Dihydroartemisinin-cyclodextrin complexation: Solubility and stability

Dihydroartemisinin (DHA) is a major metabolite of artemisinin and its derivatives, including arteether, artemether, and artesunate. To improve the solubility and stability of poorly soluble DHA, we prepared inclusion complexes with hydroxypropyl-β-cyclodextrin (HPβCD) and recrystalized DHA to study its thermal stability. The complexes were characterized by differential scanning calorimetery (DSC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction patterns (XRD), thermal stability, phase, and equilibrium solubility studies. Pure DHA was crystalline and remained crystalline after recrystallization, but its unit cell dimensions changed as exhibited by XRD. DHA-HPβCD complexes showed a phase transitions towards amorphous in DSC thermograms, FTIR spectra, and XRD patterns. The phase solubility profiles of complexes prepared in water, acetate buffer, and phosphate buffers were classified as A_L-type, indicating the formation of a 1:1 stoichiometric inclusion complex. The equilibrium solubility of DHA was enhanced as a function of HPβCD concentration. DHA-HPβCD complexes showed an 89-fold increase in solubility compared to DHA. Solubilities of complexes containing 275.1 mM HPβCD in water, acetate buffer (pH 3.0), and phosphate buffer (pH 3.0 and 7.4) were 10.04, 7.96, 6.30, and 11.61 mg/ml, respectively. Hydrogen bonding was found between DHA and HPβCD, and it was stronger in complexes prepared in water than in buffers. However, the ÄH values were higher in buffer than water. DHA-HPβCD complexes prepared using commercial (untreated) or recrystallized DHA (no detectable impurity) showed a 40% increase in thermal stability (50°C) and a 29-fold decrease in hydrolysis rates compared with DHA. The rank order of stability constants (K_s) was: water, acetate buffer (pH 3.0), phosphate buffer (pH 3.0), and phosphate buffer (pH 7.4). Thus, HPβCD complexation with recrystalized DHA increases DHA solubility and stability.     

Preparation and characterization of solid dispersions of itraconazole by using aerosol solvent extraction system for improvement in drug solubility and bioavailability

The objective of this study was to elucidate the feasibility to improve the solubility and bioavailability of poorly water-soluble itraconazole via solid dispersions by using supercritical fluid (SCF). Solid dispersions of itraconazole with hydrophilic polymer, HPMC 2910, were prepared by the aerosol solvent extraction system (ASES) under different process conditions of temperature/pressure. The particle size of solid dispersions ranged from 100 to 500 nm. The equilibrium solubility increased with decrease (15 to 10 MPa) in pressure and increase (40 to 60 degrees C) in temperature. The solid dispersions prepared at 45 degrees C/15 MPa showed a slight increase in equilibrium solubility (approximately 27-fold increase) when compared to pure itraconazole, while those prepared at 60 degrees C/10 MPa showed approximately 610-fold increase and no endothermic peaks corresponding to pure itraconazole were observed, indicating that itraconazole might be molecularly dispersed in HPMC 2910 in the amorphous form. The amorphous state of itraconazole was confirmed by DSC/XRD data. The pharmacokinetic parameters of the ASES-processed solid dispersions, such as Tmax, Cmax, and AUC(o-24 h) were almost similar to Sporanox capsule which shows high bioavailability. Hence, it was concluded that the ASES process could be a promising technique to reduce particle size and/or prepare amorphous solid dispersion of drugs in order to improve the solubility and bioavailability of poorly water-soluble drugs.     

Interaction of Omeprazole with a Methylated Derivative of β-Cyclodextrin: Phase Solubility,NMR Spectroscopy and Molecular Simulation

Purpose Cyclodextrins are known to be good solubility enhancers for several drugs, improving bioavailability when incorporated in pharmaceutical formulations. In this work we intend to assess and characterize the formation of inclusion complexes between omeprazole (OME) and a methylated derivative of β-cyclodextrin, methyl-β-cyclodextrin (MβCD). A comparison with results obtained from the most commonly used natural cyclodextrin, β-cyclodextrin (βCD) is also presented in most cases. Materials and Methods The interaction of OME with the mentioned cyclodextrins in aqueous solutions was studied by phase solubility studies, 1D ¹H and 2D rotating frame nuclear overhauser effect NMR spectroscopy (ROESY) and Molecular Dynamics. Results The solubility of OME was significantly increased by formation of inclusion complexes with each cyclodextrin. Phase solubility studies and continuous variation plots revealed that OME forms an inclusion complex in a stoichiometry of 1:1 with both cyclodextrins. ¹H NMR and ROESY spectra of the inclusion complexes indicated that the benzimidazole moiety is included within the cyclodextrins cavities. Molecular dynamics showed that OME is more deeply included in the MβCD than in βCD cavity, in agreement with a larger apparent stability constant (K _S) obtained for the inclusion complex with MβCD. Conclusions MβCD proved to be an efficient enhancer of OME solubility, thus possessing characteristics for being an useful excipient in pharmaceutical formulations of this drug.     

Improvement of the dissolution rate of artemisinin by means of supercritical fluid technology and solid dispersions

The purpose of this study was to enhance the dissolution rate of artemisinin in order to improve the intestinal absorption characteristics. The effect of: (1) micronisation and (2) formation of solid dispersions with PVPK25 was assessed in an in vitro dissolution system [dissolution medium: water (90%), ethanol (10%) and sodium lauryl sulphate (0.1%)]. Coulter counter analysis was used to measure particle size. X-ray diffraction and DSC were used to analyse the physical state of the powders. Micronisation by means of a jet mill and supercritical fluid technology resulted in a significant decrease in particle size as compared to untreated artemisinin. All powders appeared to be crystalline. The dissolution rate of the micronised forms improved in comparison to the untreated form, but showed no difference in comparison to mechanically ground artemisinin. Solid dispersions of artemisinin with PVPK25 as a carrier were prepared by the solvent method. Both X-ray diffraction and DSC showed that the amorphous state was reached when the amount of PVPK25 was increased to 67%. The dissolution rate of solid dispersions with at least 67% of PVPK25 was significantly improved in comparison to untreated and mechanically ground artemisinin. Modulation of the dissolution rate of artemisinin was obtained by both particle size reduction and formation of solid dispersions. The effect of particle size reduction on the dissolution rate was limited. Solid dispersions could be prepared by using a relatively small amount of PVPK25. The formation of solid dispersions with PVPK25 as a carrier appears to be a promising method to improve the intestinal absorption characteristics of artemisinin.     

布格呋喃固体分散体的体外研究

布格呋喃(buagafuran,AF-5)是以( )香芹酮为起始原料通过立体选择性合成的沉香呋喃类化合物[1].它具有显著的抗焦虑作用,毒副作用低,市场前景广阔.布格呋喃为油状液体,脂溶性强,不溶于水.用植物油稀释进行小鼠灌胃,抗焦虑活性与空白组比较无统计学意义,不能较好地发挥药效.室温放置易发生降解,化学稳定性差.这些缺     

Development of raloxifene-solid dispersion with improved oral bioavailability via spray-drying technique

The purpose of this study was to develop a raloxifene-loaded solid dispersion with enhanced dissolution rate and bioavailability via spray-drying technique. Solid dispersions of raloxifene (RXF) were prepared with PVP K30 at weight ratios of 1:4, 1:6 and 1:8 using a spray-drying method, and characterized by differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and solubility and dissolution tests. The bioavailability of the solid dispersion in rats was also evaluated compared to those of RXF powder and commercial product. Results showed that the RXF-loaded solid dispersion was in amorphous form with increased solubility and dissolution rate. The absorption of RXF from solid dispersion resulted in approximately 2.6-fold enhanced bioavailability compared to pure drug. Moreover, RXF-loaded solid dispersion gave similar AUC, C_max and T_max values to the commercial product, suggesting that it was bioequivalent to the commercial product in rats. These findings suggest that an amorphous solid dispersion of RXF could be a viable option for enhancing the oral bioavailability of RXF.     

Development of novel itraconazole-loaded solid dispersion without crystalline change with improved bioavailability

To develop a novel itraconazole-loaded solid dispersion without crystalline change with improved bioavailability, various itraconazole-loaded solid dispersions were prepared with water, polyvinylpyrroline, poloxamer and citric acid. The effect of carriers on aqueous solubility of itraconazole was investigated. Their physicochemical properties were investigated using SEM, DSC, and powder X-ray diffraction. The dissolution, bioavailability in rats and stability of solid dispersions were evaluated. Unlike conventional solid dispersion system, the itraconazole-loaded solid dispersion with relatively rough surface did not change crystalline form of drug. Our DSC and powder X-ray diffraction results suggested that this solid dispersion was formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in conversion of the hydrophobic drug to hydrophilic form. The itraconazole-loaded solid dispersion at the weight ratio of itraconazole/polyvinylpyrroline/poloxamer of 10/2/0.5 gave maximum drug solubility of about 20 μg/mL. It did not change the crystalline form of drug for at least 6 months, indicating that it was physically stable. It gave higher AUC, C_max and T_max compared to itraconazole powder and similar values to the commercial product, suggesting that it was bioequivalent to commercial product in rats. Thus, it would be useful to deliver a poorly water-soluble itraconazole without crystalline change with improved bioavailability.     

Enhanced solubility and bioavailability of flurbiprofen by cycloamylose

The effect of cycloamylose on the aqueous solubility of flurbiprofen was investigated. To improve the solubility and bioavailability of flurbiprofen (poor water solubility), a solid dispersion was spray dried with a solution of flurbiprofen and cycloamylose at a weight ratio of 1:1. The physicochemical properties of solid dispersions were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared with a commercial product. Cycloamylose increased solubility of flurbiprofen approximately 12-fold and dissolution of it by 2-fold. Flurbiprofen was present in an unchanged crystalline state, and cycloamylose was a solubilizing agent for flurbiprofen in this solid dispersion. Furthermore, the dispersion gave higher AUC and C_max values compared with the commercial product, indicating that it improved the oral bioavailability of flurbiprofen in rats. Thus, the solid dispersion may be useful to deliver flurbiprofen with enhanced bioavailability without changes in crystalline structure.     

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.     

Effect of Cyclodextrin Complexation on the Liposome Permeability of a Model Hydrophobic Weak Acid

Purpose  This study examines the effect of a chemically modified β-cyclodextrin on the liposome bilayer permeability of a liposomally entrapped model hydrophobic weak acid, DB-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin). Materials and Methods  Permeability studies were conducted in liposomes prepared by hydration–extrusion in the presence or absence of entrapped hydroxypropyl-β-cyclodextrin (HPβCD). A gradient HPLC method with evaporative light scattering detection was developed for analysis of HPβCD. DB-67 was analyzed by HPLC with fluorescence detection. Results  HPβCD entrapped in the aqueous compartment of liposomes was found to be membrane impermeable. Gel phase liposomes were stable in the presence of HPβCD. HPβCD complexation did not significantly alter the apparent permeability of DB67 lactone, due to its high membrane binding. However, lactone ring-opening and ionization significantly decreased the apparent permeability and improved the liposomal retention of DB-67, an effect that was amplified in the presence of 50 mM HPβCD. Conclusions  In liposomes, cyclodextrin complexation competes with liposomal membrane binding which may temper the potential benefit of complexation in prolonging hydrophobic drug retention. Cyclodextrin complexation combined with drug ionization may nevertheless significantly enhance the retention of ionizable hydrophobic drugs in liposomes as complexation may compete more favorably with membrane binding when the drug is ionized.     

Physicochemical characterization and in vivo evaluation of flurbiprofen-loaded solid dispersion without crystalline change

To develop a novel flurbiprofen-loaded solid dispersion without crystalline change, various flurbiprofen-loaded solid dispersions were prepared with water, sodium carboxylmethyl cellulose (Na-CMC), and Tween 80. The effect of Na-CMC and Tween 80 on aqueous solubility of flurbiprofen was investigated. The physicochemical properties of solid dispersions were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared to commercial product. Unlike conventional solid dispersion systems, the flurbiprofen-loaded solid dispersion gave a relatively rough surface and changed no crystalline form of drug. These solid dispersions were formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in changing the hydrophobic drug to hydrophilic form. Furthermore, the flurbiprofen-loaded solid dispersion at the weight ratio of flurbiprofen/Na-CMC/Tween 80 of 6/2.5/0.5 improved ～ 60-fold drug solubility. It gave higher AUC, T_max, and C_max compared to commercial product. The solid dispersion improved almost 1.5-fold bioavailability of drug compared to commercial product in rats. Thus, the flurbiprofen-loaded solid dispersion would be useful to deliver poorly water-soluble flurbiprofen with enhanced bioavailability without crystalline change.     

Stabilization of low glass transition temperature indomethacin formulations: impact of polymer-type and its concentration

The objectives of this study were to formulate and stabilize amorphous formulation of low T(g) drug (Indomethacin, INM) with selected polymers and compare these formulations based on solubility and dissolution rate studies. Eudragit EPO (EPO), Polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), and Polyvinylpyrrolidone K30 (PVPK30) were selected as hydrophilic polymers. The melt extrudates were characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), intrinsic dissolution rate and solubility studies. The formation of single-phase amorphous form was confirmed by DSC and PXRD. The melt extrudates showed a higher intrinsic dissolution rate (IDR), and solubility compared to the pure drug. The amorphous drug in solid solutions with EPO, PVP-VA, and PVPK30 showed tendency to revert back to crystalline form. However, the rate of reversion was dependent on the nature and concentration of the polymer. The solid solution with high ratio of EPO provided superior stabilization of the amorphous INM from crystallization. The stability of the amorphous form of INM could not be related to the glass transition temperature of the formulation as the mechanism of stabilization with EPO appears to be molecular interaction rather than immobilization. The presence of specific molecular interactions between INM and EPO was also shown by the antiplasticization effect.     

杨梅素固体分散体的制备以及体外溶出试验

目的运用固体分散技术制备杨梅素固体分散体并提高其体外溶出速率。方法选用PEG6000和PVPK30为载体,采用溶剂法和溶剂-熔融法制备杨梅素固体分散体,采用紫外分光光度法进行含量测定,并进行溶解度、体外溶出试验。结果两种载体的固体分散体均能增加药物的溶解度和溶出速率,杨梅素在载体中以高度分散状态存在。结论以PVPK30为载体的杨梅素固体分散体体外溶解度和溶出速率明显提高。杨梅素固体分散体能显著提高杨梅素的溶出速率。     

Improving the solubility of ampelopsin by solid dispersions and inclusion complexes

The aim of this study was to increase the solubility of ampelopsin (AMP) in water by two systems: solid dispersions with polyethylene glycol 6000 (PEG 6000) or polyvinylpyrrolidone K-30 (PVP K30) and inclusion complexes with beta-cyclodextrin (BCD) and hydroxypropyl-beta-cyclodextrin (HPBCD). The interaction of AMP with the hydrophilic polymers was evaluated by differential scanning calorimetry (DSC), Fourier transformation-infrared spectroscopy (FTIR), scanning electron microscopy (SEM). The results from DSC, FTIR and SEC analyses of solid dispersions and inclusion complexes showed that AMP might exist as an amorphous state or as a solid solution. On the other hand, the SEM images of the physical mixtures revealed that to some extent the drug was present in a crystalline form. The influence of various factors (pH, temperature, type of polymer, ration of the drug to polymer) on the solubility and dissolution rate of the drug were also evaluated. The solubility and dissolution rates of AMP were significantly increased by solid dispersions and cyclodextrin complexes as well as their physical mixtures. The improvement of solubility using polymers was in the following order: HPBCD approximately BCD>PVP K30>PEG 6000.     

Increased dissolution and oral absorption of itraconazole/Soluplus extrudate compared with itraconazole nanosuspension

The purpose of this article was to compare the in vitro and in vivo profiles of itraconazole (ITZ) extrudates and nanosuspension separately prepared by two different methods. And it was proved truly to form nanocrystalline and amorphous ITZ characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) analysis, Fourier transform infrared spectrum (FTIR), transmission electron microscope (TEM), and scanning electron microscope (SEM). The release of ITZ/Soluplus solid dispersions with amorphous ITZ was almost complete while only 40% release was obtained with ITZ nanocrystals. The amorphous state need not to cross over the crystal lattice energy upon dissolution while the crystalline need to overcome it. In the in vivo assay, the AUC(0–t) and C_max of ITZ/Soluplus were 6.9- and 11.6-time higher than those of pure ITZ. The formulation of the extrudate had an AUC(0–t) and C_max similar to those of ITZ and also OH-ITZ compared with the commercial capsule (Sporanox®). The relative bioavailability values with their 95% confidence limit were calculated to be 98.3% (92.5–104.1%) and 101.3% (97.9–104.1%), respectively. The results of this study showed increased dissolution and bioavailability of the solid dispersion of Soluplus-based carrier loading ITZ prepared by HME compared with the ITZ nanosuspension prepared by wet milling.     

Solubility of Small-Molecule Crystals in Polymers: <Emphasis Type="SmallCaps">d</Emphasis>-Mannitol in PVP,Indomethacin in PVP/VA,and Nifedipine in PVP/VA

Objective  Amorphous pharmaceuticals, a viable approach to enhancing bioavailability, must be stable against crystallization. An amorphous drug can be stabilized by dispersing it in a polymer matrix. To implement this approach, it is desirable to know the drug’s solubility in the chosen polymer, which defines the maximal drug loading without risk of crystallization. Measuring the solubility of a crystalline drug in a polymer is difficult because the high viscosity of polymers makes achieving solubility equilibrium difficult. Method  Differential Scanning Calorimetry (DSC) was used to detect dissolution endpoints of solute/polymer mixtures prepared by cryomilling. This method was validated against other solubility-indicating methods. Results  The solubilities of several small-molecule crystals in polymers were measured for the first time near the glass transition temperature, including d-mannitol (β polymorph) in PVP, indomethacin (γ polymorph) in PVP/VA, and nifedipine (α polymorph) in PVP/VA. Conclusion  A DSC method was developed for measuring the solubility of crystalline drugs in polymers. Cryomilling the components prior to DSC analysis improved the uniformity of the mixtures and facilitated the determination of dissolution endpoints. This method has the potential of providing useful data for designing physically stable formulations of amorphous drugs.     

New Cyclodextrin Hydrogels Cross-Linked with Diglycidylethers with a High Drug Loading and Controlled Release Ability

Purpose The goal of the study is to develop new hydrogels based on cyclodextrins cross-linked with ethyleneglycol diglycidylether (EGDE) under mild conditions, to be used as carriers of amphiphilic drugs. Also, it aims to characterize the cross-linking and the drug loading and release processes. Methods The cross-linking of hydroxypropyl-β-cyclodextrin (HPβCD) with EGDE, in the absence or presence of hydroxypropylmethylcellulose (HPMC) Methocel? K4M, was optimized applying oscillatory rheometry and Fourier transform infrared. Hydrogels were characterized regarding swelling in water, ability to load diclofenac, and release after different drying treatments. Results Solutions of HPβCD (14.28%), without or with HPMC (0.2–1.0%), provided firm and transparent hydrogels after cross-linking with EGDE (14.28%), in which around two thirds of the OH groups were cross-linked. The incorporation of HPMC progressively reduced the gel time and the swelling degree of hydrogels. HPβCD hydrogels efficiently loaded diclofenac and sustained the release for several hours. The presence of HPMC slowed the release from swollen hydrogels, but promoted it from hydrogels dried before the loading and also before the release. Conclusions HPβCD hydrogels with good mechanical properties and tunable loading and release ability can be obtained by direct cross-linking with EGDE. *The work described in this paper is the subject of patent applications filed by the University of Santiago de Compostela.     

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

Purpose  

To test the efficacy and viability of poly (lactic-co-glycolic acid) (PLGA) microspheres encapsulating an inclusion complex of prostaglandin E₁ (PGE₁) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) for pulmonary delivery of PGE₁ for treatment of pulmonary arterial hypertension (PAH), a disease of pulmonary circulation.     

Probing Beta Relaxation in Pharmaceutically Relevant Glasses by Using DSC

Purpose This study was conducted to demonstrate the use of differential scanning calorimetry (DSC) in detecting and measuring β-relaxation processes in amorphous pharmaceutical systems. Methods DSC was employed to study amorphous samples of poly(vinylpyrrolidone) (PVP), indomethacin (IM), and ursodeoxycholic acid (UDA) that were annealed at temperatures (T_a) around 0.8 of their glass transition temperatures (T_g). Dynamic mechanical analysis (DMA) was used to measure β-relaxation in PVP. Results Reheating the annealed samples gives rise to annealing peaks that occur below T_g. The peaks cannot be generated when annealing below the low temperature limit of β-relaxation. These limits are around 50°C for PVP, −20°C for IM, and 30°C for UDA. The effective activation energy (E) of the sub-T_g relaxation has been estimated for each T_a and found to increase with T_a, reflecting increasing contribution of the α-process. Estimates of E for β-relaxation have been obtained from the lowest T_a data, and are as follows: 68 (PVP), 56 (IM), 67 (UDA) kJ mol⁻¹. Conclusions DSC can be used for detecting β-relaxation processes and estimating its low temperature limit, i.e., the temperature below which amorphous drugs would remain stable. It can also provide comparative estimates of low temperature stability of amorphous drugs in terms of the activation energies of the β-relaxation.     

Preparation and Evaluation of Fast Dissolving Ibuprofen-Polyethylene Glycol 6000 Solid Dispersions

To improve its oral absorption, rapidly dissolving ibuprofen solid dispersions (SD) were prepared in a relatively easy, simple, quick, inexpensive, and reproducible manner, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). They were evaluated for solubility, in vitro release, and oral bioavailability of ibuprofen in rats. Loss of individual surface properties during melting and resolidification as revealed by SEM indicated the formation of effective SDs. Absence or shifting toward the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. However, no such interactions in the solid state were confirmed by FTIR spectra that showed the presence of drug crystalline in SDs. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C_max, and a significant decrease in T_max over pure ibuprofen. Preliminary results from this study suggested that the preparation of fast-dissolving ibuprofen SDs by low temperature melting method using PEG 6000 as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution, and absorption rate of ibuprofen.