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Abstract Solid dispersions (SDs) of ursolic acid (UA) were developed using polyvinylpyrrolidone K30 (PVP K30) in combination with non-ionic surfactants, such as D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) or poloxamer 407 (P407) with the aim of enhancing solubility and in vitro release of the UA. SDs were investigated using a 24 full factorial design, subsequently the selected formulations were characterized for water solubility, X-ray diffractometry (XRD), differential scanning calorimetry (DSC), particle diameter, scanning electron microscopy, drug content, physical-chemical stability and in vitro release profile. SDs showed higher UA water-solubility than physical mixtures (PMs), which was attributed by transition of the drug from crystalline to amorphous or molecular state in the SDs, as indicated by XRD and DSC analyses. SD1 (with P407) and SD2 (with TPGS) were chosen for further investigation because they had higher drug load. SD1 proved to be more stable than SD2, revealing that P407 contributed to ensure the stability of the UA. Furthermore, SD1 and SD2 increased UA release by diffusion and swelling-controlled transport, following the Weibull model. Thus, solid dispersions obtained with PVP k-30 and P407 proved to be advantageous to enhance aqueous solubility and stability of UA.
Subject(s)
Polyethylene Glycols/administration & dosage , Solubility , Poloxamer/adverse effects , Diffusion , X-Rays/adverse effects , In Vitro Techniques , Calorimetry, Differential Scanning/methods , Pharmaceutical Preparations/analysis , Microscopy, Electron, Scanning/methodsABSTRACT
Amorphous solid dispersions (ASDs) are popular for enhancing the solubility and bioavailability of poorly water-soluble drugs. Various approaches have been employed to produce ASDs and novel techniques are emerging. This review provides an updated overview of manufacturing techniques for preparing ASDs. As physical stability is a critical quality attribute for ASD, the impact of formulation, equipment, and process variables, together with the downstream processing on physical stability of ASDs have been discussed. Selection strategies are proposed to identify suitable manufacturing methods, which may aid in the development of ASDs with satisfactory physical stability.
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The current work is aimed to design, prepare and evaluate the trilayer matrix tablets incorporated with lovastatin solid dispersion (SD) for extend drug release. The lovastatin SD prepared by using solvent evaporation technique with varying amounts of polymers (GMS II, Soluplus, Kolliphor ELP, PEG 2000 and Urea) for enhancing the drug solubility. All the formulations examined for physicochemical parameters are within the permissible limits. The optimized SD formulation was incorporated into trilayer matrix tablets which were prepared using different polymers (HPMC 15M & K100M, Chitosan, xanthan gum) by direct compression method for sustaining the drug release. The drug dissolution of optimized lovastatin SD formulation SD15 (drug, soluplus and SLN) was 99.88±5.32% within 60 min which is higher than pure drug 47.33±2.25% and other formulations. The FT-IR, XRD and SEM data assure the compatibility of drug and excipients and amorphous nature of lovastatin. The solid dispersions were further incorporated in to trilayer matrix tablets with active layer and barrier layers. Eight formulations of lovastatin trilayer matrix tablets (AF9-HF9) designed and checked for pre compression parameters. Formulation GF9 demonstrated highest drug release of 99.41±5.28% for 24 hours sustainably over an extended period of time and excellent flow properties. The release order kinetics data indicate the zero order release with highest R2 of 0.9957 for GF9, superior than market extended release formulation (R2=0.9934). All the formulations showed best fit to Higuchi model and Korsmeyer-Peppa’s model indicating diffusion and non-Fickian diffusion process of drug release. GF90 was found to be stable for 180 days at accelerated conditions. Hence the solubility, dissolution rate of lovastatin was enhanced by SD technique further incorporated in to trilayer matrix tablets for sustainable extended drug release upto 24 h.
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Objective: To prepare magnolol solid dispersions (Mag-SD), magnolol phospholipids complex (Mag-PC) and magnolol solid lipid nanoparticles (Mag-SLN), and compare their effects on the pharmacokinetics in vivo. Methods: Solvent evaporation method was used to prepare Mag-SD and Mag-PC. Their existential state of Mag in Mag-SD and Mag-PC were analyzed by X-ray power diffraction (XRPD). High pressure homogenization method was employed to prepare Mag-SLN, its particle size and Zeta potential were also studied. The dissolution in vitro of Mag-SD, Mag-PC and Mag-SLN were also studied compared to magnolol suspension. SD rats in each group were administered intragastrically with magnolol, Mag-SD, Mag-PC and Mag-SLN, respectively. The concentration of magnolol in blood was analyzed by HPLC, and the main pharmacokinetic parameters were obtained. The pharmacokinetic behavior and bioavailability of magnolol, Mag-SD, Mag-PC and Mag-SLN were also compared. Results: The results of XRPD indicated that magnolol showed an amorphous state in Mag-SD and Mag-PC. The average particle size and Zeta potential of Mag-SLN was (161.37 ± 3.77) nm and (-29.16 ± 1.83) mV, respectively. The results of dissolution in vitro indicated that the cumulative dissolution of magnolol was 30.6% within 12 h. Mag-SD, Mag-PC and Mag-SLN enhanced its cumulative dissolution to 96.3%, 76.4% and 45.9%, respectively. The results of pharmacokinetics in vivo showed that Cmax, AUC0-t and AUC0-∞ of Mag-SD, Mag-PC and Mag-SLN were enhanced greatly compared to magnolol suspension. Mag-PC, Mag-SD and Mag-SLN increased its Cmax from (429.67 ± 53.12) ng/mL to (533.62 ± 59.01), (721.73 ± 103.44) and (1 063.21 ± 108.22) ng/mL, respectively. The bioavailability of Mag-SD, Mag-PC and Mag-SLN were enhanced to 1.38, 2.12 and 3.45 times, respectively. Conclusion: Mag-SD, Mag-PC and Mag-SLN could promote the absorption of magnolol in SD rats notably. In addition, Mag-SLN could give a better effect on the bioavailability.
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@#Solid dispersions of the insoluble compound CHMFL-KIT-110 were prepared by solvent method with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus),Poloxamer 407,PEG 6000,Copovidone (Kollidon VA64) as carriers and SLS,Tween 80,Cremophor RH40 as solubilizers. The optimal formulation was screened and obtained with dynamic solubilities and supersaturation performances as indexes. The final product was characterized by Fourier transform infrared (FT-IR),differential thermal analysis (DTA) and X-ray powder diffraction (XRPD). The stability and pharmacokinetic behavior in rats were also investigated. Results suggested that when the weight ratio of CHMFL-KIT-110/Soluplus/SLS was 1∶4∶0.5,dynamic solubility of the solid dispersions was significantly improved with no recrystallization. In the accelerated condition (40 °C,75% RH) for 30 days,CHMFL-KIT-110 in the solid dispersions was still amorphous with no crystal observed. The results of pharmacokinetics in rats showed that the cmax and AUC0→t of CHMFL-KIT-110 solid dispersions were 373.1 times and 358.7 times higher than those of free drugs,respectively. These results help to understand the formulation development and clinical practice of CHMFL-KIT-110.
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The objective of the present study was to develop a solid dispersion formulation to improve oral bioavailability of poorly water-soluble drug carvedilol. Several solid dispersions were prepared by fusion-solvent method mixing different concentrations of Gelucire 44/14 and Gelucire 50/13. To the resultant solid dispersions, microcrystalline cellulose and amorphous fumed silica were added to obtain a free-flowing powder. The dissolution of carvedilol was evaluated using an USP Type-II dissolution apparatus. Solid dispersion with Gelucire 44/14 showed, in general, a lower extent of drug release when compared to Gelucire 50/13 at the same concentrations. Gelucire 50/13 in a ratio of 1 to 1.75 (drug: Gelucire) achieved a drug release of 83% in 4 hours, a 5-fold increase compared to pure carvedilol. When incorporating 10% D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS/ TPGS) a higher drug release was observed (88%). Parallel artificial membrane permeability assay was used to evaluate the in vitro diffusion. GelucireTPGS solid dispersion showed a higher permeability coefficient compared to pure drug. After oral administration to Sprague-Dawley rats, a significant increase in the oral bioavailability of carvedilol was observed when administered as a solid dispersion in combination with Gelucire-TPGS, 169% higher compared to pure drug suspension.
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Solid dispersions (SDs) are resulted by dispersion of drug in biologically inert matrix. They can be used to increase the solubility of a drug with low aqueous solubility, thereby improving its oral bioavailability. Higher drug dissolution rates from a SD can be facilitated by optimizing the wetting characteristics of the compound surface, as well as increasing the interfacial area available for drug dissolution. Although the latter can be easily accomplished by, for example: decreasing the particle size of the drug powder but micronized powders may result in further complications as they occasionally tend to agglomerate. A more preferable solution would be to introduce the drug in the form of a molecular dispersion. The aim of present study was to enhance the dissolution rate of diclofenac a practically less water-soluble drug. The same was done by preparation of solid dispersions of the drug employing different ratios of established polymers. This was done by using polymers namely; hydrophilic polymer β-cyclodextrins, PVP and PEG. The kneading method was used to prepare solid dispersions in various ratios with polymer. The dissolution data was studied for all the three formulations. The data obtained was compared with that of physical mixtures containing drug, polymer and lactose in the same ratio as that of solid dispersions. The dissolution data showed that best release was obtained in formulation f1 containing beta –cyclodextrins, PVP and PEG as polymer. The comparative data showed 98% release at approximately 4 hours with polymer β –cyclodextrins, whereas, 90% and 88% release were obtained using PEG and PVP respectively in the same time frame.
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Objective: To prepare osthole solid dispersions (Ost-SD), osthole phospholipids complex (Ost-PC), and osthole nanosuspensions (Ost-NS), and compare their effects on the pharmacokinetics in SD rats in vivo. Methods: Solvent evaporation method was used to prepare Ost-SD and Ost-PC. Their existential state of Ost in Ost-SD and Ost-PC were analyzed by X-ray power diffraction (XRPD). High pressure homogenization method was employed to prepare Ost-NS, its particle size and Zeta potential were studied. The dissolution in vitro of Ost-SD, Ost-PC, and Ost-NS were also studied compared to Ost suspension. SD rats in each group were ig administered with Ost, Ost-SD, Ost-PC, and Ost-NS, respectively. The concentration of Ost in blood was analyzed by HPLC, and the main pharmacokinetic parameters were obtained. The pharmacokinetic behavior and bioavailability were also been compared. Results: The results of XRPD indicated that Ost showed an amorphous state in Ost-SD and Ost-PC. The average particle size and Zeta potential of Ost-NS were (161.37 ± 3.77) nm and (-29.16 ± 1.83) mV, respectively. The results of dissolution in vitro indicated that the dissolution of Ost was improved greatly by Ost-SD, Ost-PC, and Ost-NS. The results of pharmacokinetics in vivo showed that Cmax, AUC0~t and AUC0~∞ of Ost-SD, Ost-PC, and Ost-NS were enhanced greatly compared to Ost. The bioavailability of Ost-SD, Ost-PC,and Ost-NS were enhanced to 165.92%, 138.46%, and 259.35%, respectively. Conclusion: Ost-SD, Ost-PC, and Ost-NS can enhance the bioavailability of Ost in SD rats notably. In addition, Ost-NS can give a better effect.
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AIM To prepare and characterize SiO2 solid dispersions of Curcumae longae Rhizoma extract.METHODS For the solid dispersions prepared by solvent evaporation method,its ratio of extract to carrier (SiO2) was screened by in vitro dissolution test,and the characterization was achieved by determination of particle size,specific surface area,porosity,micromorphology observation,infrared spectroscopy and X-ray.RESULTS When the ratio of extract to carfer was 1:8,three main components (bisdemethoxycurcumin,demethoxycurcumin and curcumin) in the extract reached the highest accumulative dissolution rates.Compared with physical mixture,the solid dispersions demonstrated lower particle size,specific surface area and porosity.Extract was dispensed in the carrier in an amorphous state.CONCLUSION SiO2 solid dispersions can obviously improve the dissolution rates of the main components in Curcumae longae Rhizoma extract.
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AIM To compare the effects of three preparation technologies on the oral bioavailability of HB (berberine α-hydroxy β-decanoylethyl sulfonate,houttuyn berberine).METHODS Solid dispersions,HP-β-CD inclusion complexes and nanosuspension freeze-dried powders were prepared.The suspensions of crude drug and these three preparations were intragastrically administered to SD rats,respectively.HPLC-MS/MS was adopted in the content determination of HB in plasma.then pharmacokinetics parameters were calculated.RESULTS Compared with the crude drug,three preparation technologies could significantly increase the Cmax value of this component (P ＜ 0.05),especially for HP-β-CD inclusion complexes (P ＜ 0.01).And HP-β-CD inclusion complexes demonstrated much higher AUC0-6h than the crude drug and the other two preparation technologies (P ＜ 0.05).CONCLUSION HP-β-CD inclusion complexes can effectively increase the oral bioavailability of HB.
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AIM To prepare silymarin solid dispersions and to evaluate the dissolution rates of five constituents.METHODS Taking F68 and PVPk30 as a combined carrier,the solid dispersions were prepared by solvent fusion method.Then the effects of combined carrier ratio and drug-carrier ratio on dissolution rates of silybin,isosilybin,silydianin,silycristin and taxifolin were investigated.RESULTS The optimal conditions were determined to be 1 ∶ 3 for combined carrier ratio,and 1 ∶ 5 for drug-carrier ratio.These five constituents displayed much higher dissolution rates in solid dispersions than those in raw medicine and physical mixture (silymarin-carrier).CONCLUSION Solid dispersions can significantly increase the dissolution rates of effective components in silymarin.
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Objective: To compare intestinal absorption features of berberine hydrochloride phospholipid solid dispersions (BBH-PSD) by rat single-pass perfusion model, and to explore the mechanism of berberine bioavailability increasing mechanism by phospholipid solid dispersion technology. Methods: The single-pass perfusion model was established in rats, the concentration of berberine in intestinal perfusion was determined by HPLC, and phospholipid solid dispersion technology promoting intestinal absorption of berberine was investigated. Results: Compared with berberine, BBH-PSD could promote much more absorption of berberine in various intestinal segments, especially in jejunum, and the mechanism was related to improving permeability and strengthen simple diffusion of berberine. The Ka and Papp values of BBH and BBH-PSD in jejunum were obviously higher than BBH (P < 0.05); When the volumetic flow rate of BBH-PSD was 0.2, 0.4, and 0.8 mL/min, Ka and Papp were both higher than BBH (P < 0.05); The increasing mass concentration was not obvious to intestinal absorption of BBH, while the increasing mass concentration of BBH-PSD obviously increased the intestinal absorption of BBH (P < 0.05). Conclusion: Intestinal absorption characteristics of berberine phospholipid solid dispersion is beneficial to improve berberine oral bioavailability, and it can provide a scientific basis for the development of new dosage forms of berberine hydrochloride.
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AIM To prepare fisetin solid dispersions.METHODS Melting method and solvent method were used for the preparation of solid dispersions,respectively.With carrier type,drug-carrier ratio and stirring time as influencing factors,accumulative dissolution rate as an evaluation index,the preparation was optimized by orthogonal test on the basis of single factor experiment.The interaction between drug and carrier was investigated by Fourier transform infrared spectroscopy (FTIR),and the drug existing state was analyzed by differential scanning calorimetry (DSC).RESULTS Solvent method was more suitable for the preparation of solid dispersions.The optimal conditions were determined to be PVPK-30 as a carrier,1 ∶ 12 for drug-carrier ratio,and 30 min for stirring time,the accumulative dissolution rate reached 90.87％ within 20 min.There might be a hydrogen bond association between PVPK-30 and fisetin previously existing in amorphous or molecular state.CONCLUSION The dissolution rate of fisetin can be obviously increased after being prepared into solid dispersions.
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Solid dispersions (SD) as a preparation of intermediates have played an important role in improving the dissolution of insoluble drugs and its bioavailability.SD technique is one of the most promising techniques to improve the dissolution and solubility of insoluble drugs,and the development of SD technique will promote the gradual perfection in preparative field.This review focuses on the carrier materials of SD,various new preparation techniques and their comparisons,application of solid dispersion formulations,and stability problems of SD.The factors influencing the stability of SD are described,and the effective measures to prevent the aging of SD are put forward.Finally,the review puts forward the practical suggestions of the solid dispersion technique.
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Solid dispersions (SD) as a preparation of intermediates have played an important role in improving the dissolution of insoluble drugs and its bioavailability.SD technique is one of the most promising techniques to improve the dissolution and solubility of insoluble drugs,and the development of SD technique will promote the gradual perfection in preparative field.This review focuses on the carrier materials of SD,various new preparation techniques and their comparisons,application of solid dispersion formulations,and stability problems of SD.The factors influencing the stability of SD are described,and the effective measures to prevent the aging of SD are put forward.Finally,the review puts forward the practical suggestions of the solid dispersion technique.
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AIM To prepare the andrographolide-loaded solid dispersions.METHODS Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) were used for the analysis of solid dispersions previously prepared from the mixture of andrographolide and PVPK30 (1 ∶ 9) in autoclave.In addition to the evaluation index of in vitro dissolution rate,the influencing factors of pressure,temperature and reaction time were taken into consideration for the preparation optimization by Box-Behnken method.RESULTS Andrographolide was totally dispersed in solid dispersions in an amorphous state,manifesting an inhibited crystal diffraction peaks' formulation.Under the optimal conditions of 21.26 MPa for pressure,40.76 ℃ for temperature,and 1.13 h for reaction time,the in vitro dissolution rate was 85.49％.CONCLUSION After andrographolide is made into solid dispersions,its in vitro dissolution rate is obviously increased.
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The aim of this work was to improve the solubility and dissolution rate of poorly-soluble, weakly-basic, anti-emetic drug; domperidone (DMP) using solid dispersion technique. Solubility studies of DMP with various hydrophilic carriers including sorbitol, mannitol, PEG 4000, PEG 6000, pluronic F-68 and pluronic F-127 were performed. Pluronic F-68 and pluronic F-127 showed the highest solubilizing effect on DMP and therefore; they were selected for the preparation of solid dispersions in different weight ratios by the fusion method. The solid dispersions were characterized using Fourier-transform infrared spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Powder X-ray Diffractometry (P-XRD), solubility determination and in-vitro dissolution rate studies. FT-IR and DSC studies confirmed the absence of incompatibilities between DMP and the used carriers. DSC and P-XRD studies proved the transformation of drug from crystalline to amorphous state in the prepared solid dispersions. The results showed marked improvement of DMP solubility and dissolution rate from the solid dispersions compared with the pure drug and indicated the superiority of solid dispersions prepared with pluronic F-68 over those prepared with pluronic F-127. It can be concluded that solid dispersion technique was an effective tool in the enhancement of DMP dissolution.
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O efavirenz (EFZ) é considerado um dos fármacos anti- HIV mais utilizados, porém, como a grande maioria dos antirretrovirais, é classificado como fármaco de classe II, segundo o Sistema de Classificação Biofarmacêutica (SCB), por apresentar baixa solubilidade e alta permeabilidade. É bem conhecido que a solubilidade aquosa de um fármaco constitui requisito prévio à absorção e, assim, se faz uma das mais importantes barreiras à eficácia do medicamento. Desta forma, o aumento, através de tecnologias farmacêuticas, da dissolução aquosa e, conseqüentemente, da biodisponibilidade de fármacos pouco solúveis em água é considerado como um dos mais desafiantes aspectos no desenvolvimento moderno de fármacos. Este trabalho tem como objetivo realizar um levantamento da literatura cientifica e discussão sobre as principais técnicas aplicadas no melhoramento da dissolução do EFZ, dentre elas: dispersões sólidas, complexos de inclusão, sistemas multicomponentes e sistemas particulados nos últimos 10 anos (2004 ? 2014). Após levantamento bibliográfico, verificou-se maior número de publicações empregando a técnica de dispersões sólidas, provavelmente, porque a mesma é considerada uma técnica simples e de baixo custo. Desta forma, ficou claro que há grande interesse, por parte dos pesquisadores, de desenvolver métodos eficientes e econômicos que visam o melhoramento da dissolução aquosa deste fármaco e que o desenvolvimento de dispersões sólidas é, sem dúvida, uma solução interessante.(AU)
Efavirenz (EFZ) is considered one of the most used anti-HIV drugs. However, like the others anti-retroviral drugs, it is classified as a class II drug, according to the Biopharmaceutics Classification System (BCS), due to its low solubility and high permeability. It is well-known that the aqueous solubility of a drug is the prerequisite for its absorption and becomes one of the major barriers to the effectiveness of it. Thus, the improvement of the aqueous dissolution and, therefore, the bioavailability of drugs that are poorly soluble in water, is pursued by the pharmaceutical technology, once they are challenging aspects in the modern drug development. This paper aims, besides discussing, to perform a systematic review of the scientific literature regarding the main techniques applied in improving the dissolution of EFZ, including: solid dispersions, inclusion complexes, systems and multicomponent particulate systems; in the last 10 years (2004-2014). A greater number of publications using the technique of solid dispersions (SD) were found, probably because it is considered a simple and inexpensive technique. Therefore it is clear that there is great interest from researchers to develop efficient and economical methods aimed at improving the aqueous dissolution of EFZ and that the development of SD is, with no doubt, an interesting solution.(AU)
Subject(s)
Anti-Retroviral Agents , Solubility , Drug StabilityABSTRACT
Ischemic brain injury is a major disease which threatens human health and safety. (3, 5, 6-trimethylpyrazin-2-yl) methyl 3-methoxy-4-[(3, 5, 6-trimethylpyrazin-2-yl) methoxy] benzoate (VA-T), a newly discovered lead compound, is effective for the treatment of ischemic brain injury and its sequelae. But the poor solubility of VA-T leads to poor dissolution and limited clinical application. In order to improve the dissolution of VA-T, the pharmaceutical technology of solid dispersions was used in the present study. VA-T/polyvinylpyrrolidone (PVP) solid dispersion was prepared by the solvent method. The dissolution studies were carried out and solid state characterization was evaluated by differential scanning calorimetry (DSC), infrared spectroscopy (IR), x-ray diffraction (XRD) and scanning electron microscopy (SEM). The dissolution rate of VA-T was significantly improved by solid dispersion compared to that of the pure drug and physical mixture. The results of DSC and XRD indicated that the VA-T solid dispersion was amorphous. The IR spectra showed the possible interaction between VA-T and PVP was the formulation of hydrogen bonding. The SEM analysis demonstrated that there was no VA-T crystal observed in the solid dispersions. The ideal drug-to-PVP ratio was 1:5. In conclusion, the solid dispersion technique can be successfully used for the improvement of the dissolution profile of VA-T.