Enhanced oral bioavailability of acyclovir by inclusion complex using hydroxypropyl-β-cyclodextrin

Abstract

The therapeutic potential of acyclovir is limited by the low oral bioavailability owing to its limited aqueous solubility and low permeability. The present study was a systematic investigation on the development and evaluation of inclusion complex using hydroxypropyl-β-cyclodextrin for the enhancement of oral bioavailability of acyclovir. The inclusion complex of acyclovir was prepared by kneading method using drug: hydroxypropyl-β-cyclodextrin (1:1 mole). The prepared inclusion complex was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, NMR spectroscopy and evaluated in vitro by dissolution studies. In vivo bioavailability of acyclovir was compared for inclusion complex and physical mixture in rat model. Phase solubility studies indicate the formation of acyclovir–hydroxypropyl-β-cyclodextrin complex with higher stability constant and linear enhancement in drug solubility with increase in hydroxypropyl-β-cyclodextrin concentration. Characterization of the prepared formulation confirms the formation of acyclovir–hydroxypropyl-β-cyclodextrin inclusion complex. Dissolution profile of inclusion complex demonstrated rapid and complete release of acyclovir in 30?min with greater dissolution efficiency (90.05?±?2.94%). In vivo pharmacokinetic data signify increased rate and extent of acyclovir absorption (relative bioavailability ～160%; p?<?0.0001) from inclusion complex, compared to physical mixture. Given the promising results in the in vivo studies, it can be concluded that the inclusion complex of acyclovir could be an effective and promising approach for successful oral therapy of acyclovir in the treatment of herpes viruses.     

Solubilization of naphthoquinones by complexation with hydroxypropyl-β-cyclodextrin

The effects of the hydroxypropyl-β-cyclodextrin (HPCD) on the solubility of 2-hydroxy-N-(5-methyl-3-isoxazolyl)-1,4-naphthoquinone-4-imine (I) were investigated. I is an experimental drug for the treatment of cancer which exhibits low water solubility and it is therefore difficult to prepare the solutions for biological tests. The presence of an ionizable hydroxyl moiety (pK_a=5.80) increases the solubility via pH adjustment, but only a solubility of 0.124 mg/ml was obtained at pH 8.00. I was found to form inclusion complexes in either its neutral or its anionic form with HPCD. Although the stability constant of the I complex is larger in the neutral form, a greater overall solubility is obtained when I is in its ionized form. A 270-fold solubility enhancement is possible by using a combined approach of pH adjustment and complexation with HPCD.     

In vitro and in vivo evaluation of oral tablet formulations prepared with ketoconazole and hydroxypropyl-β-cyclodextrin

The objective of this study was to enhance the solubility, dissolution rate, and oral bioavailability of a very poorly water-soluble anti-fungal agent, ketoconazole (KET), by inclusion complexation with a highly-soluble cyclodextrin derivative, hydroxypropyl-β cyclodextrin (HP-β-CD). Two groups of tablets containing KET alone and KET:HP-β-CD (1:2) kneaded product (KP) including magnesium stearate and lactopress (anhydrous and spray-dried) as excipients were prepared by direct compression method. After the characterization studies, the in vitro dissolution studies of these tablets in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were carried out. To evaluate the in vivo bioavailability, the tablets were administered orally to rabbits and drug levels in serum were determined by HPLC. Tablets containing the cyclodextrin complex showed a higher in vitro dissolution rate and bioavailability compared to the tablets containing KET alone.     

Synergetic skin targeting effect of hydroxypropyl-β-cyclodextrin combined with microemulsion for ketoconazole

The objective was to develop a ternary skin targeting system for ketoconazole (KET) using a combined strategy of microemulsion (ME) and cyclodextrin (HP-β-CD), i.e., KET-CD-ME, which exploits both virtues of cyclodextrin complex and ME to obtain the synergetic effect. KET-CD-ME was formulated using Labrafil M 1944 CS as oil phase, Solutol HS 15 as surfactant, Transcutol P as cosurfactant, and HP-β-CD solution as aqueous phase. The formulation of KET-CD-ME was optimized and the optimal formulation was characterized in terms of particle size, size distribution, pH value, and viscosity. Long term stability experiment showed that HP-β-CD could increase the physical stability of ternary system and KET chemical stability. Percutaneous permeation of KET from KET-CD-ME in vitro through rat skin was investigated in comparison with KET microemulsion (KET-ME), KET HP-β-CD inclusion solution (KET-CD), KET aqueous suspension, and commercial KET cream; the results showed that the combination of ME with HP-β-CD exhibited significantly synergistic effect on KET deposition within the skin (29.38 ± 1.79 μg/cm²) and a slightly synergistic effect on KET penetration through the skin (11.3 μg/cm²/h). The enhancement of the combination on skin deposition was further visualized by confocal laser scanning microscope (CLSM). In vitro sensitivity against Candida parapsilosis test indicated that KET-CD-ME enhanced KET antifungal activity mainly owing to the solubilization of HP-β-CD on KET in the ternary system. Moreover, the interactions between HP-β-CD and KET in the ternary system were elucidated through microScale thermophoresis (MST) and 2D ¹H NMR spectroscopy. The profiles from MST confirmed the host–guest interactions of HP-β-CD with KET in the ternary system and a deep insight into the interactions between KET and HP-β-CD were obtained by means of 2D ¹H NMR spectroscopy. The results indicate that the ternary system of ME combination with HP-β-CD may be a promising approach for skin targeting delivery of KET.     

Preparation and evaluation of ketoconazole-β-cyclodextrin multicomponent complexes

Increase in poor buffer pH 5 and 6 solubility of ketoconazole was studied. Two systems were used: binary complexes prepared with β -cyclodextrin and multicomponent systems (β-cyclodextrin and an acid compound), obtained by spray-drying. X-ray diffractometry and differential scanning calorimetry showed differences between ketoconazole/cyclodextrin complexes and their corresponding physical mixtures and individual components. The solubility of ketoconazole increased significantly with the cyclodextrin complexes. However, enhancement was better from the multicomponent systems.     

Quantitative prediction of the bitterness of atomoxetine hydrochloride and taste-masked using hydroxypropyl-β-cyclodextrin: A biosensor evaluation and interaction study

The bitterness of a drug is a major challenge for patient acceptability and compliance, especially for children. Due to the toxicity of medication, a human taste panel test has certain limitations. Atomoxetine hydrochloride (HCl), which is used for the treatment of attention deficit/hyperactivity disorder (ADHD), has an extremely bitter taste. The aim of this work is to quantitatively predict the bitterness of atomoxetine HCl by a biosensor system. Based on the mechanism of detection of the electronic tongue (E-tongue), the bitterness of atomoxetine HCl was evaluated, and it was found that its bitterness was similar to that of quinine HCl. The bitterness threshold of atomoxetine HCl was 8.61 µg/ml based on the Change of membrane Potential caused by Adsorption (CPA) value of the BT0 sensor. In this study, the taste-masking efficiency of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) was assessed by Euclidean distances on a principle component analysis (PCA) map with the SA402B Taste Sensing System, and the host–guest interactions were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR) spectroscopy and scanning electron microscopy (SEM). Biosensor evaluation and characterization of the inclusion complex indicated that atomoxetine HCl could actively react with 2-hydroxypropyl-β-cyclodextrin.     

Development and evaluation of fast-dissolving tablets of meloxicam-β-cyclodextrin complex prepared by direct compression

The aim of this study was to prepare fast-dissolving tablets of meloxicam after its complexation with β-cyclodextrin (β-CD) and to investigate the effect of using different superdisintegrants on the disintegration and release of meloxicam from the tablets. A complex of meloxicam with β-CD was prepared by spray drying and then compressed in the form of tablets utilizing the direct compression technique. Three superdisintegrants were employed at various levels - sodium starch glycolate, croscarmellose sodium, and crospovidone. Co-spray dried micro-crystalline cellulose and mannitol (Avicel HFE-102) were used as diluents in the tablets. Prior to compression, the pre-compression parameters showed satisfactory flow properties. Post-compression parameters showed that all tablet formulations had acceptable mechanical properties. Wetting and disintegration times were prolonged by increasing the level of sodium starch glycolate in the tablets. This was attributed to the formation of a viscous gel layer around the tablets by sodium starch glycolate whereas this effect was not observed with croscarmellose sodium and crospovidone. Dissolution studies showed fast release of meloxicam except in tablets containing a high level of sodium starch glycolate. Complexation of meloxicam with β-CD significantly improved the solubility of the drug and improved the mechanical properties of tablets produced by direct compression.     

Improved dissolution and bioavailability of phenytoin by sulfobutylether-β-cyclodextrin ((SBE)7m-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) complexation

The inclusion complexation of phenytoin with charged and neutral water-soluble cyclodextrins (CDs), (SBE)_7m-β-CD and HP-β-CD, was studied in order to improve the low aqueous solubility and incomplete oral bioavailability of phenytoin. Effects of CDs on the aqueous solubility of phenytoin were determined by phase-solubility method at pH 7.4 and 11.0. Solubility of phenytoin increased as a function of CD concentration, showing A_L type diagrams for both (SBE)_7m-β-CD and HP-β-CD which indicate a formation of 1:1-complexes. Solid inclusion complexes of phenytoin with (SBE)_7m-β-CD and HP-β-CD were prepared by freeze-drying. Dissolution rate of phenytoin was increased with inclusion complexes as well as with phenytoin/HP-β-CD physical mixture in vitro. Also the freeze-drying of phenytoin tended to enhance the dissolution of phenytoin in vitro. However, plain phenytoin (300.0 mg) pharmacokinetics after oral administration as a crystal form and as a freeze-dried form were comparable in dogs. CD-based formulations of phenytoin increased peak plasma concentration of phenytoin about 1.6-fold and bioavailability (AUC_{0–24 h}) of phenytoin about 2-fold compared to plain phenytoin. Oral pharmacokinetics were not statistically different among various CD formulations. This study indicates that increased bioavailability of phenytoin in the presence of CDs was due to an increased extent of drug dissolution.     

Enhancement of norfloxacin solubility via inclusion complexation with β-cyclodextrin and its derivative hydroxypropyl-β-cyclodextrin

The objectives of the study were to investigate the effects of β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) on the solubility and dissolution rate of norfloxacin prepared using three different methods, at drug to cyclodextrin weight ratios of 1:1, 1:2, 1:4 and 1:8. All the methods increased the solubility and dissolution rate of norfloxacin via inclusion complexation with βCD and HPβCD. Norfloxacin was converted from crystalline to amorphous form through inclusion complexation. Solvent evaporation method was the most effective method in terms of norfloxacin solubilisation, while inclusion complex of HPβCD has higher solubility than βCD complex when prepared using the same procedure.     

Influence of hydroxypropyl-β-cyclodextrin and dimethyl-β-cyclodextrin on diphenhydramine intestinal absorption in a rat in situ model

The influence of complexation of diphenhydramine (DPHA) with hydroxypropyl-β-cyclodextrin (HPβCD) and dimethyl-β-cyclodextrin (DMβCD) on intestinal absorption of DPHA has been investigated on an in situ model in rats. The mean apparent stability constants of the complexes formed at 23°C between DPHA and the cyclodextrins DMβCD and HPβCD were 4988 and 1635 M⁻¹, respectively. At 37°C, the apparent stability constants were smaller: 895 and 494 M⁻¹ for the complexes formed between DPHA and the cyclodextrins DMβCD and HPβCD, respectively. Complexation of DPHA with DMβCD led to a significant decrease (−36%) in the percentage of DPHA absorbed (30.6±12.0 vs. 22.5±6.9%, P=0.018). On the other hand, complexation of DPHA with HPβCD only slightly decreased (−8%) the extent of absorption (43.2±9.0 vs. 40.0±7.7%, P=0.16). These data suggest that the magnitude of the apparent stability constant of drug–cyclodextrin complexes should be considered when complexes are used to increase the oral absorption of drugs.     

Inclusion complex of colchicine in hydroxypropyl-β-cyclodextrin tenders better solubility and improved pharmacokinetics

Context: Colchicine (CLC) causes cell death by destabilizing the tubulin unit. However, it ionizes at physiological pH resultant low bioavailability and therapeutic efficacy.

Objectives: We have attempted to augment the bioavailability of CLC by fabricating the inclusion complex with hydroxypropyl-β-cyclodextrin (HP-β-CD).

Materials and methods: CLC-HP-β-CD inclusion complex was prepared and evaluated with Fourier-transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy, ¹H nuclear magnetic resonance (¹H NMR) spectroscopy and rotating frame overhauser enhancement spectroscopy (ROESY). Oral bioavailability of CLC-HP-β-CD inclusion complex was analyzed using high performance liquid chromatography method.

Results and discussion: Our phase-solubility data indicated the formation of a stable complex with K_c ~0.31?mM^?1 at pH 7.4. ¹H NMR ascertains that NHCOCH₃ moiety of CLC enters in the HP-β-CD cavity and deshielded the H-3 and H-5 protons. ROESY also correlates the H_f and H_g of CLC with H-3 and H-5 protons of HP-β-CD and indicates that H_f and H_g protons of CLC are present either as cis and/or trans form in CLC-HP-β-CD inclusion complex. Pharmacokinetic studies showed a 1.82-fold increase in absolute bioavailability of CLC upon complexation.

Conclusion: CLC-HP-β-CD inclusion complex may potentially be used as a viable formulation of CLC.     

In vitro and in vivo evaluation of novel immediate release carbamazepine tablets: complexation with hydroxypropyl-β-cyclodextrin in the presence of HPMC

Carbamazepine (CBZ)-hydroxypropyl-β-cyclodextrin (HP-β-CD) complex in the presence of HPMC was prepared and characterized by differential scanning calorimetry (DSC) and X-ray diffractometer intended for improving the dissolution rate of CBZ. The phase-solubility method was used to investigate the effect of HP-β-CD and HPMC on the solubility of CBZ. Tablets of the resulting complex were prepared using direct compression method and the bioavailability was evaluated in beagle dogs using a UPLC/MS/MS method. The results showed solubility of CBZ was increased up to 95 times by complexation with HP-β-CD in the presence of 0.1% HPMC. The results of DSC and X-ray diffraction proved a formation of complex between CBZ and HP-β-CD. Dissolution rate of CBZ was notably improved from complex tablets with more than 97.39% released within 10 min; whereas for the commercial tablets, around 60% was released within 30 min. Using commercial tablets as the reference formulation, the bioavailability of complex tablets was considerably increased by 1.5-fold (P<0.05) and T(max) was reduced to 0.88 h compared with 1.25 h for commercial tablets. Furthermore, a lower inter-subject variability (49.9%) was observed compared with that of the commercial tablets (39.7%). It is evident from the results herein that complexation with HP-β-CD in the presence of HPMC is a feasible way to prepare a rapidly acting and better absorbed CBZ oral product.     

Development of orally disintegrating tablets of Perphenazine/hydroxypropyl-β-cyclodextrin inclusion complex

The aim of the present work was to prepare perphenazine (PPZ) orally disintegrating tablets (ODTs) based on the use of hydroxypropyl-β-cyclodextrin (HP-β-CD) forming inclusion complex with PPZ to improve the solubility and dissolution of this practically insoluble drug. Phase solubility studies were performed to evaluate the complexation of PPZ with HP-β-CD in three aqueous systems. The inclusion complex prepared by evaporation method was characterized by different physicochemical techniques, including the dissolution studies. The prepared complex was incorporated into ODTs containing different fillers and disintegrants. The ODTs prepared by direct compression were evaluated for drug content, hardness, porosity, friability, in vitro disintegration time (DT), wetting time (WT) and dissolution profiles. The solubility and dissolution rate were substantially improved compared with that of PPZ. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR) analyses suggested that PPZ could form true inclusion complex with HP-β-CD. The optimized formulation F6 exhibited short DT (15.5 ± 1.9 s) and WT (34.2 ± 2.3 s), sufficient hardness (30.4 ± 1.6 N/mm) and rapid drug dissolution. The developed tablet formulation could be a promising drug delivery system with improvements in PPZ bioavailability and patient compliance.     

Use of cyclodextrins as solubilizing agents for simvastatin: effect of hydroxypropyl-β-cyclodextrin on lactone/hydroxyacid aqueous equilibrium

The chemical conversion of simvastatin from the lactone (SVL) to the hydroxyacid (SVA) form is becoming an intriguing issue associated with the pharmacological use of SVL. On this matter, recent findings suggest that SVL complexation with cyclodextrins (CDs) may be a useful strategy to affect its aqueous solubility and chemical stability. In this work, a reverse-phase high-performance liquid chromatography (RP-HPLC) method able to selectively identify and quantify SVL and SVA has been set up, validated and applied to follow SVL hydrolysis in the presence of HPβCD. The combination of stability results with simvastatin/HPβCD stability constants achieved from UV-vis measurements and solubility/dissolution studies allowed to get an insight into SVL/HPβCD, SVA/HPβCD and SVL/SVA equilibria taking place in aqueous solution. Results show that in the presence of HPβCD the aqueous SVL/SVA equilibrium is shifted versus the hydroxyacid form. UV-vis results, showing that the lactone and the open-ring form of simvastatin interact with HPβCD in a similar extent, suggest that hydrolysis occurs also on SVL/HPβCD complex, thus supporting a mode of interaction that does not involve the lactone ring. This hypothesis is strengthened by NMR analysis performed on SVA, HPβCD and their inclusion complex, which indicates that the lactone ring is not included in HPβCD hydrophobic cavity. Finally, results suggest that particular attention must be paid to SVL lactonization in aqueous solution when using CD-based formulations and in demonstrating their effective benefit for a specific therapeutic use.     

Inclusion complex of clausenidin with hydroxypropyl-β-cyclodextrin: Improved physicochemical properties and anti-colon cancer activity

The long-term objective of the present study was to prepare, physicochemically characterize and determine the anticancer of clausenidin/hydroxypropyl-β-cyclodextrin (Clu/HPβCD) inclusion complex. We used differential scanning calorimetry, X-ray diffractometer, fourier transform infrared spectroscopy, ultraviolet–visible spectrophotometer and ¹³C and ¹H nuclear magnetic resonance followed by in vitro anticancer assays. The orientation and intermolecular interactions of Clausenidin within cyclodextrin cavity were also ascertained by molecular docking simulation accomplished by AutoDock Vina. The guest molecule was welcomed by the hydrophobic cavity of the host molecule and sustained by hydrogen bond between host/guest molecules. The constant drug release with time, and increased solubility were found after successful complexation with HPβCD as confirmed by physicochemical characterizations. Clausenidin had greater cytotoxic effect on colon cancer HT29 cells when incorporated into HPβCD cavity than dissolved in DMSO. Also, from a comparison of cell viability between normal and cancer cells, a reduced side effect was observed. The Clu/HPβCD inclusion complex triggered reactive oxygen species-mediated cytotoxicity in HT29 cells. The inclusion complex-treated HT29 cells showed cell cycle arrest and death by apoptosis associated with caspases activation. The presence of HPβCD seems to aid the anticancer activity of clausenidin.     

A fluorimetric,potentiometric and conductimetric study of the aqueous solutions of naproxen and its association with hydroxypropyl-β-cyclodextrin

The dissociation constant, K_a, of naproxen, a nonsteroidal antiinflammatory drug of the family of arylpropionic acids, has been determined in aqueous solutions at 25°C by using a potentiometric and a conductimetric techniques. The solubility limit of the drug in water, a controversial point in the literature, has been found to be less than 3×10⁻⁵ M. The interaction of naproxen with hydroxypropyl-β-cyclodextrin (HPBCD), in terms of the binding constants of the complexes formed by the CD and the nonionic (HNAP) and ionic (NAP⁻) species of the drug, has been evaluated at 25°C as well by means of steady-state fluorescence enhancement studies. A discussion of the results, K_HPBCD:HNAP=6500±400 M⁻¹ and K_HPBCD:NAP−=1400±80 M⁻¹, emphasizing the crucial importance of the choice of the pH at a value that pH≥pK_a +2 or pH≤pK_a −2, is also included.     

Determination of terbutaline enantiomers in human urine by capillary electrophoresis using hydroxypropyl-β-cyclodextrin as a chiral selector

A method for the determination of terbutaline enantiomers in human urine by capillary electrophoresis has been developed. Optimum resolution was achieved using 50 mM phosphate buffer, pH 2.5, containing 15 mM of hydroxypropyl-beta-cyclodextrin as a chiral selector. Urine samples were prepared by solid-phase extraction with Sep-pak silica, followed by CE. The assay was linear between 2-250 ng/mL (R = 0.9998 for (S)-(+)-terbutaline and R = 0.9999 for (R)-(-)terbutaline) and detection limit was 0.8 ng/mL. The intra-day variation ranged between 6.3 and 14.5% in relation to the measured concentration and the inter-day variation was 8.2-20.1%. It has been applied to the determination of (S)-(+)terbutaline and (R)-(-)-terbutaline in urine from healthy volunteer dosed with racemic terbutaline sulfate.     

Complexation of the sunscreen agent,butyl-methoxydibenzoylmethane,with hydroxypropyl-β-cyclodextrin.

The interaction between the sunscreen, butyl-methoxydibenzoylmethane (BM-DBM), and parent and modified α-, β- or γ-cyclodextrins was investigated in water by phase-solubility analysis. Among the available cyclodextrins, only hydroxypropyl-β-cyclodextrin (HP-β-CD) produced a significant increase in the aqueous solubility of BM-DBM. The complexation of the sunscreen agent with HP-β-CD was studied by circular dichroism, differential scanning calorimetry and X-ray diffractometry. The data from the solubility and the circular dichroism studies suggested the formation of a 1:2 (sunscreen:cyclodextrin) complex. The photodegradation of BM-DBM was reduced by inclusion complexation with HP-β-CD. Therefore the complex can be used to improve the photostability of the sunscreen agent.     

Transdermal delivery of the in situ hydrogels of curcumin and its inclusion complexes of hydroxypropyl-β-cyclodextrin for melanoma treatment

Curcumin (Cur) is a hydrophobic polyphenol with diverse pharmacological effects, especially for cancer treatment. However, its weak water solubility and stability was the major obstacle for the formulation research of Cur. The complexation of Cur and hydroxypropyl-β-cyclodextrin (HP-β-CD) was done by grinding. The increasing solubility of Cur was achieved due to complexation and the photochemical stability of Cur was improved. The inclusion of Cur could happen when two ends of Cur were embedded into the cavity of the HP-β-CD rings. The in situ hydrogels (ISGs) of Cur and its inclusion complexes were prepared using poloxamers 407 and 188 as the matrix. The extent of drug’s in vitro release from the ISGs depended on the dissolution of drugs. Both of the ISGs had transdermal effect and cytotoxicity on B16-F10 cells. However, the effects of the ISGs containing Cur inclusion complexes were much higher than those of Cur ISGs because of the improved Cur solubility in the former. The cytotoxicity of Cur on melanoma cells was related to blocking of cellular proliferation in the G₂/M stage followed by cellular apoptosis. The ISGs of Cur inclusion complexes are a promising formulation for melanoma treatment.