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1.
Kataoka M Masaoka Y Yamazaki Y Sakane T Sezaki H Yamashita S 《Pharmaceutical research》2003,20(10):1674-1680
Purpose. The aim of the present work was to develop a new in vitro system to evaluate oral absorption of poorly water-soluble drugs by utilizing Caco-2 monolayers.
Methods. Caco-2 monolayer was mounted between side-by-side chambers, which enabled the simultaneous assay of dissolution and permeation of drugs (dissolution/permeation system; D/P system). Apical and basal sides of the chamber were filled with buffer solutions. Drugs were applied to the apical side as powder, suspension, or solution, and then, the permeated amounts into the basal side were monitored for 2 h. At the same time, dissolved amounts of drugs at the apical side were detected. The amount of drug applied to the D/P system was based on its in vivo clinical dose.
Results. Sodium taurocholate (5 mM, apical side) and bovine serum albumin (4.5% w/v, basal side) increased the permeated amount of poorly water-soluble drugs. Both additives were considered to be effective at mimicking in vivo conditions of intestinal drug absorption. From the correlation between the permeated amount of 13 drugs (% dose/2 h) in the D/P system and their percentage dose absorbed in humans in vivo, this system was found to be useful in evaluating oral absorption of poorly water-soluble drugs.
Conclusions. With attempts made to mimic the physiologic conditions of the human GI tract, in vivo oral absorption of drugs was quantitatively assessed in the D/P system in vitro. This system is quite useful to predict the oral absorption of poorly water-soluble drugs after administration as solid dosage forms. 相似文献
2.
Takano R Sugano K Higashida A Hayashi Y Machida M Aso Y Yamashita S 《Pharmaceutical research》2006,23(6):1144-1156
Purpose The purpose of this study was to develop a new system for computer simulation to predict fraction absorbed (Fa) of Biopharmaceutical Classification System (BCS) class II (low solubility–high permeability) drugs after oral administration
to humans, from a miniscale dissolution test.
Methods Human oral absorption of 12 lipophilic drugs was simulated theoretically by using the dissolution and permeation parameters
of the drugs. A miniscale dissolution test and a solubility study were carried out in a conventional buffer and a biorelevant
medium (pH 6.5). A dissolution parameter, which can simulate in vivo dissolution, was obtained from the in vitro dissolution curve. Human intestinal permeability was estimated assuming that the permeation was limited by diffusion through
the unstirred water layer. The Fa in humans was predicted and then compared with clinical data.
Results The dissolution and solubility of most model drugs were faster and higher in a biorelevant medium than in a conventional buffer.
The simulated absorption was limited by the drug dissolution rate and/or solubility. Predicted Fa was significantly correlated with clinical data (correlation coefficient r2 = 0.82, p < 0.001) when the dissolution profiles in biorelevant medium were used for the simulation.
Conclusions This new system quantitatively simulated human absorption and would be beneficial for the prediction of human Fa values for BCS class II drugs. 相似文献
3.
Stéphanie Poullain-Termeau Sylvie Crauste-Manciet Denis Brossard Saleh Muhamed Georges Nicolaos Robert Farinotti 《Drug delivery》2013,20(8):503-514
The effect of oil-in-water submicron emulsion (SE) droplet surface charge on absolute bioavailability of a poorly water-soluble drug (griseofulvin, as model drug) after oral administration was studied in conscious rat. Positively, negatively, and neutrally charged SE were designed and characterized (size, polydispersity index, zeta potential, and pH). Three emulsion formulations, whose compositions included 40% oil phase and differed only in the nature of the emulsifying agent, were retained. Only the positively charged SE showed a higher area under the plasma concentration–time curve (AUC0 → ∞) in comparison with the tablet and with the other SE. 相似文献
4.
Takano R Furumoto K Shiraki K Takata N Hayashi Y Aso Y Yamashita S 《Pharmaceutical research》2008,25(10):2334-2344
PURPOSE: Nonlinear oral absorption due to poor solubility often impedes drug development. The purpose of this study was to elucidate the rate-limiting process in oral absorption of Biopharmaceutical Classification System (BCS) class II (low solubility-high permeability) drugs in order to predict nonlinear absorption of dose caused by solubility-limited absorption. METHODS: Oral absorption of danazol, griseofulvin, and aprepitant was predicted from a miniscale dissolution test and a physiologically-based model. The effect of particle size reduction and dose increase on absorption was investigated in vitro and in vivo to clarify the rate-limiting steps of dissolution-rate-limited and solubility-limited absorption. RESULTS: The rate-limiting steps of oral absorption were simulated and increase in the dissolution rate and administration dose showed a shift from dissolution rate-limited to solubility-limited absorption. In the study in dogs, particle size reduction improved the oral absorption of large particle drugs but had little effect on small particle drugs. Dose nonlinearity was observed with small particles at a high dose. Our model quantitatively predicted results observed in vivo, including but not exclusively, dissolution-rate-limited and solubility-limited absorption. CONCLUSION: The present study provides a powerful tool to predict dose nonlinearity and will aid in the success of BCS class II drug development. 相似文献
5.
Purpose. The purpose of this study was to evaluate a novel in situ micronization method avoiding any milling techniques to produce nano- or microsized drug particles by controlled crystallization to enhance the dissolution rate of poorly water-soluble drugs.
Methods. Ibuprofen, itraconazole, and ketoconazole microcrystals were prepared by the association of the previously molecularly dispersed drug using a rapid solvent change process. The drug was precipitated in the presence of stabilizing agents, such as hydrocolloids. The obtained dispersion was spray-dried. Particle size, morphology, dissolution rate, specific surface area, and wettability were analyzed. Physicochemical properties were characterized using differential scanning calorimetry and X-ray diffractometry.
Results. The obtained dispersions showed a homogeneous particle size distribution. Drugs are obtained in a mean particle size of approximately 2 m and below. A high specific surface area was created and in situ stabilized. Different stabilizers showed differences in protecting the precipitated drug from crystal growth. The surface was hydrophilized because of the adsorbed stabilizer. Thus, a drug powder with markedly enhanced dissolution rate was obtained.
Conclusions. In situ micronization is a suitable method for the production of micro-sized drugs. This technique can be performed continuously or discontinuously and uses only common technical equipment. Compared to milled products drug properties are optimized as all particle surfaces are naturally grown, the particle size is more uniformly distributed and the powder is less cohesive. 相似文献
6.
《Journal of pharmaceutical sciences》2022,111(11):3141-3148
Solid dispersions are one of methods for solubilizing water-insoluble drugs. To enhance the bioavailability, maintenance of the supersaturated state and absorption of the dissolved drug in the gastrointestinal tract are important. We designed and synthesized amphiphilic 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers as carriers for solid dispersions and evaluated the dissolution behavior in test solutions with different pH and additives. Solid dispersion of troglitazone with amphiphilic MPC copolymers having both aromatic rings and urethane bonds in the side chains showed rapid dissolution and excellent supersaturation maintenance. It was indicated that the balance between the interactions with drug molecules and the water affinity of the polymer should be considered when carriers for solid dispersions are designed. In addition, cell membrane permeability of the solid dispersion with the amphiphilic MPC copolymer was evaluated by the Dissolution / Permeation system, which consists of two liquid chambers and a monolayer of epithelial cells that mimics the intestinal dissolution and permeation process. Further, blood concentration of the drug when solid dispersions were orally administered in mice was also evaluated. The cell membrane permeability and oral absorbability were significantly improved, compared to the solid dispersions with poly(N-vinylpyrrolidone) and suspension or solution of crystalline troglitazone. 相似文献
7.
Lei Gao Guiyang Liu Jianli Ma Xiaoqing Wang Liang Zhou Xiang Li Fang Wang 《Pharmaceutical research》2013,30(2):307-324
The limited solubility and dissolution rate exhibited by poorly soluble drugs is major challenges in the pharmaceutical process. Following oral administration, the poorly soluble drugs generally show a low and erratic bioavailability which may lead to therapeutic failure. Pure drug nanocrystals, generated by “bottom up” or “top down” technologies, facilitate a significant improvement on dissolution behavior of poorly soluble drugs due to their enormous surface area, which in turn lead to substantial improvement in oral absorption. This is the most distinguished achievement of drug nanocrystals among their performances in various administration routes, reflected by the fact that most of the marketed products based on the nanocrystals technology are for oral application. After detailed investigations on various technologies associated with production of drug nanocrystals and their in vitro physicochemical properties, during the last decade more attentions have been paid into their in vivo behaviors. This review mainly describes the in vivo performances of oral drug nanocrystals exhibited in animals related to the pharmacokinetic, efficacy and safety characteristics. The technologies and evaluation associated with the solidification process of the drug nanocrystals suspensions were also discussed in detail. 相似文献
8.
《Journal of pharmaceutical sciences》2014,103(6):1811-1818
Telcagepant potassium salt(MK-0974) is an oral calcitonin gene-related peptide receptor inhibitor investigated for the treatment of acute migraine. Under gastric pH conditions, the salt rapidly gels, then converts to an insoluble neutral form that creates an impervious shell on the tablet surface, resulting in a slow and variable release dissolution rate and poor bioavailability. Early attempts to develop a solid dosage form, including solid dispersion and nanosuspension formulations, resulted in low exposures in preclinical studies. Thus, a liquid-filled soft gelatin capsule (SGC) formulation (oblong 20) was used for clinical studies. However, a solid dosage form was desirable for commercialization. The slow dissolution of the tablet formulations was overcome by using a basifying agent, arginine, and inclusion of a nonionic surfactant, poloxamer 407. The combination of arginine and poloxamer in the formulation created a local transient basic microenvironment that promoted the dissolution of the salt and prevented rapid precipitation of the neutral form on the tablet surface to form the gel layer. The tablet formulation achieved fast absorption and comparable exposure to the SGC formulation. The final optimized 280 mg tablet formulation was successfully demonstrated to be bioequivalent to the 300 mg SGC formulation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1811–1818, 2014 相似文献
9.
Chan O. Helen Schmid Heidi L. Stilgenbauer Linda A. Howson William Horwell David C. Stewart Barbra H. 《Pharmaceutical research》1998,15(7):1012-1018
Purpose. The purpose of this research was to examine a targeted prodrug strategy to increase the absorption of a poorly water-soluble lipophilic compound.
Methods. Three water-soluble prodrugs of Cam-4451 were synthesized. The amino acid (Cam-4562, Cam-4580) or phosphate (Cam-5223) ester prodrugs introduced moieties ionized at physiological pH and targeted intestinal brush-border membrane enzymes for reconversion to the parent. Selectivity for reconversion of the three prodrugs was examined in rat intestinal perfusate and brush-border membrane suspensions. Bioavailability of Cam-4451 in rats was evaluated after administering orally as the parent or as prodrugs in a cosolvent vehicle or in methylcellulose.
Results. Cam-5223 was highly selective for reconversion at the brush-border, but was rapidly reconverted in intestinal perfusate. Cam-4562 was not as selective but was more stable in the perfusate, whereas Cam-4580 was neither selective nor stable. Oral bioavailability of Cam-4451 was 14% after dosing as the parent in the cosolvent vehicle, 39% and 46%, respectively, as Cam-4562 and Cam-5223. Oral bioavailability was only 3.6% when the parent was dosed in methylcellulose, whereas the bioavailability was 7-fold higher when dosed as the phosphate prodrug.
Conclusions. Water-soluble prodrugs that target brush-border membrane enzymes for reconversion can be useful in improving drug oral bioavailability. 相似文献
10.
Naoya Matsumura Yoshiyuki Yamaura Jun Katagi Shizuka Ono Soonih Kim Shinji Yamashita Kiyohiko Sugano 《Journal of pharmaceutical sciences》2018,107(9):2489-2496
Dogs have been widely used to study the oral absorption of a drug in drug discovery. However, there has been no quantitative validation of using dogs to predict the fraction of oral dose absorbed (Fa) in humans (Fah) for poorly water-soluble drugs. Here, we report the results of using dogs for quantitative Fah prediction, focusing on poorly water-soluble free acid and neutral drugs. The Fa values of 4 acidic and 1 neutral proprietary compounds were measured in humans and dogs. Extensive literature survey was also performed to increase the number of Fa data. Fah and Fa in dogs (Fad) were then compared at equivalent body weight–normalized doses. In the case of neutral compounds, Fad was found to be similar to Fah. In the case of acidic compounds, Fad significantly overestimated Fah in most cases. A difference in intestinal pH was suggested as the main reason for this discrepancy. In conclusion, the use of dogs would not be appropriate to predict Fah for acidic compounds, but more work is required to know about neutral compounds. 相似文献
11.
12.
Harmalkar Divya Godinho Soraiya Bhide Prashant Jivaji Kumar Lalit Shirodkar Rupesh Kalidas 《Pharmaceutical Chemistry Journal》2019,53(8):720-729
Pharmaceutical Chemistry Journal - Ebastine (EBS) is a second-generation non-sedating antihistamine used for the prevention and treatment of allergic rhinitis and chronic idiopathic urticaria. It... 相似文献
13.
Rogers TL Gillespie IB Hitt JE Fransen KL Crowl CA Tucker CJ Kupperblatt GB Becker JN Wilson DL Todd C Broomall CF Evans JC Elder EJ 《Pharmaceutical research》2004,21(11):2048-2057
PURPOSE: Poorly water-soluble compounds are being found with increasing frequency among pharmacologically active new chemical entities, which is a major concern to the pharmaceutical industry. Some particle engineering technologies have been shown to enhance the dissolution of many promising new compounds that perform poorly in formulation and clinical studies (Rogers et. al., Drug Dev Ind Pharm 27:1003-1015). One novel technology, controlled precipitation, shows significant potential for enhancing the dissolution of poorly soluble compounds. In this study, controlled precipitation is introduced; and process variables, such as mixing zone temperature, are investigated. Finally, scale-up of controlled precipitation from milligram or gram to kilogram quantities is demonstrated. METHODS: Dissolution enhancement capabilities were established using two poorly water-soluble model drugs, danazol and naproxen. Stabilized drug particles from controlled precipitation were compared to milled, physical blend, and bulk drug controls using particle size analysis (Coulter), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), dissolution testing (USP Apparatus 2), and residual solvent analysis. RESULTS: Stabilized nano- and microparticles were produced from controlled precipitation. XRD and SEM analyses confirmed that the drug particles were crystalline. Furthermore, the stabilized particles from controlled precipitation exhibited significantly enhanced dissolution properties. Residual solvent levels were below FDA limits. CONCLUSIONS: Controlled precipitation is a viable and scalable technology that can be used to enhance the dissolution of poorly water-soluble pharmaceutical compounds. 相似文献
14.
15.
Kazi Mohsin Michelle A. Long Colin W. Pouton 《Journal of pharmaceutical sciences》2009,98(10):3582-3595
This study was designed to investigate the precipitation of a lipophilic drug following dispersion of lipid formulations in water. The model drug fenofibrate was formulated in representative lipid delivery systems designed for oral administration, using medium chain glycerides, polysorbates, and propylene glycol as excipients. Aqueous dispersion of water-insoluble self-emulsifying lipid formulations resulted in turbid emulsions, followed subsequently by very slow precipitation of 3–7% of the dose of fenofibrate. Self-emulsifying formulations that included water-soluble surfactants, which dissolved a lower mass of drug in solution at equilibrium, nevertheless typically maintained drugs in a metastable state, following dilution with water, for several hours or even days. Formulations with higher contents of hydrophilic materials resulted in more rapid precipitation. Extensive precipitation of fenofibrate from oil-free formulations, comprising of only surfactants and cosolvents, took place within 30 min. The results indicated that most of the lipid systems were supersaturated with respect to the drug on dilution, but the extent of precipitation varied significantly between formulations and was influenced by the extent of supersaturation after dilution. The study suggests that the use of hydrophilic formulations for delivery of lipophilic drugs may result in a greater extent of drug precipitation in the stomach. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3582–3595, 2009 相似文献
16.
Objective
The main objective of this work was to study the dissolution kinetics of poorly water-soluble drugs, indomethacin and ibuprofen, from formulated capsules or interactive mixtures containing fine lactose (FL), as ternary additive, and coarse lactose as carrier compared with selected commercially indomethacin capsules and to investigate the role of FL-drug size ratio on the dissolution.Results and Discussion
It was found that the addition of FL in lactose-indomethacin capsules enhanced the dissolution of indomethacin while it has decreased the dissolution of ibuprofen from the lactose-ibuprofen mixtures. The particle size distributions for drugs and fine lactose used in this study suggested that the difference in dissolution behaviour for the two drugs could be due to the FL-drug ratio. Results obtained from the application of different dissolution kinetic equations showed that the first-order equation can best describe the kinetic of the dissolution for Rothacin®, Indylon®, Indomin® and ternary-formulated capsules of indomethacin, while the dissolution from the binary-formulated indomethacin capsules showed that the dissolution cannot be described by zero-order or first-order equations. For ibuprofen mixtures, the results showed that the release followed the first-order kinetic for both systems, binary and ternary mixtures. Results obtained from Peppas equation showed that all indomethacin formulations used in this study released the drug by Fickian release with release exponent (n) <0.45, while all ibuprofen formulations used in this study released the drug by non-Fickian (anomalous) release with release exponent (n) >0.45 and >0.89.Conclusion
The FL-drug ratio could give an explanation to the enhanced dissolution of indomethacin and decreased dissolution of ibuprofen from interactive mixtures. 相似文献17.
Kohsaku Kawakami Aoi Miyazaki Mayuko Fukushima Keiko Sato Yuko Yamamura Kohta Mohri Shinji Sakuma 《Pharmaceutical research》2017,34(1):208-216
Purpose
A novel drug delivery platform, mesoporous phospholipid particle (MPP), is introduced. Its physicochemical properties and ability as a carrier for enhancing oral absorption of poorly soluble drugs are discussed.Methods
MPP was prepared through freeze-drying a cyclohexane/t-butyl alcohol solution of phosphatidylcholine. Its basic properties were revealed using scanning electron microscopy, x-ray diffraction, thermal analysis, hygroscopicity measurement, and so on. Fenofibrate was loaded to MPP as a poorly soluble model drug, and effect of MPP on the oral absorption behavior was observed.Results
MPP is spherical in shape with a diameter typically in the range of 10–15 μm and a wide surface area that exceeds 10 m2/g. It has a bilayer structure that may accommodate hydrophobic drugs in the acyl chain region. When fenofibrate was loaded in MPP as a model drug, it existed partially in a crystalline state and improvement in the dissolution behavior was achieved in the presence of a surfactant, because of the formation of mixed micelles composed of phospholipids and surfactants in the dissolution media. MPP greatly improved the oral absorption of fenofibrate compared to that of the crystalline drug and its efficacy was almost equivalent to that of an amorphous drug dispersion.Conclusion
MPP is a promising option for improving the oral absorption of poorly soluble drugs based on the novel mechanism of dissolution improvement.18.
Purpose. The dissolution behavior of two commercially availableglibenclamide formulations was tested in various media. The aim of thestudy was to investigate whether the use of biorelevant dissolutionmedia (BDM) would be advantageous over the use of standard mediafor predicting the in vivo performance of the two formulations.Methods. The dissolution tests were performed using USP 23 apparatus2. Conventional buffers and USP media were compared with two BDMcontaining different amounts of lecithin and sodium taurocholate.Results. The dissolution of two drug powders was highly dependenton wetting, particle size, pH, and the composition of the mediumused. In addition, the dissolution behavior of the two glibenclamideformulations showed differences in all media tested. The dissolutionresults of the two formulations were compared with those from anin vivo bioequivalence study undertaken by the central quality controllaboratory of the German pharmacists (ZL). The bioequivalencecriterion set by the ZL requires more than 80;pc drug release within 10minutes. Results in FaSSIF, one of the BDMs, met the ZL criterionand this medium was also able to discriminate between the twoformulations. This was not the case for the other media tested.Conclusions. The study indicates that BDM are better able to discriminatebetween glibenclamide formulations than standard dissolutionmedia. 相似文献
19.
《Journal of pharmaceutical sciences》2022,111(3):780-793
There is much interest in converting poorly water-soluble drugs into nanocrystals as they provide extremely high surface area that increases dissolution rate and oral bioavailability. However, nanocrystals are prepared as aqueous suspensions, and once the suspensions are dried for development of solid dosage forms, the nanocrystals agglomerate as large particles to reduce the excess surface energy. For successful development of drug products, it is essential that any agglomeration is reversible, and the dried nanocrystals regain original particle sizes after redispersion in aqueous media. We have established that sucrose laurate serves as a superb stabilizer to ensure complete redispersion of dried nanocrystals in aqueous media with mild agitation. Nanocrystals (150–300 nm) of three neutral drugs (fenofibrate, danazol and probucol) were produced with sucrose laurate by media milling, and suspensions were dried by tray drying under vacuum, spray drying, and lyophilization. Dried solids and their tablets redispersed into original particle sizes spontaneously. Preliminary studies showed that sucrose laurate can also redisperse acidic and basic drugs, indicating its versatile application. Fatty acid ester of another disaccharide, lactose laurate, also performed like sucrose laurate. Thus, we have developed a method of retaining high dissolution rate and, by implication, high bioavailability of nanocrystals from solid formulations. 相似文献
20.
PURPOSE: The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during the in vitro digestion of long-chain or medium-chain triglyceride (TG) lipid suspension formulations. METHODS: TG suspensions of model drugs (present at double their equilibrium solubilities in the respective lipid) were digested in vitro and the drug solubilization and precipitation pattern in the resulting digests analyzed. RESULTS: For griseofulvin, diazepam, and danazol, solubilization of the small mass of drug originally presented in the TG lipid was efficient with only a small proportion of the dose precipitating and being recovered in the pellet phase after digestion of the TG lipid. For the more lipophilic and lipid-soluble drugs (cinnarizine, halofantrine), in which higher drug loadings were possible, significant enhancement in drug solubilization in the postdigestion aqueous phase was not apparent compared with simple TG lipid solutions. CONCLUSIONS: Suspensions of drugs, which are poorly soluble in water and TG lipid, may prove beneficial as the relatively high solubilizing capacity of the colloidal phases produced on TG digestion will likely exceed the mass of drug that could have been administered as a simple lipid solution. However, for more lipid-soluble drugs, suspension formulations may offer little benefit as sufficiently high drug loadings can otherwise be achieved with simple solution formulations that still provide for adequate solubilization after TG digestion. 相似文献