Physical stability of ternary solid dispersions of itraconazole in polyethyleneglycol 6000/hydroxypropylmethylcellulose 2910 E5 blends

In order to understand the influence of temperature and moisture, polymer blends of polyethyleneglycol 6000 (PEG 6000) and hydroxypropylmethylcellulose 2910 E5 (HPMC 2910 E5) and solid dispersions of itraconazole in these polymer blends were spray dried, further dried for 2 weeks and stored at three different conditions: 25 degrees C, 0% relative humidity (RH); 25 degrees C, 52% RH; 60 degrees C, 0% RH. MTDSC analysis of the polymer blends revealed that at 25 degrees C, 52% RH, PEG 6000 recrystallized to a high extent. At 60 degrees C, 0% RH the two polymers were miscible, probably due to the removal of bound water. In the ternary dispersions the polymers behaved similarly. The crystallinity degree of itraconazole in samples stored at 25 degrees C, 52% RH and at 60 degrees C, 0% RH was increased compared to the samples stored at 25 degrees C, 0% RH, probably due to the plasticizing effect of moisture at 25 degrees C, 52% RH and to an increased mobility at 60 degrees C, 0% RH. XPS analysis revealed a redistribution of itraconazole at the surface as itraconazole recrystallized from the blend. Dissolution tests revealed that a decrease in the itraconazole release was directly related to its crystallinity degree, no correlation was found with the crystallinity degree of PEG 6000.     

Fast-dissolving tablets of glyburide based on ternary solid dispersions with PEG 6000 and surfactants

Marketed glyburide tablets present unsatisfying dissolution profiles that give rise to variable bioavailability. With the purpose of developing a fast-dissolving tablet formulation able to assure a complete drug dissolution, we investigated the effect of the addition to a reference tablet formulation of different types (anionic and nonionic) and amounts of hydrophilic surfactants, as well as the use of a new technique, based on ternary solid dispersions of the drug with an hydrophilic carrier (polyethylene glycol [PEG] 6000) and a surfactant. Tablets were prepared by direct compression or previous wet granulation of suitable formulations containing the drug with each surfactant or drug:PEG:surfactant ternary dispersions at different PEG:surfactant w/w ratios. The presence of surfactants significantly increased (p<0.01) the drug dissolution rate, but complete drug dissolution was never achieved. On the contrary, in all cases tablets containing ternary solid dispersions achieved 100% dissolved drug within 60 min. The best product was the 10:80:10 w/w ternary dispersion with PEG 6000 and sodium laurylsulphate, showing a dissolution efficiency 5.5-fold greater than the reference tablet formulation and 100% drug dissolution after only 20 min.     

Influence of polyethylene glycol chain length on compatibility and release characteristics of ternary solid dispersions of itraconazole in polyethylene glycol/hydroxypropylmethylcellulose 2910 E5 blends

The present study aims to elucidate the influence of the polyethylene glycol chain length on the miscibility of PEG/HPMC 2910 E5 polymer blends, the influence of polymer compatibility on the degree of molecular dispersion of itraconazole, and in vitro dissolution. PEG 2000, 6000, 10,000 and 20,000 were included in the study. Solid dispersions were prepared by spray drying and characterized with MDSC, XRPD and in vitro dissolution testing. The polymer miscibility increased with decreasing chain length due to a decrease in the Gibbs free energy of mixing. Recrystallization of itraconazole occurred as soon as a critical temperature of ca. 75 degrees C was reached for the glass transition that represents the ternary amorphous phase. Due to the lower miscibility degree between the longer PEG types and HPMC 2910 E5, the ternary amorphous phase was further separated, leading to a more rapid decrease of the ternary amorphous phase glass transition as a function of PEG and itraconazole weight percentage and hence, itraconazole recrystallization. In terms of release, an advantage of the shorter chain length PEG types (2000, 6000) over the longer chain length PEG types (10,000, 20,000) was observed for the polymer blends with 5% of PEG with respect to the binary itraconazole/HPMC 2910 E5 solid dispersion. Among the formulations with a 15/85 (w/w) PEG/HPMC 2910 E5 ratio on the other hand, there was no difference in the release profile.     

Characterization of ternary solid dispersions of Itraconazole in polyethylene glycol 6000/polyvidone-vinylacetate 64 blends.

The good compatibility between Itraconazole and polyvidone-vinylacetate 64 (PVPVA 64) was pointed out previously. However, the dissolution properties of these systems left room for improvement. Therefore polyethylene glycol 6000 (PEG 6000), known for its solubilizing and wetting properties, was added to the PVPVA 64 matrix. Physicochemical analysis showed that up to 10% of PEG 6000 could be mixed with PVPVA 64. Addition of 10%, 20% or 40% of Itraconazole rendered amorphous solid dispersions consisting of a ternary mixed phase and a PVPVA 64 rich amorphous phase. If the PEG 6000 fraction was elevated up to 25% of the carrier, the PEG 6000 crystallinity degree was around 73+/-0.6%. Up to 20% of Itraconazole could be molecularly dispersed in the 25/75 w/w polymer blend. An Itraconazole melting peak could be detected for the sample containing 40% of drug. Dissolution experiments showed that no benefit was obtained by adding PEG 6000 to the PVPVA 64 matrix for samples containing up to 20% of Itraconazole. The dissolution of the ternary dispersions with 40% of Itraconazole on the other hand showed improvement compared to binary Itraconazole/PVPVA 64 dispersions.     

半边旗二萜类化合物5F-聚乙二醇6000固体分散体中5F的含量测定

目的与方法采用紫外分光光度法,检测波长为242nm,建立半边旗二萜类化合物5F-聚乙二醇6000固体分散中5F的含量测定方法。结果5F-聚乙二醇6000固体分散体中5F在5.0～25.0μg/ml范围内,吸光度值与浓度呈良好的线性关系(r=0.9998),平均回收率为98.04%,RSD为1.06%(n=6)。结论该测定方法稳定、快速、准确、简便,可以作为5F-聚乙二醇6000固体分散体中5F的质量控制方法。     

Formulation of fast disintegrating tablets of ternary solid dispersions consisting of TPGS 1000 and HPMC 2910 or PVPVA 64 to improve the dissolution of the anti-HIV drug UC 781

Solid dispersion formulations made up of d-alpha-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) and polyvinyl pyrrolidone co-vinyl acetate 64 (PVPVA 64) or hydroxy propyl methyl cellulose 2910 (HPMC 2910) were developed in order to improve the dissolution of UC 781. UC 781 dissolution rate was markedly improved as compared to the physical mixtures and the pure drug, attaining maximum drug releases of up to 100% after only 5 min in the case of TPGS 1000-UC 781-PVPVA 64 solid dispersions and 30 min in TPGS 1000-UC 781-HPMC 2910. The increased UC 781 dissolution rate could be maintained when formulating UC 781 in PVPVA 64 tablets. The latter disintegrated in only 4 min, reaching drug releases of up to 90% (w/w). In addition, as opposed to the corresponding solid dispersions, no decrease in drug release occurred upon dissolution of PVPVA 64 tablets when the pH was increased to 6.8. Contrary to the PVPVA 64 tablet formulations, HPMC 2910 tablets showed a slow dissolution process due to the gelling nature of the polymer. The drug was slowly released as HPMC 2910 dissolved in the medium, however also in this case 90% (w/w) of the drug was dissolved after 4 h. Both polymers formed compatible blends in combination with the drug. Thermal analysis of the ternary mixtures revealed eutectic behavior exhibiting an extremely fine dispersion of the drug in the carrier. This was confirmed by the fact that no drug crystals could be detected using X-ray diffraction (XRD). As opposed to the physical mixtures, PVPVA 64 and HPMC 2910 solid dispersions did not contain any isolated polymer-rich phases, hence showed improved homogeneity. Amorphous TPGS 1000 clusters occurred in PVPVA 64 and HPMC 2910 formulations upon addition of at least 10% (w/w) UC 781, showing extremely low glass transition temperatures depending of the thermal history of the samples.     

Solubility of selected derivatives of 1,4-benzodiazepin-2-one in solid dispersions in PEG 6000

Pharmaceutical availability of diazepam, oxazepam and nitrazepam from solid dispersions of PEG 6000 have been studied in comparison with corresponding physical mixtures and pure benzodiazepines. Selected derivatives of 1,4-benzodiazepin-2-one are poorly water soluble drugs. The aim of this work was to report the properties of diazepam- and nitrazepam-PEG 6000 solid dispersions. Differential scanning calorimetry (DSC) and X-ray diffraction were used to characterize the solid dispersions. The effect of PEG 6000 on the dissolution of selected derivatives of 1,4-benzodiazepin-2-one was investigated. The dissolution of diazepam, oxazepam and nitrazepam from its solid dispersions increased in the presence of PEG 6000.     

Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion--Part I

Solid dispersions containing different ratios of itraconazole and hydroxypropylmethylcellulose (HPMC) were prepared by solvent casting. Based on dose, differential scanning calorimetry and dissolution results, a drug/polymer ratio of 40/60 w/w was selected in order to prepare dispersions by melt extrusion. The melt extrusion process was characterized using a design of experiments (DOE) approach. All parameter settings resulted in the formation of an amorphous solid dispersion whereby HPMC 2910 5 mPas prevents re-crystallization of the drug during cooling. Dissolution measurements demonstrated that a significantly increased dissolution rate was obtained with the amorphous solid dispersion compared to the physical mixture. The outcome of DOE further indicated that melt extrusion is very robust with regard to the itraconazole/HPMC melt extrudate characteristics. Stability studies demonstrated that the itraconazole/HPMC 40/60 w/w milled melt extrudate formulation is chemically and physically stable for periods in excess of 6 months as indicated by the absence of degradation products or re-crystallization of the drug.     

Characterization and stability of solid dispersions based on PEG/polymer blends

Solid dispersions were prepared by a melting method from the water-insoluble model drugs carbamazepine and nifedipine and polyethylene glycol 1500 (PEG 1500) or 1:1 mixtures of PEG 1500 and the polymers polyvinylpyrrolidone (PVP 30, PVP 12), polyvinylpyrrolidone-co-vinylacetate (PVPVA) and Eudragit EPO (Eudragit) in order to combine advantages of the different carrier polymers (recrystallization inhibition, processability and stability). The solid dispersions were characterized by dissolution, powder X-ray diffractometry and microscopy directly after preparation and after storage for 3 and 6 months at 25 °C/0% relative humidity (RH) or 3 months at 40 °C/75% RH. More than 80% drugs were released from all solid dispersions within 20 min. The dissolution rate of carbamazepine decreased in the order of PEG 1500 > PEG 1500/Eudragit > PEG 1500/PVP 30 > PEG 1500/PVPVA > PEG 1500/PVP 12. The dissolution rank order was not directly correlated to the amorphous/crystalline state of the drugs, but rather to the properties of the PEG 1500/polymer compositions. Nifedipine was released in the order of PEG 1500 > PEG 1500/PVPVA > PEG 1500/PVP 30 > PEG 1500/PVP 12 > PEG 1500/Eudragit. Amorphous nifedipine was present in all PEG 1500/polymer dispersions except in pure PEG 1500 solid dispersion. The significant increase in dissolution rate of PEG 1500 solid dispersions was due to the reduced crystallinity of the drug and the excellent solubilisation properties of PEG 1500. After 6 months storage at 25 °C/0% RH, the solid dispersions released both drugs in the order PEG 1500/PVPVA > PEG 1500/PVP 30 > PEG 1500/PVP 12 > PEG 1500/Eudragit > PEG 1500. The stabilized amorphous state of the drug resulted in stable dissolution profiles of PEG 1500/PVPVA, PEG 1500/PVP 30 and PEG 1500/PVP 12 when compared to the PEG 1500 solid dispersions, which contained a higher amount of crystalline drug. The solid dispersions with PEG 1500/PVPVA or PEG 1500/PVP stored for 3 months at 40 °C/75% RH showed phase separation due to the hygroscopic properties of the polymers. The influence of 10% (w/w) of the solubilisers polyoxyl 40 hydrogenated castor oil (Cremophor), macrogol-15-hydroxystearate (Solutol) and fatty alcohol alkoxylate (Pluronic) on the dissolution rate and the physical state of the drug was significant.     

Improvement of the dissolution kinetics of SR 33557 by means of solid dispersions containing PEG 6000

Solid dispersions of SR 33557 in preparations containing from 30 to 80% w/w polyethylene glycol 6000 (PEG 6000) were prepared by the fusion method. The solubility of the drug substance either alone or in solid dispersions was determined in pH 1.2 and 4.5 media (extraction fluid NFXII, without enzyme). A large increase in the solubility was noted from the 80% w/w PEG preparation. A wettability study performed by measuring the contact angle on tablets of either drug substance or PEG 6000, or solid dispersions, revealed a minimal contact angle for the 80% w/w PEG 6000 solid dispersion (eutectic composition of SR 33557/PEG 6000 phase diagram). Dissolution kinetic analysis performed at pH 1.2 on all solid dispersions, on the physical mixtures containing 70 and 80% w/w PEG 6000, and on SR 33557 alone, showed a maximum release rate (100%) for the solid dispersions containing 70 and 80% w/w PEG 6000. The dissolution rate of the physical mixtures was faster than that of the drug substance alone but remained, however, lower than that of the solid dispersions, at the same composition. It was also observed that the dissolution rate, at pH 1.2 and 4.5, of the 70% w/w PEG 6000 solid dispersion was practically pH independent, which was not the case for the drug substance alone. The latter solid dispersion showed a slowing down of the dissolution kinetics after 3 months storage at 50°C whereas no change in the dissolution rate was observed following storage for 12 months at 25°C.     

洛伐他汀固体分散体的制备及体外溶出特性比较

目的：利用固体分散技术制备洛伐他汀固体分散体，增加其溶出速率。方法：以不同比例的聚乙烯吡咯烷酮（PVPk-30）、聚乙二醇6000（PEG6000）为载体，采用溶剂法和熔融法制成洛伐他汀固体分散体，测定其溶出速率，并采用差示扫描量热（DSC）法、显微照相技术鉴别药物在固体分散体中的存在状态。结果：两种固体分散体均能提高洛伐他汀溶出速率，在药物载体比例大于1：5时效果较好；洛伐他汀固体分散体中晶型消失，分散在载体中。载体为PVPK30所制固体分散体的溶出速率总体优于载体PEG6000。结论：固体分散体能加速洛伐他汀溶出速率。     

Study of the physicochemical properties and stability of solid dispersions of loperamide and PEG6000 prepared by spray drying.

Solid dispersions of PEG6000 and loperamide-a poorly water-soluble agent-were prepared by spray drying. Their physicochemical properties were evaluated immediately after preparation. The dissolution was higher than that of pure crystalline loperamide. DSC- and XRD-measurements revealed that in the dispersions, loperamide is partially present in the crystalline state. A eutectic state diagram was obtained. The samples containing 20% loperamide were stored under different conditions (40 degrees C and 0% RH, 25 degrees C and 52% RH, 4 degrees C and 0% RH) to investigate their stability as a function of time. The dissolution properties deteriorate upon storage at high temperature (40 degrees C and 0% RH) and in conditions of higher relative humidity (25 degrees C and 52% RH). The DSC-curves clearly indicate an increase in the amount of crystalline compound under these conditions. From these observations it could be concluded that loperamide, which is partially crystalline and partially amorphous in the freshly prepared samples, continues to crystallize under these conditions, resulting in progressively poorer dissolution properties.     

Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30

This paper describes the physical stability of solid dispersions of UC-781 with PEG 6000, Gelucire 44/14 and PVP K30 prepared by the solvent and melting methods. The concentration of the drug in the solid dispersions ranged from 5 to 80% w/w. The solid dispersions were stored at 4-8 and 25 degrees C (25% RH), then their physicochemical properties were analysed by differential scanning calorimetry (DSC), X-ray powder diffraction and dissolution studies as a function of storage time. The DSC curves of solid dispersions of UC-781 with PVP K30 did not show any melting peaks corresponding to UC-781 after storage, indicating no recrystallization of the drug. The DSC data obtained from PEG 6000 and Gelucire 44/14 showed some variations in melting peak temperatures and enthalpy of fusion of the carriers. It was shown that the enthalpy of fusion of PEG 6000 in the dispersions increased after storage; it was more pronounced for samples stored at 25 degrees C compared to those at 4-8 degrees C indicating the reorganization of the crystalline domains of the polymer. Similarly, the enthalpy of fusion of Gelucire 44/14 in the solid dispersions increased as a function of time. Dissolution of UC-781 from all solid dispersions decreased as a function of storage time. While these observations concurred with the DSC data for all solid dispersions, they were not reflected by X-ray powder diffraction data. It was concluded that it is the change of the physical state of the carriers and not that of the drug, which is responsible for the decreased dissolution properties of the solid dispersions investigated.     

In vitro and in vivo evaluation of carbamazepine-PEG 6000 solid dispersions

The present work extended previous physico-chemical investigations on the effects of solid dispersion on the solubility, the dissolution rate and the pharmacokinetic profile of carbamazepine. Solubility studies showed a linear increase in carbamazepine solubility with the increase of PEG 6000 concentration. There is no marked difference between physical mixtures and solid dispersions for the enhancement of carbamazepine solubility by PEG 6000. Less than 60% of pure carbamazepine was dissolved in 90 min. Physical mixtures (carbamazepine phase III) and solid dispersions (carbamazepine phase II) dissolution rates were higher in comparison of the parent drug. The dissolution of carbamazepine phase III was more pronounced than that evoked by the phase II. The dissolution profiles indicated that the percentage of the drug dissolved was dependent on the proportion of PEG 6000. In solid dispersions there was a remarkable enhancement in the dissolution rates of the drug in the vicinity of the eutectic composition as compared with those of corresponding physical mixtures. Hence, the optimum value for the solid dispersion was 80.5+/-1.7% of carbamazepine having dissolved within the first 10 min compared to 40+/-1% for the corresponding physical mixtures of the same composition. Statistical analysis of pharmacokinetic parameters confirmed that the carbamazepine:PEG 6000 binary systems displayed higher bioavailability of the drug than the pure carbamazepine. The area under the curve (AUC) values highlighted the evidence that only slight differences in the bioavailability of the drug occur between physical mixtures and solid dispersions prepared at the 80:20 and 50:50 drug:carrier compositions. However, the mean normalized plasma concentrations showed that standard error deviations are rather wide intervals for pure drug and physical mixtures in comparison to solid dispersions. One additional interesting point to consider is the disappearance of the multiple peaks on the individual kinetic curves of the 50:50 solid dispersion composition. Furthermore, our investigations have highlighted the interest of solid dispersions prepared at -eutectic composition as our preliminary data show that the plasma concentration (C(5h)) of the drug for the 15:85 dispersed sample containing 150 mg of carbamazepine is not significantly different from that obtained for the 50:50 dispersed sample containing 300 mg of the drug.     

Characterization of nifedipine solid dispersions

The sublingual administration of nifedipine (NIF) is currently used in clinical practice. The sublingual administration of NIF solid dispersions (SD), by using a suitable dispenser, appears an interesting approach in the treatment of moderate and severe hypertensive emergencies. With this aim nine SD made of NIF and a low viscosity hydroxypropylmethylcellulose (HPMC) in different ratio were prepared by means of spray-drying technique and their structure was studied. Moreover, the drug dissolution properties from SD were verified. The characteristic peaks of crystalline NIF were not detectable by using the X-ray analysis when the NIF/HPMC ratios were lower than 50/50 w/w. In thermograms obtained from SD, the NIF melting endothermic peak disappeared when NIF/HPMC ratios were lower than 30/70 w/w; the experimental Tg values of SD were lower than the Tg values predicted by Gordon Taylor equation suggesting some type of non-ideality of mixing. In the SD FTIR spectra the NH stretching vibrations and the C=O stretch in esteric groups of NIF shift to free NH and C=O regions indicating the rupture of intermolecular hydrogen bond in the crystalline structure of NIF. The prepared SD improved the NIF dissolution rate in comparison with that of commercial NIF or NIF/HPMC physical mixtures. Moreover, the concentration of NIF in the dissolution medium increased decreasing the NIF content.     

Diclofenac salts, II. Solid dispersions in PEG6000 and Gelucire 50/13.

A number of systems were prepared at five compositions (5, 10, 20, 30 and 40% w/w) of diclofenac/N-(2-hydroxyethyl) pyrrolidine salt and acidic diclofenac in PEG6000 and Gelucire 50/13, as physical mixtures and as solid dispersions. Powder X-ray diffractograms for the systems examined show shifted and normal peaks, suggesting that the drug is present inside the samples in different physical states. Differential scanning calorimetry does not offer important information, since drug solubility into the carriers increases with temperature and thermograms show only the melting point peak of the carriers. Hot-stage microscopy examination explains that, in high concentration samples, the drug is present either dissolved into the carriers, or precipitated as microcrystals, or undissolved crystals of larger size. Gelucire 50/13 allows the formation of larger crystals than PEG, using both the chemical forms of the drug. The release percentage of the drug from PEG6000/acidic diclofenac reaches 50% after few minutes in the most favourable case and appears to be dependent on the composition of the samples: the more diclofenac is present as dissolved in the pre-treated samples, the higher is the release. The optimum composition was found in the range of 5-10% w/w.     

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.     

Preparation and characterization of solid dispersions of Quercetin with PEG4000

Objective To enhance the solubility,quicken the speed of digesting and absorption,and increase the bioavailability of quercetin(3,3',4',5,7-pentahydroxyflavone).Methods A series of Quercetin-PEG4000 solid dispersions were prepared by fusion method.The configuration and property of solid dispersion were characterized by solubility tests,dissolution tests,FTIR spectra,differential scanning calorimetry(DSC)and microphotograph.Results 1.According to solubility tests the the mass ratio of quercetin to PEG4000 affected strongly on the solubility of solid dispersions,on the whole,the relation of the solubility of solid dispersions to the mass ratio presented linear relationship.The preparation temperature had little effect on the solubility of solid dispersions.The surface-active agent,polysorbate80 increased strongly the solubility of solid dispersions.2.According to the dissolution tests,the mass ratio of quercetin to PEG4000 affected strongly on the dissolution of solid dispersions,the preparation temperature had little effect on the dissolution of solid dispersions.The surface-active agent,polysorbate80 increased strongly the dissolution of solid dispersions,and after addition polysorbate80,the dissolution of solid dispersions was two times of the dissolution of solid dispersions without polysorbate80.3.According to the DSC results,except that a little of quercetin molecular existed as crystalline state in the solid dispersion with the mass ratio was qu:PEG=1:2,quercetin existed as amorphous phase in other mass ratio solid dispersion.4.According to the FTIR spectra and microphotograph results,the relation of quercetin and PEG4000 was mainly physical mixing in quercetin-PEG4000 solid dispersion.Quercetin was just like solute in solution,and PEG4000 was just like solvent in solution.The force between quercetin and PEG4000 was mainly hydrogen bonding,so the biological activity of quercetin would not be influenced greatly after the formation solid dispersion.Conclusions These results suggest that quercetin existed mainly as amorphous phase in solid dispersion;the solubility and the dissolution in water were increased obviously after formation the solid dispersion.     

The formulation of Halofantrine as either non-solubilizing PEG 6000 or solubilizing lipid based solid dispersions: physical stability and absolute bioavailability assessment

A non-solubilizing solid dispersion formulation (polyethylene glycol 6000) and two solubilizing solid dispersions (Vitamin E TPGS and a Gelucire 44/14/Vitamin E TPGS blend) containing the antimalarial, Halofantrine (Hf), were formulated for bioavailability assessment in fasted beagles to determine if the oral absorption of Hf can be enhanced by these delivery systems. Solid dispersions comprising varying proportions of drug to carrier were prepared by the fusion method. Whilst the non-solubilizing formulation was assessed according to its dispersion characteristics, the solubilizing solid dispersions were assessed by their ability to form microemulsions upon dispersion. Studies in fasted beagles showed that the solid dispersions afforded a five- to seven-fold improvement in absolute oral bioavailability when compared with the commercially available tablet formulation. The delivery of Hf in either a solubilizing or non-solubilizing solid dispersion did not result in significant differences in oral bioavailability. The physical stability of the solid dispersions was studied using differential scanning calorimetry and X-ray powder diffraction.     

Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion.

The aim of this study was to investigate the performance of three new solid dispersion formulations of itraconazole in human volunteers in comparison with Sporanox, the marketed form. Solid dispersions made up of itraconazole (40%, w/w) and HPMC 2910, Eudragit E100 or a mixture of Eudragit E100-PVPVA64 were manufactured by hot-stage extrusion and filled in gelatin capsules. The formulations were tested in eight human volunteers in a double blind, single dose, and cross-over study. Concentrations of the drug and its metabolite hydroxyitraconazole in the plasma were determined using HPLC. The in vivo performance was evaluated by comparing the mean area under the plasma concentration-time curves (AUC), the mean maximum plasma concentration (C(max)), and the mean time to reach C(max) (T(max)). The mean bioavailability of itraconazole was comparable after administration of the HPMC solid dispersion, compared to Sporanox, while it was lower after administration of the Eudragit E100 or Eudragit E100-PVPVA64 dispersions. Due to high variability, a significant decrease in AUC and C(max) was only observed for the Eudragit E100-PVPVA formulation. Although the solid dispersions showed different in vitro dissolution behaviour, T(max) values were comparable. The same observations with respect to AUC, C(max) and T(max) could be made for hydroxyitraconazole. The present results indicate that hot-stage extrusion can be considered as a valuable alternative for manufacturing solid dispersions of itraconazole.