In sight into tadalafil - block copolymer binary solid dispersion: Mechanistic investigation of dissolution enhancement

Tadalafil is a phosphodiesterase-5 inhibitor that is characterized by low solubility and high permeability. Solid dispersion approach represents a promising carrier system for effective enhancement of dissolution and oral bioavailability of poorly soluble drugs. In the present work, novel tadalafil-loaded solid dispersions employing various block copolymers (Pluronics(?)) were prepared through fusion technique. Their solubility and dissolution properties were compared to the drug alone. In order to elucidate the mechanism of dissolution enhancement, solid state characteristics were investigated using scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction. Furthermore, contact angle measurements were carried out. The sign and magnitude of the thermodynamic parameters indicated spontaneity of solubilization process. The phase solubility studies revealed A(L) type of curves for the carriers. Unlike traditional solid dispersion systems, the crystal form of drug in the formulated systems could not be converted to amorphous form. Most of the studied grades showed dissolution improvement vis-à-vis pure drug, with Pluronic F-127 as the most promising carrier. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model. Thus, the results demonstrated that tadalafil/Pluronic F-127 solid dispersion system is a direct and feasible technology which represents a potential candidate for delivering a poorly water-soluble drug with enhanced solubility and dissolution.     

Solid dispersion of hydroxypropyl beta-cyclodextrin and ketorolac: enhancement of in-vitro dissolution rates, improvement in anti-inflammatory activity and reduction in ulcerogenicity in rats

Ketorolac, is a non-steroidal anti-inflammatory drug, with strong analgesic activity. It is practically insoluble in water and has been implicated in causing gastrointestinal ulceration. This study describes the formulation of solid dispersions of ketorolac using hydroxypropyl beta-cyclodextrin (HPbeta-CyD) and beta-cyclodextin (beta-CyD) as carriers, to improve the aqueous solubility of the drug, thus enhancing its bioavailability. Also, reduction in ulcerogenicity was anticipated. Differential scanning calorimetry and X-ray diffraction studies indicated loss of crystalline nature of the drug, in the dispersions prepared with HPbeta-CyD. NMR studies revealed a strong interaction between drug and HPbeta-CyD. Solid dispersions of drug with beta-CyD retained the crystalline nature of the drug. All the solid dispersions showed a remarkable improvement in the rate and extent of dissolution of ketorolac. The kneaded dispersion with HPbeta-CyD prepared using a 1:1 alcohol-water mixture showed promise in reducing the ulcer-inducing effect of ketorolac in rats. Oral administration of this dispersion was found to inhibit carrageenan-induced paw oedema in rats to a significantly greater extent compared with ketorolac or its trometamol salt. Though beta-CyD as a carrier for ketorolac gave faster release of the poorly soluble drug, HPbeta-CyD proved to be superior to beta-CyD, as a carrier in the kneaded dispersion prepared using 1:1 alcohol-water mixture. These results suggest that solid dispersions of ketorolac with HPbeta-CyD aid in faster dissolution and better bioavailability of the drug. The higher solubility of the drug in the presence of HPbeta-CyD also reduces local gastrointestinal side-effects of the drug.     

Preparation, characterization and in vitro dissolution studies of solid dispersion of meloxicam with PEG 6000

The poor solubility and wettability of meloxicam leads to poor dissolution and hence showing variations in bioavailability. The present study is aimed to increase solubility and dissolution of the drug using solid dispersion techniques. The solid binary systems were prepared at various drug concentrations (5-40%) with polyethylene glycol 6000 by different techniques (physical mixing, solvent evaporation). The formulations were characterized by solubility studies, differential scanning calorimetry, fourier transform infrared spectroscopy and in vitro dissolution rate studies. The solubility of drug increased linearly with increase in polymer concentration showing A(L) type solubility diagrams. Infrared spectroscopy studies indicated the possibility of hydrogen bonding with polymer. The differential scanning calorimetry and powder X ray diffraction demonstrated the presence of polymer as eutectica or monotectica in solid dispersion along with the physical characteristics of the drug (crystalline, amorphous or a mixture of both). The solid dispersions of the drug demonstrated higher drug dissolution rates than physical mixtures and pure meloxicam, as a result of increased wettability and dispersibility of drug in a solid dispersion system.     

Formulation of immediate release pellets containing famotidine solid dispersions

Famotidine (FM) is a potent H2-receptor antagonist used for the treatment of peptic ulcer. It has a low and variable bioavailability which is attributed to its low water solubility. In this study, the dissolution of the drug was enhanced by a preparation of solid dispersion using two hydrophilic carriers, namely Gelucire 50/13 and Pluronic F-127. The prepared solid dispersions were characterized by differential scanning calorimetry (DSC), which indicated that there were no signs of interaction of the drug with the carriers used in the case of solid dispersions containing higher polymeric contents (1:3 and 1:5). FM solid dispersions in the matrices of Gelucire 50/13 and Pluronic F-127 (1:3) were used to prepare pellets. The scanning electron microscope (SEM) images of pellets showed that the pellets have spherical shape and their size depends on the carrier used. The dissolution of the drug from either solid dispersion or pellets was performed. The dissolution study depicted that, the presence of the drug in solid dispersion enhanced its dissolution in comparison with the drug itself. Also, the drug release from the manufactured pellets was found to be improved in the case of solid dispersions (drug:carrier 1:3). A complete drug release occurred after 30 min from pellets containing solid dispersions, while only about 30% of the loaded FM was released from pellets containing untreated drug after 2 h.     

Improvement of dissolution properties of lamotrigine by inclusion complexation and solid dispersion technique

The aim of the present work was to improve the dissolution characteristics of the poorly water soluble antiepileptic drug lamotrigine (LMN) by inclusion complexation using hydroxy propyl beta-cyclodextrin (HP beta-CD) by co-evaporation technique and by, solid dispersion, prepared by the melt method using poloxamer 407 (L 127). Phase solubility studies showed AL type curves with both the carriers. Dissolution of LMN was significantly improved (p < 0.05) by inclusion complexation and solid dispersion preparation. Results of solid state characterization performed by Fourier Transform Infrared Spectroscopy, Differential Scanning Calorimetry and Powder X-ray Diffractrometry techniques revealed a decrease in the crystallinity of LMN that might be accounting for improvement in the dissolution properties as seen from dissolution studies.     

槲皮素PVP固体分散体的制备及物相鉴定

目的用溶剂法制备槲皮素-PVP固体分散体并考察其溶出特性并对物相进行鉴定。方法采用溶剂法制备槲皮素-PVP固体分散体,通过溶出实验对槲皮素溶出率的测定研究固体分散体的溶出性质,利用差热分析（Differentialscanning calorimetry,DSC）、红外光谱分析（Infrared spectroscopy,IR）、粉末X衍射（X-ray powder diffractometry,PXRD）、扫描电镜（Scanning electron microscopy,SEM）等方法对其进行物相鉴定。结果槲皮素-PVP固体分散体的溶出速率相对其物理混合物有了明显的改善; 溶解实验显示固体分散体中槲皮素的溶解度有了显著的提高;热差分析及粉末X衍射结果表明固体分散体中槲皮素呈非结晶形式;扫描电镜下固体分散体中无槲皮素晶体。结论采用溶剂法制备槲皮素-PVP固体分散体可显著提高槲皮素的溶解度及溶出速度。     

紫杉醇-PVP固体分散体的制备、物相鉴定及细胞药效

用溶剂法制备紫杉醇-PVP固体分散体，对其溶解度及体外溶出特性进行考察并对物相进行鉴定。采用溶剂法制备紫杉醇-PVP固体分散体，对固体分散体中紫杉醇的溶解度和溶出率进行测定，研究固体分散体的溶出性质。同时，利用差热分析（Differential scanning calorimetry，DSC）、粉末X衍射（X-ray powder diffractometry,PXRD）、扫描电镜（Scanning electron microscopy，SEM）等方法对其进行物相鉴定。采用SRB法对紫杉醇-PVP固体分散体对SKOV-3细胞药效进行测定。紫杉醇-PVP固体分散体中紫杉醇的溶解度和溶出速率相对其原料药和物理混合物均有了明显的提高；热差分析及粉末X衍射结果表明固体分散体中紫杉醇呈非结晶形式；扫描电镜下固体分散体中无紫杉醇晶体。细胞药效结果表明紫杉醇-PVP固体分散体的细胞药效强于紫杉醇纯药。采用溶剂法制备的紫杉醇-PVP固体分散体可显著提高紫杉醇的溶解度和溶出速度。     

Physicochemical Characterization and Dissolution Study of Solid Dispersions of Lovastatin with Polyethylene Glycol 4000 and Polyvinylpyrrolidone K30

Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, Lovastatin, by a solid dispersion technique. Solid dispersions were prepared by using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K30 (PVP K30) in different drug-to‐carrier ratios. Dispersions with PEG 4000 were prepared by fusion-cooling and solvent evaporation, whereas dispersions containing PVP K30 were prepared by solvent evaporation technique. These new formulations were characterized in the liquid state by phase solubility studies and in the solid state by differential scanning calorimetry, X-ray powder diffraction, and FT-IR spectroscopy. The aqueous solubility of Lovastatin was favored by the presence of both polymers. The negative values of the Gibbs free energy and enthalpy of transfer explained the spontaneous transfer from pure water to the aqueous polymer environment. Solid-state characterization indicated Lovastatin was present as amorphous material and entrapped in polymer matrix. In contrast to the very slow dissolution rate of pure Lovastatin, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. This can be attributed to improved wettability and dispersibility, as well as decrease of the crystalline and increase of the amorphous fraction of the drug. Solid dispersion prepared with PVP showed the highest improvement in wettability and dissolution rate of Lovastatin. Even physical mixture of Lovastatin prepared with both polymers also showed better dissolution profile than that of pure Lovastatin. Tablets containing solid dispersion prepared with PEG and PVP showed significant improvement in the release profile of Lovastatin compared with tablets containing Lovastatin without PEG or PVP.     

他达那非固体分散体的制备和性质研究

目的制备他达那非(tadalafil,TD)固体分散体并进行性质研究。方法利用喷雾干燥法制备固体分散体,以表观溶解度和溶出度为指标筛选处方,采用差示扫描量热(DSC)、粉末X-射线衍射(PXRD)和接触角测定等技术研究药物的存在状态和润湿性等理化性质。结果固体分散体将他达那非的表观溶解度提高22.6倍;20min内药物的累积溶出超过90%;固体分散体药物以分子或无定形状态存在;接触角减小,润湿性增大。结论采用十二烷基硫酸钠(SDS)和介孔硅为载体制备的他达那非固体分散体,能明显提高药物的表观溶解度和溶出度。     

Physicochemical characterization and dissolution study of solid dispersions of Lovastatin with polyethylene glycol 4000 and polyvinylpyrrolidone K30

Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, Lovastatin, by a solid dispersion technique. Solid dispersions were prepared by using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K30 (PVP K30) in different drug-to-carrier ratios. Dispersions with PEG 4000 were prepared by fusion-cooling and solvent evaporation, whereas dispersions containing PVP K30 were prepared by solvent evaporation technique. These new formulations were characterized in the liquid state by phase solubility studies and in the solid state by differential scanning calorimetry, X-ray powder diffraction, and FT-IR spectroscopy. The aqueous solubility of Lovastatin was favored by the presence of both polymers. The negative values of the Gibbs free energy and enthalpy of transfer explained the spontaneous transfer from pure water to the aqueous polymer environment. Solid-state characterization indicated Lovastatin was present as amorphous material and entrapped in polymer matrix. In contrast to the very slow dissolution rate of pure Lovastatin, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. This can be attributed to improved wettability and dispersibility, as well as decrease of the crystalline and increase of the amorphous fraction of the drug. Solid dispersion prepared with PVP showed the highest improvement in wettability and dissolution rate of Lovastatin. Even physical mixture of Lovastatin prepared with both polymers also showed better dissolution profile than that of pure Lovastatin. Tablets containing solid dispersion prepared with PEG and PVP showed significant improvement in the release profile Lovastatin compared with tablets containing Lovastatin without PEG or PVP.     

Studies on Flash Evaporation for Preparation of Porous Solid Dispersions Using Piroxicam as a Model Drug

An amalgamation of solid dispersion and capillarity has been attempted in present study for enhancement of dissolution rate of poorly soluble drugs. Flash evaporation technique was utilized for enhancement of the dissolution rate of piroxicam. One of the major problems with this drug is its very low solubility in biological fluids, which results in poor bioavailability after oral administration. An attempt was made to enhance the dissolution rate of piroxicam by converting it into porous solid dispersion by flash evaporation method using polyvinylpyrrolidone (PVP) 40,000 as a water-soluble carrier. The resulting solid dispersions were characterized by DSC, FTIR, and X-ray diffraction. In vitro dissolution study revealed significant improvement of dissolution profile of piroxicam. The release of drug from porous solid dispersions containing PVP was superior to those of marketed product, conventional nonporous solid dispersion prepared by solvent evaporation method and drug alone. The steep increase in dissolution rate of porous form is attributable to combined effect of solid dispersion and capillarity.     

Characterization of curcumin-PVP solid dispersion obtained by spray drying

Curcumin, a naturally occurring highly lipophilic molecule has wide range of pharmacological activities. However, its limited aqueous solubility and degradation at alkaline pH restricts its bioavailability. Solid dispersions of curcumin in different ratios with PVP were prepared by spray drying. Physical characterization by SEM, IR, DSC, and XRPD studies, in comparison with corresponding physical mixtures revealed the changes in solid state during the formation of dispersion and justified the formation of high-energy amorphous phase. Dissolution studies of curcumin and its physical mixtures in 0.1 N HCl showed negligible release even after 90 min. Whereas, solid dispersions showed complete dissolution within 30 min. This may aid in improving bioavailability and dose reduction of the drug.     

Dissolution behaviour of nalidixic acid solid dispersions using water soluble dispersion carriers

The oral bioavailability of nalidixic acid (NA) is low due to its poor solubility and slow dissolution. Solid dispersions of NA containing varying concentrations of polyvinylpyrrolidone (PVP), beta-cyclodextrin (BCD) and sodium starch glycolate (SSG) were prepared by solvent evaporation technique in an attempt to improve dissolution rate of NA. Physical characterization of NA, physical mixtures (PM) and solid dispersions were investigated by a variety of analytical methods including scanning electron microscopy (SEM), infrared (IR) spectroscopy and powder X-ray diffraction (XRD). SEM was useful in the verification of possible nalidixic acid inclusion in the dispersion system by studying its surface and shape characteristics of different samples. IR analysis demonstrated no strong interaction between the drug and the carrier exists in the solid dispersions. The degree of crystallinity of nalidixic acid decreased and also differed with the dispersion systems of different carriers. Disolution studies indicated that the dissolution rate and percent dissolution efficiency (DE) were significantly increased in the solid dispersions compared with drug alone. The relative potency of the carriers to enhance the dissolution rate of nalidixic acid was in the order: BCD > PVP > SSG. The dissolution rate of the drug in the solid dispersions was faster when the ration of the drug to carrier was smaller. F-test suggests that first order model may be used for explaining the kinetics of drug release from all the solid dispersion systems.     

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.     

Development of novel ibuprofen-loaded solid dispersion with improved bioavailability using aqueous solution

To develop a novel ibuprofen-loaded solid dispersion with enhanced bioavailability, various ibuprofen-loaded solid dispersions were prepared with water, HPMC and poloxamer. The effect of HPMC and poloxamer on aqueous solubility of ibuprofen was investigated. The dissolution and bioavailability of solid dispersion in rats were then evaluated compared to ibuprofen powder. When the amount of carrier increased with a decreased in HPMC/poloxamer ratio, the aqueous solubility of ibuprofen was elevated. The solid dispersion composed of ibuprofen/HPMC/poloxamer at the weight ratio of 10:3:2 improved the drug solubility approximately 4 fold. It gave significantly higher initial plasma concentration, AUC and Cmax of drug than did ibuprofen powder in rats. The solid dispersion improved the bioavailability of drug about 4-fold compared to ibuprofen powder. Thus, this ibuprofen-loaded solid dispersion with water, HPMC and poloxamer was a more effective oral dosage form for improving the bioavailability of poor water-soluble ibuprofen.     

Physicochemical characterization of tacrolimus-loaded solid dispersion with sodium carboxylmethyl cellulose and sodium lauryl sulfate

To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy, differential scanning calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction. Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced solubility and no convertible crystalline.     

微管蛋白抑制剂SUD-35固体分散体的制备、鉴定及初步体外药效学研究

目的将难溶性微管蛋白抑制剂SUD-35制备成固体分散体,以增加其溶解度及溶出速率。方法以聚乙二醇6000为载体,溶剂-熔融法制备SUD-35固体分散体。采用差示扫描量热分析与X-射线衍射观察药物在载体中的存在状态,并进行溶解度和体外溶出度研究。采用MTT法对SUD-35固体分散体对小鼠白血病L1210细胞药效进行测定。结果 SUD-35固体分散体中SUD-35的溶解度和溶出速率相对原料药和物理混合物均有明显提高,差示扫描量热分析与X-射线衍射结果显示SUD-35以无定型状态存在于固体分散体中,细胞药效结果显示SUD-35固体分散体对小鼠白血病L1210细胞增殖抑制率强于SUD-35纯药。结论聚乙二醇6000为载体制备SUD-35固体分散体,可显著提高SUD-35的溶解度及溶出速率。     

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.     

Dissolution Improvement of Atorvastatin Calcium using Modified Locust Bean Gum by the Solid Dispersion Technique

The present research was aimed at the enhancement of the dissolution rate of atorvastatin calcium by the solid dispersion technique using modified locust bean gum. Solid dispersions (SD) using modified locust bean gum were prepared by the modified solvent evaporation method. Other mixtures were also prepared by physical mixing, co-grinding, and the kneading method. The locust bean gum was subjected to heat for modification. The prepared solid dispersions and other mixtures were evaluated for equilibrium solubility studies, content uniformity, FTIR, DSC, XRD, in vitro drug release, and in vivo pharmacodynamic studies. The equilibrium solubility was enhanced in the solid dispersions (in a drug:polymer ratio of 1:6) and other mixtures such as the co-grinding mixture (CGM) and kneading mixture (KM). Maximum dissolution rate was observed in the solid dispersion batch SD3 (i.e. 50% within 15 min) with maximum drug release after 2 h (80%) out of all solid dispersions. The co-grinding mixture also exhibited a significant enhancement in the dissolution rate among the other mixtures. FTIR studies revealed the absence of drug-polymer interaction in the solid dispersions. Minor shifts in the endothermic peaks of the DSC thermograms of SD3 and CGM indicated slight changes in drug crystallinity. XRD studies further confirmed the results of DSC and FTIR. Topological changes were observed in SEM images of SD3 and CGM. In vivo pharmacodynamic studies indicated an improved efficacy of the optimized batch SD3 as compared to the pure drug at a dose of 3 mg/kg/day. Modified locust bean gum can be a promising carrier for solubility enhancement of poorly water-soluble drugs. The lower viscosity and wetting ability of MLBG, reduction in particle size, and decreased crystallinity of the drug are responsible for the dissolution enhancement of atorvastatin. The co-grinding mixture can be a good alternative to solid dispersions prepared by modified solvent evaporation due to its ease of preparation and significant improvement in dissolution characteristics.     

三维有序大孔壳聚糖/尼莫地平固体分散体的研究

目的制备孔径为470nm的三雏有序大孔壳聚糖／尼莫地平的固体分散体,研究其释药特点、稳定性和药动学。方法利用溶剂蒸发法制备固体分散体,通过药物释放试验考察固体分散体在模拟胃肠液介质中的释放行为;通过含量测定、X-射线衍射和溶出试验检查固体分散体的稳定性;大鼠分别给予自制固体分散体和市售片粉末,测定血药浓度。结果固体分散体在pH6.8的介质中的溶出度明显比pH1.2和pH4.5介质中高,在梯度pH介质中的释药曲线类似阶梯型;结晶度和溶出度在考察时间内基本无变化;自制固体分散体的AUC0.12h是市售制剂的1.91倍,具有长效作用。结论自制固体分散体稳定性良好,能够提高尼莫地平的大鼠口服生物利用度。