinos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier
3.
AAPS PharmSciTech ; 22(7): 232, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34468866

RESUMO

Cyclodextrin (CD) complexes are frequently used for enhancing the solubility or absorption of poorly water-soluble drugs. On the contrary, little is known about their complex formation with water-soluble drugs. Here, we have studied the interaction between 2-hydroxypropyl ß-CD (HPßCD) and three water-soluble drugs, namely naloxone (NX), oxycodone (OC), and tramadol (TR), by isothermal titration calorimetry (ITC) combined with molecular modeling in view of the potential impact on drug release. The results showed that the complex formation of HPßCD with all three drugs occurs spontaneously. The complexes formed with NX and OC were found to be 2NX:1HPßCD and 3OC:2HPßCD, respectively. TR was found to form 2 complexes with HPßCD; of 1:2 and 1:1 complexation ratios. The binding of HPßCD to NX was greater than to OC due to the higher hydrophobicity of the structure of the former. Moreover, the binding affinity of HPßCD to TR was higher than to OC, which indicated the effect of the higher flexibility of the guest in increasing the binding affinity. In vitro drug release experiments from the various complexes revealed a significant impact of the stoichiometry of the complex on the release profiles. Accordingly, the co-administration of cyclodextrins with water-soluble drugs should be closely monitored, as it may result in unintentional complex formation that can potentially impact the drugs' gastrointestinal absorption.


Assuntos
Ciclodextrinas , Preparações Farmacêuticas , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Calorimetria , Solubilidade , Água
4.
Int J Pharm ; 607: 121016, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34411652

RESUMO

Quercetin, a flavonoid with possible neuroprotective action has been recently suggested for the early-stage treatment of Alzheimer's disease. The low solubility and extended first pass effect render quercetin unsuitable for oral administration. Alternatively, brain targeting is more feasible with nasal delivery, by-passing, non-invasively, Blood-Brain Barrier and ensuring rapid onset of action. Aiming to increase quercetin's disposition into brain, nasal powders consisting of quercetin-cyclodextrins (methyl-ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin) lyophilizates blended with spray-dried microparticles of mannitol/lecithin were prepared. Quercetin's solubility at 37 °C and pH 7.4 was increased 19-35 times when complexed with cyclodextrins. Blending lyophilizates in various ratios with mannitol/lecithin microparticles, results in powders with improved morphological characteristics as observed by X-ray Diffraction and Scanning Electron Microscopy analysis. In vitro characterization of these powders using Franz cells, revealed rapid dissolution and permeation 17 (methyl-ß-cyclodextrin) to 48 (hydroxypropyl-ß-cyclodextrin) times higher than that of pure quercetin. Ex vivo powders' transport across rabbit nasal mucosa was found more efficient in comparison with the pure Que. The overall better performance of quercetin-hydroxypropyl-ß-cyclodextrin powders is confirmed by ex vivo experiments revealing amount of quercetin permeated ranging from 0.03 ± 0.01 to 0.22 ± 0.05 µg/cm2 for hydroxypropyl-ß-cyclodextrin and 0.022 ± 0.01 to 0.17 ± 0.04 µg/cm2 for methyl-ß-cyclodextrin powders, while the permeation of pure quercetin was negligible.


Assuntos
Ciclodextrinas , Lecitinas , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Encéfalo , Varredura Diferencial de Calorimetria , Manitol , Mucosa Nasal , Pós , Quercetina , Coelhos , Solubilidade , Difração de Raios X
5.
J Pharm Sci ; 110(11): 3623-3630, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34364701

RESUMO

The purpose of this study is to find that a small amount of 2-Hydroxypropyl-ß-cyclodextrin (HP-ß-CD) can produce a parachute effect on indomethacin (INM). From the examination of dissolution curves and concentration after several days, the supersaturation of INM was observed for the mixtures containing HP-ß-CD at a molar ratio ≤ 0.5, and the sustained deployment of supersaturation was found not only in equimolar mixtures but also in mixtures with a shortage of HP-ß-CD. In the solid state, it was compared the physical properties of INM/HP-ß-CD mixtures using two different mixing methods and determined the stoichiometry of INM and HP-ß-CD. Differential scanning calorimetry (DSC) revealed that the polymorphs of INM were converted by HP-ß-CD into an amorphous state. Furthermore, X-ray powder diffraction (XRPD) and DSC-XRPD demonstrated that INM crystals from the INM/HP-ß-CD mixture prepared from an EtOH solution were metastable. In conclusion, these phenomena may be considered the "spring" and "parachute" effects of mixtures with a shortage of HP-ß-CD, as they depended on the presence of the metastable α-form of INM. The addition of 1/3 to 1/20 equivalents of HP-ß-CD to INM enhanced INM solubility.


Assuntos
Indometacina , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Varredura Diferencial de Calorimetria , Solubilidade
6.
J Food Sci ; 86(8): 3589-3597, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34268741

RESUMO

Flavors play crucial role in food industry. Ethyl acetate, as probably one of the most used of all flavor chemicals by volume, is used widely in many industries. However, ethyl acetate is not too stable and can be slowly decomposed by moisture. Furthermore, ethyl acetate is a volatile liquid insoluble in water and it does not last long enough. In order to solve these problems, hydroxypropyl-ß-cyclodextrin was used as wall material to encapsulate ethyl acetate in this work. The product was characterized by Fourier transform infrared (FTIR) spectroscopy and thermalgravimetric analysis (TGA). The results showed that the peaks at 1,744 and 1,056 cm-1 in the FTIR spectrum of ethyl acetate disappeared in the FTIR spectrum of ethyl acetate-hydroxypropyl-ß-cyclodextrin inclusion complex. After the encapsulation of ethyl acetate, the O-H and C-H stretching absorption of hydroxypropyl-ß-cyclodextrin changed. The TGA results showed that from 77°C to 292°C ethyl acetate is released from the ethyl acetate-hydroxypropyl-ß-cyclodextrin inclusion complex in temperatures far beyond ethyl acetate 77°C boiling point. This phenomenon confirmed that the lastingness and thermal stability of ethyl acetate can be improved by the formation of an inclusion complex. The loading capacity of ethyl acetate was 4.86 ± 0.08% and ethyl acetate:hydroxypropyl-ß-cyclodextrin stoichiometry is close to 1:1. The interaction of ethyl acetate and hydroxypropyl-ß-cyclodextrin was investigated using molecular mechanics calculation. The binding energy was calculated and the possible conformation of ethyl acetate-hydroxypropyl-ß-cyclodextrin inclusion complex was optimized to the minimum energy. The binding energy minimum is at the 0.44 × 10-10  m point and its value is -103.9 kJ/mol. PRACTICAL APPLICATION: Encapsulation of ethyl acetate in hydroxypropyl-ß-cyclodextrin is a possible way to protect ethyl acetate, improve its stability, water solubility, and may also enhance its lastingness.


Assuntos
Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Acetatos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier
7.
J Phys Chem B ; 125(27): 7397-7405, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34210121

RESUMO

Cyclodextrins are cyclic oligosaccharides, widely used as drug carriers, solubilizers, and excipients. Among cyclodextrins, the functionalized derivative known as hydroxypropyl-ß-cyclodextrin (HPßCD) offers several advantages due to its unique structural features. Its optimal use in pharmaceutical and medical applications would benefit from a molecular-level understanding of its behavior, as can be offered by molecular dynamics simulations. Here, we propose a set of parameters for all-atom simulations of HPßCD, based on the ADD force field for sugars developed in our group, and compare it to the original CHARMM36 description. Using Kirkwood-Buff integrals of binary HPßCD-water mixtures as target experimental data, we show that the ADD-based description results in a considerably improved prediction of HPßCD self-association and interaction with water. We then use the new set of parameters to characterize the behavior of HPßCD toward the different amino acids. We observe pronounced interactions of HPßCD with both polar and nonpolar moieties, with a special preference for the aromatic rings of tyrosine, phenylalanine, and tryptophan. Interestingly, our simulations further highlight a preferential orientation of HPßCD's hydrophobic cavity toward the backbone atoms of amino acids, which, coupled with a favorable interaction of HPßCD with the peptide backbone, suggest a propensity for HPßCD to denature proteins.


Assuntos
Ciclodextrinas , Proteínas , 2-Hidroxipropil-beta-Ciclodextrina , Excipientes , Interações Hidrofóbicas e Hidrofílicas , Solubilidade
8.
Int J Pharm ; 605: 120799, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34126176

RESUMO

This research aimed to overcome the current challenges in the application of natural carotenoid antioxidants, such as their complex preparation processes, low bioavailability and poor drug stability. Herein, a mechanochemical method was used to prepare an inclusion complex (IC) that self-assembles into micelles in aqueous solution and achieves solid-phase loading of astaxanthin (AST). The NMR analysis, thermodynamics study, particle size analysis and electron microscopy image results showed that AST, hydroxypropyl ß-cyclodextrin (HPß-CD) and glyceryl monostearate (GMS) formed self-assembled micelles and maintained good stability in aqueous solution. The antioxidant performance experiments showed that the formation of IC increases free radical scavenging activity. The pharmacokinetic studies showed that the bioavailability of the astaxanthin inclusion complex increased 4-fold. The tissue distribution experiments showed that the astaxanthin inclusion complex targets the liver to exert its antioxidant effects. The proposed method uses an innovative preparation technology to produce an efficient drug delivery system without solvents, and it exerts powerful antioxidant activity against astaxanthin.


Assuntos
Antioxidantes , Micelas , 2-Hidroxipropil-beta-Ciclodextrina , Glicerídeos , Solubilidade , Xantofilas
9.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063471

RESUMO

The formation of cefuroxime axetil+cyclodextrin (CA+CD) complexes increases the aqueous solubility of CA, improves its physico-chemical properties, and facilitates a biomembrane-mediated drug delivery process. In CD-based tablet formulations, it is crucial to investigate the molecular details of complexes in final pharmaceutical preparation. In this study, Raman spectroscopy and mapping were applied for the detection and identification of chemical groups involved in α-, ß-, γ-, and 2-hydroxypropyl-ß-CD (2-HP- ß-CD)+CA complexation process. The experimental studies have been complemented by molecular dynamics-based investigations, providing additional molecular details of CA+CD interactions. It has been demonstrated that CA forms the guest-host type inclusion complexes with all studied CDs; however, the nature of the interactions is slightly different. It seems that both α- and ß-CD interact with furanyl and methoxy moieties of CA, γ-CD forms a more diverse pattern of interactions with CA, which are not observed in other CDs, whereas 2HP-ß-CD binds CA with the contribution of hydrogen bonding. Apart from supporting this interpretation of the experimental data, molecular dynamics simulations allowed for ordering the CA+CD binding affinities. The obtained results proved that the molecular details of the host-guest complexation can be successfully predicted from the combination of Raman spectroscopy and molecular modeling.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina , Cefuroxima/análogos & derivados , Ciclodextrinas/química , Análise Espectral Raman , 2-Hidroxipropil-beta-Ciclodextrina/química , Cefuroxima/química , Ligação de Hidrogênio , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Vibração
10.
Food Chem ; 363: 130327, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34144424

RESUMO

In this study, the inclusion complex (IC) of thymol with 2-hydroxypropyl-ß-cyclodextrin (HPßCD) was fast synthetized by ultrasonic technology and its antifungal activities were evaluated. The thymol/HPßCD-IC was characterized by UV-vis absorption spectroscopy, fluorescence emission spectroscopy, powder X-ray diffraction, FT-IR, 1H-NMR, TGA and DSC. The phase solubility studies proved that the aqueous solubility of thymol was significantly improved by forming the inclusion complex with HPßCD, and the thermal stability analysis showed that thymol/HPßCD-IC had a better thermal stability than pure thymol. The in vitro antifungal activities of thymol/HPßCD-IC against Botrytis cinerea, Penicillium digitatum and Alternaria alternata were significantly improved compared with pure thymol. Furthermore, the gray mold rot of tomatoes was evidently inhibited by thymol/HPßCD-IC treatment in vivo study. Therefore, the complexation with HPßCD assisted by ultrasound is a promising approach to solubilize and stabilize thymol for application as an antifungal agent in fruit preservation.


Assuntos
Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Alternaria , Botrytis , Varredura Diferencial de Calorimetria , Frutas , Penicillium , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Timol , Difração de Raios X
11.
Microb Cell Fact ; 20(1): 119, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162386

RESUMO

BACKGROUND: 3-Ketosteroid Δ1-dehydrogenases (KSTDs) are the enzymes involved in microbial cholesterol degradation and modification of steroids. They catalyze dehydrogenation between C1 and C2 atoms in ring A of the polycyclic structure of 3-ketosteroids. KSTDs substrate spectrum is broad, even though most of them prefer steroids with small substituents at the C17 atom. The investigation of the KSTD's substrate specificity is hindered by the poor solubility of the hydrophobic steroids in aqueous solutions. In this paper, we used 2-hydroxpropyl-ß-cyclodextrin (HBC) as a solubilizing agent in a study of the KSTDs steady-state kinetics and demonstrated that substrate bioavailability has a pivotal impact on enzyme specificity. RESULTS: Molecular dynamics simulations on KSTD1 from Rhodococcus erythropolis indicated no difference in ΔGbind between the native substrate, androst-4-en-3,17-dione (AD; - 8.02 kcal/mol), and more complex steroids such as cholest-4-en-3-one (- 8.40 kcal/mol) or diosgenone (- 6.17 kcal/mol). No structural obstacle for binding of the extended substrates was also observed. Following this observation, our kinetic studies conducted in the presence of HBC confirmed KSTD1 activity towards both types of steroids. We have compared the substrate specificity of KSTD1 to the other enzyme known for its activity with cholest-4-en-3-one, KSTD from Sterolibacterium denitrificans (AcmB). The addition of solubilizing agent caused AcmB to exhibit a higher affinity to cholest-4-en-3-one (Ping-Pong bi bi KmA = 23.7 µM) than to AD (KmA = 529.2 µM), a supposedly native substrate of the enzyme. Moreover, we have isolated AcmB isoenzyme (AcmB2) and showed that conversion of AD and cholest-4-en-3-one proceeds at a similar rate. We demonstrated also that the apparent specificity constant of AcmB for cholest-4-en-3-one (kcat/KmA = 9.25∙106 M-1 s-1) is almost 20 times higher than measured for KSTD1 (kcat/KmA = 4.71∙105 M-1 s-1). CONCLUSIONS: We confirmed the existence of AcmB preference for a substrate with an undegraded isooctyl chain. However, we showed that KSTD1 which was reported to be inactive with such substrates can catalyze the reaction if the solubility problem is addressed.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/metabolismo , Betaproteobacteria/enzimologia , Betaproteobacteria/metabolismo , Colestenonas/metabolismo , Oxirredutases/metabolismo , Rhodococcus/enzimologia , Rhodococcus/metabolismo , Proteínas de Bactérias/metabolismo , Betaproteobacteria/genética , Catálise , Clonagem Molecular , DNA Bacteriano , Isoenzimas/metabolismo , Cetosteroides/metabolismo , Cinética , Simulação de Dinâmica Molecular , Proteínas Recombinantes/metabolismo , Rhodococcus/genética , Compostos de Espiro/metabolismo , Esteroides/metabolismo , Especificidade por Substrato , Triterpenos/metabolismo
12.
Sci Total Environ ; 773: 145293, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33940723

RESUMO

Dimethyl disulfide (DMDS), a soil fumigant, is an effective, broad-spectrum compound that often replaces bromomethane (MB) in the prevention and treatment of soil-borne diseases. However, the disadvantages of DMDS include toxicity, volatility, pungent odor, risk of human exposure, and environmental pollution. Cyclodextrin (CD) has been widely used as a carrier of chemicals in many industries due to its functional advantages and safety. In this study, a DMDS-controlled release formulation was developed by encapsulating DMDS in the cavity of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD). This formulation reduced DMDS usage and production costs. Orthogonal experimental design, Fourier transform infrared (FT-IR), Scanning electron microscopy (SEM), Thermal gravity analysis (TGA) characterization, efficacy comparison, safety, and other aspects of the evaluation showed that under the best preparation conditions, the encapsulation rate was 81.49%. The efficacy of DMDS@HP-ß-CD was similar to unformulated DMDS. The efficacy duration of the formulation was about two times longer than DMDS, and it was safer to use. This study reveals a cyclodextrin-DMDS formulation with reduced toxicity, longer duration, environmental safety and sustainability.


Assuntos
Dissulfetos , 2-Hidroxipropil-beta-Ciclodextrina , Preparações de Ação Retardada , Humanos , Espectroscopia de Infravermelho com Transformada de Fourier
13.
Colloids Surf B Biointerfaces ; 204: 111784, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33984617

RESUMO

In this work, the effects of simvastatin (SIM), (2-hydroxypropyl)-ß-cyclodextrin (HPßCD) and their complex (SIM:HPßCD) on the structure and properties of lipid membranes were investigated for the first time by Langmuir technique combined with PM-IRRAS spectroscopy. An improved understanding of the differences of the interactions between free SIM, and SIM in the form of an inclusion complex with HPßCD with the lipid membrane will improve the development of preparation methods for in vivo applications. Monolayers of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), cholesterol (Chol) and their mixture DMPC:Chol (7:3) served as simple models of one leaflet of the cell membrane. The penetration of well-organized lipid layers by simvastatin lead to their fluidization but the extent of this unwanted effect was smaller when the drug was delivered in the form of the SIM:HPßCD complex. Surface pressure vs. time dependencies showed that the drug encapsulated with cyclodextrin dissociated from the complex upon contact with the lipid layer and the weak interactions between the exterior polar part of the HPßCD and the polar headgroups of the lipid layer facilitated smooth incorporation of the released lipophilic drug into the membrane. At a longer time-scale, the HPßCD ligand released from the complex removed some cholesterol, but not DMPC, from the lipid layer, hence, similarly to the enzyme inhibiting action of statins - it lead to the decrease of the amount of cholesterol in the membrane. Delivery of simvastatin in the form of an inclusion complex with HPßCD is proposed as an approach improving its bioavailability in the cholesterol-lowering therapies.


Assuntos
Ciclodextrinas , Inibidores de Hidroximetilglutaril-CoA Redutases , 2-Hidroxipropil-beta-Ciclodextrina , Colesterol , Interações Hidrofóbicas e Hidrofílicas , Sinvastatina
14.
Int J Pharm ; 603: 120728, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34029665

RESUMO

Budesonide (BUD) is used as first choice therapy for the treatment of allergic rhinitis, a chronic allergic-immune condition with an increased incidence in the pediatric population. The main problem of BUD nasal formulations is related to its poor aqueous solubility (S0 = 5.03·10-5 M), sometimes compensated by the administration of high doses of the drug. The ability of thiolated hydroxypropyl-ß-cyclodextrin (HP- ß -CD-SH, 100 mM) to increase the water solubility of BUD (SHP- ß-CD-SH = 10.9·10-3 M) more than pristine hydroxypropyl- ß -cyclodextrin (HP- ß-CD, SHP- ß-CD = 4.3·10-3 M) has been previously demonstrated. Considering that S-protected thiomers have the advantage of increasing the stability of thiols over a wide pH range prolonging their residence time at the target site, 2-mercapto-nicotinic acid (MNA) was used in this study to protect the free thiol groups on HP- ß -CD-SH generating the corresponding S-protected cyclodextrin (HP-ß-CD-MNA). Besides, given the increased stability and processability of HP-ß-CD-MNA, mucoadhesive microparticles (MPs) were prepared via spray-drying of aqueous solutions of the inclusion complex HP-ß-CD-MNA/BUD. MPs were morphologically and dimensionally homogeneous exhibiting an average diameter of 3.24 ± 0.57 µm. Over time these MPs formed larger aggregates with an average diameter of 10-50 µm, suitable for the design of intranasal delivery systems. Differential scanning calorimetry analyses revealed the absence of crystalline BUD from spray-dried complexes. Dissolution studies shown that spray-dried MPs dissolved quickly and the complexed drug was completely solubilized within the first 20 min of the dissolution process. Cell viability assay indicated that spray-dried complexes are safe. In vitro mucoadhesion studies on freshly excised porcine nasal mucosa showed a 1.4- and 2.3-fold prolonged mucosal residence time of HP- ß -CD-SH/BUD and HP-ß-CD-MNA/BUD in comparison to the unmodified cyclodextrin (CD), respectively. Rheological behaviour of spray-dried MPs complexes/mucus mixtures confirmed the results of the mucoadhesion studies, as the dynamic viscosity of the spray-dried inclusion complexes HP-ß-CD-SH/BUD and HP-ß-CD-MNA/BUD was 1.1-fold and 2.4 fold increased in comparison to the unmodified HP-ß-CD/BUD complex. According to these results, MPs comprising HP- ß -CD-MNA/BUD might be a promising tool for nasal delivery of poorly water-soluble corticosteroids such as BUD.


Assuntos
Budesonida , Compostos de Sulfidrila , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Criança , Composição de Medicamentos , Humanos , Solubilidade , Suínos
15.
J Agric Food Chem ; 69(21): 5871-5881, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34013730

RESUMO

In this study, flexible and self-standing hydroxypropyl-ß-cyclodextrin/difenoconazole inclusion complex (HPßCD/DZ-IC) nanofibers were prepared by polymer-free electrospinning, which exhibited potential to be a new fast-dissolving pesticide formulation. Scanning electron microscopy and optical microscopy were applied to evaluate the morphology of nanofibers, which showed that the resulting HPßCD/DZ-IC nanofibers were bead-free and uniform. In addition, the proton nuclear magnetic resonance (1H NMR) spectrum suggested a stoichiometric ratio of 1:0.9 (HPßCD/DZ). Other characterization methods, such as UV-vis absorption, fluorescence spectroscopy, Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), and thermogravimetric analysis (TGA), were applied in this study. On the one hand, UV-vis absorption, fluorescence spectroscopy, FT-IR, XRD, and TGA provided useful information for the successful formation of an inclusion complex; on the other hand, the results of TGA indicated the thermal stability of DZ was enhanced after the formation of inclusion complexes. Besides, the phase solubility test could explain the increased water solubility of the nanofibers of inclusion complexes formed by DZ and HPßCD. The results of molecular docking studies demonstrated the most favorable binding interactions when HPßCD combined with DZ. The dissolution test and the antifungal performance test exhibited the characteristics of fast dissolution and the excellent antifungal performance of HPßCD/DZ-IC nanofibers, respectively.


Assuntos
Nanofibras , 2-Hidroxipropil-beta-Ciclodextrina , Antifúngicos , Varredura Diferencial de Calorimetria , Dioxolanos , Portadores de Fármacos , Simulação de Acoplamento Molecular , Polímeros , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Triazóis
16.
J Control Release ; 335: 191-202, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34019946

RESUMO

Recently, many studies have shown that plant metabolites, such as geraniol (GER), may exert anti-inflammatory effects in neurodegenerative diseases and, in particular, Parkinson's disease (PD) models. Unfortunately, delivering GER to the CNS via nose-to-brain is not feasible due to its irritant effects on the mucosae. Therefore, in the present study ß-cyclodextrin (ßCD) and its hydrophilic derivative hydroxypropyl-beta-cyclodextrin (HPßCD) were selected as potential carriers for GER nose-to-brain delivery. Inclusion complexes were formulated and the biocompatibility with nasal mucosae and drug bioavailability into cerebrospinal fluid (CSF) were studied in rats. It has been demonstrated by DTA, FT-IR and NMR analyses that both the CDs were able to form 1:1 GER-CD complexes, arising long-term stable powders after the freeze-drying process. GER-HPßCD-5 and GER-ßCD-2 complexes exhibited comparable results, except for morphology and solubility, as demonstrated by SEM analysis and phase solubility study, respectively. Even though both complexes were able to directly and safely deliver GER to CNS, GER-ßCD-2 displayed higher ability in releasing GER in the CSF. In conclusion, ßCD complexes can be considered a very promising tool in delivering GER into the CNS via nose-to-brain route, preventing GER release into the bloodstream and ensuring the integrity of the nasal mucosa.


Assuntos
Ciclodextrinas , Doenças Neurodegenerativas , 2-Hidroxipropil-beta-Ciclodextrina , Monoterpenos Acíclicos , Animais , Encéfalo , Doenças Neurodegenerativas/tratamento farmacológico , Pós , Ratos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier
17.
Molecules ; 26(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802031

RESUMO

Nimesulide (NIM, N-(4-nitro-2-phenoxyphenyl)methanesulfonamide) is a relatively new nonsteroidal anti-inflammatory analgesic drug. It is practically insoluble in water (<0.02 mg/mL). This very poor aqueous solubility of the drug may lead to low bioavailability. The objective of the present study was to investigate the possibility of improving the solubility and the bioavailability of NIM via complexation with polysaccharide arabinogalactan (AG), disodium salt of glycyrrhizic acid (Na2GA), hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and MgCO3. Solid dispersions (SD) have been prepared using a mechanochemical technique. The physical properties of nimesulide SD in solid state were characterized by differential scanning calorimetry and X-ray diffraction studies. The characteristics of the water solutions which form from the obtained solid dispersions were analyzed by reverse phase and gel permeation HPLC. It was shown that solubility increases for all complexes under investigation. These phenomena are obliged by complexation with auxiliary substances, which was shown by 1H-NMR relaxation methods. The parallel artificial membrane permeability assay (PAMPA) was used for predicting passive intestinal absorption. Results showed that mechanochemically obtained complexes with polysaccharide AG, Na2GA, and HP-ß-CD enhanced permeation of NIM across an artificial membrane compared to that of the pure NIM. The complexes were examined for anti-inflammatory activity on a model of histamine edema. The substances were administered per os to CD-1 mice. As a result, it was found that all investigated complexes dose-dependently reduce the degree of inflammation. The best results were obtained for the complexes of NIM with Na2GA and HP-ß-CD. In noted case the inflammation can be diminished up to 2-fold at equal doses of NIM.


Assuntos
Galactanos/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina/química , Animais , Anti-Inflamatórios não Esteroides/química , Disponibilidade Biológica , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Galactanos/química , Ácido Glicirrízico/química , Magnésio/química , Masculino , Camundongos , Permeabilidade , Preparações Farmacêuticas , Solubilidade , Difração de Raios X/métodos , beta-Ciclodextrinas/química
18.
J Chromatogr A ; 1646: 462066, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-33845265

RESUMO

Maslinic acid and corosolic acid with high purity were successfully separated from Eriobotrya japonica (Thunb.) leaves by two-step countercurrent chromatographic separation. Two biphasic solvent systems composed of petroleum ether-ethyl acetate-ethanol-water (6:4:5:5, v/v) and petroleum ether-ethyl acetate-ethanol-0.10 mol/L of hydroxypropyl-ß-cyclodextrin with pH 7.0 (8:2:3.5:6.5, v/v) were selected according to the partition performance of the main structural isomeric pentacyclic triterpenes. The influences of pH value and concentration of hydroxypropyl-ß-cyclodextrin in separation of two isomers were investigated. In first step countercurrent chromatographic separation, a mixture of two target structural isomers (14.12 mg of sample I) was separated from 40.00 mg of a partially purified sample. In second step countercurrent chromatographic separation, maslinic acid and corosolic acid were completely isolated from 12.00 mg of sample I with hydroxypropyl-ß-cyclodextrin as aqueous phase additive. The recoveries of the two isomers were over 90%, yielding 5.18 mg of maslinic acid and 5.47 mg of corosolic acid, respectively.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Distribuição Contracorrente/métodos , Eriobotrya/química , Triterpenos Pentacíclicos/isolamento & purificação , Folhas de Planta/química , Cromatografia Líquida de Alta Pressão/métodos , Triterpenos Pentacíclicos/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Estereoisomerismo
19.
Molecules ; 26(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33806952

RESUMO

A drug nanocrystals self-stabilized Pickering emulsion (NSSPE) with a unique composition and microstructure has been proven to significantly increase the bioavailability of poorly soluble drugs. This study aimed to develop a new solid NSSPE of puerarin preserving the original microstructure of NSSPE by spray-drying. A series of water-soluble solid carriers were compared and then Box-Behnken design was used to optimize the parameters of spray-drying. The drug release and stability of the optimized solid NSSPE in vitro were also investigated. The results showed that hydroxypropyl-ß-cyclodextrin (HP-ß-CD), rather than solid carriers commonly used in solidification of traditional Pickering emulsions, was suitable for the solid NSSPE to retain the original appearance and size of emulsion droplets after reconstitution. The amount of HP-ß-CD had more influences on the solid NSSPE than the feed rate and the inlet air temperature. Fluorescence microscopy, confocal laser scanning microscopy and scanning electron microscopy showed that the reconstituted emulsion of the solid NSSPE prepared with HP-ß-CD had the same core-shell structure with a core of oil and a shell of puerarin nanocrystals as the liquid NSSPE. The particle size of puerarin nanocrystal sand interfacial adsorption rate also did not change significantly. The cumulative amount of released puerarin from the solid NSSPE had no significant difference compared with the liquid NSSPE, which were both significantly higher than that of puerarin crude material. The solid NSSPE was stable for 3 months under the accelerated condition of 75% relative humidity and 40 °C. Thus, it is possible todevelop the solid NSSPE preserving the unique microstructure and the superior properties in vitro of the liquid NSSPE for poorly soluble drugs.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Portadores de Fármacos , Isoflavonas , Nanopartículas/química , Secagem por Atomização , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Emulsões , Isoflavonas/química , Isoflavonas/farmacocinética
20.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802605

RESUMO

In a mouse model of Niemann-Pick disease type C1 (NPC1), a combination therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-ß-cyclodextrin (HPßCD) has previously resulted in, among other things, significantly improved motor function. The present study was designed to compare the therapeutic effects of the COMBI therapy with that of MIGLU or HPßCD alone on body and brain weight and the behavior of NPC1-/- mice in a larger cohort, with special reference to gender differences. A total of 117 NPC1-/- and 123 NPC1+/+ mice underwent either COMBI, MIGLU only, HPßCD only, or vehicle treatment (Sham), or received no treatment at all (None). In male and female NPC1-/- mice, all treatments led to decreased loss of body weight and, partly, brain weight. Concerning motor coordination, as revealed by the accelerod test, male NPC1-/- mice benefited from COMBI treatment, whereas female mice benefited from COMBI, MIGLU, and HPßCD treatment. As seen in the open field test, the reduced locomotor activity of male and female NPC1-/- mice was not significantly ameliorated in either treatment group. Our results suggest that in NPC1-/- mice, each drug treatment scheme had a beneficial effect on at least some of the parameters evaluated compared with Sham-treated mice. Only in COMBI-treated male and female NPC+/+ mice were drug effects seen in reduced body and brain weights. Upon COMBI treatment, the increased dosage of drugs necessary for anesthesia in Sham-treated male and female NPC1-/- mice was almost completely reduced only in the female groups.


Assuntos
1-Desoxinojirimicina/análogos & derivados , 2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Doença de Niemann-Pick Tipo C/tratamento farmacológico , 1-Desoxinojirimicina/farmacologia , Animais , Ciclodextrinas/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pregnanolona/farmacologia
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