•The best CyD for LPV complexation was predicted by in silico studies.•The predicted CyD was successfully synthesized (HP17-γ-CyD).•LPV complexes were prepared by two methods i.e.SASD and ...CoEva.•HP17-γ-CyD facilitated higher LPV amorphization and solubilization.•SASD processing technique enhanced LPV complexation and solubilization.
Lopinavir (LPV) is currently used in combination with ritonavir for the clinical management of HIV infections due to its limited oral bioavailability. Herein, we report the application of an in silico method to study cyclodextrin (CyD) host-guest molecular interaction with LPV for the rational selection of the best CyD for developing a CyD based LPV delivery system. The predicted CyD, a (2-hydroxy)propyl-gamma derivative with high degree of substitution (HP17-γ-CyD) was synthesized and comparatively evaluated with γ-CyD and the commercially available HP-γ-CyD. All complexes were prepared by supercritical assisted spray drying (SASD) and co-evaporation (CoEva) at molar ratios (1:1 and 1:2); and afterwards fully characterized. Results indicate a higher LPV amorphization and solubilization ability of HP17-γ-CyD. The SASD processing technology also enhanced LPV solubilization and release from complexes. The application of in silico methodologies is a feasible approach for the rational and/or deductive development of CyD drug delivery systems.
Abstract
Novel multifunctional excipients were prepared by coprocessing tapioca starch with mannitol using two methods viz; co-grinding and co-fusion. The flow, packing and compaction properties of ...the native and novel excipients were evaluated by using density, Hausner's ratio, angle of repose, the maximum volume reduction, consolidation index, the rate of consolidation, angle of internal friction, morphological properties, Heckel analysis, tensile strength and dilution potential as evaluation parameters. The study revealed that the method of coprocessing, particle size and particle shape influenced the properties of the resulting novel excipients. Co-grinding was less effective than co-fusion in the preparation of excipients with enhanced properties. The study concluded that coprocessing tapioca starch and mannitol will enhance the flow, packing and compaction properties of the novel excipient and that the co-fusion method of coprocessing would produce novel excipients with enhanced direct compression potential compared to the co-grinding method.
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Oral delivery of many therapeutic agents remains challenging due to gastric insolubility/poor dissolution, inefficient intestinal permeability and pre-systemic inactivation. These ...problems limit the advantages of convenience and increased compliance they provide in the therapy of many chronic diseases. Cyclodextrin nanosystems have emerged as promising platforms for drug-specific construction of the oral delivery nanosystems able to optimize the desired physicochemical properties and pharmacokinetic parameters; without a compromise on safety. This review focuses on some recent and encouraging advances in the application of cyclodextrin nanosystems for oral drug delivery. A general overview of cyclodextrins and pharmaceutical nanotechnology in oral delivery systems is provided. Some of the strategies being exploited for the synthesis of these nanosystems, and their potential for the intelligent navigation of the gastrointestinal tract for optimal bioavailability and biodistribution are then illustrated. Perspectives for translating these nanosystems from laboratory efficient formulations to clinically useful medicines are also discussed.
•Cyclodextrins are complexing excipients in tablets mainly for potent drugs.•Methods to enhance the complexation efficiency decrease the cyclodextrin quantity.•Inclusion complex flow properties play ...a crucial part in the tablet manufacture process.•Commercial tablets containing cyclodextrins are available on the market.•3D-printed tablets can be developed containing cyclodextrins as excipients.
This paper aims to provide a critical review of cyclodextrins as excipients in tablet formulations, highlighting: (i) the principal pharmaceutical applications of cyclodextrins; (ii) the most relevant technological aspects in pharmaceutical formulation development; and (iii) the actual regulatory status of cyclodextrins. Moreover, several illustrative examples are presented. Cyclodextrins can be used as complexing excipients in tablet formulations for low-dose drugs. By contrast, for medium-dose drugs and/or when the complexation efficiency is low, the methods to enhance the complexation efficiency play a key part in reducing the cyclodextrin quantity. In addition, these compounds are used as fillers, disintegrants, binders and multifunctional direct compression excipients of the tablets.
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•Ibuprofen and hydroxypropyl-γ-cyclodextrin were successfully co-atomized by SASD.•Samples were characterized by ATR-FTIR, XRD, UV, 13C CP/MAS NMR, SEM and DSC.•Results strongly ...suggest the formation of amorphous inclusion complexes.•SASD is a green alternative to conventional methods of CyD complex formation.
Herein we report the formation of dry powder complexes of ibuprofen (IBU) and hydroxypropyl-γ-cyclodextrin (HP-γ-CyD) by supercritical CO2-assisted spray-drying (SASD). SASD of HP-γ-CyD alone, IBU/HP-γ-CyD, as well as the physical mixture were prepared and characterized using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), X-ray diffraction (XRD), ultra-violet spectroscopy (UV), 13C cross-polarization magic angle spinning nuclear magnetic resonance (13C CP/MAS NMR), differential scanning calorimetry (DSC) and morphological studies. Results indicate the successful formation of amorphous inclusion complexes. SASD is a clean technology, suitable for processing thermolabile APIs, thus an interesting alternative to conventional spray drying and other methods of CyD solid complex formation.
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•HPβCD was used for the first time to prepare 3D printed formulations (printlets).•Micro-extrusion printing enabled in situ formation of HPβCD-carbamazepine complexes.•Orodispersible ...and immediate release printlets were successfully prepared.•Small changes in cellulose ethers ratio allowed fine tuning of drug release profile.
This work aimed to explore for the first time the use of cyclodextrins to prepare printlets of poorly soluble drugs, such as carbamazepine, which require fine dose adjustment and rapid release. Orodispersible (flash) and immediate release formulations were 3D printed via semisolid extrusion of wet masses of hydroxypropyl-β-cyclodextrin (HPβCD) and cellulose ethers and regulating tablet porosity. Rheology of the wet masses allowed identifying printable compositions. Printing robustness was assessed evaluating weight, dimensions, hardness, drug content, and microstructure. Drug crystallinity, printlet disintegration and dissolution profiles were also characterized. The results highlight the feasibility of using HPβCD as excipient in printlets of poorly soluble drugs, and the possibilities of tuning drug release profiles through small changes in cellulose ethers nature and ratio. Semisolid extrusion-based 3D printing is revealed as a feasible approach to in situ form carbamazepine-HPβCD complexes and to produce printlets with suitable physical and drug release properties for oral delivery.
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•Soluble cyclodextrin polymers were successfully synthesised.•Sub-micron sized particles of lopinavir loaded CD polymers were prepared.•pHPβCD and pMβCD produced dose independent ...anti-HIV-1 effect.•LPV loaded pHPβCD exhibited the typical dose dependent activity of LPV against HIV-1.•LPV loaded pMβCD produced a synergistic anti-HIV-1 effect.
We report the synthesis of water soluble cyclodextrin (CD) polymers prepared by crosslinking pyromellitic dianhydride (PMDA) with two CD derivatives (methyl-β-CD - MβCD and (2-hydroxy)propyl-β-CD - HPβCD) and their evaluation as functional sub-micron sized carriers in the development of antiretroviral drug delivery systems. Using the protease inhibitor lopinavir (LPV) as model drug, LPV loaded CD polymers (pHPβCD and pMβCD) were prepared and fully characterized. The physicochemical characterization and in vitro drug release confirmed the successful synthesis of pHPβCD and pMβCD, the formation of sub-micron sized particles and a 12–14 fold increase in LPV solubility. Cytotoxicity assays indicated that both pHPβCD and pMβCD were able to improve the safety profile of LPV while the viral infectivity assay revealed a concentration independent anti-HIV-1 effect for both pHPβCD and pMβCD with a maximum percentage inhibition (MPI) of 79 and 91% respectively. After LPV loading, the antiviral profile of pHPβCD was reversed to the sigmoidal dose–response profile of LPV, while pMβCD maintained its dose-independent profile followed by a LPV mediated increase in viral inhibition. Overall, both pHPβCD and pMβCD demonstrated anti-HIV-1 activity, while drug loaded pMβCD indicated its potential as functional sub-micron sized drug delivery polymers for achieving synergistic anti-HIV activity.
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The aim of this work was to prepare and characterize inclusion complexes between a synthetic curcumin analog (dibenzalacetone, DBA) and beta-cyclodextrin (β-CD); and to evaluate their ...in vitro antileishmanial activity. DBA was synthetized and characterized by spectroscopic methods and the inclusion complexes were obtained by kneading and lyophilization (LIO) in 1:1 and 1:2 stoichiometries. Phase solubility and dissolution assays showed a 40-fold increase in the aqueous solubility of DBA and its complete dissolution from LIO 1:1 formulation after 120 min respectively. Solid-state characterization by differential scanning calorimetry and near infrared spectroscopy demonstrated the inclusion of DBA in the β-CD cavity at the molar ratios tested, with LIO 1:1 formulation being the most stable. Using nuclear magnetic resonance experiments, the protons inside the cavity of β-CD were the most affected after the inclusion of DBA molecule. The cellular viability of THP-1 macrophage cells treated with plain DBA, β-CD and DBA/CD inclusion complexes showed that the plain DBA and DBA/CD at 1:2 stoichiometry presented toxicity, while β-CD alone and DBA/CD at 1:1 stoichiometry showed no toxicity up to 640 μg mL−1. The in vitro assay with free-living promastigotes demonstrated that plain DBA and β-CD had IC50 of < 10 and > 320 μg mL−1 respectively, while only inclusion complexes with 1:1 stoichiometry showed antiproliferative activity with IC50 = 51.3 μg mL−1. Using the amastigote intracellular forms, there was also a difference between the plain and β-CD complexed DBA with complexes of 1:1 and 1:2 stoichiometry presenting EC50 = 66.3 μg mL−1 and 58.9 μg mL−1 respectively. The study concluded that DBA/CD at 1:1 molar ratio has the potential to decrease the intrinsic toxicity of plain DBA towards Leishmania host cells, which may be a therapeutic advantage in the application of these compounds.
•The multicomponent synthesis of a hexahydroquinoline compound was performed.•β-cyclodextrin inclusion complexes were prepared to increase aqueous solubility.•Complexes demonstrated to have a slower ...release improving its biological properties.
Multicomponent synthesis are convergent reactions in which three or more starting materials react in a single step to form the product. In the discovery and development of new drugs, multicomponent reactions offer several advantages over traditional synthesis: shorter experiment time, less need for laboratory techniques and scalability. Thus, the objective of this work was to perform the multicomponent synthesis of a hexahydroquinoline compound whose pharmacological activity has been described previously. The synthesis product was characterized by spectroscopic techniques such as Fourier transform infrared spectrometry and 1H, 13C and HMQC nuclear magnetic resonance (NMR). The mechanism of the reaction was proposed to include a conjugated Michael addition. Subsequently, inclusion complexes (ICs) at 1:1 and 1:2 stoichiometries were prepared with the appropriate cyclodextrin to increase the aqueous solubility and bioavailability of this molecule. Kneading and lyophilization (LYO) methods were used to prepare the inclusion complexes, which were evaluated by phase solubility and 1H NMR spectroscopy, with LYO at a 1:2 stoichiometry having the best results. The ICs were then characterized by differential scanning calorimetry, near-infrared spectroscopy and in vitro dissolution tests, which verified a slower release of the compound with the potential to improve its biological properties.
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The development of orodispersible tablets (ODTs) for poorly soluble and poorly flowable drugs
via
direct compression is still a challenge. This work aimed to develop ODTs of poorly soluble drugs by ...combining cyclodextrins that form inclusion complexes to improve wetting and release properties, and directly compressible co-processed excipients able to promote rapid disintegration and solve the poor flowability typical of inclusion complexes. Carbamazepine (CBZ) and hydroxypropyl-β-cyclodextrin (HPβCD) were used, respectively, as a model of a poorly soluble drug with poor flowability and as a solubilizing agent. Specifically, CBZ—an antiepileptic and anticonvulsant drug—may benefit from the studied formulation approach, since some patients have swallowing difficulties or fear of choking and are non-cooperative. Prosolv® ODT G2 and F-Melt® type C were the studied five-in-one co-processed excipients. The complex was prepared by kneading. Flow properties of all materials and main properties of the tablets were characterized. The obtained results showed that ODTs containing CBZ/HPβCD complex can be prepared by direct compression through the addition of co-processed excipients. The simultaneous use of co-processing and cyclodextrin technologies rendered ODTs with an
in vitro
disintegration time in accordance with the European Pharmacopoeia requirement and with a fast and complete drug dissolution. In conclusion, the combination of five-in-one co-processed excipients and hydrophilic cyclodextrins may help addressing the ODT formulation of poorly soluble drugs with poor flowability, by direct compression and with desired release properties.
