Controlled Release Applications of Organometals John S. Thayer University of Cincinnati. Cincinnati, OH 45221 Recent years have seen a substantial crowth in thedevelonmelit and nnnlicati~rns of "controlled release" formulati~ws. . These preparations contain some biologically active material embedded in a matrix. usuallv a oolvmer. Such fmnulations release the bioactive substance'to'its intended target a t a controlled rate (usuallv slow) over some specific period of time. '['he nature of these formulations nnh mntl;ematical descriptims of their action have k e n desrrlhed i n cons~deral~le detail (1-5). Controlled release formulations receive widespread applications in medicine and as pesticides. Biological effects and pesticidal applications of organometals are well established (6, 7). In particular, orpanotin compounds have received the most extensive biocidal applicat.ions (7-11 ). During the last decade, orpanotin (and, to a lesser extent, organdead) compounds have been combined with controlled release technology for pesticide and antifouling control. These combinations fall into two major categories (with some overlapping):
.
1)isfribuftonnlCnnfrdl~dRrlensr: those preparations intended to distribute the bioactive material into a specificenvironment for the purpose ofccmtrolling the population of a cerlain urge1 organism. I'rofcrliue Conlroll~dR~elcnsc:those preparations intended to protect the surface or interior of mme structure from attack by organisms. Both types almost always deal with water and aquatic organisms. They will differ to some extent in the nature of their formulations, depending on the specific purpose for which they are intended. The two subclasses will be discussed separately. Dlstrlbutlonal Controlled Release Of the various formulations in this sub-class, the most common will be an organometal impregnated into some form of elastomer ( 1 , 4 ) . In contact with water, the elastomer gradually releases the nrganometal, which diffuses through the aauatic environment. The matrix can be designed to float o n t h e surface, he suspended in water, be attached to plants, or be nlaced on the bottom. Probahlv the most widesnread use of thib type of controlled release forkulation has heen for the control of schistosomiasis. Schistosomiasis (also called bilharziasis) is an infection of humans and other mammals bv parasitic worms of the genus Schistosomo. These organism; have a rather complicated life cvcle, which is descrihed in Table 1. Thev are widespread in waterways throughout the tropical a r e a i d the worid. Estimates of the number of victims of schistosomiasis range from 180 million (12) to 300 million (13). One unexpected side effect following the construction of the Aswan Dam in Egypt was a sharp increase in the incidence of schistosomiasis (1.1). Snails and schistosomes, formerly swept into the ocean hy the floods of the Nile River, now survived and propagated to spread the infection. Schistosomiasis has been attacked in a number of ways (12). Perhaps the most direct approach has been to control the population of the snails which serve as intermediate hosts. Numerous molluscicides have been used, most commonly copper salts (12, 13). In applying such molluscicides, it is important that the chemical agent attack the snail without also destroying other aquatic organisms, such as fishes or 764
Journal of Chemical Education
Table 1. Stages in the Llte Cycle of Schisfosomes ( 12) excreted from final host. In water it hatches to produce
EGG
"
a free-swimming, short-lived larval form.It seeks out a snail (IntermediateHosf) and enters. Once inside. it becomes a MOTHER a small sac-likestructure which buds offcells. Each . SPOROCYST cell m8oratss wbthln the host and becomes a - ... . DAUGriTER whoen om turn wall generate 0811. . ~bod s es Thcoe leave the nost and each becomes a SPOROCYST a tree-swimming forktailed larval form. it seeks outa CERCARIUM warmblwded creature (Ultimate or Final Host), penetrates through the skin. and is now known as a SCHISTOSOMULA which is a juvenile wwm. Each migrates through lymphatic and circulatory systems 10an organ I~Suallv . . the liver or the bladderl. where It matures into the adult form, the These mate and produce EGGS. SCHISTOSOME MlRAClDlUM
Table 2. Cornparatlve Torlclty of Trl-n-butytlln Oxlde toward Fish and Snail (16) Daily
Dosage
5 Days
30 Days
60 Days
(ppb)
B.g.
L.r.
B.g.
L.r.
B.g.
L.r. 0 2 0 2
0.0
2
0.7 1I
0 0
0 0 0
4 6 4
0 0 0
4 20 14
7.0
6
2
80
2
96
me ligues reprarsnt me cumulativep e m t rmxtaliv. 6.g. = Wlomphalaris glemla L.r. = Lebirres reVcvhm loow Pmnm n)rlcul~ral, the m y , wMch k wll know tropical fish hgbbyisls.
K,
plants. Controlled release ensures that the concentration remains a t the desired and most effective level over a reasonable period of time. Tri-n-butvltin compounds have a sur~risinelvstrnneeffect ... on both snail\ and paiaqites. At 10--.~;the oxide suppressed the mohilitv (and hence the infectivitv) of both miracidiaand cercaria afier a 30-min exposure (15): The same compound drastically reduced both the hatchina rate of e-m s of Aiomphalaria &brnta (a species of tropical snail that serves as intermediate host for Schistosoma mansoni) and the number of hatching snail larvae that survive to maturity. Even a t 10-12 M (one part per trillion), tri-n-butyltin oxide suppressed snail egg-laying (1.5). Another investigation showed that this compound was considerably more toxic tosnails than to fish (see Table 2) a t low concentrations (16).As a result, formulations containing ( C ~ H S ) ~ S ~orOits H derivatives (acetate, chloride, fluoride) are receiving increasingly wider use as molluscicides. One experiment in Zimbabwe-Rhodesia, using bottom-sinking pelleticontaining tri-n-butyltin oxide, showez that the snail population fell by 80%within two weeks, relative to a control area and remained substantially below the control area for the next several months (17). Other bottom-dwelling fauna were not noticeably affected. Protective Controlled Release Formulations in this subclass are designed to protect surfaces in continual (or frequent) contact with water from attack
hy aquatic organisms. These fnrmulations are generally coatings ofsome sort-paints, varnishes, plastics-spread on the surface to 11eprotected. As in the prece~li~~gsul~rlass. the specific preparalinn will depend on various factors, most partirularly the nature of the surface to he protected. I3oals and ships, especially in marine waters, will have their hulls used as anchorage by various organisms such as algae. Irarnacles. and the like. The accumulation of these organisms can become quite sul~stantialon vessels t hat remain at sea for munths at a time. Individually. such organisms weigh very little; cr,llectivelv they hecome very massive. For example, a ship weighing 1tH)O tons would not. be apprecia1)l.v affected by one 50t1 mg harnacle; however, 10!'suclr barnacles weigh 500 My. or 560 tons! In addition. such nryanisms destroy the mnot11 regularityof the hr~ll'ssurface,therehy hampering its passage thrnugh t he water, slowing its speed, and causing the wnswnption 01' more fuel. Controlled release paints prevent this. They are believed to act by a sluw release, by hyrlrnlysis of orranotin esters. to form a narrow layer of hiocidal solutinn
Current research aims toward learning more ahout the mechanisms involved, the factors that control the actual rate of release. and the fate of the organumetals that are released. New applications are being developed; fnr instance, c~mtrolled release preparations oftri-n-hutyltin compounds have heen proposed as larvicides fur the nmtrnl nfmosquitoes (2.5). Controlled release technology up lo now has heen used primarily in industrial and comn~ercialapplications. There are, however, some fascinating possibilities fnr their application in academic lalxm4ories. There are. f < sexample, uses in syntheses invnlving scarce nr expensive reagents; kineticmechanistic inveatiratinns: reagents in analvtical chemistry. T h e readers may think uf others as well. Certainly this is in an area that will become increasingly important and studied as years go by. ~
~
Literature Cited ( I I rd~,rcl~i.x. ~.:~',,~~r,,ll,.d
l ~ e l ~ ~ ~ ~ ! ~ ~ ~ t i ~ i ~ ~ ~ ~ . ~ ~ ~ ~ ~ ~ ~ ~ l , ~ ~ i
~rrfiinisnis,thcrely preventing them irnm settling on the s u r h r e ( 5 , 6 , I). 18, I.')). Such paints are now commercially a\xilal)lc and have heen discussed in some popular iournals . . (20-22). Similar orenarations mav he used for the prtrtection of . . statimary nurkces. Heavy machinery in plants on ships and on shorr often use seawater for coding. Metal pipes . . and valves carrying this water are just as susceptible Lo attack as ships at sea; they may he protected in the same way (23). Wnwlen surfaces (docks, wharves. pilings. hnoys. etc.) present an addit ihnal ~ m ~ h l e m Not . onlv will marine organisms grow nn the used for wrrnd are designed to permeate the entire hody, therehv protecting the interior as well as the exterior. Wnod treated in this manner lasts consideral)ly longer in exposed The porosity environments than similar untreated wood (8). of cement allows water to penetrate, therehy providing an environment for the growth of molds. Controlled release preparations have heen used here as well. Cement, mortar, and plaster cnntaining 0.005% tri-n-Iiutyltm acetale remained free from mold after four years ( 2 4 ) .
(151 Her, ~ I : l L p p 7 78. ~
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ltei,,,:~,.,>.!,.->. (17, Il~i.~l.%l>.2.l.l. 1181 ';nwr. S. I.. rind C~dli. Y . .I..m "Orp~~~~~mnnllir I'l~lsmm."Carrohcr. C. F...Shertr. ll6,
. I I?.. imcl
I'illmnn.
C . 1'. l l : ' d # r o r ~ An8dc.mir I.
h % r .New York. 1978. pp,
1%
. %I.Church.
Concluslon At present, the use of organometal-containing controlled release preparations is in an early stage of development.
Volume 58 Number 10 October 1981
765
