[Studies on octanol-water partition coefficient and nasal drug absorption].

In order to find out the quantitative relationship between physicochemical properties of drugs and their nasal absorption, diltiazem hydrochloride and paracetamol were selected as model drugs and their octanol-water partition coefficient was determined. In situ nasal recirculation method at different pH values was used to estimate the rate constant of nasal drug absorption in rats. Results showed that quantitative relationship existed between partition coefficient and nasal absorption constant, with correlation coefficient being 0.9761(n = 9). Besides methods of partition coefficient determination, the in situ nasal recirculation manipulation was also improved.

[Artificial reconstituted pulmonary surfactant used for prevention and treatment of adult respiratory distress syndrome. II. Bioluminescence method for optimizing formulation].

Based on optimizing the formulations of artificial reconstituted pulmonary surfactant (APS) used for the prevention and treatment of adult respiratory distress syndrome (ARDS) by a surface chemical method, a quartz lung animal model to obtain active alveolar macrophages (AMs) was established, using a bioluminescence technique to optimize APS's formulation according to the free-radical-scavenging abilities of APS. An optimal formulation was obtained, which showed good surface properties and free-radical-scavenging abilities. The APS preparation will be used in ARDS animal model test.

[Artificial reconstituted pulmonary surfactant used for prevention and treatment of adult respiratory distress syndrome. III. Prevention in animal model].

Based on two major factors resulted in adult respiratory distress syndrome (ARDS), lack of pulmonary surfactant and damage of free radicals, an artificial reconstituted pulmonary surfactant (APS) was prepared. The results of prevention of ARDS in ARDS rats showed that APS reduced the mortality of animal model significantly (from 46.47% to 16.17%) and the ratio of wet/dry lung weight (from 5.55 to 4.84). The surface properties of lung lavage of treated animals were improved effectively [balancing surface tension from 61.86 mN.m-1 to 47.02 mN.m-1, (normal 43.94 mN.m-1), minimal surface tension from 30.41 mN.m-1 to 7.16 mN.m-1(normal 3.49 mN.m-1)]. These results indicate that the APS preparation showed better effect on prevention of ARDS in rats.

[Studies on HPLC method for determination of 4-methylaminoantipyrine and relative bioavailabilities of analgin nasal drops in human volunteers].

A new HPLC method for the determination of a metabolite of analgin, MAA (4-methylaminoantipyrine), in plasma and its application to determine the bioavailabilities of analgin nasal drops in human volunteers is reported in this paper. A Waters Model 481 instrument was used throughout the experiment. IAA (isopropylaminoantipyrine) was shown to be the most suitable internal standard at absorption wavelength of 254 nm. A mixture of phosphate buffer (pH 5.5) and methanol (68:32) was used as the mobile phase with a flow rate of 2 ml.min-1, and YWG-C18H37 as stationary phase. Calibration curve was linear (gamma = 0.9998) in the concentration range of 0.1-5 micrograms.ml-1. The within day and day-to-day precision (RSD) of this method were 2.35% and 2.61%, respectively, with average recoveries of 99.3%-103.9%. No interference was found in the body fluid. The plasma samples of healthy volunteers were treated with acid and extracted with ether. The system of mobile phase and the process of blood sample treatment were simpler than those reported in literature. So, the method is suitable for the study of pharmacokinetics and clinical determination of blood level of analgin. The studies on bioavailabilities of analgin nasal drops were carried out in 8 men relative to intramuscular injection and 6 men relative to oral tablets, respectively, at the dose of 250 mg analgin in different preparations administered by cross-over method. The main pharmacokinetic parameters were shown in Table 3. The results indicate that analgin nasal drops exhibited a higher bioavailability (relative to injection) and faster absorption (relative to tablet). So, analgin is suitable to be developed as a nasal preparation.

[Toxicity of drugs on nasal mucocilia and the method of its evaluation].

Effect of solutions or suspensions of eight drugs including analgin, paracetamol, propafenone hydrochloride, propranolol hydrochloride, ephedrine hydrochloride, gentamycin sulfate, sodium deoxycholate and hydrocortisone on ciliary movement were evaluated with in vitro or in situ toad palate model and scanning electron microscope. In vitro toad palate model: 0.2 ml of test drug solution or suspension was applied to a piece of freshly dissected upper palate of toad. The mucocilia were examined with an optical microscope and the lasting time of ciliary movement was recorded after drug application. The upper palate was rinsed with physiological saline when the ciliary movement stopped. The lasting time of ciliary movement after rinsing was then recorded again. In situ palate model: 0.5 ml of test drug solution or suspension was applied to the upper palate of toad for 30 min, and rinsed with physiological saline. The palate was dissected out and the operation was carried out in a similar manner. The results showed that the in situ toad palate model is a satisfactory method for studying the ciliotoxicity of drugs. The in vitro toad palate model is unsuitable for suspension and gel. The results of the eight drugs revealed that ciliary movement is frequently affected by many drugs and, therefore, care must be taken in developing any nasal dosage form to ensure its least ciliotoxicity.

[Comparison of concentration of piroxicam in blood and local site after two routes of administration].

The systematic and local concentrations of piroxicam after oral and transdermal administration were determined and compared. Mice were randomly grouped, and oral suspensions (0.72 mg.ml-1) or transdermal gels 1 mg.ml-1 were given. Systematic concentration (Cs) and local concentration (C1) of the drug in each mouse were determined by HPLC method. After transdermal administration of 0.25 mg of piroxicam gels Cmax(s) = 8.06 micrograms.ml-1 and AUC(s)0-24(s) = 58.36 micrograms.h.ml-1 were obtained, whereas after oral administration of 0.026 mg.10 g-1 body weight of piroxicam suspensions Cmax(s) was 36.82 micrograms.ml-1 and AUC(s)0-24 was 155.59 micrograms.h.ml-1. The C1/Cs ratio (0.01) through oral route was far lower than the C1/Cs ratio (0.13) through transdermal route. The area under local concentration-time curve (15.85 micrograms.h.ml-1) calculated from transdermal administration was much higher than that from oral administration (1.93 micrograms.h.ml-1). So, it seems to be unreasonable that only serum concentration is taken as a criterion for bioavailability test of piroxicam for local dosage forms, the local drug concentration should also be investigated and evaluated.

[A reversed-phase HPLC method for determining tretinoin].

Tretinoin (Tre) and its active stereo isomer isotretinoin (Iso) were simultaneously determined by reversed-phase high pressure liquid chromatographic method with a uv detector adjusted to 348 nm. Separation was accomplished on YWG-C18 column by using a MeOH:NH4Ac buffer (pH 6.0) 85:15 (vol:vol), chlorpromazine (Chl) being chosen as internal standard. Minimal detectable amount of Tre was 0.5 ng. Calibration curve was linear (r = 0.9999) in the concentration range of 25-2500 ng.ml-1. This method was used to determinate the transdermal amounts of Tre from three different preparations in Franz diffusion cell in vitro. The results showed that the proposed method could distinguish the transdermal differences from various formulations or different skin samples. In addition, it is able to be used in quantitative analysis of Tre and Iso.

[A HPLC method for determining piroxicam in body fluids].

Minimal detectable concentration of serum piroxicam by using HPLC reported in literature was mostly around 50 ng.ml-1 serum. Though the sensitivity was enough for pharmacokinetics study, it could not meet the needs of drug formulation screen study in developing precision drug delivery system (DDS) such as transdermal delivery system. A new HPLC method providing a detection limit of 0.75 ng, sensitive enough to quantify low concentrations of serum piroxicam down to 5 ng.ml-1 was reported in this paper. A Waters Model 481 instrument was used throughout the experiment. Isoxicam was proved to be the most suitable internal standard at maximum absorption wave length of 360 nm. A mixture of methanol and ammonium acetate 0.1 mol.L-1 (1:0.9 vol.vol-1) was selected as mobile phase with a flow rate of 1 ml.min-1. 0.025% tetramethyl ethylene diamine was added to ammonium acetate solution and adjusted to pH 4.5 with citric acid before mixing. Calibration curve was linear (r = 0.9999) in the concentration range of 10-5,000 ng.ml-1. The within-day and day-to-day precisions (CV) of this method were 2.88% and 2.89% respectively, with average recoveries of 96.0-102.4% (10-5,000 ng.ml-1). No interference was found in the body fluids of subjects who took piroxicam concomitantly with other commonly used non-steroidal anti-inflammatory medicines such as indomethacin, ibuprofen, naproxen, phenylbutazone and acetylsalicylic acid.

[Effect of enhancers on cutaneous permeation of piroxicam in vitro].

Enhancing effects on the permeation of piroxicam (Pir) through excised hairless mouse (inbred HRS mice) skin were investigated by measuring flux. Azone 1% was found to be the most effective enhancer studied, increasing the flux about 21 times. The effect of Azone was enhanced by the presence of propylene glycol. Oleic acid, ethylacetate, and ethanol promoted the diffusion of Pir. Other enhancers, such as DMSO, PEG 400, acetone, urea and salicylic acid, showed little or no effect. Pir-beta-cyclodextrin inclusion compound increased the flux about 3 times. The results revealed that lipophilic enhancers were more effective than lipophobic ones.