Dermal formulations

Drug molecules with amphiphilic character may form lyotropic mesophases, and amphiphilic excipients in drug formulations also form lyotropic liquid crystals. Especially surfactants, which are commonly used as emulsifiers in dermal formulations, associate to micelles after dissolution in a solvent. With increasing concentration of these micelles the probability of interaction between these micelles increases and thus the formation of liquid crystals. 

Although sensitising properties can be also detected in the classical development program of a drug substance, the need for dermal sensitization studies is of importance for the development of certain drugs. The increasing importance of trans-dermal formulations demonstrate the need of testing for dermal sensitization on the one side, on the other side, there are classical examples which cause dermal sensitization (e.g. neomycin, procaine, sulphonamides). 

Clark, C.R., Smith, J.R., Shih, M.L. (1999). Development of an in vitro screening method for evaluating decontamination of sulfur mustard by reactive dermal formulations. J. Appl. Toxicol. 19 S77-81. 

Cutaneous preparatimis are inefficient formulations since only small amounts of the applied active substance penetrate the skin and reach the site of action. The first attempts to understand the mechanism of skin permeation and formulation effects of cutaneous preparations were described in 1960 [10]. Since then more research has been performed on rational design of dermal formulations. Much research is focused on improved skin penetration [11, 12]. Skin... 

Encapsulated dia2innon sold as Knox-Out 2FM is a commercial encapsulated pesticide formulation said to have reduced dermal and oral toxicity as well as prolonged effectiveness. The capsules, prepared by interfacial polymeri2ation, are claimed to be highly effective against cockroaches with no objectionable odor and low insect repeUence. The capsules are beheved to function as a contact poison when insects walk on it and as a stomach poison when insects preen capsules stuck to their legs and ingest them (71). 

In a case-control study of pesticide factory workers in Brazil exposed to methyl parathion and formulating solvents, the incidence of chromosomal aberrations in lymphocytes was investigated (De Cassia Stocco et al. 1982). Though dichlorodiphenyltrichloroethane (DDT) was coformulated with methyl parathion, blood DDT levels in the methyl parathion-examined workers and "nonexposed" workers were not significantly different. These workers were presumably exposed to methyl parathion via both inhalation and dermal routes however, a dose level was not reported. The exposed workers showed blood cholinesterase depressions between 50 and 75%. However, the baseline blood cholinesterase levels in nonexposed workers were not reported. No increases in the percentage of lymphocytes with chromosome breaks were found in 15 of these workers who were exposed to methyl parathion from 1 week to up to 7 years as compared with controls. The controls consisted of 13 men who had not been occupationally exposed to any chemical and were of comparable age and socioeconomic level. This study is limited because of concomitant exposure to formulating solvents, the recent history of exposure for the workers was not reported, the selection of the control group was not described adequately, and the sample size was limited. 

Although the extent of absorption was not measured, the above evidence suggests that absorption in humans occurs rapidly following dermal exposure to commercial pesticide formulations of methyl parathion. 

Only two studies were available that reported detection of a metabolite of methyl parathion in the urine of persons dermally exposed to methyl parathion (Ware et al. 1974, 1975). Four subjects were exposed for 5 hours to a methyl parathion formulation in a field that had been sprayed 24 hours prior to exposure (Ware et al. 1974). At 48 hours, an average of 0.5 mg 4-nitrophenol was found in the urine, but... 

Palmer JS. 1978. Toxicologic evaluation of a microencapsulated formulation of methyl parathion applied dermally to cattle. Am J Vet Res 39 429-431. 

Wolff MS, McCoimell R, Cedillo L, et al. 1992. Dermal levels of methyl-parathion, organochlorine pesticides, and acetylcholinesterase among formulators. Bull Environ Contam Toxicol 48 671-678. 

Indirect evidence indicates that dermal absorption occurs in animals. Calves dusted with a 4% dust formulation of endosulfan had neurological symptoms (tremors, twitching, convulsions) and died within a day after exposure (Nicholson and Cooper 1977). Neurological effects have also been reported in preclipped rabbits and rats after repeated application of endosulfan to the skin (Dikshith et al. 1988 Gupta and Chandra 1975). Dikshith et al. (1988) reported levels of a-, [3-, and total endosulfan in liver, kidney, brain, testes, fatty tissue, and blood 30 days after dermal application of endosulfan. 

Three animal studies were located regarding distribution of endosulfan in animals following dermal exposure (Dikshith et al. 1988 Hoechst 1986 Nicholson and Cooper 1977). Endosulfan was detected in the brain (0.73 ppm), liver (3.78 ppm), and rumen contents (0.10 ppm) of calves that died after dermal exposure to a dust formulation of endosulfan (Nicholson and Cooper 1977). Following a single dermal application of aqueous suspensions of 0.1, 0.83, and 10.13 mg/kg C-endosulfan to male Sprague-Dawley rats, low concentrations of endosulfan (ng/g levels) appeared in the blood and tissues (other than skin at and around the application site) after 1 hour (Hoechst 1986). The concentrations of endosulfan in the blood and tissues increased with the time of exposure and were proportional to the dose applied. The liver and kidney appeared to sequester radiolabel relative to the concentrations of radiolabel in the blood or fat. Endosulfan levels were approximately 10 times higher in the liver and kidney than in the fat, blood, and brain throughout the study (Hoechst 1986). 

In occupational settings, exposure to endosulfan is mainly via the dermal and inhalation routes. Although workers involved in the manufacture and formulation of pesticide products containing endosulfan are potentially exposed to high concentrations of the compound, actual exposure is probably limited by the use of engineering controls and personal protection equipment. The highest documented dermal and inhalation exposures have been reported for agricultural workers involved in the spray... 

Applicators, mixers, loaders, and others who mix, spray, or apply pesticides to crops face potential dermal and/or inhalation exposure when handling bulk quantities of the formulated active ingredients. Although the exposure periods are short and occur only a few times annually, an estimate of this exposure can be obtained by quantifying the excreted polar urinary metabolites. Atrazine is the most studied triazine for potential human exposure purposes, and, therefore, most of the reported methods address the determination of atrazine or atrazine and its metabolites in urine. To a lesser extent, methods are also reported for the analysis of atrazine in blood plasma and serum. 

Field fortifications were prepared to check the field/storage stability of the dermal dosimeters, handwashes, and air filters. The field fortifications were prepared using the formulated product undiluted for "high" level spikes and diluted with water (-1 pg/mL chlorpyrifos) for the "low" level field spikes. Field fortification solutions for urine were prepared from a 3,5,6-TCP standard in acetonitrile utilizing an 1.2-pg/mL solution for the "high" field fortifications and an -0.01-ug/mL solution for the "low" level fortifications. 

Trigard 75 WP is a new insecticide with a unique mode of action and a unique triazine structure. It is a solid formulated as a wettable powder and is packaged in water-soluble bags. The active ingredient in Trigard has the common name cyromazine. Cyromazine is a triazine, but, unlike the well-known triazine herbicides, this compound has insecticidal properties and no herbicidal activity. Cyromazine has low mammalian toxicity and low vapor pressure. It is hydrophilic, so dermal penetration is expected to be... 

Irritating and lachrymatory agents are primarily an eye and respiratory hazard however, at elevated vapor/aerosol concentrations or in contact with bulk material, agents may also pose a dermal hazard. In addition, solvents used in agent formulations may also pose respiratory or contact hazards. 

Figure 2.5 A broken, spherical silica particle entrapping an API has 85% free volume. Such particles are used in formulations such as Eusolex UV-Pearls that reduce dermal uptake compared to free UV filters thus they do not irritate the skin while they make new application possibilities for hydrophobic UV filters. (Photo courtesy of Sol-Gel Technologies Ltd.)... 

For the skin, this scale is used in the primary dermal irritation test, which is performed for those agents that are to be administered to patients by application to the skin. As with all local tolerance tests, it is essential that the material be evaluated in condition of use, that is, in the final formulated form, applied to test animals in the same manner that the agent is to be used clinically. 

Blodinger, J. (1982). Formulation of Veterinary Dosage Forms. Marcel Dekker, New York. Borowitz, J.L., Moore, P.F., Yim, G.K.W. and Miya, T.S. (1971). Mechanism of enhanced drug effects produced by dilution of the oral dose. Toxicol. Appl. Pharmacol. 19 164-168. Brandau, R. and Lippold, B.H. (1982). Dermal and Transdermal Absorption. Wissenschaf-tliche, Verlagsgesellschaft mbH, Stuttgart. 

In a second experiment (Hanhijarvi, Nevalainen, and Mannisto, 1985), the chronic, cumulative dermal effects of anthralin chemicals were studied in minipigs. Using only 12 animals, they were able, by having 32 sites per animal, to study the effects of two different chemicals (dithranol and butantrone both anthralins) in three different formulations at three different concentrations each. The protocol also included observations for systemic toxicity, clinical laboratory measurements, plasma drug analyses, and gross and histopathological examinations. 

Dermal LDso values suggest that, irrespective of strain, female rats are more sensitive than male rats when disulfoton is administered dermally. The dermal LDso for disulfoton was determined to be 15.9 and 3.6 mg/kg in male and female Wistar rats, respectively (Mihail 1978). In Sherman rats, the dermal LDso was determined to be 15 and 6 mg/kg in males and females, respectively (Gaines 1969). In male Sprague-Dawley rats, the dermal LDso was determined to be 20 mg/kg (DuBois 1957). A dermal LDso value of 0.285 mL/kg (187 mg/kg) was reported for rats given a liquid formulation... 

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