Effect of poloxamer on physicochemical properties of tacrolimus solid dispersion improving water solubility and dissolution rate

Tacrolimus (TCR; also FK-506 and trade name prograf^?), an antibiotic of macrolide family and a novel immunosuppressive agent, is a natural product of actinomycete Streptomyces tskubaensis. But TCR is poorly soluble in water (0.012?mg/mL), so its bioavailability is low and irregular. The aim of this study is to characterize physicochemical properties of TCR and investigate the improvement of solubility and dissolution rate of TCR solid dispersion (SD) with poloxamer. TCR SDs, consisting of various grades and ratios of poloxamer were prepared by hot-melting method and were characterized by DSC, PXRD, and FT-IR. The dissolution profile and solubility of TCR from the SDs were evaluated. SD of TCR prepared with poloxamer 188 at the ratio of 1:1 by the hot-melting method resulted in a significant increase in TCR solubility and enhanced dissolution profile over the TCR crystalline powder.     

Nimodipine semi-solid capsules containing solid dispersion for improving dissolution

The aim of this study was to improve the dissolution and, therefore, bioavailability of the poorly water-soluble and highly permeable drug nimodipine (NMD). Present research involved the preparation of a solid dispersion (SD) consisting of NMD, Eudragit-E100 and Plasdone-S630 by hot-melt extrusion (HME). Compared with pure drug and physical mixture, the dissolution of NMD was enhanced dramatically (about 80% within 30min). Adding the nimodipine solid dispersion (NMD-SD) powder to a mixture of Plasdone-S630 and PEG400, and then transferring it to hard HPMC capsules, resulted in nimodipine semi-solid capsules (NMD-SSC). The dissolution from NMD-SSC was increased further (about 95% in 20min). In addition, the relative bioavailability of the NMD-SSC (test) and Nimotop (reference) was determined in beagle dogs after a single dose (120mg NMD) in a randomized crossover, own-control study. The results suggested that there was no significant difference in the areas under the plasma concentration-time curve and the mean peak concentration between NMD-SSC (AUC(0-infinity)=2488+/-433nghmL(-1), Cmax=321+/-78ngml(-1)) and Nimotop (AUC0-infinity=2272+/-398nghmL(-1), Cmax=293+/-73ngmL(-1)) (P>0.05). However, the apparent rate of absorption of NMD from NMD-SSC (tmax=1.3h) was markedly faster than that from Nimotop (tmax=3.1h) (P<0.05), which indicates that as a fast release preparation, NMD-SSC is well absorbed.     

Improvement of dissolution rate of tacrolimus by solid dispersion technique

Tacrolimus has a poor solubility in water ranging from 4 to 12 μg mL^?1. The mean bioavailability is ~21 %.The present study was carried out with a view to enhance the dissolution rate of poorly water-soluble drug tacrolimus using Gelucire 44/14^® and Gelucire 50/13^® as carriers and lactose monohydrate as an adsorbent. A combination of melt and adsorption techniques was employed for the preparation of solid dispersions (SD) to make final product easy for handling. Phase solubility study was conducted to evaluate the effect of carriers on aqueous solubility of tacrolimus. In order to elucidate the mechanism of dissolution enhancement, solid state characteristics were investigated using Fourier transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer–Peppas model and the drug release kinetics primarily as Fickian/anomalous diffusion. All prepared solid dispersions showed dissolution improvement compared to pure drug, with Gelucire 50/13^® as the superior carrier over Gelucire 44/14^®. Almost similar dissolution profile was obtained as a function of storage time; this can be explained by no change in XRD and DSC pattern after 45 days storage period.     

Development of solid dispersion lipid nanoparticles for improving skin delivery

Applications of poorly water-soluble drugs in skin delivery pose several challenges to pharmaceutical formulation. This research originally developed solid lipid nanoparticles (SLNs) packaging a modified core of a solid dispersion (SD) in the lipid matrix to modulate the skin release patterns. Curcumin (CUR) was selected as the poorly water-soluble drug applied in the formulation. The designed system, so-called solid dispersion lipid nanoparticles (SD-SLNs), was fabricated by incorporating a solidifying SD or a non-solidifying SD into the core of the SLNs by ultrasonication. Release studies illustrated an important enhancement in the drug release of the proposed system compared to pure CUR and SLN formulations without the presence of SD as the modified core, which indicated the positive effect of the combined colloidal method of SD and SLNs. The physicochemical properties of the SD-SLN systems were also elucidated using powder X-ray diffraction, Fourier transform infrared spectroscopy, and particle size analysis. The drug was found to change to an amorphous state without any molecular interactions along with a marked particle size reduction. This work demonstrated the strong potential of applying a novel SD-SLN system for the skin delivery of a drug with poor water solubility.     

Enhanced solubility and dissolution rate of itraconazole by a solid dispersion technique.

The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, itraconazole, by a solid dispersion technique. Solid dispersion particles of itraconazole were prepared with various pH-independent and -dependent hydrophilic polymers and were characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. Of the polymers tested, pH-dependent hydrophilic polymers, AEA and Eudragit E 100, resulted in highest increases in drug solubility (range, 141.4-146.9-fold increases). The shape of the solid dispersion particles was spherical, with their internal diameter ranging from 1-10 microm. The dissolution rate of itraconazole from the tablets prepared by spray drying (SD-T) was fast, with > 90% released within 5 min.SD-T prepared with AEA or Eudragit E 100 at a 1:1 drug hydrophilic polymer ratio (w/w) showed approximately 70-fold increases in the dissolution rate over a marketed product.     

三元固体分散体提高利多卡因溶解度研究（英文）

使用熔融法制备利多卡因-泊洛沙姆固体分散体以提高利多卡因的溶解度及溶出度。以利多卡因(LIC)作为模型药物,分别使用泊洛沙姆188 (P188)和泊洛沙姆407 (P407)作为单一及混合载体,制备三元及二元固体分散体并进行比较。使用DSC、XRD、SEM及FTIR进行一系列表征,通过溶出度试验研究固体分散体的溶出特性,药物以晶体形式存在于载体中,药物溶出度及溶解度结果较原料药均有明显提高。相溶解度研究显示出药物与载体呈AL型曲线,有分子相互作用的存在。此外,还考察了固体分散体在不同相对湿度下的长期稳定性,稳定性测试结果表明三元及二元利多卡因-泊洛沙姆固体分散体在不同湿度下,6个月内保持稳定。研究结果表明,混合泊洛沙姆三元固体分散体可以显著提高难溶性利多卡因的溶出度和溶解度。     

Revealing facts behind spray dried solid dispersion technology used for solubility enhancement

Poor solubility and bioavailability of an existing or newly synthesized drug always pose challenge in the development of efficient pharmaceutical formulation. Numerous technologies can be used to improve the solubility and among them amorphous solid dispersion based spray drying technology can be successfully useful for development of product from lab scale to commercial scale with a wide range of powder characteristics. Current review deals with the importance of spray drying technology in drug delivery, basically for solubility and bioavailability enhancement. Role of additives, selection of polymer, effect of process and formulation parameters, scale up optimization, and IVIVC have been covered to gain the interest of readers about the technology. Design of experiment (DoE) to optimize the spray drying process has been covered in the review. A lot more research work is required to evaluate spray drying as a technology for screening the right polymer for solid dispersion, especially to overcome the issue related to drug re-crystallization and to achieve a stable product both in vitro and in vivo. Based on the recent FDA recommendation, the need of the hour is also to adopt Quality by Design approach in the manufacturing process to carefully optimize the spray drying technology for its smooth transfer from lab scale to commercial scale.     

Enhanced solubility and permeability of exemestane solid dispersion powders for improved oral delivery

The aim of the present investigation was to enhance the solubility of exemestane (EXM), by solid dispersion (SD) technique using PEG 6000 as a carrier. Phase solubility studies were conducted with PEG 6000 and PEG 20000 to evaluate the effect of carriers on aqueous solubility of EXM. The aqueous solubility of EXM was favoured with PEG 6000 compared to PEG 20000. SDs of EXM using polyethylene glycol 6000 (PEG 6000) as carrier were prepared in different drug to carrier ratios. Solid-state characterization indicated decrease in crystallinity of the drug. The in vitro dissolution rate of EXM was enhanced from both SDs and tablet formulations prepared using SD compared to pure EXM. The in situ permeability studies investigated using single-pass intestinal perfusion technique in rats revealed increase in effective intestinal permeability (P_eff, cm/s) by 4.45 folds with SDs. Thus, EXM-PEG 6000 SDs showed improved solubility and permeability.     

Enhancement of solubility and dissolution of cilostazol by solid dispersion technique

Cilostazol is practically insoluble in water and thus results in poor bioavailability. Only a few approaches have been reported for improving the bioavailability of cilostazol. Solid dispersion technique via solvent evaporation method was applied to improve the solubility and dissolution of cilostazol. Various polymers, mixture of polymer and surfactant, and mixture of polymers were screened as a carrier for the solid dispersion. Solubility of cilostazol was improved significantly when Eudragit^® L100 was used as a carrier. However, addition of surfactant to Eudragit^® L100 decreased the solubility slightly. Whereas, the mixture of Eudragit^® L100 and Eudragit^® S100 as a carrier system further increased the solubility. Based on the highest solubility obtained among the carriers screened, 1:1 ratio of Eudragit^® L100 and Eudragit^® S100 was selected as a carrier, and drug to carrier ratio was optimized to 1:5. Differential scanning calorimetry and X-ray diffraction studies showed that the characteristic peak of cilostazol disappeared in the solid dispersion, indicating that cilostazol existed in amorphous form in this formulation. Spray drying method was superior to vacuum drying method in terms of dissolution rate. Meanwhile, it was observed that the disintegration rate and the concentration of polymer had some effect on the crystallization of cilostazol in dissolution medium. Tablet formulation containing spray dried solid dispersion showed significant improvement in dissolution as compared to the commercial tablet.     

High efficiency dry coating of non-subcoated pellets for sustained drug release formulations using amino methacrylate copolymers

Abstract

Dry coating utilizing a fluidized bed was evaluated in order to produce films with sustained drug release using amino methacrylate copolymers as film former. In contrast to other dry coating procedures using amino methacrylate copolymers, the described method enables an appropriate polymer adhesion by the selection of a plasticizer additive mixture in combination with the use of a three-way nozzle for simultaneous application. Well spreading fatty acid esters were found to increase the coating efficiency from 73% to approximately 86%, when they were used in conjunction with the plasticizer. Pellets were used as drug cores without previous treatment. After a curing step at 55?°C, the pellets exhibited a prolongation of the drug release over a period of about 6?h. Mainly the three parameters, coating level, composition of the polymers in the coating mixture, and the type of plasticizer, were found to exert distinct influence on the dissolution profile. Despite the differences in the coating procedure, the dissolution profiles of the coated pellets as well as the influencing parameters were similar to those known from conventional coating techniques.     

Formulation and process considerations affecting the stability of solid dosage forms formulated with methacrylate copolymers.

General considerations concerning the stability of coated dosage forms are discussed, in order to avoid predictable interactions which may cause long-term stability problems. As polymers themselves maintain a high chemical stability and a low reactivity, instability phenomena mainly have to be explained by interactions of low molecular weight substances or physical changes. Possible interactions of functional groups can be predicted easily and insulating subcoates are proper countermeasures. Impurities, remaining in the polymeric material from the manufacturing process, may accelerate the hydrolysis of sensitive drugs. Instabilities of coated dosage forms are mainly based on physical interactions, caused by improper formulations of coating suspensions (i.e. plasticizers or pigments) or the film coating process. Residual moisture or solvents, probably enclosed in the core and migrating over time, may increase the permeability of coatings, due to plasticizing effects. The functionality of coatings from aqueous dispersions is linked to coalescence of latex particles. Thus any incomplete film formation, caused by too high or too low coating temperatures, may result in high permeable coatings. During storage, preferably under stress conditions this process will continue and thus change the release profile. Therefore bed temperatures of 10-20 degrees C above MFT must ensure the formation of homogeneous polymer layers during the coating process. Stability test procedures and packaging materials also need to be adapted to the physicochemical properties of the dosage form, in order to get meaningful results in stability tests.     

Drug release from a new family of graft copolymers of methyl methacrylate. I.

Hydrophilic matrices are an interesting option when developing an oral drug release device. In this work we have produced hydrophilic matrices tablets by direct compression. Previously graft copolymers were synthesized as an important component of the tablets: hydroxypropyl starch-methyl methacrylate (HS-MMA), carboxymethyl starch-MMA (CS-MMA) and hydroxypropyl cellulose-MMA (HC-MMA). The polymeric component was mixed with Emcompress®, stearic acid and theophylline. All the products fulfilled the requirements for good flow according to literature. L-formulations show lower values of plasticity than O-formulations. However, L-formulations exhibit higher compactibility values than O-formulations. In general, all the formulations with O-polymers show faster release of the drug at three pHs used. On the other hand, these tablets have the capacity to hydrate quickly forming a gelatinous layer, so it is necessary to achieve controlled drug release from hydrophilic matrices. In relation with the dissolution efficiency over 8 h, formulations with HS-MMAL and NaCMC show very similar results, although the release of theophylline from NaCMC tablets at different pHs was always slightly slower than HS-MMAL tablets.     

Enhancement of drug solubility and absorption by copolymers of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate

Poly[2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate]s (PMBs) are water-soluble solid copolymers of 2-methacryloyloxyethyl phosphorylcholine (MPC) and n-butyl methacrylate with a molecular weight of 30,000 (PMB50T) or 100,000 (PMB100T). Here, we characterized the solubilizing properties of PMBs using miconazole (MCZ), vidarabine (Ara-A) and griseofulvin (GRF), which are class 2, 3 and 4 compounds, respectively, in the Biopharmaceutics Classification System (BCS). Moreover, we evaluated the enhancement of gastric absorption of GRF dissolved in PMB solutions and the toxicity of PMBs in rats. PMB50T solution dramatically increased the solubility of GRF and MCZ compared with Ara-A, and these drugs became more soluble as the concentration of PMB50T was increased. The solubility of GRF in 10% PMB solutions was higher than with any other tested aqueous solubilizer. When a solution of GRF (20 mg/10 mL/kg) in 10% PMB was orally administered to rats, GRF absorption was greatly increased compared with that following administration of a suspension in water or Gelucire. After repeated oral administration of PMBs once daily for 14 successive days, no organ lesions or changes in biochemical parameters were observed. Thus, the polymers are expected to be useful and safe solubilizers and oral absorption enhancers for poorly soluble lipophilic drugs.     

Bioavailability of 10-hydroxycamptothecin-phospholipid complex loaded by solid dispersion and lipid-based formulations

Previous study has shown that 10-hydroxycamptothecin (HCPT) has well-established pharmacological effectsin vitro. However, its in vivo bioavailability is very poor due to various problems, which severely restricts its clinical applications. In the present study, phospholipid complex (PC) technology was employed to improve the solubility and bioavailability of HCPT. XRD data confirmed the formation of HCPT-PC. However, our previously prepared HCPT-PC is too sticky, which may result in the slow dissolution rate and negative effects on its absorption. Therefore, we prepared HCPT-PC-solid dispersion (HCPT-PC-SD) and lipid-based formulations of HCPT-PC through simple preparation process. The results showed that the dissolution rate of HCPT-PC was effectively improved by solid dispersion technology, which reached 91.73% in 45 min. Pharmacokinetic study revealed that the AUC_0–t of HCPT-PC-SD and HCPT-PC lipid-based formulations was effectively further increased compared with HCPT-PC. Moreover, we found that the combination of SD technology and lipid-base formulations could be a promising drug-delivery system to improve the oral bioavailability of HCPT-PC. In addition, we showed that the bioavailability of HCPT-PC lipid-base formulations was even greater than that of HCPT-PC-SD. In particular, lipid-base formulations could be prepared just by a simple method, suggesting its feasibility of industrialization.     

Enhancement of solubility and dissolution of Coenzyme Q10 using solid dispersion formulation

This study aimed to develop a stable solid dispersion of Coenzyme Q₁₀ (CoQ₁₀) with high aqueous solubility and dissolution rate. Among various carriers screened, poloxamer 407 was most effective to form a superior solid dispersion of CoQ₁₀ having significantly enhanced solubility. Particularly, solid dispersion of CoQ₁₀ with poloxamer 407 in the weight ratio of 1:5 prepared by melting method enhanced the solubility of CoQ₁₀ to the greatest extent. However, it exhibited poor stability and hence Aerosil^® 200 (colloidal silicon dioxide) was incorporated into the solid dispersion as an adsorbent to inhibit the recrystallization process. The solid dispersion of CoQ₁₀, poloxamer 407 and Aerosil^® 200 in the weight ratio of 1:5:6 exhibited improved stability with no significant change in solubility during the 1-month stability test. Moreover, the solid dispersion formulation containing Aerosil^® 200 significantly enhanced the extent of drug release (approx. 75% release) as well as the dissolution rate of CoQ₁₀. In conclusion, the present study has developed the stable solid dispersion formulation of CoQ₁₀ with poloxamer 407 and Aerosil^® 200 for the enhanced solubility and dissolution of CoQ₁₀, which could also offer some additional advantages including ease of preparation, good flowability and cost-effectiveness.     

他克莫司制剂临床换用的安全性考虑

他克莫司是一种强效的免疫抑制剂,但治疗指数窄,个体变异大,剂量或者浓度的微小改变就有可能导致不良反应甚至治疗失败。目前,生物等效性研究的常规可接受范围、研究人群及考察指标等并不完全适用于他克莫司等治疗指数狭窄药物,导致批准上市的他克莫司仿制药与原研药可能不具有临床上的治疗等效性。因此临床治疗中随意换用他克莫司制剂存在一定的风险,需要临床医生谨慎决策。     

The use of solid dispersion systems in hydrophilic carriers to increase benzonidazole solubility

The present study investigates the release mechanism of benznidazole (BNZ) in solid dispersions with polyethylene glycol 6000 (PEG 6000) and polyvinylpirrolydone K-30 (PVP K-30), with a view to observing the increase in solubility of BNZ in water in the presence of these two hydrophilic polymers. The interaction of BNZ with the polymers was evaluated using scanning electron microscopy, Fourier-transformation infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and in vitro dissolution tests, and a theoretical study of molecular modeling was also carried out. The drug-polymer interaction was studied trough molecular modeling, using density functional theory with the B3LYP exchange correlation function. The corrected interaction energies were calculated to be -20.9 kJ/mol with PVP and -6.6 kJ/mol with PEG. The experimental and theoretical results indicate that a powerful interaction occurred between BNZ and the polymers, which was especially strong in the case of PVP, and that this interaction contributed to improvement of BNZ solubility.     

Evaluation of solid dispersion particles prepared with SEDS

Formation of solid solution particles in the Solution Enhanced Dispersion by Supercritical fluids (SEDS) process from a model drug and two different types of carriers, mannitol and Eudragit® E100 was evaluated. The crystal properties of samples and molecular interactions were investigated with DSC and FTIR, respectively. The effect of co-crystallisation of drug and mannitol on dissolution rate was studied. Even if a true one-phase solid dispersion was not obtained, the crystal structure of both drug and mannitol was mutually affected by the presence of the other. The drug was not in highly crystalline form in the co-precipitates. The interactions between the drug and mannitol could also be identified as hydrogen bonding between the amine or hydroxyl groups of the drug and the hydroxyl groups of mannitol. These interactions and changes in the crystal structure are probably directly related to the increase in the dissolution rate observed. A true solid solution was obtained when the drug was co-processed with Eudragit® E100. A clear interaction between the acid hydroxyl group of the drug and the basic carbonyl group on the Eudragit® E100 was observed. SEDS was shown to be an effective process for forming intimate blends and solid solutions for the drug and two different types of carriers.