Development of implants for sustained release of 5-fluorouracil using low molecular weight biodegradable polymers.

Anticancer drugs have poor efficacy especially against solid tumors that hinder drug penetration into the tumor. Thus, the dose has to be increased, but toxicity is a limiting factor. Local administration of a polymeric biodegradable poly-L-lactic acid (PLA) and poly(L-lactic acid-co-glycolic acid) copolymer (PLGA) implant containing an anticancer drug may be an acceptable method of concentrating the drug near the tumor site. This work sought to synthesize low molecular weight PLA and PLGA by polycondensation to yield polymers with good physical properties to make them suitable for use in implantable therapy. The synthesized polymers were characterized by determining their molecular weight, melting point, and percentage crystallinity using DSC. Fourier transformationinfra red spectrum (FT-IR), nuclear magnetic resonance (NMR) and specific optical rotation measurement were also used to characterize the synthesized polymers. Morphological characteristics were assessed using scanning electron microscopy (SEM). Implants were manufactured using compression (C) and injection molding (IM) and were loaded with 12 mg 5-fluorouracil (5-FU) per 120 mg implant. In vitro release patterns of all implants were assessed in phosphate buffered saline pH 7.4 (PBS 7.4) at 37°C. Factors affecting the release of 5-FU from implants were the polymer species, manufacturing technique, drug particle size, drug concentration, implant dimensions, and coating of the implant. Implants prepared with PLGA had significantly faster release of 5-FU than those prepared with PLA. Those manufactured using compression had significantly faster drug release than those prepared by injection molding. A PLA implant that contained 12 mg 5-FU/120 mg with a diameter of 0.3 cm and that was loaded with a drug particle size smaller than 150 µm and prepared by injection molding and then subsequently coated with PLA had the longest release period of 45 days.

Preventable deaths among major trauma patients in Mersey Region, North Wales and the Isle of Man.

Preventable and unexpected deaths following injury were identified from among 1088 victims of major injuries arising in a defined population and area during a 12-month period. In hospital, 44 (16 per cent) deaths from blunt injury, one death from penetrating injury and one death from drowning were preventable. In patients sustaining blunt injuries, 22 per cent of non-head-injury deaths and 13 per cent of head-injury deaths were preventable. In all preventable head-injury deaths either a delay in operation (35 per cent) or no operation for mass lesions (65 per cent) occurred, often because of misdiagnosis as alcohol intoxication (22 per cent) or CVA (22 per cent). Multiple preventable factors were more likely in non-head-injury deaths and included missed injuries (67 per cent), poor airway care (57 per cent), delayed or no operation (52 per cent), undertransfusion (38 per cent) and inadequate surgery (19 per cent). By TRISS methodology the outcome was unexpected, in 53 per cent blunt injury deaths in hospital and 2.8 per cent of survivors. Three preventable blunt injury deaths (6.8 per cent) had probabilities of survival < 50 per cent and were not, therefore, identified as unexpected by TRISS. A preventable death rate of 16 per cent for blunt injuries equates to 638 preventable blunt injury deaths each year in England and Wales.

The epidemiology of major injuries in Mersey Region and North Wales.

A prospective epidemiological study was undertaken to determine the workload and patient characteristics for a putative trauma centre in a large defined area. One thousand and eighty-eight patients were included: 430 brought in dead, 309 hospital deaths and 349 survivors. Types of injury were: blunt 76 per cent, penetrating 3.6 per cent, burns 5.8 per cent, other 14 per cent. The incidence of blunt injury was 19/100,000 for patients arriving alive at hospital and accounted for 0.08 per cent of new A & E attendances. Eight per cent of blunt injury patients were children, 68 per cent were adults and 24 per cent elderly. Major causes of injury were: road accidents 67 per cent and falls 26 per cent. In patients arriving alive after blunt injuries, those who subsequently died were significantly older, more severely injured and more physiologically impaired. Hospital mortality was 45 per cent for blunt, 43 per cent for penetrating injuries, and 67 per cent for burns. TRISS methodology indicated 53 per cent of hospital deaths from blunt injuries were unexpected. Practically, it is questionable whether the incidence of major injuries is sufficient to provide the volume of patients necessary to sustain a Level I Trauma Centre. Nevertheless, concentration of injury service is essential, since no hospital receives sufficient patients to develop and maintain expertise.

Effect of storage on the bioavailability of cephalexin from its capsules.

Three brands of locally available cephalexin capsules were stored in paper bags at 40 degrees C/90% relative humidity. Samples were taken at different time intervals and tested for the effect of storage on disintegration, dissolution and drug content for up to 70 days. Bioavailability testing was carried by administering the capsules to four volunteers before storage and after 70 days of storage. Two brands (A and B) showed increase in disintegration time associated with decrease in the rate of dissolution. The third brand (C) showed similar effect but later on irregular disintegration and dissolution were observed. Such behavior was found to be a result of storage effect on the capsule shell. No effect on drug content was observed for brands A and B but significant loss of activity was observed with some samples of brand (C). Bioavailability testing based upon urine analysis for excreted drug indicated that the rate but not the extent of drug absorption for brands A and B decreased by storage. The results with brand C showed serious fluctuations in absorption after storage for more than 25 days. These findings point out to the importance of proper formulation and protection of solid dosage forms handled in places where high temperature and humidity conditions are likely to exist.

Phenobarbital solubility in propylene glycol-glycerol-water systems.

Phenobarbital solubility in various binary and ternary propylene glycol-glycerol-water solvent systems was determined. Phenobarbital concentrations several times those of the ethanol-containing USP and BPC elixirs were obtained. From log solubility-solvent composition plots, a general equation was developed for phenobarbital solubility prediction in propylene glycol-water, glycerol-water, and propylene glycol-glycerol-water solvent systems. Solubility predictions using another equation, based on linear log solubility-dielectric constant relationships, were limited by the need to use different constants for different solvent blends. Heats of solution for phenobarbital determined in selected solvent blends as well as in USP and BPC elixirs varied within a very narrow range, suggesting similar solute-solvent interactions.

Neutron activation analysis of trace elements in skin. VIII. Selenium in normal skin.

Selenium(Se) has been determined in skin by neutron activation analysis applying selective irradiation and cooling time, followed by measurement of the activity on a high resolution germanium lithium (Ge(Li)) detector. The levels and distribution of Se in normal abdominal and plantar skin, together with other available evidence, lead us to believe that it is an essential trace element in man. It is suggested that Se has an essential role in skin keratinization.

Dissolution rates of model gallstones in human and animal biles and importance of interfacial resistance.

Cholesterol monohydrate dissolution kinetics in human gallbladder bile were studied to determine the magnitudes of the in vitro dissolution rates, the rate resistances in human gallbladder bile, and the extent that the interfacial resistance is the rate-determining factor. Dissolution rate studies also were conducted using human duodenal bile and animal bile for comparison. The dissolution rate resistance, R, ranged from 10(4) sec/cm for chicken bile to 10(4)-10(6) sec/cm for human bile. Interfacial resistance was the rate-determining factor for essentially all results. Where chemical composition data were obtained, the R values for the human bile samples were consistent with predictions made from the simulated bile studies. In two human gallbladder specimens having low bile acid-lecithin molar ratios (i.e., 2.9 and 2.3), very high R values of 1.9 X 10(5) and 4.1 X 10(5) sec/cm were found. These values were in good agreement with the findings in the simulated bile studies and suggest that stone dissolution in patients with low bile acid-lecithin ratios may proceed very slowly, even when the bile is highly undersaturated with respect to cholesterol.

Dissolution kinetics of cholesterol in simulated bile I: Influence of bile acid type and concentration, bile acid-lecithin ration, and added electrolyte.

A physical model approach was utilized to investigate cholesterol monohydrate dissolution kinetics in simulated bile. The static pellet method and the Berthoud theory were employed to assess the contributions of the diffusion-convection mass transfer resistance and those of the interfacial resistance to the overall kinetics. For almost all situations studied, the interfacial resistance was the dominant rate-determining factor. The effects of four bile acids and their concentrations, the bile acid-lecithin ratio, and the added electrolytes and their concentrations on the interfacial resistance were examined. The results were correlated with those obtained with human bile samples, and the indications were that the kinetics of cholesterol dissolution in bile may be explainable on the basis of the principal bile acids, lecithin, and the electrolytes in the bile.

Cholesterol gallstone dissolution rate accelerators I: Exploratory investigations.

Various compounds that might function as cholesterol gallstone dissolution accelerators were studied. The dissolution rates of cholesterol monohydrate pellets in synthetic bile (116 mM sodium cholate-32 mM lecithin) containing the agent at various concentration levels were determined. In the absence of any dissolution rate accelerator, the dissolution kinetics for cholesterol previously were found to be interfacial resistance controlled, and the rates were around 20 times less than the diffusion-controlled rates in the present experiments. Primary, secondary, and tertiary amines and quaternary ammonium compounds were effective accelerators. When the alkyl chain lengths were long enough and/or when the agent concentrations were high enough, the dissolution rates generally approached diffusion-controlled rates. Steroidal amines generally had good activity. Anionic and nonionic surfactants had little or negative activity.

Systems approach to vaginal delivery of drugs III: Simulation studies interfacing steroid release from silicone matrix and vaginal absorption in rabbits.

A composite physical model involving the simultaneous receding boundary release of drug from a drug suspension-silicone polymer matrix system, diffusion across the aqueous layer, and passive transport across the vaginal membrane consisting of parallel lipoidal and aqueous pore pathways is described. Simulation studies with progesterone and hydrocortisone illustrate matrix release-limiting, membrane absorption, and aqueous diffusion layer-limiting cases when the cylindrical silicone delivery device is interfaced with the vaginal membrane of the rabbit.

Dissolution rate studies of cholesterol monohydrate in bile acid-lecithin solutions using the rotatingdisk method.

A physical model approach was used to investigate cholesterol gallstone dissolution kinetics in simulated bile. Critical experimental and theoretical investigations simulating in vivo conditions showed that, in the bile acid-lecithin solutions, there is a significant interfacial barrier for both cholesterol gallstone and cholesterol monohydrate pellet dissolution. In the present study, the rotating-disk dissolution method and the accompanying Levich theory were applied to assess the contributions of the diffusion convection mass transfer resistance and of the interfacial barrier to the overall kinetics. Cholesterol dissolution rates in bile acid solutions were about 2-20 times slower than diffusion-controlled rates depending upon the degree of agitation. As found in previous studies, these rates in the presence of sufficient concentrations of dissolution accelerators approached the theoretical diffusion-convection-controlled rates. To account for the much slower dissolution rates in bile acid-lecithin solutions, two possible kinetic interpretations were investigated. The first is based upon slow crystal-micellar solution interfacial kinetics, and the second is based upon a slow rate of cholesterol solubilization in the aqueous diffusion layer. For the latter, an analytical mathematical solution was obtained.

Systems approach to vaginal delivery of drugs I: development of in situ vaginal drug absorption procedure.

In the framework of the development of drug delivery systems for locally administered contraceptive drugs, a reliable method that can afford quantitative evaluation of drug absorption behavior was explored using the rabit doe. A system was constructed based upon perfusing the drug solution in the vaginal tract. For this purpose, a "rib-cage" type cell was constructed and surgically implanted in the rabbit prior to an experiment. The primary purpose of the present paper is to evaluate the method, including the surgical operation and the perfusion system. The absorption experiments were carried out using n-butanol-1minus 14C as the model solute to survey the reproducibility of the absorption behavior. Experiments were conducted with a number of rabbits on several successive days to determine the day-to-day and animal-to-animal variations. The drug disappearance in the reservoir followed first-order kinetics from which the apparent permeability coefficient was calculated. The results indicated that a set of experiments may be carried out on a single animal and that the method generally affords rather high precision.