Lipophilicities of Baclofen Ester Prodrugs Correlate with Affinities to the ATP-Dependent Efflux Pump P-Glycoprotein: Relevance for Their Permeation Across the Blood-Brain Barrier?

Purpose. Distribution to the effect site is a prerequisite for the therapeutic effect and determined by physicochemical properties and affinities to inside- and outside-directed transporters. Based on the hypothesis that lipophilic esters of the GABA-derivative baclofen have a higher affinity to brain tissue, baclofen esters (methyl, ethyl, 1-propyl, 2-propyl, butyl) were studied regarding their penetration through the blood-brain barrier and their affinities to P-glycoprotein (P-gp). Methods. Octanol-water distribution coefficients (D) served as lipophilicity parameters. Blood and brain concentrations of baclofen and its methyl ester were determined in vivo in rats following intraperitoneal administration. Affinities to P-gp were evaluated using a radioligand binding assay based on P-gp-overexpressing cells and [³H]-talinolol as radioligand. Results. Log D values for baclofen and ester derivatives were -0.96 (baclofen), 0.48 (methyl), 0.77 (ethyl), 1.31 (1-propyl), 1.27 (2-propyl), and 1.42 (butyl). In-vitro studies yielded negligible affinity of baclofen to P-gp, whereas IC₅₀-values for the esters ranged between 1300 M (methyl) and 290 M (2-propyl). Affinity parameters correlated well with the lipophilicity parameters. Conclusions. Despite the P-gp affinity, brain concentrations of methyl ester were significantly higher than those of baclofen, however, baclofen levels following administration of the ester were smaller than with baclofen administration indicating only partial hydrolysis.     

The effect of polymer properties on direct compression and drug release from water-insoluble controlled release matrix tablets

The objective of this study was to identify and evaluate key polymer properties affecting direct compression and drug release from water-insoluble matrices. Commonly used polymers, such as Kollidon^® SR, Eudragit^® RS and ethyl cellulose, were characterized, formulated into tablets and compared with regard to their properties in dry and wet state. A similar site percolation threshold of 65% v/v was found for all polymers in dry state. Key parameters influencing polymer compactibility were the surface properties and the glass transition temperature (T_g), affecting polymer elasticity and particle size-dependent binding. The important properties observed in dry state also governed matrix characteristics and therefore drug release in wet state. A low T_g (Kollidon^® SR < Eudragit^® RS) decreased the percolation threshold, particle size effect and tortuosity, but increased permeability and sensitivity to heat/humidity treatment. Hence, lower permeability and higher stability are benefits of a high-T_g polymer (ethyl cellulose). However, release retardation was observed in the same order as matrix integrity (Eudragit^® RS < ethyl cellulose < Kollidon^® SR), as the high permeability was counteracted by PVP in case of Kollidon^® SR. Therefore, the T_g and composition of a polymer need to be considered in polymer design and formulation of controlled-release matrix systems.     

Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot: In vitro/in vivo evaluation

Microemulsion (ME) and poloxamer microemulsion-based gel (PMBG) were developed and optimized to enhance transport of diclofenac epolamine (DE) into the skin forming in-skin drug depot for sustained transdermal delivery of drug. D-optimal mixture experimental design was applied to optimize ME that contains maximum amount of oil, minimum globule size and optimum drug solubility. Three formulation variables; the oil phase X₁ (Capryol^®), Smix X₂ (a mixture of Labrasol^®/Transcutol^®, 1:2 w/w) and water X₃ were included in the design. The systems were assessed for drug solubility, globule size and light absorbance. Following optimization, the values of formulation components (X₁, X₂, and X₃) were 30%, 50% and 20%, respectively. The optimized ME and PMBG were assessed for pH, drug content, skin irritation, stability studies and ex vivo transport in rat skin. Contrary to PMBG and Flector^® gel, the optimized ME showed the highest cumulative amount of DE permeated after 8 h and the in vivo anti-inflammatory efficacy in rat paw edema was sustained to 12 h after removal of ME applied to the skin confirming the formation of in-skin drug depot. Our results proposed that topical ME formulation, containing higher fraction of oil solubilized drug, could be promising for sustained transdermal delivery of drug.     

Parenteral oil-based drospirenone microcrystal suspensions-evaluation of physicochemical stability and influence of stabilising agents

Drospirenone (DRSP) is a contraceptive drug substance with challenging physicochemical properties, due to insufficient solubility in aqueous and oil-based vehicles as well as low chemical stability in aqueous fluids. Although it is one of the most popular orally used progestins, no parenteral long-acting contraceptive containing the drug substance is marketed. An oil-based DRSP microcrystal suspension (MCS) might be an attractive formulation option. The main focus of this study was to investigate the physicochemical stability of such preparations. Moreover, syringeability and injectability via autoinjector were analysed using a materials testing machine. A high chemical stability of DRSP was found in oil-based vehicles. Span^® 83, cholesteryl oleate, lecithin, methyl cholate, Aerosil^® R972 and 200 Pharma were tested for increasing the physical stability of DRSP dispersions. Changes in viscosity, rheological properties, and solubility were analysed. The intention was to show a stabilising effect of the excipients without increasing viscosity and solubility. To evaluate the physical stability of DRSP MCS with and without addition of stabilising agents, sedimentation and particle growth after storage were examined. Especially, the silica derivatives Aerosil^® 200 and R972 Pharma influenced the physical stability positively.     

Properties of Free Films Prepared from Aqueous Polymers by a Spraying Technique

A spray method for the preparation of free films from aqueous polymeric dispersions was investigated. Free films were prepared from aqueous dispersions of methacrylic acid-ethyl methacrylate copolymer (Eudragit^® L 30D), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), and ethyl cellulose (EC) by a spray method and a cast method, and their mechanical properties and reproducibility were investigated. Uniform films were obtained from the dispersions of Eudragit^® L 30D, HPMCAS, and EC by the spray method, but films could not be formed by spraying the CAP dispersion. The tensile strength, elongation, and elastic modulus of the sprayed Eudragit^® L 30D films were similar to the properties of the cast films, and good reproducibility was obtained from both methods. Marked within-run variation in the mechanical properties was observed for the cast HPMCAS and CAP films, which could be due to a settling of the solid particles during the drying step. The variation in the mechanical properties of the sprayed HPMCAS films was lower and the tensile strength significantly higher than that of the cast films. There were also significant differences in tensile strength and elongation of EC films between products of the two methods. The results indicated that the spray method used to prepare the free films from aqueous polymeric dispersions provided uniform films with consistent and reproducible properties.     

灯盏乙素酯类前药的合成、理化性质及降解研究

目的对口服难吸收中药活性成分灯盏乙素进行结构改造，为寻找和设计合理前药及其剂型提供依据。方法通过先成盐后酯化的方法合成灯盏乙素乙酯、苄酯并改进文献方法合成羟乙酰胺酯，用质谱和氢谱确证结构。研究3种前药在不同pH水溶液中的稳定性、溶解度、分配系数和在人血浆中的降解。制备灯盏乙素羟乙酰胺酯环糊精包合物和乳剂，比较包合物和乳剂在肠液中对该前药的保护作用，考察该前药在不同肠段黏膜匀浆中的降解情况。结果合成的3种前药经确证为目标物；灯盏乙素羟乙酰胺酯在缓冲液(pH 4.2)和水中的溶解度比灯盏乙素分别提高近10倍和35倍，分配系数也由原来的-2.56提高到1.48；该酯水溶液的稳定性较好(t_1/2≈16 d，pH 4.2)，在人血浆的半衰期最短(t_1/2≈7 min)，但在肠黏膜匀浆中的降解可能影响酯的吸收，不同肠段黏膜匀浆降解羟乙酰胺酯的次序为：十二指肠>回肠≥空肠>结肠。乳剂在肠黏膜匀浆中对前药有显著的保护作用，包合物次之。结论与灯盏乙素乙酯和苄酯比较，羟乙酰胺酯的理化性质较好，但其在肠道中的稳定性有待提高，可以选择乳剂或结肠定位给药减少前药的降解。     

Dry powder inhalers: mechanistic evaluation of lactose formulations containing salbutamol sulphate

The purpose of this study was to evaluate the relationships between physicochemical properties and aerosolisation performance of different grades of lactose. In order to get a wide range of physicochemical properties, various grades of lactose namely Flowlac^®100 (FLO), Lactopress anhydrous^®250 (LAC), Cellactose^®80 (CEL), Tablettose^®80 (TAB), and Granulac^®200 (GRA) were used. The different lactose grades were carefully sieved to separate 63-90 μm particle size fractions and then characterised in terms of size, shape, density, flowability, and solid state. Formulations were prepared by blending each lactose with salbutamol sulphate (SS) at ratio of 67.5:1 (w/w), and then evaluated in terms of SS content uniformity, lactose-SS adhesion properties, and in vitro aerosolisation performance delivered from the Aerolizer^®. Sieved lactose grades showed similar particle size distributions (PSDs) and good flow properties but different particle shape, particle surface texture, and particle solid state. Content uniformity assessments indicated that lactose particles with rougher surface produced improved SS homogeneity within DPI formulation powders. Lactose-SS adhesion assessments indicated that lactose particles with more elongated shape and the rougher surface showed smaller adhesion force between lactose and salbutamol sulphate. Lactose powders with higher bulk density and higher tap density produced smaller emission (EM) and higher drug loss (DL) of SS. In vitro aerosolisation for various lactose grades followed the following rank order in terms of deposition performance: GRA > TAB > LAC ≈ CEL > FLO. Linear relationships were established showing that in order to maximize SS delivery to lower airway regions, lactose particles with more elongated shape, more irregular shape, and rougher surface are preferred. Therefore, considerable improvement in DPI performance can be achieved by careful selection of grade of lactose included within DPI formulations.     

Optimization of separation and determination of moxifloxacin and its related substances by RP-HPLC

A RP-HPLC method for the separation and determination of impurities of moxifloxacin, in its pharmaceutical forms as well as moxifloxacin degradation products, was developed with the aid of DryLab^® software and chemometric (response surface) approach. The separation of four synthesis-related impurities was achieved on a Waters C₁₈ XTerra column using a mobile phase of (water + triethylamine (2%, v/v)): acetonitrile = 90:10 (v/v%); the pH of water phase being adjusted with phosphoric acid to 6.0. Flow rate of the mobile phase was 1.5 ml/min and UV detection at 290 nm was employed. The column was thermostated at 45 °C. The resolution between the two least resolved impurity peaks was in average, R_s,min > 1.5. Method validation parameters indicate linear dynamic range 0.2–2.0 μg/ml with LOQ ca. 0.20 μg/ml and LOD ca. 0.05 μg/ml for all analytes.     

Effects of liquisolid formulations on dissolution of naproxen

The aim of this study was to investigate the use of liquisolid technique in improving the dissolution profiles of naproxen in a solid dosage form. This study was designed to evaluate the effects of different formulation variables, i.e. type of non-volatile liquid vehicles and drug concentrations, on drug dissolution rates. The liquisolid tablets were formulated with three different liquid vehicles, namely Cremophor^® EL (polyoxyl 35 castor oil), Synperonic^® PE/L61 (poloxamer 181, polyoxyethylene-polyoxypropylene copolymer) and poly ethylene glycol 400 (PEG400) at two drug concentrations, 20%w/w and 40%w/w. Avicel^® PH102 was used as a carrier material, Cab-o-sil^® M-5 as a coating material and maize starch as a disintegrant. The empirical method as introduced by Spireas and Bolton (1999) [1] was applied strictly to calculate the amounts of coating and carrier materials required to prepare naproxen liquisolid tablets. Quality control tests, i.e. uniformity of tablet weight, uniformity of drug content, tablet hardness, friability test, disintegration and dissolution tests were performed to evaluate each batch of prepared tablets. In vitro drug dissolution profiles of the liquisolid formulations were studied and compared with conventional formulation, in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.2) without enzyme. Stability studies were carried out to evaluate the stability of the tablets under humid conditions. Differential scanning calorimetry and Fourier transform infrared were used to investigate physicochemical interaction between naproxen and the excipients. It was found that liquisolid tablets formulated with Cremophor^® EL at drug concentration of 20%w/w produced high dissolution profile with acceptable tablet properties. The stability studies showed that the dissolution profiles of liquisolid tablets prepared with Cremophor^® EL were not affected by ageing significantly. Furthermore, DSC revealed that drug particles in liquisolid formulations were completely solubilised.     

Design of fenofibrate microemulsion for improved bioavailability

The objective of the present study was to formulate a microemulsion system for oral administration to improve the solubility and bioavailability of fenofibrate. Various formulations were prepared using different ratios of oils, surfactants and co-surfactants (S&CoS). Pseudo-ternary phase diagrams were constructed to evaluate the microemulsification existence area. The formulations were characterized by solubility of the drug in the vehicles, mean droplet size, and drug content. The stability was also investigated by store for 3 months under 4 °C, 25 °C and 40 °C and diluted 100 times for 3 days. The optimal formulation consists of 25% Capryol 90, 27.75% Cremophore EL, 9.25% Transcutol P and 38% water (w/w), with a maximum solubility of fenofibrate up to ∼40.96 mg/mL. The microemulsion was physicochemical stable and mean droplet size was about 32.5-41.7 nm. The pharmacokinetic study was performed in dogs and compared with Lipanthy^® capsule. The result showed that microemulsion has significantly increased the C_max and AUC compared to that of Lipanthy^® capsule (p < 0.05). The oral bioavailability of fenofibrate microemulsions (FEN-MEs) in ME-3 and ME-4 were 1.63 and 1.30-fold higher than that of the capsule. Our results indicated that the microemulsions could be used as an effective formulation for enhancing the oral bioavailability of fenofibrate.     

An approach to a cold chain free oral cholera vaccine: in vitro and in vivo characterization of Vibrio cholerae gastro-resistant microparticles

The present work describes the formulation of Eudragit^® L30 D-55 microparticles (MP) alone or with mucoadhesive agents, alginate or Carbopol^®, as an approach for the development of an oral cholera vaccine. In the first part, a spray drying technique was optimized for microparticle elaboration, obtaining a microparticle size ranging from 7 to 9 μm with high encapsulation efficiencies. Moreover, gastro resistant properties and Vibrio cholerae (VC) antigenicity were maintained, but for Eudragit^®-Carbopol^® microparticles which showed low antigenicity values, ≈25%. Next, a stability study was performed following ICH Q1 A (R2) guidelines, i.e. 25 °C-60% relative humidity (RH) for 12 months, and 30 °C-65% RH and 40 °C-75% RH for 6 months. Upon storage, microparticle size changed slightly, 1 μm for Eudragit^®-alginate MPs and 0.36 μm for Eudragit^®MP. However, gastro resistance and antigenicity values were kept in an acceptance range. In the third stage of this work, in vivo experiments were performed. The immune response evoked was measured by means of vibriocidal titer quantification, observing that Eudragit^®-alginate MPs were able to induce stronger immune responses, comparable to the free VC. Therefore, microencapsulation of VC by spray drying could be proposed as an approach to a cold chain free and effective oral cholera vaccine.     

HPLC法测定盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯的平衡溶解度和脂水分配系数

目的:测定盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯在乙醇、乙腈、丙酮、乙酸乙酯等溶剂中的平衡溶解度以及在正辛醇-水和正辛醇-缓冲液体系中的表观油水分配系数。方法:采用HPLC法测定盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯的浓度,采用摇瓶法测定其表观油水分配系数。结果:25℃时盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯在乙醇、乙腈、丙酮、乙酸乙酯中的平衡溶解度分别为31.36,141.50,575.77,598.68 g.L-1。pH=4时此目的化合物的平衡溶解度最小,而表观油水分配系数最大。结论:盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯的平衡溶解度及油水分配系数与介质的pH有关。其水溶性较差,脂溶性好。     

Development and validation of a stability-indicating HPLC method for simultaneous determination of salicylic acid,betamethasone dipropionate and their related compounds in Diprosalic Lotion

Diprosalic Lotion^® is an anti-inflammatory drug product that contains salicylic acid and betamethasone dipropionate as active pharmaceutical ingredients (APIs). A reversed-phase high performance liquid chromatography (RP-HPLC) method was developed for simultaneous determination of salicylic acid, betamethasone dipropionate, and their related compounds in Diprosalic Lotion^®. A 150 mm × 4.6 mm I.D. YMC J'sphere ODS-H80 column at 35 °C and UV detection at 240 nm was used. A gradient elution was employed using 0.05% (v/v) methanesulfonic acid solution and acetonitrile as mobile phases. A total of thirty three compounds from Diprosalic Lotion^® samples were separated in 38 min. The stability-indicating capability of this method has been demonstrated by the adequate separation of all the impurities and degradation products in expired stability samples of Diprosalic Lotion^®. The method was validated as per the current ICH guidelines.     

Der Einfluß von 2-(2,6-Dichlorphenylamino)-2-imidazolin-hydrochlorid (Catapresan®) auf die Funktion von Magen und Pankreas

Zusammenfassung In klinischen Untersuchungen wurde der Einfluß von 2-(2,6-Dichlorphenylamino)-2-imidazolin-hydrochlorid (Catapresan^®) auf die Magensaftsekretion sowie die exokrine und endokrine Pankreassekretion geprüft. Nach intravenöser Gabe von 4 µg/kg Catapresan^® wird die nichtstimulierte sowie die Insulin-, Betazol-und Pentagstrin-stimulierte Säuresekretion des Magens gehemmt. Die secretininduzierte Pankreassekretion wird gleichfalls durch Catapresan^® vermindert. Eine Beeinträchtigung der basalen Insulinsekretion konnte bei Personen ohne Kohlenhydratstoffwechselstörung und einer Patientin mit Hyperinsulinismus nicht nachgewiesen werden.

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The effect of 2-(2,6-dichlorophenylamino)-2-imidazolin hydrochloride (Catapresan^®) on gastric secretion

Summary The effect of 2-(2,6-dichlorophenylamino)-2-imidazolin hydrochloride (Catapresan^®) on gastric secretion, duodenal bicarbonate secretion and plasma insulin levels has been examined in clinical studies. The acidity and bicarbonate concentration were not affected, but the basal gastric secretion, and the betazol (2 mg/kg) —, pentagastrin 6 µg/kg — and insulin (0.2 U/kg) induced gastric secretion and the secretin (1 U/kg) induced duodenal bicarbonate secretion were decreased after the intravenous administration of 4 µg/kg of this substance. There was no change in blood sugar and basal insulin levels in normal persons.

     

Antibacterial optimization of 4-aminothiazolyl analogues of the natural product GE2270 A: identification of the cycloalkylcarboxylic acids

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.     

Plasticizer extraction of Taxol?-infusion solution from various infusion devices

Taxol^® solution extracts the plasticizer DEHP (di(2-ethylhexyl)phthalate) from polyvinyl chloride (PVC) materials. In order to minimize patient exposure to DEHP, Taxol^® solutions should be prepared and administered in PVC-free materials. Particulate matter may form in Taxol^® infusion solution over time, so that in-line filtration with microporous membranes not greater than 0.22 m is advisable. The purpose of this study was to evaluate the suitability of various administration- and in-line filter-sets for Taxol^® application. The extent of leached DEHP was determined using a Reversed Phase HPLC assay specific for DEHP.The four tested administration-sets labeled as PVC-free, were all found to be suitable for Taxol^® application. The tested standard PVC-lined administration-set should not be used for Taxol^® application. Baxter Intermate^® LV 250 can be recommended as a disposable infusion device for ambulatory Taxol^® application. It can be connected with all the tested filter sets.     

Radiosynthesis of [11C]ximelagatran via palladium catalyzed [11C]cyanation

N‐hydroxyamidines (amidoximes) may be used in prodrug technology in improving oral bioavailability of drugs containing amidino functional groups. In the body, amidoximes are reduced quickly to amidines by enzymes that are present in several organs. Ximelagatran is a benzamidoxime and ethyl ester prodrug of melagatran, which is a thrombin inhibitor. Our aim was to develop a fast and efficient labeling route for the synthesis of [¹¹C]ximelagatran ([¹¹C]3) with a label in a metabolically stable position. [¹¹C]3 was synthesized via a two‐step synthesis sequence, starting from palladium catalyzed [¹¹C]cyanation of its corresponding bromide precursor (2‐[2‐(4‐bromo‐benzylcarbamoyl)‐azetidin‐1‐yl]‐1‐cyclohexyl‐2‐oxo‐ethyl amino‐acetic acid ethyl ester) (1), followed by a reaction with hydroxylamine. [¹¹C]3 was synthesized with 27±17% total overall decay corrected yield (specific radioactivity of 2360±165 Ci/mmol at EOS), with a total synthesis time of 45 min. A fast and efficient labeling route for the synthesis of [¹¹C]3 was developed. Copyright © 2008 John Wiley & Sons, Ltd.     

比卡鲁胺相关物质B的合成和表征及理化性质

目的 合成比卡鲁胺有关物质B并测定其理化性质。方法 以1,2-环氧-2-甲基-N-[4-氰基-3-(三氟甲基)苯基]丙酰胺为起始原料,经缩合、氧化两步反应制得N-[4-氰基-3-(三氟甲基)苯基]-3-(3-氟苯硫酰基)-2-甲基-2-羟基丙酰胺(比卡鲁胺有关物质B),用IR、¹H-NMR、¹³C-NMR、质谱、元素分析及差热分析对其结构进行表征,使用UV和DSC对其在不同溶剂中的溶解度和熔点进行分析。结果 合成总收率达到74.6%,纯度为99.58%。通过溶解度的测定说明其在醇酮等有机溶剂中有一定的溶解度,但在不同pH值的水介质中几乎不溶。结论 本合成方法操作简单、反应条件温和,能容易地制备比卡鲁胺有关物质B,在此基础上测定的物化数据可为相关研究提供有益参考。     

助悬剂用量对糠酸氟替卡松鼻喷剂喷雾特性的影响

目的 研究混悬型鼻喷剂中助悬剂Avicel^®浓度对鼻喷剂喷雾模式、喷雾形态以及雾滴粒径的影响。方法 制备不同Avicel^®浓度的糠酸氟替卡松鼻用混悬液。通过SprayVIEW^®喷雾测试系统测试鼻喷剂的喷雾特性参数,使用Box-Behnken响应面法分析Avicel^®浓度对鼻喷剂体外喷雾特性的影响,同时考察Avicel^®浓度对喷雾雾滴粒径的分布影响以及在不同检测距离下雾滴的粒径变化。结果 增大Avicel^®浓度会显著减小喷雾面积以及喷雾角度和宽度（P<0.001）,同时增大D₅₀和整体粒径。增大驱动速度会显著增大喷雾面积、喷雾角度和宽度（P<0.05）,驱动加速度对喷雾特性的影响远小于Avicel^®浓度和驱动速度。随着检测距离的增加,雾滴粒径分布变得更加集中,雾滴粒径分布跨度变小。结论 本研究通过Box-Behnken响应面法发现Avicel^®的浓度与驱动速度对喷雾特性的影响存在拮抗作用,为鼻喷剂Avicel^®浓度的选择以及装置推荐驱动参数提供了参考。     

Synthesis, in vitro and in vivo characterization of novel ethyl dioxy phosphate prodrug of propofol

A novel ethyl dioxy phosphate prodrug of propofol (3) was synthesized and characterized in vitro and in vivo as safer alternative for phosphonooxymethyl prodrugs. The synthesis of 3 was achieved via vinyl and 1-chloroethyl ether intermediates, followed by addition of phosphate group. Aqueous solubility and chemical stability of 3 was determined in buffer solutions and the bioconversion of 3 to propofol was determined in vitro and in vivo. The results show that 3 greatly enhanced the aqueous solubility of propofol (solubility over 10 mg/mL) and the stability in buffer solution (t1/2=5.2+/-0.2 days at pH 7.4, r.t.) was sufficient for i.v. administration. The enzymatic hydrolysis of 3 to propofol was extremely rapid in vitro (t1/2=21+/-3s) and 3 was readily converted to propofol in vivo in rats. During bioconversion, 3 releases acetaldehyde, a less toxic compound than the formaldehyde released from the phosphonooxymethyl prodrug of propofol (Aquavan), currently undergoing clinical trials. The maximum plasma concentration of propofol, 3.0+/-0.2 microg/mL, was reached within 2.1+/-0.8 min after the i.v. administration of 3. The present study indicates that ethyl dioxy phosphate represents a potentially useful water-soluble prodrug structure suitable for i.v. administration.