Effects of Permeation Enhancers on the Transport of a Peptidomimetic Thrombin Inhibitor (CRC 220) in a Human Intestinal Cell Line (Caco-2)

Purpose. The effects of five different permeation enhancer systems on the transport properties of a peptidomimetic thrombin inhibitor, CRC 220, were investigated in monolayers of a human intestinal cell line (Caco-2). Methods. The transepithelial transport rates and additionally the cytotoxic properties of these enhancers were characterized using the following tests: measurement of the transepithelial electrical resistance (TEER), the MTT-transformation, the protein content and the release of cytosolic lactate dehydrogenase (LDH), as well as FITC-phalloidin and propidium iodide staining. Results. All permeation enhancer systems showed concentration-dependent effects on cell permeability and toxicity. The most prominent effects on peptide transport were seen at the highest concentration (40 mM), yielding the rank order, NaTC > NaTC/Cholesterol > Solulan C24 > NaTC/Oleic acid > NaTC/PC18. Using the TEER after 120 min exposure as the most sensitive parameter describing cytotoxicity, the following order was obtained: Solulan C24 > NaTC > NaTC/ PC 18 = NaTC/Cholesterol > NaTC/Oleic acid > NaTC/PC. Generally, efficient enhancement of peptide transport was associated with a noticeable influence on cell viability under in-vitro conditions. Conclusions. Taking into account permeation and cytotoxicity as a function of concentration, both NaTC at 15 mM and the mixed micellar system NaTC/oleic acid at 0.75 mM offer interesting enhancement properties, showing an 18-fold increase in CRC 220 transport rates. The effects on cell viability and cytotoxicity were comparatively low and of reversible nature.     

Subacute toxicity of all-trans- and 13-cis-isomers of N-ethyl retinamide, N-2-hydroxyethyl retinamide, and N-4-hydroxyphenyl retinamide

The major limitation for continuous administration of natural retinoids for chemoprevention of cancer is their high toxicity; however, synthetic retinamides have the desirable quality of reduced toxicity while retaining most of the biological activity. We have presently evaluated the comparative toxicity of all-trans- and 13-cis-isomers of N-ethyl retinamide (ER), N-2-hydroxyethyl retinamide (HER), and N-4-hydroxyphenyl retinamide (HPR) in mice and rats after po and ip administration. The computed LD90, DL50, and LD10 values for combined sexes of mice following 21 daily doses of the above retinoids were determined. Identical doses of the same retinoid by ip administration produced more toxicity and deaths than by the po route. The 13-cis-isomers exhibited comparatively less toxicity than the corresponding all-trans-isomer. Based on the lethality data, all-trans-retinoic acid was most toxic followed by all-trans-HER greater than all-trans-HPR greater than all-trans-ER. Changes in clinical chemistry and hematological parameters associated with administration of the retinamides include a dose-dependent peripheral anemia evidenced by erythrocytopenia and decreased hemoglobin concentration and packed cell volume. Retinoid treatment also caused increased plasma alkaline phosphatase activity and decreased serum albumin levels. Histopathological changes associated with retinoid administration primarily included liver lesions as characterized by degeneration and enlargement of hepatocytes. The present studies indicate that synthetic retinoids are less toxic than the natural ones.     

Diffusivity of Bile Salt/Phospholipid Aggregates in Mucin

Purpose. The objective of this study is to evaluate the effect of the mucous layer on the transport of the drug-solubilizing bile salt/phosphatidylcholine (BS/PC) aggregates. Methods. The self-diffusion coefficient of BS/PC aggregates in bovine submaxillary mucin (BSM) was measured by Fourier-transform pulsed-field gradient spin-echo (FT-PGSE) ¹H NMR spectroscopy. Results. In spite of the complexity of the mixture, the FT-PGSE technique allowed the unambiguous determination of the diffusivity of PC and ¹H²HO (HDO, natural abundance in D₂O). With a series of BS/ PC total lipid concentrations ranging from 1 to 7 g/dl, a progressive decrease in the effective diffusivity of HDO was observed with an increase in the both the BSM and total lipid concentration. The effective diffusivity of PC decreased with increasing lipid concentrations in the presence of mucin, while in the controls it increased. After correcting the effective diffusivity of PC for the obstruction effect of mucin, the size of the BS/PC mixed micelle was assessed. It appears that PC associates with BSM resulting in a decrease in the available PC for micellization. This reduces the average size of the mixed micelle within the mucous layer. Conclusions. The aggregation state of BS/PC micelle is altered by the presence of mucin which would have a direct impact on the transport of dietary lipid and solubilized drug through the aqueous boundary layer of the intestinal tract.     

Intestinal lymphatic transport of three retinoids in the rat after oral administration: Effect of lipophilicity and lipid vehicle

The retinoids are highly lipophilic molecules and are known to be transported in the intestinal lymph after oral administration. Three retinoids, isotretinoin, etretinate and temarotene were used to study the effects of solubility and lipophilicity on lymphatic uptake in the rat after oral administration in each of three oily vehicles, cottonseed oil, Miglyol 812 and linoleic acid. Lipid solubility showed a general increase with increasing log P of the retinoid. The most lipophilic retinoid, temarotene, showed solubilities between 109.5 mg/ml (linoleic acid) and 170.6 mg/ml (Miglyol 812), whereas the least lipophilic retinoid, isotretinoin showed much lower solubilities between 5.1 (cottonseed oil) and 30.5 mg/ml (linoleic acid). Lymphatic uptake of temarotene was 4000-times and from etretinate 1000-times greater than that for isotretinoin after administration in linoleic acid. The lymphatic uptake of temarotene and etretinate from cottonseed oil were 27- and 26-times greater than that for isotretinoin and from Miglyol 812, 22-and 10-times greater than isotretinoin. These decreases in absorption via the lymphatic route reflect a decrease in log P value from temarotene (log P ≈ 8.7) to etretinate (log P ≈ 7.8) to isotretinoin (log P ≈ 6.8). The rank order of increasing lymphatic uptake from each of the three oils shows an inverse relationship with solubility of the retinoid in each of the oils     

Experimental and Computational Screening Models for Prediction of Aqueous Drug Solubility

Purpose. To devise experimental and computational models to predict aqueous drug solubility. Methods. A simple and reliable modification of the shake flask method to a small-scale format was devised, and the intrinsic solubilities of 17 structurally diverse drugs were determined. The experimental solubility data were used to investigate the accuracy of commonly used theoretical and semiexperimental models for prediction of aqueous drug solubility. Computational models for prediction of intrinsic solubility, based on lipophilicity and molecular surface areas, were developed. Results. The intrinsic solubilities ranged from 0.7 ng/mL to 6.0 mg/mL, covering a range of almost seven log₁₀ units, and the values determined with the new small-scale shake flask method agreed well with published solubility data. Solubility data computed with established theoretical models agreed poorly with the experimentally determined solubilities, but the correlations improved when experimentally determined melting points were included in the models. A new, fast computational model based on lipophilicity and partitioned molecular surface areas, which predicted intrinsic drug solubility with a good accuracy (R ²of 0.91 and RMSE_tr of 0.61) was devised. Conclusions. A small-scale shake flask method for determination of intrinsic drug solubility was developed, and a promising alternative computational model for the theoretical prediction of aqueous drug solubility was proposed.     

Comparison of the Mechanism of Dissolution of Hydrocortisone in Simple and Mixed Micelle Systems

Lecithin, a major phospholipid component of human bile, is instrumental in the formation of mixed micelles in vivo, with implications for the dissolution and absorption of poorly soluble compounds administered orally. Hydrocortisone, a poorly aqueous soluble drug (S _aq = 1.08 × 10^–3 M), was chosen to compare the rate and mechanism of dissolution in a NaTC/lecithin (mixed micelle) system with its NaTC-only (simple micelle) counterpart. Surface tension, solubility studies, contact angles, rotating disk dissolution rates, and powder dissolution rates were compared for hydrocortisone between solutions containing NaTC/lecithin (4:1) and NaTC-only under conditions representative of the small intestine (0–30 mM NaTC, pH 5.5, 0.1 M NaCl). At all concentrations, the solubility of hydrocortisone in NaTC/lecithin was slightly higher (up to twofold) than in the corresponding NaTC-only solutions. At low NaTC concentrations, initial powder dissolution rates were faster in the NaTC/lecithin solutions than in corresponding NaTC-only solutions. In contrast, at high NaTC concentrations, initial powder dissolution rates in the NaTC-only solutions were faster. Results indicated that in the NaTC-only system wetting effects predominated for dissolution, while in the NaTC/lecithin system, the dissolution rate of hydro-cortisone was enhanced mainly via solubilization.     

Synthesis and In Vitro Evaluation of Aminoacyloxyalkyl Esters of 2-(6-methoxy-2-naphthyl)propionic Acid as Novel Naproxen Prodrugs for Dermal Drug Delivery

Purpose. To synthesize and evaluate various novel aminoacyloxyalkyl esters of naproxen (3a-i) and naproxenoxyalkyl diesters of glutamic and aspartic acids (3j-m) as potential dermal prodrugs of naproxen. Methods. The prodrugs 3a-m were synthesized, and their aqueous solubilities, lipophilicities and hydrolysis rates were determined in a buffered solution and in human serum. The permeation of selected prodrugs across excised postmortem human skin was studied in vitro. Results. The aminoacyloxyalkyl prodrugs showed higher aqueous solubilities and similar lipid solubilities, in terms of octanol-buffer partition coefficients (log P_app) at pH 5.0, when compared with naproxen. At pH 7.4 the prodrugs were significantly more lipophilic than naproxen. Prodrugs3a-i showed moderate chemical stability in aqueous solutions at pH 5.0 and were rapidly converted to naproxen in human serum (t_1/2 = 4–19 min). The selected aminoacyloxyalkyl prodrugs possessed a higher flux across the skin than naproxen, with a maximum enhancement of 3-fold compared to naproxen. Prodrugs 3j-mshowed poor aqueous solubility and permeation across the skin. Conclusions. Combinations of adequate aqueous solubility and lipophilicity of naproxen aminoacyloxyalkyl prodrugs having fast rates of enzymatic hydrolysis resulted in improved dermal delivery of naproxen.     

lonization and Solubilization of 4 Alkyl Benzole Acids and 4 Alkyl Anilines in Sodium Taurodeoxycholate Solutions

Purpose. The aqueous solubility and the extent of solubilization and ionization constant in sodium taurodeoxycholate (NaTDC) solutions of a series of benzoic acid and aniline derivatives were measured as a basis to characterize and thereby help predict the nature of the interaction of drugs with bile aggregates. Methods. The aqueous solubility and the solubilization of two series of compounds, 4-alkyl benzoic acids and 4-alkyl anilines, was measured as a function of NaTDC in 0 and 150 mM NaCl. The ionization constants were determined in water and in 50 mM NaTDC at sodium chloride concentrations of 0, 75 and 150 mM by spectrophotometric titration. The diffusion coefficients of NaTDC and the solutes were measured by pulsed-field gradient spin echo NMR spectroscopy. Results. The aqueous solubilities decreased with increasing alkyl chain length in both series, and the aniline derivatives had larger solubilities than the benzoic acid derivatives. The number of moles of solute solubilized per mole of bile salt ranged from 0.17 to 0.31 for the benzoic acid derivatives and from 1.3 to 3.0 for the aniline derivatives. The pKa values of the benzoic acid derivatives in the presence of NaTDC were higher relative to the controls, and the difference in the pKa (pKa,obs) increased with increasing chain length. With the aniline derivatives, the pKa values were also shifted to higher values in NaTDC relative to the control but only in the absence of salt. The presence of the solute caused a decrease in the diffusion coefficient of NaTDC, and the diffusion coefficients of the solutes decreased with increasing alkyl chain length. With the hexyl derivatives, the diffusion coefficient of the solute was smaller than the diffusion coefficient of the bile salt. The chemical shift of the protons attached to carbon 18 and 19 of the bile salt were decreased to a greater extent in the presence of the solutes than the protons attached to carbon 26. Conclusions. Both the solubilization and ionization behavior of solutes were affected by the presence of bile salt aggregates. The surface potential and effective polarity of NaTDC aggregates were found to be dependent on the alkyl chain length for these two homologous series of solutes. The solubilization ratio was largely independent of alkyl chain length, but the unitary partition coefficient was dependent on both the alkyl chain length as well as ionization state. The derivatives reduced the diffusivity of the micelles suggesting the formation of larger sized aggregates and the solutes (hexyl derivatives) appear to favor association with the larger sized aggregates. The phenyl ring of the solutes appears to be oriented parallel to the plane of the steroid frame with preferential positioning near the hydrophobic rings.     

Pharmacokinetic Screening of o-Naphthoquinone 5-Lipoxygenase Inhibitors

The o-naphthoquinone derivative, CGS 8515 (I), is a potent inhibitor (IC₅₀, 0.1 µM) of 5-lipoxygenase, but its therapeutic potential is compromised by a short plasma half-life (22 min) and extremely poor oral bioavailability (<2%). Poor biopharmaceutical properties of CGS 8515 were attributed to poor aqueous solubility and rapid in vivo hydrolysis of its methyl ester function to an inactive metabolite (IC₅₀, 100 µM). An active amide analogue (II) was synthesized to prevent rapid hydrolysis. While analogue II appeared to be stable in vivo, its plasma half-life was also short (10 min), possibly because of rapid tissue distribution rather than metabolic elimination. Therefore, three potent analogues with increased aqueous solubilities were synthesized and compared with respect to their pharmacokinetic properties. The analogue with the highest aqueous solubility (V) demonstrated a plasma concentration vs time profile with the largest area under the curve (AUC) and the smallest distribution () phase of all the analogues studied. The percentage AUC of the terminal phase () for three analogs paralleled their aqueous solubilities. The oral bioavailability of V was improved to 27%, compared to 2% for the parent compound, CGS 8515.     

Physicochemical Characterization and Solubility Analysis of Thalidomide and Its N-Alkyl Analogs

Purpose. The present study was primarily aimed at exploring the feasibility of improving percutaneous delivery via chemical manipulation of the thalidomide molecule to form analogs with improved physicochemical properties. N-Alkyl analogs were synthesized with the belief that these would be suitably hydrophobic and far less crystalline than the reference compound. This article presents their physicochemical properties. Methods. Thalidomide and three of its N-alkyl analogs were synthesized. Identification and levels of purity (>96%) were assured through element analysis, fast atom-bombardment mass spectrometry, nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. N-Octanol/water partition coefficients were determined at pH 6.4. Solubilities in water and a series of n-alkanols were obtained. Best-fit solubility parameters were determined from the solubilities of the respective compounds in London solvents and were also calculated from respective hexane solubilities, melting points and heats of fusion. Results. Methylation of the thalidomide molecule at its acidic nitrogen led to an aqueous solubility about 6-fold higher than thalidomide but, because the alkyl chain length was further extended from methyl to pentyl, aqueous solubilities decreased essentially exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increased solubility in nonpolar media. The log partition coefficient increased linearly with increasing alkyl chain length and the solubility parameters declined systematically through this series. By adding a methyl group to the thalidomide structure, the melting point dropped by more than 100°C. Adding to the alkyl chain length led to further, more modest decreases. Heats of fusion decreased dramatically upon thalidomide's alkylation as well. Conclusion. Alkylation of the thalidomide molecule resulted in compounds with physicochemical properties that appear to be markedly better suited for percutaneous delivery.     

Tazarotene foam, 0.1%, for the treatment of acne

Introduction: Acne is a common skin condition of the pilosebaceous units that affects the young and old, ranges from moderate to severe and can be treated with an array of options. Topical retinoids are the initial treatment for acne due to their ability to treat comedones, the starting point of acne.

Areas covered: Tazarotene is a topical retinoid available as a cream, gel and foam. Tazarotene 0.1% foam was FDA approved in 2012 for the treatment of acne in patients ages ≥12 and is the first foam topical retinoid on the market. Phase I and III trials support the efficacy and safety of tazarotene foam for acne.

Expert opinion: The foam vehicles may increase compliance and satisfaction in some patients and as retinoids are commonly first line acne treatments, this new topical retinoid foam may be a useful option for some acne patients.     

What is the True Solubility Advantage for Amorphous Pharmaceuticals?

Purpose. To evaluate the magnitude of the solubility advantage foramorphous pharmaceutical materials when compared to their crystallinecounterparts.Methods. The thermal properties of several drugs in their amorphousand crystalline states were determined using differential scanningcalorimetry. From these properties the solubility advantage for theamorphous form was predicted as a function of temperature using a simplethermodynamic analysis. These predictions were compared to theresults of experimental measurements of the aqueous solubilities of theamorphous and crystalline forms of the drugs at several temperatures.Results. By treating each amorphous drug as either an equilibriumsupercooled liquid or a pseudo-equilibrium glass, the solubilityadvantage compared to the most stable crystalline form was predicted to bebetween 10 and 1600 fold. The measured solubility advantage wasusually considerably less than this, and for one compound studied indetail its temperature dependence was also less than predicted. It wascalculated that even for partially amorphous materials the apparentsolubility enhancement (theoretical or measured) is likely to influencein-vitro and in-vivo dissolution behavior.Conclusions. Amorphous pharmaceuticals are markedly more solublethan their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simplethermodynamic considerations. This appears to be the result of difficulties indetermining the solubility of amorphous materials under trueequilibrium conditions. Simple thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage foramorphous pharmaceuticals, which directly reflects the driving forcefor their initial dissolution.     

Sterically Stabilized Phospholipid Mixed Micelles: In Vitro Evaluation as a Novel Carrier for Water-Insoluble Drugs

Purpose. Sterically stabilized phospholipid micelles (SSMs) composed of poly(ethylene glycol-2000)-grafted distearoyl phosphatidylethanolamine (PEG(2000)-DSPE) are new and promising lipid-based carriers for water-insoluble drugs. This study investigates and compares sterically stabilized mixed micelles (SSMM), composed of (PEG(2000)-DSPE) plus egg-phosphatidylcholine, with SSM as a novel delivery system for improved solubilization of water-insoluble drugs using paclitaxel as a model. Methods. Paclitaxel was solubilized in SSM (P-SSM) and SSMM (P-SSMM) by coprecipitation and rehydration with isotonic 0.01M HEPES buffer, pH 7.4. After separation of excess drug by centrifugation, mean particle size and morphology of particles in the supernatant were determined by quasi-elastic light scattering and transmission electron microscopy. The solubilization potentials of SSMM and SSM for paclitaxel were determined by reverse phase high pressure liquid chromatography (RP-HPLC). Cytotoxic activity of paclitaxel in SSMM, SSM, and dimethyl sulfoxide (10% DMSO) was determined against human breast cancer cells (MCF-7). Results. Mean hydrodynamic diameter of P-SSMM and P-SSM were 13.1 ± 1.1 nm and 15 ± 1 nm (n = 3), respectively. SSMM solubilized 1.5 times more paclitaxel than SSM for the same total lipid concentration. Solubilized paclitaxel amount increased linearly with an increase in lipid concentration. A therapeutically relevant lipid concentration (15 mM) of SSMM solubilized 1321 ± 48g/ml of paclitaxel. Paclitaxel in the absence of sufficient SSM aggregated to form lipid-coated crystals. P-SSMM, P-SSM, and paclitaxel in DMSO had comparable cytotoxic activities against MCF-7 cells. Conclusions. SSMM showed increased solubilization potential compared with SSM while retaining all of its own advantages. Therefore, it can be used as an improved lipid-based carrier for water-insoluble drugs.     

Solvent Effects on the Solubility and Physical Stability of Human Insulin-Like Growth Factor I

Purpose. The solubility and physical stability of human Insulin-like Growth Factor I (hIGF-I) were studied in aqueous solutions with different excipients. Methods. The solubility of hIGF-I was determined by UV-absorption and quantification of light blocking particles. The physical stability of hIGF-I was studied with differential scanning calorimetry (DSC) and circular dichroism (CD) spectroscopy. Results. Human IGF-I precipitated at low temperature in the presence of 140 mM benzyl alcohol and 145 mM sodium chloride. CD data showed that the tertiary structure of hIGF-I during these conditions was perturbed compared to that in 5 mM phosphate buffer. In the presence of benzyl alcohol 290 mM mannitol stabilized hIGF-I. Sodium chloride or mannitol by themselves had no effect on either the solubility or the tertiary structure. Benzyl alcohol was attracted to hIGF-I, whereas sodium chloride was preferentially excluded. The attraction of benzyl alcohol was reinforced by sodium chloride leading to salting-out of hIGF-I. The CD-data indicated interactions of benzyl alcohol with phenylalanine in hIGF-I. Thermal denaturation of hIGF-I occurred in all solutions with sodium chloride, whereas mannitol or benzyl alcohol had no effect on the thermal stability. The thermal stability of hlGF-I was thus decreased in 145 mM sodium chloride although it was excluded from hIGF-I. Conclusions. The self-association and thermal aggregation of hIGF-I is driven by hydrophobic interactions. Benzyl alcohol is attracted to hIGF-I and induces changes in the tertiary structure causing hydrophobic attraction of the protein at low temperatures.     

N-(4-乙氧羰基苯基)维生素甲酰胺与维生素甲酸衍生物的毒性比较

本文比较了我所合成的N-(4-乙氧羰基苯基)维生素甲酰胺(简称RI)及N-(4-羧酸苯基)维生素甲酰胺(简称RII)与维生素甲酸及其已知衍生物Ro10-9359、Ro 11-1430及Ro 4-3780的毒性。维生素甲酸、Ro10-9359及Ro11-1430可引起维生素甲过多症等毒性。Ro11-1430对精子有抑制作用。Ro4-3780对动物体重增长有影响。RII可导致肝组织损伤和脂肪变性,对精子亦有抑制作用。RI比维生素甲酸、Ro10-9359及Ro11-1430剂量高达4倍以上,比Ro4-3780剂量高33%,比RII剂量高1倍仍未见明显毒性。     

The effects of common solubilizing agents on the intestinal membrane barrier functions and membrane toxicity in rats

The use of solubilizing agents to improve the solubility of poorly water-soluble drugs often results in an alteration of intestinal membrane barrier function and intestinal membrane damage. In this study, 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-labeled dextran (MW 4400, FD4) were used as model compounds to examine the effects of twelve common solubilizing agents, sodium taurocholate (NaTC), Labrasol, polyethylene glycol 400 (PEG 400), Transcutol P, propylene glycol, Gelucire 44/14, HCO-60, ethanol, Cremophor EL, Tween 80, 2 hydroxypropyl-β-cyclodextrin (2HP-β-CyD) and dimethylsulfoxide (DMSO), on intestinal membrane barrier function and membrane toxicity in rats. Intestinal transport and absorption of CF were examined using an in vitro diffusion chamber and an in situ closed-loop technique. The in vitro diffusion chamber study showed that only 5 and 10% (w/v) NaTC significantly increased the transport of CF across the intestinal membrane. The in situ closed-loop study showed a remarkable increase in the absorption of CF and a bioavailability of more than 30% in the presence of 5 and 10% (v/v) Labrasol, 5 and 10% (w/v) NaTC and 10% (v/v) Transcutol P. Furthermore, we evaluated the effect of NaTC and Labrasol on the intestinal absorption of FD4, a high molecular weight compound. The results indicated that the absorption of FD4 also increased in the presence of 5 and 10% (w/v) NaTC and 10% (v/v) Labrasol, suggesting that these concentrations of NaTC and Labrasol may alter the intestinal membrane barrier functions in rats. We measured the release of protein and lactate dehydrogenase (LDH) from the intestinal membrane to examine the safety of solubilizing agents in the intestine. 5 and 10% (w/v) NaTC and 5 and 10% (v/v) Gelucire 44/14 significantly increased the presence of these toxicity markers compared to the control. The LDH level was also increased in the presence of 10% (v/v) of Cremophor EL. These findings suggest that the solubilizing agents at these concentrations except for NaTC, Gelucire 44/14 and Cremophor EL are considered safe and do not cause intestinal membrane damage. In conclusion, this study provides a basic approach in screening and predicting the effects of solubilizing agents for intestinal absorption studies using drugs poorly soluble in water.     

A Mixed Micellar Formulation Suitable for the Parenteral Administration of Taxol

Taxol is a promising antitumor agent with poor water solubility. Intravenous administration of a current taxol formulation in a non-aqueous vehicle containing Cremophor EL may cause allergic reactions and precipitation upon aqueous dilution. In this study a novel approach to formulate taxol in aqueous medium for i.v. delivery is described. The drug is solubilized in bile salt (BS)/phospholipid (PC) mixed micelles. The solubilization potential of the mixed micelles increased as the total lipid concentration and the molar ratio of PC/BS increased. Precipitation of the drug upon dilution was avoided by the spontaneous formation of drug-loaded liposomes from mixed micelles. The formulation can be stored in a freeze-dried form as mixed micelles to achieve optimum stability, and liposomes can be prepared by simple dilution just before administration. As judged by a panel of cultured cell lines, the cytotoxic activity of taxol was retained when formulated as a mixed-micellar solution. Further, for the same solubilization potential, the mixed-micellar vehicle appeared to be less toxic than the standard nonaqueous vehicle of taxol containing Cremorphor EL.     

Role of Na+/Ca++ exchange in the relaxant effect of sodium taurocholate on the guinea-pig ileum smooth muscle

Summary Sodium taurocholate (NaTC), at concentrations below the critical micellar concentration, caused a transient relaxation of isolated guinea-pig ileum smooth muscle strips. The relaxation was not inhibited by previous incubation with either 10 M ouabain, 0.4 mM d-tubocurarine or 0.5 M apamin, ruling out the participation of hyperpolarization of the plasma membrane induced by either stimulation of Na⁺/K⁺ ATPase or by opening of Ca⁺⁺-dependent K⁺ channels. In guinea-pig ileum smooth muscle cultured cells, addition of NaTC (1 mM) stimulated Na⁺ uptake and Ca⁺⁺ efflux. The relaxation induced by NaTC was inhibited by 3, 4-dichlorobenzamil, a blocker of the Na⁺/Ca⁺⁺ exchanger. Preincubation with NaTC, or its addition during the early stage of the tonic response of the ileum to acetylcholine, enhanced that response, whereas a relaxation was observed when NaTC was added at the late stage of the acetylcholine response. In cultured cells, NaTC potentiated the stimulation of Ca²⁺ influx by acetylcholine. Our results suggest that NaTC acts on the smooth muscle cell membrane causing a stimulation of the Na⁺/Ca⁺⁺ exchange mechanism. Correspondence to A. C. M. Paiva at the above address     

N-(4-羟基苯基)维生素甲酰胺诱导肿瘤细胞凋亡的机制

N-(4-羟基苯基)维生素甲酰胺(4-HPR)是一种维甲酸类化合物，通过诱导肿瘤细胞凋亡抑制肿瘤生长，其诱导凋亡的机制包括升高活性氧、神经酰胺的水平和增加Caspase活性等不依赖受体的机制和依赖维甲酸受体的机制，以及在其中发挥作用的其他因素。     

Estimation of the Increase in Solubility of Drugs as a Function of Bile Salt Concentration

Purpose. The objective of this study was to develop a model to predict the extent to which bile salts can enhance the solubility of a drug, based on the physicochemical properties of the compound. The ability to predict bile salt solubilization of poorly soluble drugs would be a key component in determining which drugs will exhibit fed vs. fasted differences in drug absorption. Methods. A correlation between the logarithm of the octanol/water partition coefficient [log P] of six steroidal compounds and their solubilities in the presence of various concentrations of sodium taurocholate at 37°C, log [SR] = 2.234 + 0.606 log [P] (r² = 0.987) where SR is the ratio of the solubilization capacity of the bile salt to the solubilization capacity of water for the drug, was used to predict the solubility of five further compounds with diverse structures. The solubilities of the compounds in presence of sodium taurocholate were then measured. Results. The predicted solubilities were within 10% of the experimentally observed solubilities for griseofulvin, cyclosporin A and pentazocine. The model overpredicted the solubility of phenytoin and diazepam in 15 mM sodium taurocholate solution by a factor of 1.33 and 1.62 respectively. Conclusions. The expected increase in solubility as a function of bile salt concentration can be estimated on the basis of the partition coefficient and aqueous solubility of the compound.