Preparation of curcumin-hydroxypropyl-β-cyclodextrin inclusion complex by cosolvency-lyophilization procedure to enhance oral bioavailability of the drug

Abstract

The curcumin (CUR)-hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex (CUR-HP-β-CD) was prepared to erase its therapeutic restrictions of poor aqueous solubility and low oral bioavailability. CUR-HP-β-CD was prepared by a simple procedure of water-ethanol cosolvent incubation-lyophilization which may be suitable for scale up production, and characterized by Fourier transform-infrared spectroscopy (FT-IR), powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), phase solubility method and dissolution study; the in vitro cytotoxicity was assayed by MTT, whereas the in vivo pharmacokinetics was tested by HPLC in rats receiving formulations via intravenous and oral administration, respectively. CUR was successfully encapsulated in HP-β-CD with a loading capacity of about 1:7 of CUR to HP-β-CD mole ratio, which remarkably enhanced drug water solubility and maintained well the antitumour activity of CUR. The CUR-HP-β-CD and free CUR have a similar pharmacokinetic behaviour in rats after intravenous administration; however, the oral bioavailability of CUR was enhanced to 2.77-fold by the HP-β-CD. The CUR-HP-β-CD can be successfully prepared by a simple method, which may be feasible for industrial scaling up, to remarkably increase drug water solubility and oral bioavailability while maintaining its bioactivity and may be a promising therapeutic preparation.     

Preparation and characterization of self nano-emulsifying drug delivery system (SNEDDS) for oral delivery of heparin using hydrophobic complexation by cationic polymer of β-cyclodextrin

Objective: The aim of this study was the preparation of a self nano-emulsifying drug delivery system (SNEDDS) for oral delivery of heparin.

Significance: Preparation of hydrophobic complexes between heparin as the hydrophilic macromolecule and cationic polymer of β-cyclodextrin (CPβCD) was considered for preparation of orally administered SNEDDS in which the drug incorporated in internal oil phase of O/W nano-droplets.

Methods: Hydrophobic complexes of heparin-CPβCD were prepared by electrostatic interaction. The lipophilic feature of complexes was characterized by determining their partition co-efficients. SNEDDS prototypes were prepared by mixing liquid paraffin, Tween 80, propylene glycol and ethanol, diluted 1:100 in an aqueous medium. Central composite response surface methodology was applied for statistical optimization. Independent variables were the amount of liquid paraffin and the amount of Tween 80, while responses were size and poly dispersity index (PdI). Optimized SNEDDS were studied morphologically using transmission electron microscopy (TEM). In vitro release of heparin was studied in the simulated gastric and simulated intestinal media.

Results: The data revealed that in molar ratio 1:3 (heparin:CPβCD), the n-octanol recovery was maximized and reached 67.6?±?11.86%. Size, PdI, zeta potential, EE% in gastric medium and EE% in intestinal medium for optimized nano-droplets were reported as 307?±?30.51?nm, 0.236?±?0.02,?+2.1?±?0.66?mV, 90.2?±?0.04 and 96.1?±?0.73%, respectively. Microscopic images revealed spherical nano-droplets. The obtained data revealed no burst release of heparin from nano-droplets.

Conclusions: The obtained results indicate that SNEDDS could be regarded as a good candidate for oral delivery of heparin as the hydrophilic macromolecule.     

Host–guest inclusion system of mangiferin with β-cyclodextrin and its derivatives

The characterization, inclusion complexation behavior and binding ability of the inclusion complexes of mangiferin (MGF) with β-cyclodextrin and its derivatives (hydroxypropyl-β-cyclodextrin (HPβCD), sulfobutyl ether β-cyclodextrin (SBEβCD) and mono (6-ethylene-diamino-6-deoxy)-β-cyclodextrin (ENβCD)) were investigated in both solution and solid state by means of PL spectroscopy, ¹H and 2D NMR, XRD, TG and DSC. The results showed that the water solubility and thermal stability of MGF were significantly increased in the inclusion complex with cyclodextrins. The MGF/CDs complexes will be potentially useful for the design of a novel formulation of mangiferin for herbal medicine.     

Preparation and stability of iodine/α-cyclodextrin inclusion complex

Abstract

Inclusion complexes of iodine and α-cyclodextrin were prepared using the coprecipitation method. The complexes obtained were characterized in their solid state using differential scanning calorimetry and in their liquid phase using spectrophotometry, titrimetry and electrochemistry assays. The inclusion and preparation yields were determined. The 1:1 stoichiometry ratio of the inclusion compound was estimated on the basis of the inclusion yield. After optimization of the parameters of the laboratory assays, a scale-up experiment for the complex preparation was carried out. Stability studies showed that, after 16 months preservation, the inclusion complex remained quite stable and suitable for industrial scale-up according to a number of conditions.     

Mg–Al layered double hydroxide–methotrexate nanohybrid drug delivery system: Evaluation of efficacy

Mg–Al layered double hydroxide nanoparticles were synthesized by one-pot co-precipitation method and anticancerous drug methotrexate was incorporated into it by in-situ ion exchange. The LDH–MTX nanohybrid produced moderately stable suspension in water, as predicted by zeta potential measurement. X-ray diffraction revealed that the basal spacing increased to nearly twice the same for pristine LDH on MTX intercalation. Thermogravimetric analyses confirmed an increase in thermal stability of the intercalated drug in the LDH framework. A striking enhancement in efficacy/sensitivity of MTX on the HCT-116 cells was obtained when intercalated within the LDH layers, as revealed by the attainment of half maximal inhibitory concentration of LDH–MTX nanohybrid by 48 h, whereas, bare MTX required 72 h for the same. The MTX release from MgAl-LDH–MTX hybrids in phosphate buffer saline at pH 7.4 followed a relatively slow, first order kinetics and was complete within 8 days following diffusion and crystal dissolution mechanism.     

Design of oral drug delivery systems – Past,present and future

Abstract

This paper reviews the past and the present thinking about peroral delivery research and development and how future approaches may be significantly different, both qualitatively and quantitatively. The future should involve the use of comprehensive models capable of incorporating physico-chemical data and biological information such as gastrointestinal flow, how and where drug absorption occurs, and whether and where metabolism of the drug occurs during gastrointestinal transit. Special challenges would involve the use of such models in research protocols in the optimization of drug delivery systems.     

Sulfobutylether-β-cyclodextrin/chitosan nanoparticles enhance the oral permeability and bioavailability of docetaxel

The aim of this research is to develop novel chitosan nanoparticles including cyclodextrins complexes for docetaxel (DTX), evaluate the performance of nanoparticles which could enhance the oral permeability and bioavailability of DTX in vitro and in vivo. DTX/sulfobutylether-β-cyclodextrin inclusion complexes were made and it was the main ingredient to prepare the DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles due to their promising physicochemical properties. DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles were prepared by the ionic gelation of chitosan with tripolyphosphate in the presence of cyclodextrins. Results indicated that DTX/sulfobutylether-β-cyclodextrin inclusion complexes and docetaxel/sulfobutylether-β-cyclodextrin/chitosan nanoparticles both had good performances in the studies of release and the rat small intestinal absorption in vitro. DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles showed preferable capability in improving the small intestinal absorption and inhibiting the efflux of DTX. In pharmacokinetics study, the DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles increased the AUC_0→t and decreased the clearance significantly, and the oral relative bioavailability of the DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles was as high as 1447.53% compared to the pure DTX formulation. The DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles prepared in this study have a good prospect for oral administration as an alternative of current DTX formulations.     

Characterization of the tableting properties of β-cyclodextrin and the effects of processing variables on inclusion complex formation,compactibility and dissolution

Abstract

The tableting properties of a number of commercially available β-cyclodextrins were characterized. Fluidity was insufficient for routine direct compression. Compactibility varied by source but was excellent. Lubrication requirements were minimal. An inclusion complex of β-cyclodextrin/Progesterone was formed and the tableting properties of the complex were compared to those of a physical mixture in both directly compressed and wet granulated products. Inclusion complexes spontaneously formed during wet granulation processing. Substantial differences in tableting properties were found as processing variables were changed. β-cyclodextrin exhibits considerable promise as a standard filler binder in tableting.     

Solid lipid nanoparticles with and without hydroxypropyl-β-cyclodextrin: a comparative study of nanoparticles designed for colonic drug delivery

New solid lipid nanoparticles (SLN), composed of Compritol ATO888 (C) and hydroxypropyl-β-cyclodextrin (HP), were developed in order to study a new colon-specific formulation for diclofenac sodium (D) delivery. The prepared batches differ from each other by the molecular ratio between HP and D and by the composition of the matrix. Nanoparticles composed of an exclusively lipid matrix and nanoparticles with an oligomeric and lipid matrix were compared in order to establish the effect of both components on the drug delivery tests performed. The SLN preparation method was based on the oil/water hot homogenization process. Emulsions produced were cooled at room temperature and lyophilized in order to obtain dried nanoparticles; possible damage to nanoparticle shape and size was avoided by the addition of cryoprotectants to the aqueous dispersion of nanoparticles before exsiccation. An in vitro toxicity study was performed using CaCo(2) cells to establish the safety of the prepared SLN. Data obtained showed that production method studied guarantees emulsions composed of nanosized drops which can be dried by lyophilization into SLN with a size range of 300-600 nm. In vitro and ex vivo tests demonstrated that dried SLN can be considered as colon delivery systems; however, the matrix composition as well as the presence of cryoprotectant on their surface influences the release and permeation rate of D. The in vitro toxicity studies indicated that the SLN are well tolerated.     

Formulation design and optimization of novel soft glycerosomes for enhanced topical delivery of celecoxib and cupferron by Box–Behnken statistical design

Background: The present study describes glycerosomes (vesicles composed of phospholipids, glycerol and water) as a novel drug delivery system for topical application of celecoxib (CLX) and cupferron (CUP) compound.

Aim: The goal of this research was to design topical soft innovative vesicles loaded with CLX or CUP for enhancing the efficacy and avoiding systemic toxicity of CLX and CUP.

Methods: CLX and CUP loaded glycerosomes were prepared by hydrating phospholipid-cholesterol films with glycerol aqueous solutions (20–40%, v/v). Box–Behnken design, using Design-Expert® software, was the optimum choice to statistically optimize formulation variables. Three independent variables were evaluated: phospholipid concentration (X₁), glycerol percent (X₂) and tween 80 concentration (X₃). The glycerosomes particle size (Y₁), encapsulation efficiency percent (Y₂: EE %) and drug release (Y₃) were selected as dependent variables. The anti-inflammatory effect of CLX and CUP glycerosomal gel was evaluated by carrageenan-induced rat paw edema method followed by histopathological studies.

Results: The optimized formulations (CLX2* and CUP1*) showed spherical morphology under transmission electron microscopy, optimum particle size of 195.4?±?3.67?nm, 301.2?±?1.75?nm, high EE of 89.66?±?1.73%, 93.56?±?2.87%, high drug release of 47.08?±?3.37%, 37.60?±?1.89% and high cumulative amount of drug permeated in 8?h of 900.18?±?50.24, 527.99?±?34.90?µg.cm^?2 through hairless rat skin, respectively. They also achieved significant remarkable paw edema inhibition in comparison with the control group (p? Conclusion: Finally, the administration of CLX2* and CUP1* loaded glycerosomal gel onto the skin resulted in marked reduction of edema, congestive capillary and inflammatory cells and this approach may be of value in the treatment of different inflammatory disorders.     

Development of porous HAp and β-TCP scaffolds by starch consolidation with foaming method and drug-chitosan bilayered scaffold based drug delivery system

The inability to maintain high concentrations of antibiotic at the site of infection for an extended period of time along with dead space management is still the driving challenge in treatment of osteomyelitis. Porous bioactive ceramics such as hydroxyapatite (HAp) and beta-tri calcium phosphate (β-TCP) were some of the alternatives to be used as local drug delivery system. However, high porosity and high interconnectivity of pores in the scaffolds play a pivotal role in the drug release and bone resorption. Ceftriaxone is a cephalosporin that has lost its clinical popularity. But has recently been reported to exhibit better bactericidal activity in vitro and reduced probability of resistance development, in combination with sulbactam, a β-lactamase inhibitor. In this article, a novel approach of forming HAp and pure β-TCP based porous scaffolds by applying together starch consolidation with foaming method was used. For the purpose, pure HAp and β-TCP were prepared in the laboratory and after thorough characterization (including XRD, FTIR, particle size distribution, etc.) the powders were used for scaffold fabrication. The ability of these scaffolds to release drugs suitably for osteomyelitis was studied in vitro. The results of the study indicated that HAp exhibited better drug release profile than β-TCP when drug was used alone indicating the high influence of the carrier material. However, this restriction got relaxed when a bilayered scaffold was formed using chitosan along with the drug. SEM studies along with EDAX on the drug-chitosan bilayered scaffold showed closest apposition of this combination to the calcium phosphate surface.     

Synthesis of β-cyclodextrin hydrogel nanoparticles for improving the solubility of dexibuprofen: characterization and toxicity evaluation

Objective: This study was aimed to enhance aqueous solubility of dexibuprofen through designing β-cyclodextrin (βCD) hydrogel nanoparticles and to evaluate toxicological potential through acute toxicity studies in rats.

Significance: Dexibuprofen is a non-steroidal analgesic and anti-inflammatory drug that is one of safest over the counter medications. However, its clinical effectiveness is hampered due to poor aqueous solubility.

Methods: βCD hydrogel nanoparticles were prepared and characterized by percent yield, drug loading, solubilization efficiency, FTIR, XRD, DSC, FESEM and in-vitro dissolution studies. Acute oral toxicity study was conducted to assess safety of oral administration of prepared βCD hydrogel nanoparticles.

Results: βCD hydrogel nanoparticles dramatically enhanced the drug loading and solubilization efficiency of dexibuprofen in aqueous media. FTIR, TGA and DSC studies confirmed the formation of new and a stable nano-polymeric network and interactions of dexibuprofen with these nanoparticles. Resulting nanoparticles were highly porous with 287?nm in size. XRD analysis revealed pronounced reduction in crystalline nature of dexibuprofen within nanoparticles. Release of dexibuprofen in βCD hydrogel nanoparticles was significantly higher compared with dexibuprofen tablet at pH 1.2 and 6.8. In acute toxicity studies, no significant changes in behavioral, physiological, biochemical or histopathologic parameters of animals were observed.

Conclusions: The efficient preparation, high solubility, excellent physicochemical characteristics, improved dissolution and non-toxic βCD hydrogel nanoparticles may be a promising approach for oral delivery of lipophilic drugs.     

Development and evaluation of a novel drug delivery: Soluplus®/TPGS mixed micelles loaded with piperine in vitro and in vivo

Background: Although piperine can inhibit cells of tumors, the poor water solubility restricted its clinical application. This paper aimed to develop mixed micelles based on Soluplus^® and D-α-tocopherol polyethylene glycol succinate (TPGS) to improve the aqueous solubility and anti-cancer effect.

Methods: Piperine-loaded mixed micelles were prepared using a thin-film hydration method, and their physicochemical properties were characterized. The cellular uptake of the micelles was confirmed by confocal laser scanning microscopy in A549 lung cancer cells and HepG₂ liver cancer cells. In addition, cytotoxicity of the piperine mixed micelles was studied in A549 lung cancer cells and HepG₂ liver cancer cells. Free piperine or piperine-loaded Soluplus^®/TPGS mixed micelles were administered at an equivalent dose of piperine at 3.2?mg/kg via a single intravenous injection in the tail vain for the pharmacokinetic study in vivo.

Results: The diameter of piperine-loaded Soluplus^®/TPGS (4:1) mixed micelles was about 61.9?nm and the zeta potential –1.16?±?1.06?mV with 90.9% of drug encapsulation efficiency and 4.67% of drug-loading efficiency. Differential scanning calorimetry (DSC) studies confirmed that piperine is encapsulated by the Soluplus^®/TPGS. The release results in vitro showed that the piperine-loaded Soluplus^®/TPGS mixed micelles presented sustained release behavior compared to the free piperine. The mixed micelles exhibited better antitumor efficacy compared to free piperine and physical mixture against in A549 and HepG₂ cells by MTT assay. The pharmacokinetic study revealed that the AUC of piperine-loaded mixed micelles was 2.56 times higher than that of piperine and the MRT for piperine-loaded mixed micelles was 1.2-fold higher than piperine (p?Conclusion: The results of the study suggested that the piperine-loaded mixed micelles developed might be a potential nano-drug delivery system for cancer chemotherapy. These results demonstrated that piperine-loaded Soluplus^®/TPGS mixed micelles are an effective strategy to deliver piperine for cancer therapy.     

A microemulsion of puerarin–phospholipid complex for improving bioavailability: preparation,in vitro and in vivo evaluations

Puerarin is a phytochemical with various pharmacological effects, but poor water solubility and low oral bioavailability limited usage of puerarin. The purpose of this study was to develop a new microemulsion (ME) based on phospholipid complex technique to improve the oral bioavailability of puerarin. Puerarin phospholipid complex (PPC) was prepared by a solvent evaporation method and was characterized by X-ray diffraction and infrared spectroscopy. Pseudo-ternary phase diagrams were constructed to investigate the effects of different oil on the emulsifying performance of the blank ME. Intestinal mucosal injury test was conducted to evaluate safety of PPC-ME, and no sign of damage on duodenum, jejunum and ileum of rats was observed using hematoxylin-eosin staining. In pharmacokinetic study of PPC-ME, a significantly greater C_max (1.33?µg/mL) was observed when compared to puerarin (C_max 0.55?µg/mL) or PPC (C_max 0.70?µg/mL); the relative oral bioavailability of PPC-ME was 3.16-fold higher than puerarin. In conclusion, the ME combined with the phospholipid complex technique was a promising strategy to enhance the oral bioavailability of puerarin.     

Complexation of novel thiomers and insulin to protect against in vitro enzymatic degradation – towards oral insulin delivery

A significant barrier to oral insulin delivery is its enzymatic degradation in the gut. Nano-sized polymer-insulin polyelectrolyte complexes (PECS) have been developed to protect insulin against enzymatic degradation. Poly(allylamine) (Paa) was trimethylated to yield QPaa. Thiolation of Paa and QPaa was achieved by attaching either N-acetylcysteine (NAC) or thiobutylamidine (TBA) ligands (Paa-NAC/QPaa-NAC and Paa-TBA/QPaa-TBA thiomers). PEC formulations were prepared in Tris buffer (pH 7.4) at various polymer: insulin mass ratios (0.2:1–2:1). PECS were characterized by %transmittance of light and photon correlation spectroscopy. Insulin complexation efficiency and enzyme-protective effect of these complexes were determined by HPLC. Complexation with insulin was found to be optimal at mass ratios of 0.4–1:1 for all polymers. PECS in this mass range were positively-charged (20–40?mV), nanoparticles (50–200?nm), with high insulin complexation efficiency (>90%). Complexation with TBA polymers appeared to result in disulfide bridge formation between the polymers and insulin. In vitro enzymatic degradation assays of QPaa, Paa-NAC, and QPaa-NAC PECS showed that they all offered some protection against insulin degradation by trypsin and α-chymotrypsin, but not from pepsin. QPaa-NAC complexes with insulin are the most promising formulation for future work, given their ability to offer protection against intestinal enzymes. This work highlights the importance of optimizing polymer structure in the delivery of proteins.     

Nanodispersions stabilized by β-cyclodextrin nanosponges: application for simultaneous enhancement of bioactivity and stability of sage essential oil

The aim of this work was to stabilize oil-in-water nanoemulsion containing sage (salvia officinalis) essential oil, for enhancing its physicochemical stability and enlarging its industrial applications. New β-cyclodextrin nanosponges were synthesized by polycondensation using naphthalene dicarboxylic acid as cross-linking agent, the latter system was characterized by FTIR spectroscopy, SEM, BET, and powder XRD. Nanoemulsions stabilized by free β-cyclodextrin or nanosponges were prepared, their physicochemical properties were determined (particles size, zeta potential, viscosity, turbidity, and essential oil content) and their stability was studied at different storage temperatures (4?°C, 20?°C, and 40?°C) during 3?months. Pharmaceutical application of prepared nanoemulsions was investigated in vitro by dissolution test study and in vivo by their antidiabetic activity evaluation in rats. Sage essential oil nanoemulsion stabilized by β-cyclodextrin-naphthalene dicarboxylic acid nanosponges presents very high stability and promising uses in pharmaceutical industry.     

Evaluating elevated release liner adhesion of a transdermal drug delivery system (TDDS): A study of Daytrana™ methylphenidate transdermal system

Background: Complaints from healthcare providers that the adhesive on the Daytrana? methylphenidate transdermal drug delivery system (TDDS) adhered to the release liner to such an extent that the release liner could not be removed prompted this study. Daytrana? has a packaging system consisting of a moisture-permeable pouch contained within a sealed tray containing a desiccant; the tray is impermeable to ambient moisture. The objective of this project was to determine if the Daytrana? packaging system influenced the difficulty in removing the release liner.

Method: Both a sealed tray and an open tray containing sealed pouches were placed into an environmental chamber at 25°C and 60% relative humidity for 30 days; afterwards, release liner removal testing using a peel angle of 90° and a peel speed of 300?mm/min was performed.

Results: TDDS from open chamber trays required less force to remove the release liner than did TDDS from closed chamber trays. For the 10?mg/9?h TDDS and the 15?mg/9?h TDDS (the dosages examined), there were substantial differences in release liner removal force between an old lot and a new lot for closed chamber trays but not for open chamber trays.

Conclusion: The results demonstrate that for this particular TDDS, storage conditions such as humidity influence release liner adhesion. This project also demonstrates that, to ensure adequate product quality, adhesion needs to become an important design parameter, and the design of a TDDS should consider the ability to remove the release liner under anticipated storage conditions.     

Use of sorbitol as pharmaceutical excipient in the present day formulations – issues and challenges for drug absorption and bioavailability

Sorbitol is a popular sugar alcohol which has been used as an excipient in formulations of various drugs. Although from a safety perspective the presence of sorbitol in drug formulations does not raise a concern, reports have emerged and these suggest that sorbitol in drug formulations may alter oral absorption and bioavailability of certain drugs. The focus of this article was to review the published literature of various drugs where pharmacokinetic data has been reported for the drug alone versus drug administered with sorbitol and provide perspectives on the pharmacokinetic findings. Interestingly, for BCS class I drugs such as theophylline, metoprolol, the oral absorption, and bioavailability were generally not affected by sorbitol. However, theophylline oral absorption and bioavailability were decreased when sustained release formulation was used in place of immediate release formulation. For drugs such as risperidone (BCS class II) and lamivudine and ranitidine (BCS class III), the solution formulations showed diminished oral bioavailability in presence of sorbitol, whereas cimetidine and acyclovir (BCS class III), did not show any changes in pharmacokinetic profiles due to sorbitol. Finally, the presence of activated charcoal with sorbitol showed different pharmacokinetic outcome for BCS class I and II drugs.