HPβCD Inclusion Complex Research Articles

Cyclodextrin inclusion complex and amorphous solid dispersions as formulation approaches for enhancement of curcumin’s solubility and nasal epithelial membrane permeation

BackgroundCurcumin is a compound that occurs in the rhizomes of the turmeric plant (Curcuma longa) and has shown potential for the treatment of illnesses including certain neurodegenerative diseases. The bioavailability of curcumin is hindered by its extremely poor aqueous solubility.ResultsThis study aimed to apply formulation strategies such as inclusion complex formation with hydroxypropyl-β-cyclodextrin (HPβCD), as well as amorphous solid dispersion (ASD) formation with poly(vinylpyrrolidone-co-vinyl acetate) (PVP VA64) and hydroxypropyl methylcellulose (HPMC) to increase curcumin’s solubility and thereby its nasal epithelial membrane permeation. The curcumin formulations were evaluated by means of DSC, TGA, FT-IR, XRPD, microscopic imaging, aqueous solubility and membrane permeation across nasal respiratory and olfactory epithelial membranes. The solubility of curcumin was substantially increased by the formulations from 8.4 µg/ml for the curcumin raw material to 79.0 µg/ml for the HPβCD inclusion complex, 256.4 µg/ml for the HPMC ASD and 314.9 µg/ml for the PVP VA64 ASD. The HPMC ASD only slightly changed the membrane permeation of curcumin, while the PVP VA64 ASD decreased the membrane permeation of curcumin. The HPβCD inclusion complex enhanced the nasal epithelial membrane permeation of curcumin statistically significantly across the olfactory epithelial tissue and extensively across the respiratory epithelial tissue.ConclusionComplexation of curcumin with HPβCD enhanced the solubility of curcumin and thereby also increased its permeation across excised nasal respiratory and olfactory epithelial tissue. This indicated high potential of the curcumin-HPβCD complex for nose-to-brain delivery of curcumin for treatment of neurodegenerative diseases by means of intranasal administration.Graphical abstract

An integrated approach using ozone nanobubble and cyclodextrin inclusion complexation to enhance the removal of micropollutants

Ozone (O3) has been widely used for the elimination of recalcitrant micropollutants in aqueous environments, due to its strong oxidation ability. However, the utilization efficiency of O3 is constrained by its low solubility and short half-life during the treatment process. Herein, an integrated approach, using nanobubble technology and micro-environmental chemistry within cyclodextrin inclusion cavities, was studied in order to enhance the reactivity of ozonisation. Compared with traditional macrobubble aeration with O3 in water, nanobubble aeration achieved 1.7 times higher solubility of O3, and increased the mass transfer coefficient 4.7 times. Moreover, the addition of hydroxypropyl-β-cyclodextrin (HPβCD) further increased the stability of O3 through formation of an inclusion complex in its molecule-specific cavity. At a HPβCD:O3 molar ratio of 10:1, the lifespan of O3 reached 18 times longer than in a HPβCD-free O3 solution. Such approach accelerated the removal efficiency of the model micropollutant, 4-chlorophenol by 6.9 times, compared with conventional macrobubble ozonation. Examination of the HPβCD inclusion complex by UV–visible spectroscopy and Nuclear Magnetic Resonance analyses revealed that both O3 and 4-chlorophenol entered the HPβCD cavity, and Benesi-Hildebrand plots indicated a 1:1 stoichiometry of the host and guest compounds. Additionally, molecular docking simulations were conducted in order to confirm the formation of a ternary complex of HPβCD:4-chlorophenol:O3 and to determine the optimal inclusion mode. With these results, our study highlights the viability of the proposed integrated approach to enhance the ozonation of organic micropollutants.

Anaesthetic benefits of a ternary drug delivery system (Ropivacaine-in-Cyclodextrin-in-Liposomes): in-vitro and in-vivo evaluation.

To evaluate whether a ternary system composed of hydroxypropyl-β-cyclodextrin (HP-βCD) further encapsulated into egg phosphatidylcholine liposomes (LUV) could prolong the action and reduce the toxicity of ropivacaine (RVC). Dynamic light scattering and NMR were used to characterize the inclusion complex (RVC:HP-βCD), liposomal (RVC:LUV) and ternary (LUV:RVC:HP-βCD) systems containing 0.25% RVC. Their encapsulation efficiency, release kinetics, in-vitro cytotoxicity and in-vivo anaesthetic effect (paw-withdraw tests in mice) were also evaluated. 1:1 RVC:HP-βCD inclusion complex was encapsulated in liposomes (220.2±20.3nm size, polydispersity <0.25, zeta potentials=-31.7±1.4mV). NMR (diffusion-ordered spectroscopy (DOSY)) revealed stronger anaesthetic binding to LUV:RVC:HP-βCD (Ka =342m-1 ) than to RVC:HP-βCD (Ka =128m-1 ) or liposomal formulation (Ka =22m-1 ). The formulations promoted in-vitro sustained drug release and partially reverted the cytotoxicity of RVC against 3T3 fibroblasts in the profile: LUV:RVC:HP-βCD≥RVC:HP-βCD>RVC:LUV. Accordingly, in-vivo sensory block of free RVC (180min) was prolonged ca. 1.7 times with the ternary system and RVC:HP-βCD (300min) and 1.3 times with RVC:LUV (240min). These results confirm the suitability of this double-carrier system in clinical practice, to decrease the toxicity and prolong the anaesthesia time evoked by RVC.

An investigation into the anti-microbial properties of bacterial cellulose wound dressings loaded with curcumin:hydroxypropyl-β-cyclodextrin supramolecular inclusion complex An investigation into the anti-microbial properties of bacterial cellulose wound dressings loaded with curcumin:hydroxypropyl-β-cyclodextrin supramolecular inclusion complex

Wounds from various sources such as burns and ulcers which have been in a prolonged state of inflammation and rubor, both exudative and non-exudative, are decidedly prone to becoming infected by various opportunistic and commensal microorganisms, both bacterial and fungal due to the warm moist environment at the wound site (Que et al.,2019). The typical approach in treating these wounds is to reduce the level of infection and inflammation, thus encouraging an appropriate environment for successful re-epithelisation resulting in faster healing of the wound. Bacterial cellulose (BC) is an ideal material to produce wound dressings due to the intrinsic properties such as; high chemical stability, high tensile strength and flexibility, large water holding capacity, permeable to gases and liquids, and excellent biocompatibility (Gupta et al., 2016; Gupta et al.,2017, Wahid et al., 2019). In this study, BC produced by Komagataeibacter xylinus was used as a hydrogel matrix and loaded with a well-known antimicrobial agent- curcumin encapsulated in solubility enhancing carriers, hydroxypropyl- β-cyclodextrin (CUR:HPβCD) (Abbas et al., 2019, Gupta et al., 2019). BC was loaded with 2% (w/v) aqueous CUR:HPβCD inclusion complex under constant agitation at 170 rpm at 20°C (room temperature) for 24 hours. Antimicrobial activity was tested against two representative organisms: Candida albicans and Staphylococcus aureus by disc diffusion method. We have previously reported the antibacterial activity of CUR:HPβCD-loaded BC (Gupta et al., 2019). The current study is an extension of our ongoing research where we made an attempt of testing the anti-fungal activity of CUR:HPβCD-loaded BC and compared it with anti-bacterial activity. 8mm discs were aseptically cut and placed on TSA plates seeded with overnight cultures of one of the microorganisms under investigation and incubated at 37°C for 24 hours. The results indicated that C. albicans and S. aureus were both susceptible to CUR:HPβCD inclusion complex with an average zone of inhibition of 12.25±2.2mm and 11±1.2mm respectively (n=4, ±=SD, p &lt;0.05). The results against S. aureus are in accordance with our previously reported findings (Gupta et al., 2019). Current findings support the wound management applications of CUR:HPβCd-loaded BC hydrogels for chronic wounds. References Abbas, M., Hussain, T., Arshad, M., Ansari, A., Irshad, A., Nisar, J., Hussain, F., Masood, N., Nazir, A. and Iqbal, M. (2019). Wound healing potential of curcumin cross-linked chitosan/polyvinyl alcohol. International Journal of Biological Macromolecules, 140, pp.871-876. Gupta, A., Keddie, D., Kannappan, V., Gibson, H., Khalil, I., Kowalczuk, M., Martin, C., Shuai, X. and Radecka, I. (2019). Production and characterisation of bacterial cellulose hydrogels loaded with curcumin encapsulated in cyclodextrins as wound dressings. European Polymer Journal, 118, pp.437-450. Gupta, A., Low, W., Britland, S., Radecka, I. and Martin, C. (2017). Physicochemical characterisation of biosynthetic bacterial cellulose as a potential wound dressing material. British Journal of Pharmacy, 2(2), pp.S37-S38. Gupta, A., Low, W., Radecka, I., Britland, S., Mohd Amin, M. and Martin, C. (2016). Characterisation and in vitro antimicrobial activity of biosynthetic silver-loaded bacterial cellulose hydrogels. Journal of Microencapsulation, 33(8), pp.725-734. Que, A., Nguyen, N., Do, N., Nguyen, N., Tran, N. and Le, T. (2019). Infection of burn wound by Aspergillus fumigatus with gross appearance of fungal colonies. Medical Mycology Case Reports, 24, pp.30-32. Wahid, F., Hu, X., Chu, L., Jia, S., Xie, Y. and Zhong, C. (2019). Development of bacterial cellulose/chitosan based semi-interpenetrating hydrogels with improved mechanical and antibacterial properties. International Journal of Biological Macromolecules, 122, pp.380-387.

Development of gallic acid/cyclodextrin inclusion complex in freeze-dried bacterial cellulose and poly (vinyl alcohol) hydrogel: Controlled-release characteristic and antioxidant properties

Cyclodextrin (HPβCD) inclusion complex enhances the stabilization of active ingredients during processing, storage, and usage. This work presents gallic acid (GA)/HPβCD inclusion complex through lyophilization. Complexation powder (5 and 10 wt%) was loaded into bacterial cellulose hydrogel composite. Fourier Transform infrared spectroscopy, X-ray diffraction, and 1H NMR were employed to investigate the structural properties of encapsulation. Thermogravimetric analysis reported that the thermal degradation region can be categorized into three regions. Scanning electron microscope revealed no significant change on the morphological properties. Swelling behavior was observed on distilled water and phosphate buffer solution for 180 min. The inclusion complex exhibited slow release compared with pristine GA. The antioxidant activity of this complex was verified by 2, 2′- diphenyl-1-picrylhydrazyl and 2, 2-azinobis (3-ethylbenzothioazoline-6-sulfonic acid) radical scavenging methods.

A 5,7-dimethoxyflavone/hydroxypropyl-β-cyclodextrin inclusion complex with anti-butyrylcholinesterase activity.

This study aimed to improve the water solubility of 5,7-dimethoxyflavone (5,7-DMF) isolated from Kaempferia parviflora by complexation with 2-hydroxypropyl-β-cyclodextrin (HPβ-CD). The phase solubility profile of 5,7-DMF in the presence of HPβ-CD was classified as AL-type and indicated a 1:1 mole ratio. Differential scanning colorimetry, X-ray diffraction, NMR and SEM analyses supported the formation of a 5,7-DMF/HPβ-CD inclusion complex involving the A ring of 5,7-DMF inside the HPβ-CD cavity. This is the first example of CD inclusion with the A ring of non-hydroxyl flavones. The stability and binding constants of the complexes were determined using the phase solubility and UV-vis absorption spectroscopy, respectively. The water solubility of 5,7-DMF was increased 361.8-fold by complexation with HPβ-CD and overcame the precipitation problem observed in aqueous buffers, such as during in vitro anti-butyrylcholinesterase activity assays. The 1:1 mole ratio of the 5,7-DMF/HPβ-CD complex showed a 2.7-fold higher butyrylcholinesterase inhibitory activity (in terms of the IC50 value) compared to the non-complexed compound.

Designing an extended release waxy matrix tablet containing nicardipine–hydroxy propyl β cyclodextrin complex

Aim The current study aimed to prepare a sustained release tablet for a drug which has poor solubility in alkaline medium using complexation with cyclodextrin. Nicardipine hydrochloride (NC) a weak basic drug was chosen as a model drug for this study. Method Firstly the most suitable binary system NC-HPβCD was selected in order to improve drug solubility in the intestinal media and then embedding the complexed drug into a plastic matrix, by fusion method, consists of glycerol monostearate (GMS) as an inert waxy substance and polyethylene glycol 4000 (PEG4000) as a channeling agent, after that the final solid dispersion [(NC:HPβCD):GMS:PEG4000] which was prepared at different ratios was mixed with other excipients, avicel PH101, lactose, and talc, to get a tablet owning dissolution profile complying with the FDA and USP requirements for the extended release solid dosage forms. Results Infrared spectroscopy (IR), differential scanning colorimetry (DSC), polarized microscopy and X-ray diffractometry proved that the coevaporation technique was effective in preparing amorphous cyclodextrin complexes with NC and trapping of NC within the HPβCD cavity by dissolving both in ethanol and evaporate the solvent using a rotavapor at 65 °C. Dissolution profile of NC enhanced significantly in pH 6.8 from NC:HPβCD inclusion complex prepared by the rotavapor ( t-test Student p < 0.05). The release of NC from tablet containing [(NC:HPβCD):GMS:PEG4000] [(1):0.75:0.5] (w/w/w) solid dispersion (F8) was complying with the FDA dissolution requirements for extended release dosage forms, and studying the kinetics of the release showed that the diffusional contribution is the major factor controlling the drug release from that formula. Conclusion The prepared waxy matrix tablet containing NC complexes with CD shows promising results as extended release tablets.

PLGA Microparticles Encapsulating Prostaglandin E1-Hydroxypropyl-β-cyclodextrin (PGE1-HPβCD) Complex for the Treatment of Pulmonary Arterial Hypertension (PAH)

To test the efficacy and viability of poly (lactic-co-glycolic acid) (PLGA) microspheres encapsulating an inclusion complex of prostaglandin E(1) (PGE(1)) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) for pulmonary delivery of PGE(1) for treatment of pulmonary arterial hypertension (PAH), a disease of pulmonary circulation. PLGA-based microparticulate formulations of PGE(1)-HPβCD inclusion complex or plain PGE(1) were prepared by a double-emulsion solvent evaporation method. HPβCD was used as a complexing agent to increase the aqueous solubility of PGE(1), act as a porosigen to produce large porous particles, and promote absorption of PGE(1). Particles were characterized for micromeritic properties, in vivo absorption, metabolic degradation, and acute safety. Incorporation of HPβCD in the microparticles resulted in development of large particles with internal pores, which, despite large mean diameters, had aerodynamic diameters in the inhalable range of 1 to 5 μm. HPβCD incorporation also resulted in a significant increase in the amount of drug released in vitro in simulated interstitial lung fluid, showing a desirable burst release profile required for immediate hemodynamic effects. Compared to plain PLGA microparticles, entrapment efficiency was decreased upon complexation with HPβCD. In vivo absorption profile indicated prolonged availability of PGE(1) in circulation following pulmonary administration of the optimized microparticulate formulations, with an extended half-life of almost 4 hours. Metabolic degradation and acute toxicity studies suggested that microparticulate formulations were stable under physiological conditions and safe for the lungs and respiratory epithelium. This study demonstrates the feasibility of PGE(1)-HPβCD complex encapsulated in PLGA microparticles as a potential delivery system for controlled release of inhaled PGE(1).

Stability and enzymatic studies with omeprazole:hydroxypropyl-β-cyclodextrin

Omeprazole (OME) exhibits low stability to light, heat and humidity. In stress conditions OME stability should improve under inclusion complex form with hydroxypropyl-β-cyclodextrin (HPβCD). Stability of OME, its physical mixture (PM) with HPβCD and OME:HPβCD inclusion complex was assessed during 60 days. The inclusion complexes were prepared by kneading and freeze-drying techniques and characterized by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). A molecular modelling was also held to predict the most probable tridimensional conformation of inclusion complex OME:HPβCD. The inhibitory activity of free and complexed OME on selected enzymes, namely, papain (protease model of the proton pump) and acetylcholinesterase (enzyme present in cholinergic neurons and also involved in Alzheimer’s disease) was compared. The results obtained show that HPβCD do not protect against OME degradation, in any prepared powder, in the presence of light, heat and humidity. This may indicate that the reactive group of OME is not included in the HPβCD cavity. This fact is supported by molecular modelling data, which demonstrated that 2-pyridylmethyl group of OME is not included into the cyclodextrin cavity. In relation to enzymatic assays it was observed that free OME and OME in the binary systems showed identical inhibitory activity on papain and acethylcolinesterase, concluding that HPβCD do not affect OME activity on these two enzymes.

Effect of PVP K30 and/or l-Arginine on Stability Constant of Etoricoxib–HPβCD Inclusion Complex: Preparation and Characterization of Etoricoxib–HPβCD Binary System

The effect of polyvinyl pyrrolidone (PVP) K30 and/or l-arginine on etoricoxib–HPβCD complex was investigated. The phase solubility profiles were classified as AL-type, both in absence or presence of auxiliary substances used. The apparent stability constant (Kc) of binary complex obtained at room temperature, 371.80 ± 2.61 M−1, was decreased with the addition of PVP and arginine indicating no benefit of addition of auxiliary substances to promote higher complexation efficiency. Therefore, solid etoricoxib–HPβCD binary systems were prepared and characterized by proton nuclear magnetic resonance spectroscopy (1HNMR), X-ray powder diffractometry, Fourier transformation-infrared spectroscopy, and dissolution studies. Among all binary systems, a lyophilized product showed superior performance in enhancing dissolution of etoricoxib.

Effect of chitosan on progesterone release from hydroxypropyl-β-cyclodextrin complexes

An inclusion complex composed of progesterone (Prog) and hydroxypropyl-β-cyclodextrin (HPβCD) was prepared by the spray-drying and freeze-drying methods. Prog alone and its inclusion complex with HPβCD were incorporated into chitosan by spray-drying and freeze-drying. The inclusion complex was characterized by IR and DSC. The inclusion complex was investigated in solution by phase solubility diagrams and stability constant was determined at pH 7.4 and at different temperatures (10, 25 and 37 °C) to obtain the thermodynamic parameters of inclusion. The results indicate that the Prog–HPβCD inclusion complex is more water soluble than Prog alone. Release data from all samples showed significant improvement of the dissolution rate of Prog and a controlled release is obtained in the presence of chitosan.

Influence of Piroxicam: Hydroxypropyl-Beta-Cyclodextrin Complexation on the in vitro Permeation and Skin Retention of Piroxicam

The interactions between piroxicam (Px) and hydroxypropyl-β-cyclodextrin (HPβCD) were thoroughly investigated both in solution and the solid state. The solubility studies have demonstrated the formation of a Px:HPβCD inclusion complex with 1:1 stoichiometry. The addition of propylene glycol to the medium produced less stable complexes, revealing the fact of this co-solvent probably acting as a competing agent. Equimolecular Px:HPβCD solid systems were prepared using the co-precipitation method and then fully characterized by X-ray diffractometry, infrared spectra and differential scanning calorimetry. A topical gel formulation containing Px, as inclusion complex with HPβCD, was developed in order to study the influence of Px complexation on its release rate and skin percutaneous permeation. The formation of Px:HPβCD complexes did not increase either Px release from the vehicle or its skin permeation. However, Px complexation with HPβCD allowed the incorporation of a higher quantity of Px into the gel, which resulted in a considerable increase in the Px released and permeated. Skin pretreatment with different HPβCD solutions, followed by the application of control gel, showed no enhancing capacity. The amount of Px retained in the skin, after pretreatment experiments, was found to be very similar to that obtained without skin pretreatment and was observed to be related to flux values through the skin.

Drugs, in cyclodextrins, in liposomes: a novel approach to the chemical stability of drugs sensitive to hydrolysis

The entrapment in multilamellar liposomes of the inclusion complexes of cyclodextrins with drugs sensitive to hydrolysis, is being examined. The anti-inflammatory drug indomethacin (IND), rapidly hydrolyzed in alkaline media, can be stabilized 75-fold when its inclusion complex with the hydroxypropylated derivative of β-cyclodextrin (HP βCD) is entrapped in multilamellar liposomes. These liposomes were composed of egg phosphatidylcholine and cholesterol of 1:1 molar ratio and were prepared according to the dehydration-rehydration method. The molar ratio for the IND:HP βCD inclusion complex was estimated to be 1:1 using the continuous variation method based on the 1H NMR data. Furthermore, the binding constant (K 11) of the IND:HP βCD complex was estimated kinetically and by 1H NMR.