CA2190852A1 - Method of preparing a predetermined active agent stock solution for liposomal microencapsulation of active agents for agricultural uses - Google Patents
Method of preparing a predetermined active agent stock solution for liposomal microencapsulation of active agents for agricultural usesInfo
- Publication number
- CA2190852A1 CA2190852A1 CA 2190852 CA2190852A CA2190852A1 CA 2190852 A1 CA2190852 A1 CA 2190852A1 CA 2190852 CA2190852 CA 2190852 CA 2190852 A CA2190852 A CA 2190852A CA 2190852 A1 CA2190852 A1 CA 2190852A1
- Authority
- CA
- Canada
- Prior art keywords
- organic solvent
- agricultural
- solution
- lecithin
- formulation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
- A01N25/28—Microcapsules or nanocapsules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
Abstract
The present invention relates generally to the method for the production of liposomal microencapsulated products to be used for agricultural formulations. More specifically, a new method of production of liposomal microencapsulated is disclosed for active agents such as pesticides. A lecithin is mixed with an organic solvent in a certain proportion so as to provide solutions with varied levels of solubilized lecithin. The particular solvent being used will depend on the amount of active agent (AA) desired in the final solution. The formulation of the lecithin/organic solvent mixture is then allowed to settle. After settling, the top layer is separated and saved, while the bottom layer is discarded. An AA is then added to form a concentrate that is added to water for vesicle formation.
Description
WO 95/31970 ~ U~ ~'C-~72 METHOD OF PREPARING A ~ lN~;V ACTIVE
AGENT STOCK SOLUTION FOR LIPOSOMAL MICROENCAPSULATION OF
ACTIVE AGENTS FOR AGRICULTURAL USES
RELATED APPLICATIONS
This international application c~ q to copending U.S. Applicatlon Serial No. 08/248,480 filed May 24, 1994, which i8 a contlnuation-in-part of rop~ntl~n~ U.S. Applica-tion Serial No. 08/067, 530 filed May 25, 1993, which is a contlnuatlon-ln-part of U. S . Application Serial No .
07/737, 202 filed July 29, 1991.
FIELD OF THE lhVl:.h~lU_.
The present invention relates generally to the method for the ~Ludu._~lon of l ~_ 1 mi~L~ ted ~Ludu~l,s.
More sp~c1flc~lly the lnventlon relates to a new method of produclng l ~ 1 mi~;Lu~ lated agrlcultural active agents such as pesticides 1n~ rl~n~ herblcldes, flln~ c, lnsectlcldes, bacterlcldes and other _ In~lc2, Rl~r~ Grl OF THE lhV~
Pestlcides such as herblcldes, flln~ , insecti-cldes, bacterlcldes and other 2ctlve agents and ] ~
are applled per~ l ly ln the home, agrlculture, and other places and can be dal-y~:Luux to humans. Farmers, however, still need to spray their crops and anlmals wlth these actlve agents and ,_ '-. To thls end, there have been several lln~ e4~rul ai.i , Lx to provlde a method of dellv-ering these, ,_ ac~ in a manner that is safe, effective, and 9 'C~l~ as well as envii, lally acceptable.
W0 95131970 r~ 7~
., Various encapsulating techniques have been trled with agrlcultural active agents wlth results Gonc~ red lnsuffl-clent to justlfy r-~rl e 1 of exlstlng agrlcultural formu-latlons. Nothlng ln the prlor art elther ~ yy~ , teaches, or ~1e~ 8~ the use of l~ro 1 ml~,L~ 5~latlon tech-nlques to actlve agents such as pestlcldes ln agrlcultural formulatlons .
T.l~ 1 ml~;L~ latlon lS known ln the rh;~rr~
tlcal lndustry and has flve steps. Ethanol (95%) 18 mlxed ln a partlcular proportlon wlth hlgh grade soybean leclthln containlng 50% pho,,~ha Lldyl rh~l 1 nP ( PC ) . The ethanol soy-bean leclthin mixture 18 agltated untll the PC and other soluble portlons of the leclthln have been dlssolved lnto the ethanol. The mlxture is then allowed to stand for a perlod of tlme, so that the lnsoluble portlons can settle to the bottom of the container, and the top becomes a clear 2mber color . The top portion 18 then drawn of f and saved .
The bottom sludge 18 dlscarded. A certaln amount of water 18 added to the mlxture, fol l~ _d by a ~Lt:det~ n~d amount of ethanol.
The steps fol 1 C~ up to thls polnt result ln a basic "stock" solution that is mixed wlth an active agent (AA) of cholce ln the l~ lcal lndustry. The next step is the addition of a preselected AA to the stock solution. The flnal step 18 to then add the preselected AA solutlon to water, thereby effectlng formatlon of the mlcro~rs~ q or veslcles .
Thls known rh~ u l,lcal method ls llmlted to the u6e of 95% ethanol as a solvent and a hlgh grade ( 50% PC ) granu-lar soybean leclthln as the only llpld source. Thls proce-dure produces a dllute solutlon because of the low amount of leclthln used and the addltlon of extra ethanol and water.
Thls is acceptable in the medlcal field because dose rates ~re very low, thus requlrlng low loading potentlals. Thls WO 95131970 1~,1/L.IJ_. 72 2 1 9~
known process is not acceptable in other fields, however, which require hlgher loading potentials such as in agricul-tural formulations used for pesticides.
Ethanol is the only solvent that is usable in the pharmaceutical industry and that is a problem in many agri-cultural applications, because not all agricultural com-pounds are soluble in ethanol. Ful I ' ~, ethanol is a highly f7' hle solvent, and expensive EPA regulations on the proper p~n~ ng of f 1 hl e materials make ethanol i a~Llcal to use in most agricultural uses necessitating a lesg fl, hle 801vent 8y8tem. For these reasong, there is no suggestion in the ~h~ Llcal use of ethanol to use ethanol ln agricultural formulations.
The mere extraction of lecithin from animal sources such as egg yolks does not relate to the agricultural indus-try. Japanese Patent No. C87-154187 i1crlnc~-q the extrac-tion of leclthin from egg yolks. It states that the uses and advc.l~Lay~s are for food, drugs and toiletries. Japanese Patent Nos. C88-116693 and C89-086119 ~iicrlnc~ methods of further ~L~ ;Llon and purification of phosphatidylrhn7 1n~
( PC ) from egg lecithin. These patents disclose the use of egg lecithin as an 1s~1f~or for food, drugs, and toilet-ries, but do not gugge8t making 1 1~- ~ or 1 1~-- 1 carrier systems. These Japanese patent l~:ft:~elloes specify a method of e~Lla.,Llon and purification of PC from egg leci-thin .
As det~rm1n~d in the rh~rr~ utical industry, animal or egg lecithin contains a higher percentage of sc-LulaLed fatty acid side chains, which impart a more rigid gelatinous 30 guality to resulting 11 r - when used or liposomal ~nr~r51 1ation of drugs. In turn, there is a slower, more t"~L~IIded release rate of the ~ Lla~ç,ed drugs. This charac-teristic is advc..~Lc.y~uus for drug delivery systems but is not desirable in agricultural applications of pesticides WO 95131970 . ~ ..,5.~ ''7 2;1 9085;2;
where there may be a risk of causing rh~mir;~l residue prob-lems .
The average prlce Por high purity ( 99% ) animal PC at S75.00 per lOO milllgrams is S340,194.00 per pound. The aversge price for high purity ( 99% ) egg PC at $76 . 00 per 100 milligrams is S34,473.00 per pound. Low purity (60%) PC egg PC at S0 . 68 per 100 milligrams is $308 . 44 per pound. Soy-bean lecithin with PC content between twenty percent ( 2096 ) to forty percent ( 40% ) can be purchased for under $10 . 00 per pound.
~ In~ n Patent No. 834, 472 ,ii Cf~l nc~-5 the process of e..~ au~lng PC from crude vegetable oils using monoglycerides to aid the process. This reference discloses varying the levels of the monoglycerides and different ways of using the monoglycerides in the process. The reference does not mention, suggest, teach, or riiq~loc~ liposome formation or, more cper~ f irrl l l y~ n~ re~ tion of active agents for agricultural uses. Its use is strictly for food addi-tives, bakery uses, cosmetics, and a one word mention of a medical use.
Active agents of particular interest in the agricultur-al industry are pesticides, which is a generic term for h~rh1r1~i.oc, f~ln~ 5~ bactericides, and insecticides.
Other agricultural active agents include dyes and stains.
It has been dis~uv~l~d in this invention that the key to - nrS~ ting such active agents for agricultural applica-tions is the amphipathic material known as lecithin and, more spe~lfl~lly, plant lecithin.
In the American Oil Chemists ' Society book entitled Lecitl~ns and edited by Bernard F. Szuha~ and Gary R. List, 2Lt page 289, author Y. Pomeranz states that the "term 'leci-thin ' is the ulal or popular name for a naturally occurring mixture of similar ~ c more auuuLa~uly identified as pho~ha~ldes or rhr~crh~l iri-iC. The principal ~ wo 95131970 r~l,u~ ~72 2 ~;90~52 components of the natural mixture are phosphatidylcholine, phosphatidyleth~nnl; ~no, inositol phosphatides and related rhn~ ., uS-COntaining lipids. "
At page 1 of the book, Lecithins, author C. R. Schol-field says that " [I]n modern usage, lecithin generally refers to a complex, naturally occurring mixture to phospha-tides obtained by water-washing crude vegetable oil and sl:yalaLlng and drying the l.ydLaLed gums. In addition to the phosphatides, such products contain triglycerides and other 2jub~La~ s that are removed in an: lclnn with gums.
Soybean lecithin, the most common commercial product, has been L~ JUl Led to contain 25-35% triglycerides and smaller amounts of other nnnrhnc-rh~tide materials. "
C .,lally available plant lecithin is , _ ~1 Of the rhnerhnl 1 ri ~lc called phosphatldyl nhnl 1 n~ ( PC ), phospha-tidylef h~nn l ' no ( PE ), phosphatldyllnosltol ( PI ), and phosphatidic acld (PA), carotenold, and, ~lorPn~l~n~ on the grade of the plant leclthln, varylng levels of oils, trl-glycerides, fibrous materials and, ln some cases, addltives and ~uLLa.;L~IL~. Commerclal leclthlns are avallable ln dry granular, llquid, gel, paste, and powder forms.
The invention is llmlted to the use of plant leclthins as ~;u--LL~sLc:d with animal lecithlns that are obtalned from animal sources such as egg yolks. As is well known, plant lecithins are found in soybean oil, ~uLLu~seed oil, canola oil, wheat oil, kelp, peanuts, and sunflower seeds.
At pages 185-188 and 195 of the book Lecithins pub-lished in 1985, authors J.C. Schmidt and F.T. Orthoefer discuss nonfood uses of lecithin. A known ml q~.ol 1 ;~noollc functlon of lecithln 18 as a 1 1r 1 encapsulatlng agent.
Among nonfood appllcatlons, however, leclthln 18 used as a n~;lrcul atlng agent only ln the phaL.,.ac;~:uLical industry. The authors dlscuss agrlcultural and agrlproduct prQcosc1 n~ uses of leclthln wlth a partlcular small sectlon Wo ss/31970 P~l/~)., _ 72~
~ 2`~ 9b852 r concernlng pesticides.
Nothin3 in the book, Lecithins, teaches, fl{ crl OSPS, or suggests the use of plant leclthin as the key to uslng liposomal Pnf~r81-1 ~ting techniques for encapsulation of active agents such as pesticides for ayricultural applica-tions. ~I~,Le~vt:I, there is nothing in any prior art to suggest, teach, cr fl1 c~ RP the liposomal ~nr~rs~l ation of active agents for agricultural applications.
It is known that rh~ licals and drugs are applled in low doses such as in m11 l ~ J and parts per million for human C~ I lon. In comparison, pesticides are applied in known quantities measured in terms of pounds of active agent per acre of crop. All commercially available agricultural rh~mi-~lc such as pesticides have known formulations for effecting their desired results. Some known pesticides contain as much a 48% and even up to 72% active agent in their known formulations.
The pha, Llcal applicatlon of lecithin, consequent-ly, does not offer any help in using plant lecithin as a liposomal Pn~Arsul ating agent in agricultural applications that require loading high .:u~ r.L-aLlons of active agent into the initial stock solution composition of the inven-tion. For e~ample, the initial stock solution used in rh~ Llcal applications uses a very low lipid content so that lar~e amounts of active agent cannot be loaded into it.
It is known that PC is the material in plant lecithln that actually does the Pn~Rrclll~ting in the liposomal micro-.nr~rs~llation process. The lPc-~le of PC has a phoa~ha~
head with a choline moiety and some fatty acid chains that form a tail portion. The fatty acid chains are nr~nrnl ~r and therefore repel water. The phosphate head of the PG mole-cule attracts water. When placed in water, the lec--l~q roal~cr~ SO that the -leCI~lP tails are directed one way and the heaas another to produce the vesicle formation of the Wo 95131970 . ~I/U.. ~ 72 2 1 9~852 nr;~rs~l Ation technique.
PURPOSE OF THE lhvl~
The prim2ry ob~ect of the lnvention ls to provide a method of 1 1 1 miulu~ r~ tion that will lead to EPA
and FDA approval of onr~r8 -1 ~ted active agents such as pesticides, which are readily available at low cost.
Another ob~ect is to provide an ~YrPl 1 Dnt pLul ~:~Live barrier for pesticides and other active agents from ultravi-olet radiation, thereby Pnh::~nrl ng the active life of ultra-violet-degradable active agents in agricultural uses.
A further object is to provide a method that will Pn~'ilr5- l ate more active ingredient per unit of volume than is available in any l1E -1 Pnr;-rQ--lption of the prior art .
Another object of the invention is to provide a safe delivery system of pesticldes for agrlcultural uses that does not require ~r~rl~ sd h;:~n~llng and storage faclll-ties .
A still further object of the inventlon is to provide an ~nr~rsul ation method that will produce an ~nr~rs~ ted product having a slow release of the Pnc ~rQ~ ted ~
Another obJect of ls to produce an c.nrArQ--l ated actlve agent that gives ~luLe-,Llon against microbial breakdown if the actlve agent $s applied to the 80il and that allows for the delivery of the actlve agent, which will not be removed by rain or irrigation.
Another object of the present invention i8 to provide a process of l l rn~ 1 ml.,l..~ l atlon that requlres fewer and more cost effective lngredients and ls, therefore, less expenslve and tlme rnn ' n~ to produce.
A further object of the present inventlon i8 to provlde a method of ~nr~rs~ll atlon that pludll~es an ~nr~rsul ~ted actlve agent, whlch blnds the veslcles to the organlc frac-WO95/31970 1~~ 'C-'7 21 90852 ~
tion of the 80il thereby reducing le~h~n~ or runoff.
Another object of the present invention is to provide an encapsulator having better n~lhPI:Il nn to plant cuticular waxes thereby preventing removal caused by rain or irriga-tion.
Still another ob; ect of the present invention is to reduce acute resldue levels e..~e.iL,c:d in plant tissue.
SUMMARY OF THE lhvl!~n~_ The invention is directed to preselecting a particular active agent such as a pesticide and an organic solvent for carrying the active agent. The same organic solvent must be effective to solubilize a plant lecithin to a lecithin-~a LUL c~ Lc:d level .
According to the invention, a plant lecithin is mixed with an organic solvent that is selected because it also dissolves the preselected active agent. The lecithin is present in a certain proportion so as to provide a solution with varied levels of lecithin saturation. In other words, ~n effective amount of lecithin is mixed in the organic solvent to form a ~dLuLc-Led solution of lecithin. And it is well known that different organic solvents nF~cess;~rily dissolve differing amounts of lecithin because of their varied levels of lecithin saturation from one organic sol-vent to the other.
The lecithin-saturation level will be ~lep~ L upon the amount of active agent (AA) desired in the final solu-tion. That is, the organic solvent selected for dissolving the lecithin at its saturation level will also be effective to dissolve and otherwise carry the particular amount of AA
desired in the final solution to be mixed with water to produce the vesicle formation.
Depr~n-ltn!J on the formulation of organic solvent and lecithin, the lecithin/organic solvent mixture is then WO9S/31970 r~ s,, c- 72 2 t 90~2~
g allowed to settle. That is, when the formulatlon produces a mixture having a saturated solution of lecithin and undis-solved portions of the lecithin, the ~n~l1qRolved portions are allowed to settle to the bottom of the mixture leaving the solution at its lecithin-saturation level of the organic solvent .
After settling, the top layer of lecithin-saturated solution of the lecithin/organic solvent mixture is separat-ed and saved, while the bottom layer i8 discarded. The lecithin-saLul~ted solution is called the "stock solution"
for the purpose of rlc-qrr~ h~ n~ this invention . An AA is then added to the stock solution and the resulting conce-~Lle-Le is added to water for the agricultural application.
The resulting o.,llcel~LLdLe is an i~L~ te active agent solution and includes the lecithin-~c~LulaL~d solution plus the amount of AA required to be used in the prior art as a pesticide in the subsequent agricultural application.
The invention is limited to dissolving a plant lecithin to be used in combination with the pesticide R~ hi 1~ ~sd in the organic solvent thereby producing the desired initial prede-t~rm1n~d lecithin-.,~-Lul&Lt:d stock solution.
The invention is directed to a method for preparing an ini '~ Flte active agent solution containing a preselected active agent and being effective to produce 1~ 1 micro-f-nni~rR ll ~tion of the active agent by mixing the illL~ ate active agent solution with water.
An organic solvent solution is selected that is capable of carrying the preselected active agent in the solvent solution in an amount sufficient for agricultural applica-` 30 tions.
The organic solvent solution is also capable of dis-solving a preselected plant lecithin in an amount sufficient to produce in the solution an amount of phosphotidyl rhnl ~ n~
effective to f~nn~rs~llate the pesticide when the i"t 'l~te Wo 95/31970 r~ 'C '7~
21 90852~: :
pesticlde solution is mixed with water.
The preselected plant lecithin is mixed with the organ-ic solvent solution to produce an initial predet~r-m~ nc-~
lecithin stock solution containing the desired amounts of pho2 ,~hotidylrhnl 1 n~ in the organic solvent solution.
The pl ~de ~ n-~d lecithin stock solution produced in said process mixing step is isolated and then at the desired time, mixed with an amount of the preselected active agent to form the i.~t ~ te active agent solution having an active agent content sufficient for agricultural uses. The il.t ~ te active agent solution is mixed with water forming an agricultural liquid formulation having the active agent Pnr~r81ll ated in a 1 1 ~ - 1 composition.
A particular feature of the invention is directed to the use of a pesticide mixed with a solution having a w/v or v/v ratio of lecithin to organic solvent in the solvent solution of 1:1 or 1: 2 . The method is limited to the use of a plant lecithin . In a specif ic ' - ' 1 1, the organic solvent solution includes n-methyl pyrolidone and the plant lecithin has a phosphotidyl rhnl 1 n~ content in the range of from 596 to 5096 of the lecithin.
11~S~,K1~ J.. OF THE ~KI:.I"I!.KK~;IJ ~
The present application rl1 crl oc~c a method of deliver-ing an active agent onto plants, animals, ~t.lU~;I,Ult~ surfac-es, soils, and the like. The active agent is micrQ~nrs~rsu-lated 1~ lly, thereby providing a delivery ' n1Fm and a controlled relea8e ~ m for the active agent.
In the present process, a plant lecithin is mixed with an organic solvent in a certain proportion 80 as to provide a 801ution at a desired lecithin-saturation level rl~r~n~ll n~
on the formulation. The amounts of a particular form of plant lecithin required to obtain a desired level of solu-bility in certain organic solvents are known to the skilled Wo 95/31970 1 ~~ 72 2 1 90852 `-artisan. The leclthin/organic solvent mlxture is then allowed to settle. After settling, the top layer is sepa-rated and saved, while the bottom layer is discarded. An AA
18 then added to this stock solution and the resulting ~w~ llLLaL~ is added to water for the particular agricultur-al application. The .,~-..cenLlc-L~ must be added to water for vesicle formation.
Although, in the present invention, 100% denatured anhydrous ethanol may be used, it is only one of many sol-vents that can be used fl~r~n-l i n~ on the particular applica-tion . N-methyl pyrolidone ( NMP ) is used as a solvent in some applications. NMP is neither hlghly flammable nor car~nf-g~n1c and should pose little or no problem with the Envi . Lal Protection Agency.
Other solvents that may be used are acetone, 100%
denatured anhydrous ethanol, methylene chloride, 95% etha-nol, 95% denatured ethanol, dimethylf. 'de, and gamma butyrolactone, to name a few. In practice, the solvents used with the active agents are generally known in the agricultural industry. Each pLuduc;~L or deliverer of the active agents generally knows which solvents can be used with its active agent.
Although any active agent can be used, the preferred L uses Alnr~hl~r, ~lp~ ~LI.Lln, Atrazine, Carbaryl, ChlorothAl ~n~ 1, Cymiazole, Cupric hydroxide, Cyl Ll,rln, EPTC, Fll tUL-~ll, Lambda Cyhalothrin, P~:L Ll,Lln, Piperonyl Butoxide, SLLl:p~ ~;ln, or Trifluralin. This list is not intended to be comprehensive but merely illustrative.
The skilled artisan in the agricultural industry knows the effective amounts of a particular pesticide to be used to a_ _ 1 i ch its purposes in terms of pounds of pesticide per acre ( lb/A ) for the particular crop . The particular organic solvent for a desired pesticide is also known.
Table I shows the known effective agricultural use rates and WO 95/31970 I ~I/U~.~ C '7~
21 9~852 solvents for known pesticides. In other words, the known agricultural use rate n~ g~rily defines an amount of active agent sufficient for agricultural applications.
TA}3LE I
TrrlT~TuRAL
USE RATE
5 COMMON NAME (lb/A) SOLVEN~
U~-rb ~
Alachlor 1. 5 - 8 Soluble in ether, acetone, benzene, chloroform, etha-nol, ethyl acetate, slightly soluble in heptane.
Atrazine 2 - 4 Dimethyl sulfoxide (18.3%), chloroform ( 5 . 2% ), ethyl acetate ( 2 . 8% ), methanol ( 1. 896 ), diethylether ( 1. 2% ), n-pentane ( . 035% ), water ( . 0033% ) -ESPTC 2 - 6 Miscible in acetone, ethyl alcohol kef~5(:1 .e, methyl isobutyi ketone, and xylene.
Only . 037% in water .
Fl, ~ I,ULUI~ . 8 - 4 Soluble in dimethylforma-mide, acetone, ethanol, and iso~Lu~l.ol. Only .009% in water .
Trifluralin . 5 - l >50% soluble w/v in acetone, acetonitrile, chloroform, dimethylr, rlc~, dioxane hexane methyl ethyl ketoné
and xyiene. 44% soluble w/v in methyl c~ solve, and . 00003% in water. Formulated with xylene, ethyl benzene, and naphthalene.
Insecticides:
Carbaryl . 5 - 2 Soluble in most polar organ-ic solvents such as acetone.
Only . 004% in water.
Wo 95/31970 P~I/IJV~' -'72 21 90852 - `
Cy~ LIIL ln . 025 - .1 Soluble in methanol, ace-tone, xylene, and methylene dichloride. Tn~ol llhl e in water .
5 Lambda . 025 - . 04 Soluble in most organic sol-cyhalothrin vents. Low ~ lhl 1 ity ln water. Formulated with xy-lene based petroleum 801-vent .
10 Malathion . 9 - 2 . 5 Soluble in most organlc 801-vents. Only . 0145% soluble in water. Formulated with xylene .
P, - Ll.Lln .05 - .4 Very soluble in most organic solvents except ethylene ~lycol . < . 0001% soluble in water .
Piperonyl .1 - . 8 Soluble in most common or-butoxide ganic solvents and petroleum distillates. Very slightly soluble in water.
F-~n~i ~; ~lt~.
Chlorotha- . 56 - 4 .13 Slightly soluble in organic lonil solvents and t nç:ol llhl e in water.
M; ~ n~ -c Dyes & stains Available in water soluble and solvent soluble forms.
Cymiazole and R~n7ol-~ine are used as active agents to~r~l ly applied to animals, and SL. ~ n is a bacteri-cide used on fruit trees. In such agricultural applica-tions, these pesticides are used in amounts measured in parts per million ( ppm ) .
Cymiazole is an experimental insecticide, which is not registered in the United States. It is soluble to obtain an application amount of about 300 ppm o~ the solvent. It is 80% soluble in dichlol, Lll~ne, 75% in methanol, 70% in toluene, 35% in octanol, 35% in NMP, 3096 in isuL,LulJallol, 5%
Wo 95/31970~ r~ 'c ~72--2~ 9~85~ ` , hexane, and . 005% in water. It is formulated in an aromatic golvent .
SLL~L 2,,ln is used in an amount of about 100 ppm of the liquid for its agricultural use and is water soluble.
SLLc:pl ~,in is not very soluble in organic solvents.
Ran7o~A1 na is used for various agricultural uses and in a particular application on animals, in combination with Cymiazole. Generally, Ran7ocA1na is used in an amount of about 1, 000 ppm of the solution being used and is very soluble in ethanol and ether . It is 1 n~ol l-hl a in water.
N-methyl pyrolidone ls an aYr-al 1 ant general solvent.
It dissolves most of the granulated plant lecithin constitu-ents into it in the production of 2 NMP lecithin-containing stock solution. However, ethanol dissolves ~L~ ' 'nAtely the pho~huLldyl~h~ na (PC) in the production of an ethanol lecithin-containing stock solution. The other n-methyl pyrolidone soluble constituents in the n-methyl pyrolidone stock solution may prevent n-methyl pyrolidone from solubi-lizing PC to its capacity from the plant lecithin being used.
To UVt:L~_ - this problem, ethanol is first used to form a lecithin solution wherein the PC is e~ LLauLt:d (solubi-lized) from the granulated or liquid lecithin into the lecithin solution. Then the ethanol is removed and the PC
redissolved in the n-methyl pyrolidone. This helps to raise the PC content in the NMP stock. The extraction method does not add much to the total cost of the production process, but has e5~LL~ ly high PC levels. The extraction process could be done on any of the lecithins ( hiqh or low grade ), flapanfl~n~ on the desired result. Less expensive (14% PC) lecithins may be used as opposed to the more expensive ( 50%
PC) granular lecithin flapanflln~ on the desired result.
In mixing the lecithin and the solvent Loy~ LlleL, the preferred embodiment calls for a w/v ratio of lecithin to Wo 95131970 r~ OG'72 solvent of 1:1 or 1. 2, which ls contrasted with the 1: 3 as used ln the prlor art. This allows for the loading of high ~ullcel~LLaLlons of AA into the stock, since it contains such high levels of PC.
The present process uses only one solvent in the formu-lation as a carrier for the lecithin and the AA. However, a "double solvent system" can be employed when certaln actlve agents may not be soluble ln a partlcular solvent that dlssolves a conq~ flPrable amount of leclthln. In thls case, the AA may be dlssolved ln another solvent system, that may dlssolve less leclthln but have a hlgh capaclty for the AA.
The second solvent system may be used to dlssolve the AA, whlle the addltlon to the flrst solvent system lncreases the amount of leclthln materlal into the solution, thereby ensuring the enr~ps~ tion of the AA. A double solvent system uses two, and the ~l~yLe:~lon contlnues.
For each solvent system, the solvents are mlxed wlth the leclthln before anything else. ~n a double solvent system, one will take two slngle solvent systems and mlx them Luy~LlleI. For example, for a double solvent system uslng solvents A and B, slngle solvent system A 18 produoed when ethanol and a leclthln are mlxed, and slngle solvent system B is pL.duc:~d when n-methyl pyrolldone is mixed with a lecithin. The AA would be added to the solvent system that had the higher qrl llhl 1; ty level for that particular AA.
The amounts of each slngle solvent system mlxed togeth-er to form a double, trlple or multlple solvent system, would vary ~ep~n~ln~ upon the AA and what the partlcular golvent systems were.
More than one AA ln a formulation can necessltate a solutlon requirlng a trlple solvent system. The addltlon of - bulklng agents suoh as methyl rel 1--1 os~ or Carbopol and other st~h~ 1 1 71 ng agents reslulred ln some formulatlons could requlre a trlple solvent system.
WO9S/31970 r~"-J.. '72--21 90852 . . .
. ,.,-A large number of agricultural compounds degrade in the presence of ultraviolet light. The micro~nm~rs~l ation ~ uL~:cL~ any AA ~nrloep~l within from the environment and ultrl~violet light. CaluL~IOids are natural p1~ L-' that act as ultraviolet filters and are present in the lecithin material purchased from the manufacturer. High carotenoid ~:ullcel-LL~Llons are generally present in lecithin due to the lecithin extraction and r~f~n L process.
The .;~lro L~-loid concentration in the stock material may be regulated either by selective extraction or by total e- Llc-.iLlon from the lecithin material and then metering it back into the stock material. Regulating the carotenoid ~,UIl1~:llLLC-tiOn would also regulate the rate of ultraviolet ~1P~ tion of the AA. Therefore, the length of time the AA will remain in the field can be controlled by the amount of the carotenolds in the leclthin.
pl r L of a large amount of carotenoid in the system can protect the AA in the field for an ~--Lt:-~d~d period of time. Controlling the rate of release and breakdown of the ~nn~rS~ ted AA in this manner will al50 reduce the poss~hle acute toxic effects when applied to crops or animals.
npr~n(~ng on the AA uged and itg desired ~;u-l-:~-lLLc-Llon in the final formulation, the PC content in the stock mate-rial may be selected for the AA by $imple extraction tech-ni~ues from less expensive lecithin materials with lower PC
collcel-LL~L10ns. The desired c;c,~ LL~tion of the AA in the final formulation is detc~rm~ nP(l in accoL~ ~ with the particular 2gricultural use rate est~hl 1 ~hPd for the active agent such as the pesticides in Table I.
In a~coLd~sn-~ with the invention, first the organic solvent is selected to carry the n~-c~ y amounts of active agent to produce the re~uired agricultural use rate in the final formulation of the Pnm~r5~ ted active agent. At the same time, the organic solvent selected for the active agent wo 95/31970 r~ 72 must dlssolve an effective amount of plant leclthin in solution to provide an int ~ qte active agent solution having a sufficient PC content for producing the vesicle formatlon of the 1~ 1 encapsulation when the i.~t '~-ate active agent solution is mixed with water.
Unlike the prior art, the most expensive lecithin is not reguired. Lecithin comes in different grades, r1~rc.n~91n~
upon the peL~ s of the, , ~. with p~lo~hoLldylcho-line as the most ~, Lalll ~- , 1. The higher the cullcel~LLa-tion of PC in the lecithin, the better the lecithin and the more expensive the process. D~p~n-lin~ upon the active agent, the present method uses between five ( 5 ) to fifty (50) percent and, more particularly, fUUL~e:el~ (14) to fifty ( 50 ) percent PC lecithin.
The p~esent invention can use a "batch" process to produce lts stock solutlon. The l Ludu~;Llon of the stock solutions under the present process may be au L ~ed to ellminate the slowness of the batch process. In doing so, the present lnventlon utllizes augers and centrifuges to schieve the deslred automatlon.
A system of a speclflc ~ -~1 L utilizes an auger to mix the lecithin and the solvent. As the mixin~ takes place the materlals are moved down the auger leaving room for the addition of new unmixed materials on an automatically me-tered basis. As the materials become thoroughly mixed they are emptied into centrifuges for separation.
The centrifuges operate on 2 rotational basis. The rate of rotational speed of the centrifuges no~n~ PR with the flow rate of the auger and is ~ e1 ~n~A to produce little or no backup in the system. The materials sepaLc~ d in the centrifuges are pumped into st:yari.te tanks for storage and tl1 RrOR~l . Other ~LU~ 85~:8 such as those used in the alcohol distillery industry could also be utilized.
Wo 95/31970 r~l~u. ~ 7~
Due to the low flash polnt of ethanol and its extreme fl; h~l~ty all drive ~h~n~ for the system must be air-driven. The use of this technigue in other industrial applications using ethanol has proven to be the most econom-ic c-~Lva~ as opposed to providing a totally ~Yrl 0~ nn proof electrical ystem. All ~ 5VL 4 and other equlp-ment for the pneumatic system would be located ln other rooms or b~ n~R away from the ~Lvdu.;Llon area. The compressed air would be piped to each location.
Although any active agent can be used, in the preferred o~mhorl~ L, the following active agents are used: Alachlor, Al~l~ -LI.lln, Atrazine, B~n7orA1n~ Carbaryl, Chlorothalo-nil, Cymiazole, cupric hydroxide, Cy~ Ll-lln, dyes, EPTC, Fl~ Lulul-, Lambda Cyhalothrin, Malathion, P~ Ll.Lln, piperonyl butoxide, stains, SLL~p~ y~;ln~ and Trifluralin.
Although any organic solvent can be used, in the pre-ferred '~ , the following organic solvents are used:
~cetone, 100% de.laLuLt:d ethanol, 95% denatured anhydrous ethanol, dimethylr~ , gamma butyrolactone, methylene chloride, and N-methyl pyrolidone.
In the preferred I ' '~ ~, the lecithin is selected from a group consisting of soybean oil, cottonseed oil, canola oil, wheat oil, kelp, peanuts, and sunflower seeds.
The lecithin form is selected from a group consisting of liquid, granular, powder, gel, and paste. The lecithin has ~I PC content ranging from, but not limited to, 5% to 50% in the pref erred ' ~ ' 1 L . The PC content may be achieved by direct e. LLuvLlon, commercial preparation or custom blend-ing .
Although any carotenoid content may be used, the pre-ferred '_fll t uses a carotenoid content from between substantially 0 to 1 percent to avold active agent buildup.
The vaLvLenvid content may be ~rhlev~fl by direct e~LLLa~iLlon~
commercial ~L~alaLlon or custom hl~n~l~n!J, WOgS/31970 r~.l,-J,,,"'i72 21 90852 1 ` `
C ~.lally available plant lecithin is composed of the phncphn7 ~ r1 ~le phosphatidy] rhnl i n~ ( PC ), phosphatidyle-th;lnnl ' n~ ( PE ), phosphatldyllnosltol ( PI ), and phospha-tidic acld (PA), carotenolds, and, d~ppn~l~ng on the grade, varylng levels of olls, trlglycerldes, flbrous materials and, in some cases, additives and -uLrauLc~ . C~ uLal lecithin is available in dry granular, liquid, gel, paste, and powder f orms .
A solvent is selected for a partlcular stock material from available solvents that will dissolve the active agent and a compatible grade of lecithin and also be soluble in water. Different forms of plant lecithin (i.e. dry granu-lar, liquid, gel, paste, and powder) have different levels of solubility in certain solvents. The form of lecithin chosen is thus ~l~L~ t upon the solvent required to dis-solve the active agent. For instance, if an active agent is soluble in ethanol then a lecithin form with low oil content such as a dry granular or gel would be selected because oily liquid lecithin forms are not very soluble in ethanol.
Flocculation problems sometimes arise when mixing with water due to 2n 1 , Llbility of the solvent-~ctive agent-lecithin form mixture. To vv~ this problem, solvents and lecithin forms must be substituted with others to find the best combination for optimum 5~1qp~nc1 t~nc in water.
Also, when there is an active agent that is only soluble in l~ydlu~hObic nnnrlol~r solvents, a co-solvent that is m1ct~1hlP
in water and the nnnrnl ~r solvent must be introduced into the solvent system in order to mix with water.
Since lecithin is made up of many - , L~, dissolv-ing lecithin regardless of its form in a sclvent will dis-solve some of the ., LY other than PC as well.
SrPr~f1n, ,l~c of the invention are as follows:
Example I
An industry available liquid lecithin was mixed with n-Wo95131970 r~ v, rr72--21 90~52 . ~ -, . .
methyl pyrolidone ( NMP ) in a l: 2 v/v ratio. This mixture was stirred until it became visibly homo~enized. It was then poured into a separatory funnel and allowed to settle.
After sufficient time for settling took place ( 24-48 hr. ), the bottom sludge fraction was drawn off and discarded while the top portion was de.~ ted and saved as usable stock material .
This stock material is the prlmary carrler system for Chloroth~1 on~ 1, the actlve agent to be added. The followlng formulatlon of one gallon provldeg an optimum g~1cpDnc1 nn with mlnimal rapid settling when ultimately added to water to effect ~nr~rC111 ation.
Chloroth~lnn~l tDrhn1r~1 (98% purity) 0.90 lbs Anti-microbial agent 0. 29 ozs ( 0 . 24 f l . oz . ) Anti-foaming agent 0.14 ozs (0.14 fl.oz. ) h1rkDn~n~ agent 1.43 ozs Stock materlal 7.90 lbs (0.83 gal. ) Materials mixed wlth the .,U~lCt:lltL ~t~ add to stabllity and ef f icacy of the entire system . The anti-microbial agent retards bacterial dD_ _ - 91 tion of Chloroth~1 on1 l when applied to the fleld. The anti-foaming agent is added because the stock material has a Lender cy to foam when agitated which would hamper the concentration ' 8 ability to be accurately measured out for field application. Due to Chloro~h~ n~l '5 1ncnlllh111ty, it settles out in the concen-trate rapidly which necessitates the need for a ~hlrkl~n~ng or 5~1cpDn~l~n~ agent. The th1rk~n~ng agent is to be dis-pensed accurately.
A rate of 1.5 lb ChlorothAlnn1 1 is required to spray an ~cre of L Lues to control various fungal fl1 cD~eC-~ To WO 95/31970 1 ~ `''72 2190852 fj i~
Al-- l~eh this using the ChlorothAlnnll cu..c~ La~ of the invention, 1.7 gal of the ~o-~ tlal,e was added to a water ln a spray tank previously calibrated, according to standard practice, to deliver 20-40 gallons of finished aqueous spray solution to the acre.
Liposome formation is caused when the uullu~lll,La~e comes into contact with the water in spray tank. With the Chloro-thAl on~ 1 mi.;Lot:-.aap,iulated according to the invention, the longevity of the pesticide is extended sc that it does not have to be applied as often as other ChlorothAl nn~ 1 prod-ucts. Other new and ~..-e~euLt:d results such as a signifi-cant increase in crop harvest have been obtained using the procedure of this invention in the field.
Example II
An agricultural industry available dry granular or powder lecithin was mixed with absolute ethanol in a 1: 2 w/v ratio and agitated until all the lecithin was dissolved in the solvent . ( For safety concerns, it ls not ro ' - ' to heat mixtures for ~onhAnni ng the dissolving of the solid material in volatile organic solvents such as ethanol. ) After all the lecithin dissolved, the mixture was transferred to a s~y~Lal,uLy funnel and allowed to settle.
After s~lffi~1ont settling time, the bottom sludge layer was drawn off and discarded and the top fraction saved as usable stock material.
Permethrin toohn~cAl (92% purity) 1.02 lb _ _ _ . ...... . . . .. . . . . . . .
WO 95131970 r~ '72 Stock material 6 . 48 lb ( O. 9 gal ) An average rate of 0 . 2 lb P, ~IIL Ln per acre is usual-ly required to control most insect problems in a variety of cropping situations. To r _ l; ch this, 1. 7 pints Permeth-rin cullcel~Lal~ of the invention was added to a previously calibrated spray tank, according to :i~,".daL,I practice, to deliver 20-40 gal of fin1 Ch.~(l aqueous spray solution to the acre .
Here again, liposome formation is caused when the ~;OI~C~II~LC~I ~ comes into contact with the water in the spray tank. By mi~;Lu~ l ating, the effective longevity of Pl l l-Lln with its other unique features produce new and u--~n~e.;l,ed results in the field.
Example III
The stock material for SLL~ y.;ln was made in the s~me manner as for P, - ~I.Lln using a 1:2 w/v ratio of lecithin to solvent. A 25% w/v S~LC~t yuln uu--c~--LL~ was formulated to control fireblight in apples. A gallon of S~Le~ uin cu..cJ..~Lc.l~ was made by bringing 2.09 lb of SLLepL ~,ln sulfate up to a gallon with stock material.
The L~ - rlF'Cl rate to control fireblight in fruit trees is to prepare a 100 parts per million 5 I L~ t ~uln spray solu-tion. Thus, 5.1 fl.oz. of the S~Lt~Ç,t ~uln cu--~ei~l.L,,(.~ of the invention was added to 100 gallons of water in a cali-brated air-blast orchard sprayer. On the average, this volume of spray solution will cover approximately an acre of ~ WO 95/31970 P(,ll~J.,.~ '72 2 ~ Y3852 . i `.
fruit trees.
Whlle the METHOD OF PREPARING A ~K~ c.~INED ACTIVE
AGENT STOCK SOLUTION POR LIPOSOMAL MICROENCAPSULATION OF
ACTIVE AGENTS FOR AGRICULTURAL USES has been shown and described in detail, it is obvious that this invention is not to be c~nci~l~red as limited to the exact form A~ losed, and that changes in detail and construction may be made therein within the scope of the invention without departing from the spirit thereof.
.
AGENT STOCK SOLUTION FOR LIPOSOMAL MICROENCAPSULATION OF
ACTIVE AGENTS FOR AGRICULTURAL USES
RELATED APPLICATIONS
This international application c~ q to copending U.S. Applicatlon Serial No. 08/248,480 filed May 24, 1994, which i8 a contlnuation-in-part of rop~ntl~n~ U.S. Applica-tion Serial No. 08/067, 530 filed May 25, 1993, which is a contlnuatlon-ln-part of U. S . Application Serial No .
07/737, 202 filed July 29, 1991.
FIELD OF THE lhVl:.h~lU_.
The present invention relates generally to the method for the ~Ludu._~lon of l ~_ 1 mi~L~ ted ~Ludu~l,s.
More sp~c1flc~lly the lnventlon relates to a new method of produclng l ~ 1 mi~;Lu~ lated agrlcultural active agents such as pesticides 1n~ rl~n~ herblcldes, flln~ c, lnsectlcldes, bacterlcldes and other _ In~lc2, Rl~r~ Grl OF THE lhV~
Pestlcides such as herblcldes, flln~ , insecti-cldes, bacterlcldes and other 2ctlve agents and ] ~
are applled per~ l ly ln the home, agrlculture, and other places and can be dal-y~:Luux to humans. Farmers, however, still need to spray their crops and anlmals wlth these actlve agents and ,_ '-. To thls end, there have been several lln~ e4~rul ai.i , Lx to provlde a method of dellv-ering these, ,_ ac~ in a manner that is safe, effective, and 9 'C~l~ as well as envii, lally acceptable.
W0 95131970 r~ 7~
., Various encapsulating techniques have been trled with agrlcultural active agents wlth results Gonc~ red lnsuffl-clent to justlfy r-~rl e 1 of exlstlng agrlcultural formu-latlons. Nothlng ln the prlor art elther ~ yy~ , teaches, or ~1e~ 8~ the use of l~ro 1 ml~,L~ 5~latlon tech-nlques to actlve agents such as pestlcldes ln agrlcultural formulatlons .
T.l~ 1 ml~;L~ latlon lS known ln the rh;~rr~
tlcal lndustry and has flve steps. Ethanol (95%) 18 mlxed ln a partlcular proportlon wlth hlgh grade soybean leclthln containlng 50% pho,,~ha Lldyl rh~l 1 nP ( PC ) . The ethanol soy-bean leclthin mixture 18 agltated untll the PC and other soluble portlons of the leclthln have been dlssolved lnto the ethanol. The mlxture is then allowed to stand for a perlod of tlme, so that the lnsoluble portlons can settle to the bottom of the container, and the top becomes a clear 2mber color . The top portion 18 then drawn of f and saved .
The bottom sludge 18 dlscarded. A certaln amount of water 18 added to the mlxture, fol l~ _d by a ~Lt:det~ n~d amount of ethanol.
The steps fol 1 C~ up to thls polnt result ln a basic "stock" solution that is mixed wlth an active agent (AA) of cholce ln the l~ lcal lndustry. The next step is the addition of a preselected AA to the stock solution. The flnal step 18 to then add the preselected AA solutlon to water, thereby effectlng formatlon of the mlcro~rs~ q or veslcles .
Thls known rh~ u l,lcal method ls llmlted to the u6e of 95% ethanol as a solvent and a hlgh grade ( 50% PC ) granu-lar soybean leclthln as the only llpld source. Thls proce-dure produces a dllute solutlon because of the low amount of leclthln used and the addltlon of extra ethanol and water.
Thls is acceptable in the medlcal field because dose rates ~re very low, thus requlrlng low loading potentlals. Thls WO 95131970 1~,1/L.IJ_. 72 2 1 9~
known process is not acceptable in other fields, however, which require hlgher loading potentials such as in agricul-tural formulations used for pesticides.
Ethanol is the only solvent that is usable in the pharmaceutical industry and that is a problem in many agri-cultural applications, because not all agricultural com-pounds are soluble in ethanol. Ful I ' ~, ethanol is a highly f7' hle solvent, and expensive EPA regulations on the proper p~n~ ng of f 1 hl e materials make ethanol i a~Llcal to use in most agricultural uses necessitating a lesg fl, hle 801vent 8y8tem. For these reasong, there is no suggestion in the ~h~ Llcal use of ethanol to use ethanol ln agricultural formulations.
The mere extraction of lecithin from animal sources such as egg yolks does not relate to the agricultural indus-try. Japanese Patent No. C87-154187 i1crlnc~-q the extrac-tion of leclthin from egg yolks. It states that the uses and advc.l~Lay~s are for food, drugs and toiletries. Japanese Patent Nos. C88-116693 and C89-086119 ~iicrlnc~ methods of further ~L~ ;Llon and purification of phosphatidylrhn7 1n~
( PC ) from egg lecithin. These patents disclose the use of egg lecithin as an 1s~1f~or for food, drugs, and toilet-ries, but do not gugge8t making 1 1~- ~ or 1 1~-- 1 carrier systems. These Japanese patent l~:ft:~elloes specify a method of e~Lla.,Llon and purification of PC from egg leci-thin .
As det~rm1n~d in the rh~rr~ utical industry, animal or egg lecithin contains a higher percentage of sc-LulaLed fatty acid side chains, which impart a more rigid gelatinous 30 guality to resulting 11 r - when used or liposomal ~nr~r51 1ation of drugs. In turn, there is a slower, more t"~L~IIded release rate of the ~ Lla~ç,ed drugs. This charac-teristic is advc..~Lc.y~uus for drug delivery systems but is not desirable in agricultural applications of pesticides WO 95131970 . ~ ..,5.~ ''7 2;1 9085;2;
where there may be a risk of causing rh~mir;~l residue prob-lems .
The average prlce Por high purity ( 99% ) animal PC at S75.00 per lOO milllgrams is S340,194.00 per pound. The aversge price for high purity ( 99% ) egg PC at $76 . 00 per 100 milligrams is S34,473.00 per pound. Low purity (60%) PC egg PC at S0 . 68 per 100 milligrams is $308 . 44 per pound. Soy-bean lecithin with PC content between twenty percent ( 2096 ) to forty percent ( 40% ) can be purchased for under $10 . 00 per pound.
~ In~ n Patent No. 834, 472 ,ii Cf~l nc~-5 the process of e..~ au~lng PC from crude vegetable oils using monoglycerides to aid the process. This reference discloses varying the levels of the monoglycerides and different ways of using the monoglycerides in the process. The reference does not mention, suggest, teach, or riiq~loc~ liposome formation or, more cper~ f irrl l l y~ n~ re~ tion of active agents for agricultural uses. Its use is strictly for food addi-tives, bakery uses, cosmetics, and a one word mention of a medical use.
Active agents of particular interest in the agricultur-al industry are pesticides, which is a generic term for h~rh1r1~i.oc, f~ln~ 5~ bactericides, and insecticides.
Other agricultural active agents include dyes and stains.
It has been dis~uv~l~d in this invention that the key to - nrS~ ting such active agents for agricultural applica-tions is the amphipathic material known as lecithin and, more spe~lfl~lly, plant lecithin.
In the American Oil Chemists ' Society book entitled Lecitl~ns and edited by Bernard F. Szuha~ and Gary R. List, 2Lt page 289, author Y. Pomeranz states that the "term 'leci-thin ' is the ulal or popular name for a naturally occurring mixture of similar ~ c more auuuLa~uly identified as pho~ha~ldes or rhr~crh~l iri-iC. The principal ~ wo 95131970 r~l,u~ ~72 2 ~;90~52 components of the natural mixture are phosphatidylcholine, phosphatidyleth~nnl; ~no, inositol phosphatides and related rhn~ ., uS-COntaining lipids. "
At page 1 of the book, Lecithins, author C. R. Schol-field says that " [I]n modern usage, lecithin generally refers to a complex, naturally occurring mixture to phospha-tides obtained by water-washing crude vegetable oil and sl:yalaLlng and drying the l.ydLaLed gums. In addition to the phosphatides, such products contain triglycerides and other 2jub~La~ s that are removed in an: lclnn with gums.
Soybean lecithin, the most common commercial product, has been L~ JUl Led to contain 25-35% triglycerides and smaller amounts of other nnnrhnc-rh~tide materials. "
C .,lally available plant lecithin is , _ ~1 Of the rhnerhnl 1 ri ~lc called phosphatldyl nhnl 1 n~ ( PC ), phospha-tidylef h~nn l ' no ( PE ), phosphatldyllnosltol ( PI ), and phosphatidic acld (PA), carotenold, and, ~lorPn~l~n~ on the grade of the plant leclthln, varylng levels of oils, trl-glycerides, fibrous materials and, ln some cases, addltives and ~uLLa.;L~IL~. Commerclal leclthlns are avallable ln dry granular, llquid, gel, paste, and powder forms.
The invention is llmlted to the use of plant leclthins as ~;u--LL~sLc:d with animal lecithlns that are obtalned from animal sources such as egg yolks. As is well known, plant lecithins are found in soybean oil, ~uLLu~seed oil, canola oil, wheat oil, kelp, peanuts, and sunflower seeds.
At pages 185-188 and 195 of the book Lecithins pub-lished in 1985, authors J.C. Schmidt and F.T. Orthoefer discuss nonfood uses of lecithin. A known ml q~.ol 1 ;~noollc functlon of lecithln 18 as a 1 1r 1 encapsulatlng agent.
Among nonfood appllcatlons, however, leclthln 18 used as a n~;lrcul atlng agent only ln the phaL.,.ac;~:uLical industry. The authors dlscuss agrlcultural and agrlproduct prQcosc1 n~ uses of leclthln wlth a partlcular small sectlon Wo ss/31970 P~l/~)., _ 72~
~ 2`~ 9b852 r concernlng pesticides.
Nothin3 in the book, Lecithins, teaches, fl{ crl OSPS, or suggests the use of plant leclthin as the key to uslng liposomal Pnf~r81-1 ~ting techniques for encapsulation of active agents such as pesticides for ayricultural applica-tions. ~I~,Le~vt:I, there is nothing in any prior art to suggest, teach, cr fl1 c~ RP the liposomal ~nr~rs~l ation of active agents for agricultural applications.
It is known that rh~ licals and drugs are applled in low doses such as in m11 l ~ J and parts per million for human C~ I lon. In comparison, pesticides are applied in known quantities measured in terms of pounds of active agent per acre of crop. All commercially available agricultural rh~mi-~lc such as pesticides have known formulations for effecting their desired results. Some known pesticides contain as much a 48% and even up to 72% active agent in their known formulations.
The pha, Llcal applicatlon of lecithin, consequent-ly, does not offer any help in using plant lecithin as a liposomal Pn~Arsul ating agent in agricultural applications that require loading high .:u~ r.L-aLlons of active agent into the initial stock solution composition of the inven-tion. For e~ample, the initial stock solution used in rh~ Llcal applications uses a very low lipid content so that lar~e amounts of active agent cannot be loaded into it.
It is known that PC is the material in plant lecithln that actually does the Pn~Rrclll~ting in the liposomal micro-.nr~rs~llation process. The lPc-~le of PC has a phoa~ha~
head with a choline moiety and some fatty acid chains that form a tail portion. The fatty acid chains are nr~nrnl ~r and therefore repel water. The phosphate head of the PG mole-cule attracts water. When placed in water, the lec--l~q roal~cr~ SO that the -leCI~lP tails are directed one way and the heaas another to produce the vesicle formation of the Wo 95131970 . ~I/U.. ~ 72 2 1 9~852 nr;~rs~l Ation technique.
PURPOSE OF THE lhvl~
The prim2ry ob~ect of the lnvention ls to provide a method of 1 1 1 miulu~ r~ tion that will lead to EPA
and FDA approval of onr~r8 -1 ~ted active agents such as pesticides, which are readily available at low cost.
Another ob~ect is to provide an ~YrPl 1 Dnt pLul ~:~Live barrier for pesticides and other active agents from ultravi-olet radiation, thereby Pnh::~nrl ng the active life of ultra-violet-degradable active agents in agricultural uses.
A further object is to provide a method that will Pn~'ilr5- l ate more active ingredient per unit of volume than is available in any l1E -1 Pnr;-rQ--lption of the prior art .
Another object of the invention is to provide a safe delivery system of pesticldes for agrlcultural uses that does not require ~r~rl~ sd h;:~n~llng and storage faclll-ties .
A still further object of the inventlon is to provide an ~nr~rsul ation method that will produce an ~nr~rs~ ted product having a slow release of the Pnc ~rQ~ ted ~
Another obJect of ls to produce an c.nrArQ--l ated actlve agent that gives ~luLe-,Llon against microbial breakdown if the actlve agent $s applied to the 80il and that allows for the delivery of the actlve agent, which will not be removed by rain or irrigation.
Another object of the present invention i8 to provide a process of l l rn~ 1 ml.,l..~ l atlon that requlres fewer and more cost effective lngredients and ls, therefore, less expenslve and tlme rnn ' n~ to produce.
A further object of the present inventlon i8 to provlde a method of ~nr~rs~ll atlon that pludll~es an ~nr~rsul ~ted actlve agent, whlch blnds the veslcles to the organlc frac-WO95/31970 1~~ 'C-'7 21 90852 ~
tion of the 80il thereby reducing le~h~n~ or runoff.
Another object of the present invention is to provide an encapsulator having better n~lhPI:Il nn to plant cuticular waxes thereby preventing removal caused by rain or irriga-tion.
Still another ob; ect of the present invention is to reduce acute resldue levels e..~e.iL,c:d in plant tissue.
SUMMARY OF THE lhvl!~n~_ The invention is directed to preselecting a particular active agent such as a pesticide and an organic solvent for carrying the active agent. The same organic solvent must be effective to solubilize a plant lecithin to a lecithin-~a LUL c~ Lc:d level .
According to the invention, a plant lecithin is mixed with an organic solvent that is selected because it also dissolves the preselected active agent. The lecithin is present in a certain proportion so as to provide a solution with varied levels of lecithin saturation. In other words, ~n effective amount of lecithin is mixed in the organic solvent to form a ~dLuLc-Led solution of lecithin. And it is well known that different organic solvents nF~cess;~rily dissolve differing amounts of lecithin because of their varied levels of lecithin saturation from one organic sol-vent to the other.
The lecithin-saturation level will be ~lep~ L upon the amount of active agent (AA) desired in the final solu-tion. That is, the organic solvent selected for dissolving the lecithin at its saturation level will also be effective to dissolve and otherwise carry the particular amount of AA
desired in the final solution to be mixed with water to produce the vesicle formation.
Depr~n-ltn!J on the formulation of organic solvent and lecithin, the lecithin/organic solvent mixture is then WO9S/31970 r~ s,, c- 72 2 t 90~2~
g allowed to settle. That is, when the formulatlon produces a mixture having a saturated solution of lecithin and undis-solved portions of the lecithin, the ~n~l1qRolved portions are allowed to settle to the bottom of the mixture leaving the solution at its lecithin-saturation level of the organic solvent .
After settling, the top layer of lecithin-saturated solution of the lecithin/organic solvent mixture is separat-ed and saved, while the bottom layer i8 discarded. The lecithin-saLul~ted solution is called the "stock solution"
for the purpose of rlc-qrr~ h~ n~ this invention . An AA is then added to the stock solution and the resulting conce-~Lle-Le is added to water for the agricultural application.
The resulting o.,llcel~LLdLe is an i~L~ te active agent solution and includes the lecithin-~c~LulaL~d solution plus the amount of AA required to be used in the prior art as a pesticide in the subsequent agricultural application.
The invention is limited to dissolving a plant lecithin to be used in combination with the pesticide R~ hi 1~ ~sd in the organic solvent thereby producing the desired initial prede-t~rm1n~d lecithin-.,~-Lul&Lt:d stock solution.
The invention is directed to a method for preparing an ini '~ Flte active agent solution containing a preselected active agent and being effective to produce 1~ 1 micro-f-nni~rR ll ~tion of the active agent by mixing the illL~ ate active agent solution with water.
An organic solvent solution is selected that is capable of carrying the preselected active agent in the solvent solution in an amount sufficient for agricultural applica-` 30 tions.
The organic solvent solution is also capable of dis-solving a preselected plant lecithin in an amount sufficient to produce in the solution an amount of phosphotidyl rhnl ~ n~
effective to f~nn~rs~llate the pesticide when the i"t 'l~te Wo 95/31970 r~ 'C '7~
21 90852~: :
pesticlde solution is mixed with water.
The preselected plant lecithin is mixed with the organ-ic solvent solution to produce an initial predet~r-m~ nc-~
lecithin stock solution containing the desired amounts of pho2 ,~hotidylrhnl 1 n~ in the organic solvent solution.
The pl ~de ~ n-~d lecithin stock solution produced in said process mixing step is isolated and then at the desired time, mixed with an amount of the preselected active agent to form the i.~t ~ te active agent solution having an active agent content sufficient for agricultural uses. The il.t ~ te active agent solution is mixed with water forming an agricultural liquid formulation having the active agent Pnr~r81ll ated in a 1 1 ~ - 1 composition.
A particular feature of the invention is directed to the use of a pesticide mixed with a solution having a w/v or v/v ratio of lecithin to organic solvent in the solvent solution of 1:1 or 1: 2 . The method is limited to the use of a plant lecithin . In a specif ic ' - ' 1 1, the organic solvent solution includes n-methyl pyrolidone and the plant lecithin has a phosphotidyl rhnl 1 n~ content in the range of from 596 to 5096 of the lecithin.
11~S~,K1~ J.. OF THE ~KI:.I"I!.KK~;IJ ~
The present application rl1 crl oc~c a method of deliver-ing an active agent onto plants, animals, ~t.lU~;I,Ult~ surfac-es, soils, and the like. The active agent is micrQ~nrs~rsu-lated 1~ lly, thereby providing a delivery ' n1Fm and a controlled relea8e ~ m for the active agent.
In the present process, a plant lecithin is mixed with an organic solvent in a certain proportion 80 as to provide a 801ution at a desired lecithin-saturation level rl~r~n~ll n~
on the formulation. The amounts of a particular form of plant lecithin required to obtain a desired level of solu-bility in certain organic solvents are known to the skilled Wo 95/31970 1 ~~ 72 2 1 90852 `-artisan. The leclthin/organic solvent mlxture is then allowed to settle. After settling, the top layer is sepa-rated and saved, while the bottom layer is discarded. An AA
18 then added to this stock solution and the resulting ~w~ llLLaL~ is added to water for the particular agricultur-al application. The .,~-..cenLlc-L~ must be added to water for vesicle formation.
Although, in the present invention, 100% denatured anhydrous ethanol may be used, it is only one of many sol-vents that can be used fl~r~n-l i n~ on the particular applica-tion . N-methyl pyrolidone ( NMP ) is used as a solvent in some applications. NMP is neither hlghly flammable nor car~nf-g~n1c and should pose little or no problem with the Envi . Lal Protection Agency.
Other solvents that may be used are acetone, 100%
denatured anhydrous ethanol, methylene chloride, 95% etha-nol, 95% denatured ethanol, dimethylf. 'de, and gamma butyrolactone, to name a few. In practice, the solvents used with the active agents are generally known in the agricultural industry. Each pLuduc;~L or deliverer of the active agents generally knows which solvents can be used with its active agent.
Although any active agent can be used, the preferred L uses Alnr~hl~r, ~lp~ ~LI.Lln, Atrazine, Carbaryl, ChlorothAl ~n~ 1, Cymiazole, Cupric hydroxide, Cyl Ll,rln, EPTC, Fll tUL-~ll, Lambda Cyhalothrin, P~:L Ll,Lln, Piperonyl Butoxide, SLLl:p~ ~;ln, or Trifluralin. This list is not intended to be comprehensive but merely illustrative.
The skilled artisan in the agricultural industry knows the effective amounts of a particular pesticide to be used to a_ _ 1 i ch its purposes in terms of pounds of pesticide per acre ( lb/A ) for the particular crop . The particular organic solvent for a desired pesticide is also known.
Table I shows the known effective agricultural use rates and WO 95/31970 I ~I/U~.~ C '7~
21 9~852 solvents for known pesticides. In other words, the known agricultural use rate n~ g~rily defines an amount of active agent sufficient for agricultural applications.
TA}3LE I
TrrlT~TuRAL
USE RATE
5 COMMON NAME (lb/A) SOLVEN~
U~-rb ~
Alachlor 1. 5 - 8 Soluble in ether, acetone, benzene, chloroform, etha-nol, ethyl acetate, slightly soluble in heptane.
Atrazine 2 - 4 Dimethyl sulfoxide (18.3%), chloroform ( 5 . 2% ), ethyl acetate ( 2 . 8% ), methanol ( 1. 896 ), diethylether ( 1. 2% ), n-pentane ( . 035% ), water ( . 0033% ) -ESPTC 2 - 6 Miscible in acetone, ethyl alcohol kef~5(:1 .e, methyl isobutyi ketone, and xylene.
Only . 037% in water .
Fl, ~ I,ULUI~ . 8 - 4 Soluble in dimethylforma-mide, acetone, ethanol, and iso~Lu~l.ol. Only .009% in water .
Trifluralin . 5 - l >50% soluble w/v in acetone, acetonitrile, chloroform, dimethylr, rlc~, dioxane hexane methyl ethyl ketoné
and xyiene. 44% soluble w/v in methyl c~ solve, and . 00003% in water. Formulated with xylene, ethyl benzene, and naphthalene.
Insecticides:
Carbaryl . 5 - 2 Soluble in most polar organ-ic solvents such as acetone.
Only . 004% in water.
Wo 95/31970 P~I/IJV~' -'72 21 90852 - `
Cy~ LIIL ln . 025 - .1 Soluble in methanol, ace-tone, xylene, and methylene dichloride. Tn~ol llhl e in water .
5 Lambda . 025 - . 04 Soluble in most organic sol-cyhalothrin vents. Low ~ lhl 1 ity ln water. Formulated with xy-lene based petroleum 801-vent .
10 Malathion . 9 - 2 . 5 Soluble in most organlc 801-vents. Only . 0145% soluble in water. Formulated with xylene .
P, - Ll.Lln .05 - .4 Very soluble in most organic solvents except ethylene ~lycol . < . 0001% soluble in water .
Piperonyl .1 - . 8 Soluble in most common or-butoxide ganic solvents and petroleum distillates. Very slightly soluble in water.
F-~n~i ~; ~lt~.
Chlorotha- . 56 - 4 .13 Slightly soluble in organic lonil solvents and t nç:ol llhl e in water.
M; ~ n~ -c Dyes & stains Available in water soluble and solvent soluble forms.
Cymiazole and R~n7ol-~ine are used as active agents to~r~l ly applied to animals, and SL. ~ n is a bacteri-cide used on fruit trees. In such agricultural applica-tions, these pesticides are used in amounts measured in parts per million ( ppm ) .
Cymiazole is an experimental insecticide, which is not registered in the United States. It is soluble to obtain an application amount of about 300 ppm o~ the solvent. It is 80% soluble in dichlol, Lll~ne, 75% in methanol, 70% in toluene, 35% in octanol, 35% in NMP, 3096 in isuL,LulJallol, 5%
Wo 95/31970~ r~ 'c ~72--2~ 9~85~ ` , hexane, and . 005% in water. It is formulated in an aromatic golvent .
SLL~L 2,,ln is used in an amount of about 100 ppm of the liquid for its agricultural use and is water soluble.
SLLc:pl ~,in is not very soluble in organic solvents.
Ran7o~A1 na is used for various agricultural uses and in a particular application on animals, in combination with Cymiazole. Generally, Ran7ocA1na is used in an amount of about 1, 000 ppm of the solution being used and is very soluble in ethanol and ether . It is 1 n~ol l-hl a in water.
N-methyl pyrolidone ls an aYr-al 1 ant general solvent.
It dissolves most of the granulated plant lecithin constitu-ents into it in the production of 2 NMP lecithin-containing stock solution. However, ethanol dissolves ~L~ ' 'nAtely the pho~huLldyl~h~ na (PC) in the production of an ethanol lecithin-containing stock solution. The other n-methyl pyrolidone soluble constituents in the n-methyl pyrolidone stock solution may prevent n-methyl pyrolidone from solubi-lizing PC to its capacity from the plant lecithin being used.
To UVt:L~_ - this problem, ethanol is first used to form a lecithin solution wherein the PC is e~ LLauLt:d (solubi-lized) from the granulated or liquid lecithin into the lecithin solution. Then the ethanol is removed and the PC
redissolved in the n-methyl pyrolidone. This helps to raise the PC content in the NMP stock. The extraction method does not add much to the total cost of the production process, but has e5~LL~ ly high PC levels. The extraction process could be done on any of the lecithins ( hiqh or low grade ), flapanfl~n~ on the desired result. Less expensive (14% PC) lecithins may be used as opposed to the more expensive ( 50%
PC) granular lecithin flapanflln~ on the desired result.
In mixing the lecithin and the solvent Loy~ LlleL, the preferred embodiment calls for a w/v ratio of lecithin to Wo 95131970 r~ OG'72 solvent of 1:1 or 1. 2, which ls contrasted with the 1: 3 as used ln the prlor art. This allows for the loading of high ~ullcel~LLaLlons of AA into the stock, since it contains such high levels of PC.
The present process uses only one solvent in the formu-lation as a carrier for the lecithin and the AA. However, a "double solvent system" can be employed when certaln actlve agents may not be soluble ln a partlcular solvent that dlssolves a conq~ flPrable amount of leclthln. In thls case, the AA may be dlssolved ln another solvent system, that may dlssolve less leclthln but have a hlgh capaclty for the AA.
The second solvent system may be used to dlssolve the AA, whlle the addltlon to the flrst solvent system lncreases the amount of leclthln materlal into the solution, thereby ensuring the enr~ps~ tion of the AA. A double solvent system uses two, and the ~l~yLe:~lon contlnues.
For each solvent system, the solvents are mlxed wlth the leclthln before anything else. ~n a double solvent system, one will take two slngle solvent systems and mlx them Luy~LlleI. For example, for a double solvent system uslng solvents A and B, slngle solvent system A 18 produoed when ethanol and a leclthln are mlxed, and slngle solvent system B is pL.duc:~d when n-methyl pyrolldone is mixed with a lecithin. The AA would be added to the solvent system that had the higher qrl llhl 1; ty level for that particular AA.
The amounts of each slngle solvent system mlxed togeth-er to form a double, trlple or multlple solvent system, would vary ~ep~n~ln~ upon the AA and what the partlcular golvent systems were.
More than one AA ln a formulation can necessltate a solutlon requirlng a trlple solvent system. The addltlon of - bulklng agents suoh as methyl rel 1--1 os~ or Carbopol and other st~h~ 1 1 71 ng agents reslulred ln some formulatlons could requlre a trlple solvent system.
WO9S/31970 r~"-J.. '72--21 90852 . . .
. ,.,-A large number of agricultural compounds degrade in the presence of ultraviolet light. The micro~nm~rs~l ation ~ uL~:cL~ any AA ~nrloep~l within from the environment and ultrl~violet light. CaluL~IOids are natural p1~ L-' that act as ultraviolet filters and are present in the lecithin material purchased from the manufacturer. High carotenoid ~:ullcel-LL~Llons are generally present in lecithin due to the lecithin extraction and r~f~n L process.
The .;~lro L~-loid concentration in the stock material may be regulated either by selective extraction or by total e- Llc-.iLlon from the lecithin material and then metering it back into the stock material. Regulating the carotenoid ~,UIl1~:llLLC-tiOn would also regulate the rate of ultraviolet ~1P~ tion of the AA. Therefore, the length of time the AA will remain in the field can be controlled by the amount of the carotenolds in the leclthin.
pl r L of a large amount of carotenoid in the system can protect the AA in the field for an ~--Lt:-~d~d period of time. Controlling the rate of release and breakdown of the ~nn~rS~ ted AA in this manner will al50 reduce the poss~hle acute toxic effects when applied to crops or animals.
npr~n(~ng on the AA uged and itg desired ~;u-l-:~-lLLc-Llon in the final formulation, the PC content in the stock mate-rial may be selected for the AA by $imple extraction tech-ni~ues from less expensive lecithin materials with lower PC
collcel-LL~L10ns. The desired c;c,~ LL~tion of the AA in the final formulation is detc~rm~ nP(l in accoL~ ~ with the particular 2gricultural use rate est~hl 1 ~hPd for the active agent such as the pesticides in Table I.
In a~coLd~sn-~ with the invention, first the organic solvent is selected to carry the n~-c~ y amounts of active agent to produce the re~uired agricultural use rate in the final formulation of the Pnm~r5~ ted active agent. At the same time, the organic solvent selected for the active agent wo 95/31970 r~ 72 must dlssolve an effective amount of plant leclthin in solution to provide an int ~ qte active agent solution having a sufficient PC content for producing the vesicle formatlon of the 1~ 1 encapsulation when the i.~t '~-ate active agent solution is mixed with water.
Unlike the prior art, the most expensive lecithin is not reguired. Lecithin comes in different grades, r1~rc.n~91n~
upon the peL~ s of the, , ~. with p~lo~hoLldylcho-line as the most ~, Lalll ~- , 1. The higher the cullcel~LLa-tion of PC in the lecithin, the better the lecithin and the more expensive the process. D~p~n-lin~ upon the active agent, the present method uses between five ( 5 ) to fifty (50) percent and, more particularly, fUUL~e:el~ (14) to fifty ( 50 ) percent PC lecithin.
The p~esent invention can use a "batch" process to produce lts stock solutlon. The l Ludu~;Llon of the stock solutions under the present process may be au L ~ed to ellminate the slowness of the batch process. In doing so, the present lnventlon utllizes augers and centrifuges to schieve the deslred automatlon.
A system of a speclflc ~ -~1 L utilizes an auger to mix the lecithin and the solvent. As the mixin~ takes place the materlals are moved down the auger leaving room for the addition of new unmixed materials on an automatically me-tered basis. As the materials become thoroughly mixed they are emptied into centrifuges for separation.
The centrifuges operate on 2 rotational basis. The rate of rotational speed of the centrifuges no~n~ PR with the flow rate of the auger and is ~ e1 ~n~A to produce little or no backup in the system. The materials sepaLc~ d in the centrifuges are pumped into st:yari.te tanks for storage and tl1 RrOR~l . Other ~LU~ 85~:8 such as those used in the alcohol distillery industry could also be utilized.
Wo 95/31970 r~l~u. ~ 7~
Due to the low flash polnt of ethanol and its extreme fl; h~l~ty all drive ~h~n~ for the system must be air-driven. The use of this technigue in other industrial applications using ethanol has proven to be the most econom-ic c-~Lva~ as opposed to providing a totally ~Yrl 0~ nn proof electrical ystem. All ~ 5VL 4 and other equlp-ment for the pneumatic system would be located ln other rooms or b~ n~R away from the ~Lvdu.;Llon area. The compressed air would be piped to each location.
Although any active agent can be used, in the preferred o~mhorl~ L, the following active agents are used: Alachlor, Al~l~ -LI.lln, Atrazine, B~n7orA1n~ Carbaryl, Chlorothalo-nil, Cymiazole, cupric hydroxide, Cy~ Ll-lln, dyes, EPTC, Fl~ Lulul-, Lambda Cyhalothrin, Malathion, P~ Ll.Lln, piperonyl butoxide, stains, SLL~p~ y~;ln~ and Trifluralin.
Although any organic solvent can be used, in the pre-ferred '~ , the following organic solvents are used:
~cetone, 100% de.laLuLt:d ethanol, 95% denatured anhydrous ethanol, dimethylr~ , gamma butyrolactone, methylene chloride, and N-methyl pyrolidone.
In the preferred I ' '~ ~, the lecithin is selected from a group consisting of soybean oil, cottonseed oil, canola oil, wheat oil, kelp, peanuts, and sunflower seeds.
The lecithin form is selected from a group consisting of liquid, granular, powder, gel, and paste. The lecithin has ~I PC content ranging from, but not limited to, 5% to 50% in the pref erred ' ~ ' 1 L . The PC content may be achieved by direct e. LLuvLlon, commercial preparation or custom blend-ing .
Although any carotenoid content may be used, the pre-ferred '_fll t uses a carotenoid content from between substantially 0 to 1 percent to avold active agent buildup.
The vaLvLenvid content may be ~rhlev~fl by direct e~LLLa~iLlon~
commercial ~L~alaLlon or custom hl~n~l~n!J, WOgS/31970 r~.l,-J,,,"'i72 21 90852 1 ` `
C ~.lally available plant lecithin is composed of the phncphn7 ~ r1 ~le phosphatidy] rhnl i n~ ( PC ), phosphatidyle-th;lnnl ' n~ ( PE ), phosphatldyllnosltol ( PI ), and phospha-tidic acld (PA), carotenolds, and, d~ppn~l~ng on the grade, varylng levels of olls, trlglycerldes, flbrous materials and, in some cases, additives and -uLrauLc~ . C~ uLal lecithin is available in dry granular, liquid, gel, paste, and powder f orms .
A solvent is selected for a partlcular stock material from available solvents that will dissolve the active agent and a compatible grade of lecithin and also be soluble in water. Different forms of plant lecithin (i.e. dry granu-lar, liquid, gel, paste, and powder) have different levels of solubility in certain solvents. The form of lecithin chosen is thus ~l~L~ t upon the solvent required to dis-solve the active agent. For instance, if an active agent is soluble in ethanol then a lecithin form with low oil content such as a dry granular or gel would be selected because oily liquid lecithin forms are not very soluble in ethanol.
Flocculation problems sometimes arise when mixing with water due to 2n 1 , Llbility of the solvent-~ctive agent-lecithin form mixture. To vv~ this problem, solvents and lecithin forms must be substituted with others to find the best combination for optimum 5~1qp~nc1 t~nc in water.
Also, when there is an active agent that is only soluble in l~ydlu~hObic nnnrlol~r solvents, a co-solvent that is m1ct~1hlP
in water and the nnnrnl ~r solvent must be introduced into the solvent system in order to mix with water.
Since lecithin is made up of many - , L~, dissolv-ing lecithin regardless of its form in a sclvent will dis-solve some of the ., LY other than PC as well.
SrPr~f1n, ,l~c of the invention are as follows:
Example I
An industry available liquid lecithin was mixed with n-Wo95131970 r~ v, rr72--21 90~52 . ~ -, . .
methyl pyrolidone ( NMP ) in a l: 2 v/v ratio. This mixture was stirred until it became visibly homo~enized. It was then poured into a separatory funnel and allowed to settle.
After sufficient time for settling took place ( 24-48 hr. ), the bottom sludge fraction was drawn off and discarded while the top portion was de.~ ted and saved as usable stock material .
This stock material is the prlmary carrler system for Chloroth~1 on~ 1, the actlve agent to be added. The followlng formulatlon of one gallon provldeg an optimum g~1cpDnc1 nn with mlnimal rapid settling when ultimately added to water to effect ~nr~rC111 ation.
Chloroth~lnn~l tDrhn1r~1 (98% purity) 0.90 lbs Anti-microbial agent 0. 29 ozs ( 0 . 24 f l . oz . ) Anti-foaming agent 0.14 ozs (0.14 fl.oz. ) h1rkDn~n~ agent 1.43 ozs Stock materlal 7.90 lbs (0.83 gal. ) Materials mixed wlth the .,U~lCt:lltL ~t~ add to stabllity and ef f icacy of the entire system . The anti-microbial agent retards bacterial dD_ _ - 91 tion of Chloroth~1 on1 l when applied to the fleld. The anti-foaming agent is added because the stock material has a Lender cy to foam when agitated which would hamper the concentration ' 8 ability to be accurately measured out for field application. Due to Chloro~h~ n~l '5 1ncnlllh111ty, it settles out in the concen-trate rapidly which necessitates the need for a ~hlrkl~n~ng or 5~1cpDn~l~n~ agent. The th1rk~n~ng agent is to be dis-pensed accurately.
A rate of 1.5 lb ChlorothAlnn1 1 is required to spray an ~cre of L Lues to control various fungal fl1 cD~eC-~ To WO 95/31970 1 ~ `''72 2190852 fj i~
Al-- l~eh this using the ChlorothAlnnll cu..c~ La~ of the invention, 1.7 gal of the ~o-~ tlal,e was added to a water ln a spray tank previously calibrated, according to standard practice, to deliver 20-40 gallons of finished aqueous spray solution to the acre.
Liposome formation is caused when the uullu~lll,La~e comes into contact with the water in spray tank. With the Chloro-thAl on~ 1 mi.;Lot:-.aap,iulated according to the invention, the longevity of the pesticide is extended sc that it does not have to be applied as often as other ChlorothAl nn~ 1 prod-ucts. Other new and ~..-e~euLt:d results such as a signifi-cant increase in crop harvest have been obtained using the procedure of this invention in the field.
Example II
An agricultural industry available dry granular or powder lecithin was mixed with absolute ethanol in a 1: 2 w/v ratio and agitated until all the lecithin was dissolved in the solvent . ( For safety concerns, it ls not ro ' - ' to heat mixtures for ~onhAnni ng the dissolving of the solid material in volatile organic solvents such as ethanol. ) After all the lecithin dissolved, the mixture was transferred to a s~y~Lal,uLy funnel and allowed to settle.
After s~lffi~1ont settling time, the bottom sludge layer was drawn off and discarded and the top fraction saved as usable stock material.
Permethrin toohn~cAl (92% purity) 1.02 lb _ _ _ . ...... . . . .. . . . . . . .
WO 95131970 r~ '72 Stock material 6 . 48 lb ( O. 9 gal ) An average rate of 0 . 2 lb P, ~IIL Ln per acre is usual-ly required to control most insect problems in a variety of cropping situations. To r _ l; ch this, 1. 7 pints Permeth-rin cullcel~Lal~ of the invention was added to a previously calibrated spray tank, according to :i~,".daL,I practice, to deliver 20-40 gal of fin1 Ch.~(l aqueous spray solution to the acre .
Here again, liposome formation is caused when the ~;OI~C~II~LC~I ~ comes into contact with the water in the spray tank. By mi~;Lu~ l ating, the effective longevity of Pl l l-Lln with its other unique features produce new and u--~n~e.;l,ed results in the field.
Example III
The stock material for SLL~ y.;ln was made in the s~me manner as for P, - ~I.Lln using a 1:2 w/v ratio of lecithin to solvent. A 25% w/v S~LC~t yuln uu--c~--LL~ was formulated to control fireblight in apples. A gallon of S~Le~ uin cu..cJ..~Lc.l~ was made by bringing 2.09 lb of SLLepL ~,ln sulfate up to a gallon with stock material.
The L~ - rlF'Cl rate to control fireblight in fruit trees is to prepare a 100 parts per million 5 I L~ t ~uln spray solu-tion. Thus, 5.1 fl.oz. of the S~Lt~Ç,t ~uln cu--~ei~l.L,,(.~ of the invention was added to 100 gallons of water in a cali-brated air-blast orchard sprayer. On the average, this volume of spray solution will cover approximately an acre of ~ WO 95/31970 P(,ll~J.,.~ '72 2 ~ Y3852 . i `.
fruit trees.
Whlle the METHOD OF PREPARING A ~K~ c.~INED ACTIVE
AGENT STOCK SOLUTION POR LIPOSOMAL MICROENCAPSULATION OF
ACTIVE AGENTS FOR AGRICULTURAL USES has been shown and described in detail, it is obvious that this invention is not to be c~nci~l~red as limited to the exact form A~ losed, and that changes in detail and construction may be made therein within the scope of the invention without departing from the spirit thereof.
.
Claims (56)
1. A method for producing a stock intermediate agricultural pesticide formulation, said method comprising the steps of:
a) mixing plant lecithin with an organic solvent capable of carrying in solution a preselected agricultural pesticide to form a mixture of said organic solvent and plant lecithin with the lecithin being in solution at a lecithin saturation level, b) settling said mixture to create a lecithin-saturated solution portion and an undissolved portion, c) separating the lecithin-saturated solution portion from the undissolved portion for subsequent use of the lecithin-saturated solution in a later pesticide mixing step, and d) mixing the preselected agricultural pesticide with the lecithin-saturated solution for the preselected agricultural pesticide to be in solution to form said stock intermediate agricultural pesticide formulation having an amount of said agricultural pesticide in solution that is effective for an agricultural use and for subsequent mixing with water to produce liposomal encapsulation of said preselected agricultural pesticide.
a) mixing plant lecithin with an organic solvent capable of carrying in solution a preselected agricultural pesticide to form a mixture of said organic solvent and plant lecithin with the lecithin being in solution at a lecithin saturation level, b) settling said mixture to create a lecithin-saturated solution portion and an undissolved portion, c) separating the lecithin-saturated solution portion from the undissolved portion for subsequent use of the lecithin-saturated solution in a later pesticide mixing step, and d) mixing the preselected agricultural pesticide with the lecithin-saturated solution for the preselected agricultural pesticide to be in solution to form said stock intermediate agricultural pesticide formulation having an amount of said agricultural pesticide in solution that is effective for an agricultural use and for subsequent mixing with water to produce liposomal encapsulation of said preselected agricultural pesticide.
2. A method for producing a stock agricultural formulation for use in preparing an intermediate agricultural pesticide formulation containing in solution a preselected agricultural pesticide, said method comprising the steps of:
a) mixing plant lecithin with an organic solvent capable of carrying in solution the preselected agricultural pesticide to form a mixture of said organic solvent and plant lecithin with the lecithin being in solution at a lecithin saturation level, b) settling said mixture to create a lecithin-saturated solution portion and an undissolved portion, and c) separating the lecithin-saturated solution portion from the undissolved portion for subsequent use of the lecithin-saturated solution in preparing said intermediate agriculutral pesticide formulation.
a) mixing plant lecithin with an organic solvent capable of carrying in solution the preselected agricultural pesticide to form a mixture of said organic solvent and plant lecithin with the lecithin being in solution at a lecithin saturation level, b) settling said mixture to create a lecithin-saturated solution portion and an undissolved portion, and c) separating the lecithin-saturated solution portion from the undissolved portion for subsequent use of the lecithin-saturated solution in preparing said intermediate agriculutral pesticide formulation.
3. (New) The method as defined in Claims 1 or 2 wherein the w/v or v/v ratio of lecithin to organic solvent is 1:1 or 1:2.
4. (New) The method as defined in Claims 1 or 2 wherein the organic solvent includes N-methyl pyrrolidone.
5. (New) The method as defined in Claims 1 or 2 wherein said organic solvent includes carotenoid for controlling the ultraviolet degradability of liposomal encapsulated agricultural pesticide produced when the intermediate agricultural pesticide formulation is mixed with water.
6. (New) A method for preparing an initial lecithin-containing stock agricultural formulation to provide an intermediate active agent formulation containing a preselected active agent and being effective to produce a liposomal encapsulated active agent by mixing the intermediate active agent formulation with water, said method comprising the steps of:
a) selecting an organic solvent solution capable of carrying the preselected active agent in solution in an amount sufficient for effecting an agricultural application, b) said organic solvent solution further being capable of dissolving plant lecithin in an amount sufficient to produce an amount of phosphotidylcholine in solution effective to encapsulate the active agent when the intermediate active agent formulation is mixed with water, c) mixing said plant lecithin with said organic solvent solution to produce said initial lecithin-containing stock agricultural formulation containing said amounts of phosphotidylcholine in solution, and d) isolating said lecithin-containing stock agricultural formulation produced for subsequent use in a later active agent mixing step including mixing an amount of the preselected active agent into said initial lecithin-containing stock agricultural formulation to form said intermediate active agent formulation having an active agent content in solution sufficient for effecting an agricultural use.
a) selecting an organic solvent solution capable of carrying the preselected active agent in solution in an amount sufficient for effecting an agricultural application, b) said organic solvent solution further being capable of dissolving plant lecithin in an amount sufficient to produce an amount of phosphotidylcholine in solution effective to encapsulate the active agent when the intermediate active agent formulation is mixed with water, c) mixing said plant lecithin with said organic solvent solution to produce said initial lecithin-containing stock agricultural formulation containing said amounts of phosphotidylcholine in solution, and d) isolating said lecithin-containing stock agricultural formulation produced for subsequent use in a later active agent mixing step including mixing an amount of the preselected active agent into said initial lecithin-containing stock agricultural formulation to form said intermediate active agent formulation having an active agent content in solution sufficient for effecting an agricultural use.
7. (New) The method as defined in Claim 6 wherein said active agent is selected from the group consisting of alachlor, alphamethrin, atrazine, carbaryl, chlorothalonil, cymiazole, cupric hydroxide, cypermethrin, S-ethyl dipropylthiocarbamate, fluometuron, lambda cyhalothrin, permethrin, piperonyl butoxide, streptomycin, trifluralin, benzocaine, dyes, malathion, and stains.
8. (New) The method as defined in Claim 6 wherein said organic solvent solution includes a carotenoid for controlling the ultraviolet degradability of said liposomal encapsulated active agent.
9. (New) A method for preparing a lecithin-containing stock agricultural formulation useful in providing an intermediate agricultural pesticide formulation, said method comprising the steps of:
a) selecting an organic solvent solution capable of carrying a preselected agricultural pesticide in solution in an amount sufficient for effecting an agricultural application, b) said organic solvent solution further being capable of dissolving plant lecithin in an amount sufficient to produce an amount of phosphotidylcholine in solution effective to encapsulate said pesticide when said intermediate agricultural pesticide formulation is mixed with water, c) mixing said plant lecithin with said organic solvent solution to produce said lecithin-containing stock agricultural formulation containing said amounts of phosphotidylcholine in solution, and d) isolating said lecithin-containing stock agricultural formulation for subsequent mixing of an amount of the preselected agricultural pesticide with said lecithin-containing stock agricultural formulation to form said intermediate agricultural pesticide formulation having a pesticide content in solution sufficient for producing a liposomal encapsulated agricultural pesticide for agricultural use.
a) selecting an organic solvent solution capable of carrying a preselected agricultural pesticide in solution in an amount sufficient for effecting an agricultural application, b) said organic solvent solution further being capable of dissolving plant lecithin in an amount sufficient to produce an amount of phosphotidylcholine in solution effective to encapsulate said pesticide when said intermediate agricultural pesticide formulation is mixed with water, c) mixing said plant lecithin with said organic solvent solution to produce said lecithin-containing stock agricultural formulation containing said amounts of phosphotidylcholine in solution, and d) isolating said lecithin-containing stock agricultural formulation for subsequent mixing of an amount of the preselected agricultural pesticide with said lecithin-containing stock agricultural formulation to form said intermediate agricultural pesticide formulation having a pesticide content in solution sufficient for producing a liposomal encapsulated agricultural pesticide for agricultural use.
10. (New) The method as defined in Claims 6 or 9 wherein said lecithin-containing stock agricultural formulation includes a mixture of a first organic solvent in which plant lecithin has been dissolved and a second organic solvent which is mixed with the first organic solvent to enhance the amount of phosphotidylcholine in solution in said lecithin-containing stock agricultural formulation.
11. (New) The method as defined in Claim 10 wherein said first organic solvent is ethanol and said second organic solvent is N-methyl pyrrolidone.
12. (Amended) A method for producing a liposomal encapsulated agricultural pesticide, said method comprising the steps of:
a) selecting an organic solvent solution capable of carrying a preselected agricultural pesticide in solution in an amount sufficient for effecting an agricultural application, b) said organic solvent solution further being capable of dissolving a plant lecithin in an amount sufficient to produce in solution an amount of phosphotidylcholine effective to encapsulate said sufficient amount of said agricultural pesticide when an organic solvent solution containing said plant lecithin and said agricultural pesticide is mixed with water, c) mixing said plant lecithin with said organic solvent solution to produce an undissolved portion and an initial plant lecithin stock solution containing said effective amount of phosphotidylcholine in solution, and d) isolating said initial plant lecithin stock solution from said undissolved portion, e) mixing an amount of the preselected agricultural pesticide into said initial plant lecithin stock solution to form an intermediate agricultural pesticide stock solution having said preselected agricultural pesticide in solution in said amount sufficient for effecting an agricultural use, and f) mixing said intermediate agricultural pesticide stock solution with water to produce a liposomal encapsulated agricultural pesticide in said amount sufficient for effecting an agricultural use.
a) selecting an organic solvent solution capable of carrying a preselected agricultural pesticide in solution in an amount sufficient for effecting an agricultural application, b) said organic solvent solution further being capable of dissolving a plant lecithin in an amount sufficient to produce in solution an amount of phosphotidylcholine effective to encapsulate said sufficient amount of said agricultural pesticide when an organic solvent solution containing said plant lecithin and said agricultural pesticide is mixed with water, c) mixing said plant lecithin with said organic solvent solution to produce an undissolved portion and an initial plant lecithin stock solution containing said effective amount of phosphotidylcholine in solution, and d) isolating said initial plant lecithin stock solution from said undissolved portion, e) mixing an amount of the preselected agricultural pesticide into said initial plant lecithin stock solution to form an intermediate agricultural pesticide stock solution having said preselected agricultural pesticide in solution in said amount sufficient for effecting an agricultural use, and f) mixing said intermediate agricultural pesticide stock solution with water to produce a liposomal encapsulated agricultural pesticide in said amount sufficient for effecting an agricultural use.
13. (Amended) The method as defined in Claim 12 wherein said organic solvent solution includes carotenoid for controlling the ultraviolet degradability of said liposomal encapsulated agricultural pesticide.
14. (Amended) A method for preparing a stock interme-diate agricultural pesticide formulation, said method comprising the steps of:
a) selecting an organic solvent solution capable of carrying a preselected agricultural pesticide in solution in an amount sufficient for effecting an agricultural application, b) said organic solvent solution further being capable of dissolving a plant lecithin in an amount sufficient to produce in solution an amount of phosphotidylcholine effective to encapsulate said agricultural pesticide when the intermediate agricultural pesticide formulation is mixed with water, c) first mixing said plant lecithin with said organic solvent solution to produce a plant lecithin stock solution containing said amounts of phosphotidylcholine in solution, d) isolating said plant lecithin stock solution produced in said first mixing step, and then e) mixing an amount of said preselected agricultural pesticide into said plant lecithin stock solution to form said stock intermediate agricultural pesticide formulation having an agricultural pesticide content in solution sufficient for effecting an agricultural use.
a) selecting an organic solvent solution capable of carrying a preselected agricultural pesticide in solution in an amount sufficient for effecting an agricultural application, b) said organic solvent solution further being capable of dissolving a plant lecithin in an amount sufficient to produce in solution an amount of phosphotidylcholine effective to encapsulate said agricultural pesticide when the intermediate agricultural pesticide formulation is mixed with water, c) first mixing said plant lecithin with said organic solvent solution to produce a plant lecithin stock solution containing said amounts of phosphotidylcholine in solution, d) isolating said plant lecithin stock solution produced in said first mixing step, and then e) mixing an amount of said preselected agricultural pesticide into said plant lecithin stock solution to form said stock intermediate agricultural pesticide formulation having an agricultural pesticide content in solution sufficient for effecting an agricultural use.
15. (New) The method as defined in Claim 12 or 14 wherein said organic solvent solution includes a mixture of a first organic solvent in which plant lecithin has been dissolved and a second organic solvent which is mixed with the first organic solvent to enhance the amount of phosphotidylcholine in solution in said organic solvent solution.
16. The method as defined in Claim 15 wherein said first organic solvent is ethanol and said second organic solvent is N-methyl pyrrolidone.
17. The method as defined in Claim 9 or 14 wherein said organic solvent solution includes carotenoid ior controlling the ultraviolet degradability of liposomal encapsulated agricultural pesticide produced when the intermediate agricultural pesticide formulation is mixed with water.
18. The method as defined in Claim 1 or 2 wherein said organic solvent is selected from the group consisting of acetone, 100% denatured anhydrous ethanol, 95%
denatured ethanol, dimethylformamide, gamma butyrolactone, methylene chloride, and N-methyl pyrrolidone.
denatured ethanol, dimethylformamide, gamma butyrolactone, methylene chloride, and N-methyl pyrrolidone.
19. The method as defined in any one of Claims 6, 9, 12, or 14 wherein said organic solvent solution includes an organic solvent selected from the group consisting of acetone, 100%
denatured anhydrous ethanol, 95% denatured ethanol, dimethylformamide, gamma butyrolactone, methylene chloride, and N-methyl pyrrolidone.
denatured anhydrous ethanol, 95% denatured ethanol, dimethylformamide, gamma butyrolactone, methylene chloride, and N-methyl pyrrolidone.
20. (New) The method as defined in any one of Claims 6, 9, 12, or 14 wherein the w/v or v/v ratio of lecithin to organic solvent in said solvent solution is 1:1 or 1:2.
21. (New) The method as defined in any one of Claims 6, 9, 12, or 14 wherein the organic solvent solution includes the organic solvent N-methyl pyrrolidone.
22. (New) The method as defined in any one of Claim 1, 2, 9, 12 or 14 wherein said preselected agricultural pesticide is selected from the group consisting of alachlor, alphamethrin, atrazine, carbaryl, chlorothalonil, cymiazole, cupric hydroxide, cypermethrin, S-ethyl dipropylthiocarbamate, fluometuron, lambda cyhalothrin, permethrin, piperonyl butoxide, streptomycin, malathion, and trifluralin.
23. (New) The method as defined in any one of Claims 1, 2, 6, 9, 12 or 14 wherein said plant lecithin is obtained from a lecithin source selected from a group consisting of soybean oil, cottonseed oil, canola oil, wheat oil, kelp, peanuts, and sunflower seeds.
24. (New) The method as defined in any one of Claims 1, 2, 6, 9, 12 or 14 wherein said plant lecithin has a phosphotidylcholine content in the range of from about 5% to about 50%.
25. (New) The method as defined in any one of Claims 1, 2, 6, 9, 12 or 14 wherein said agricultural pesticide is first dissolved in a second organic solvent, and said second organic solvent is capable of dissolving plant lecithin therein.
26. The method as defined in any one of Claims 1, 2, 6, 9, 12, or 14 wherein the plant lecithin is in a form selected from the group consisting of liquid, granular, powder, gel, and paste.
27. A stock lecithin-containing agricultural formulation comprising:
a) an organic solvent capable of carrying a preselected active agent in solution in an amount sufficient for effecting an agricultural application, b) said organic solvent including a saturation level of a preselected plant lecithin in solution, c) said organic solvent saturated with said plant lecithin being effective to mix with said preselected active agent for forming an intermediate active agent formulation to produce liposomal microencapsulation of the preselected active agent by mixing the intermediate active agent formulation with water.
a) an organic solvent capable of carrying a preselected active agent in solution in an amount sufficient for effecting an agricultural application, b) said organic solvent including a saturation level of a preselected plant lecithin in solution, c) said organic solvent saturated with said plant lecithin being effective to mix with said preselected active agent for forming an intermediate active agent formulation to produce liposomal microencapsulation of the preselected active agent by mixing the intermediate active agent formulation with water.
28. The formulation as defined in Claim 27 wherein said organic solvent includes carotenoid for controlling the ultraviolet degradability of said preselected active agent when liposomally microencapsulated.
29. The formulation as defined in Claim 27 wherein said active agent is selected from the group consisting of alachlor, alphamethrin, atrazine, carbaryl, chlorothanlonil, cymiazole, cupric hydroxide, cypermethrin, S-ethyl dipropylthiocarbamate, fluometuron, lambda cyhalothrin, permethrin, piperonyl butoxide, streptomycin, trifluralin, benzocaine, dyes, malathion, and stains.
30. (New) The formulation as defined in Claim 27 wherein said active agent is first dissolved in a second organic solvent, and said second organic solvent is capable of dissolving plant lecithin therein.
31. (New) The formulation as defined in Claim 27 wherein the organic solvent includes N-methyl pyrrolidone.
32. (New) A stock agricultural formulation comprising:
a) an organic solvent solution including an organic solvent capable of carrying in solution a preselected agricultural pesticide in an amount sufficient for effecting an agricultural application, b) said organic solvent including a saturation level of plant lecithin in solution, c) said organic solvent solution being effective to mix with said preselected agricultural pesticide for forming an intermediate agricultural pesticide solution useful for producing a liposomal encapsulated agricultural pesticide by mixing said intermediate agricultural pesticide solution with water.
a) an organic solvent solution including an organic solvent capable of carrying in solution a preselected agricultural pesticide in an amount sufficient for effecting an agricultural application, b) said organic solvent including a saturation level of plant lecithin in solution, c) said organic solvent solution being effective to mix with said preselected agricultural pesticide for forming an intermediate agricultural pesticide solution useful for producing a liposomal encapsulated agricultural pesticide by mixing said intermediate agricultural pesticide solution with water.
33. (New) A stock agricultural formulation comprising:
a) an organic solvent solution including an organic solvent carrying in solution a preselected agricultural pesticide in an amount sufficient for effecting an agricultural application, b) said organic solvent solution including an amount of plant lecithin dissolved in said organic solvent solution sufficient to produce in solution an amount of phosphotidylcholine effective to encapsulate agricultural pesticide dissolved in said organic solvent solution when said stock agricultural formulation is mixed with water.
a) an organic solvent solution including an organic solvent carrying in solution a preselected agricultural pesticide in an amount sufficient for effecting an agricultural application, b) said organic solvent solution including an amount of plant lecithin dissolved in said organic solvent solution sufficient to produce in solution an amount of phosphotidylcholine effective to encapsulate agricultural pesticide dissolved in said organic solvent solution when said stock agricultural formulation is mixed with water.
34. (New) A stock formulation as defined in Claim 32 or 33 wherein the organic solvent solution includes carotenoid for controlling the ultraviolet degradability of said liposomal encapsulated agricultural pesticide.
35. (New) A stock formulation as defined in Claim 32 or 33 wherein said organic solvent solution includes the organic solvent N-methyl pyrrolidone.
36. (New) A stock formulation as defined in Claim 32 or 33 wherein said agricultural pesticide is first dissolved in a second organic solvent, and said second organic solvent is capable of dissolving plant lecithin therein.
37. (New) A stock formulation as defined in Claim 32 or 33 wherein said organic solvent solution includes a mixture of a first organic solvent in which plant lecithin has been dissolved and a second organic solvent which is mixed with the first organic solvent to enhance the amount of phosphotidylcholine in said organic solvent solution.
38. (New) A stock formulation as defined in Claim 37 wherein said first organic solvent is ethanol and said second organic solvent is N-methyl pyrrolidone.
39. (New) A stock formulation as defined in any one of Claims 27, 32, or 33 wherein the w/v or v/v ratio of lecithin to organic solvent is 1:1 or 1:2.
40. (New) A stock formulation as defined in Claim 32 or 33 wherein said organic solvent is selected from the group of acetone, 100% denatured anhydrous ethanol, 95% denatured ethanol, dimethylformamide, gamma butyrolactone, methylene chloride, and N-methyl pyrrolidone.
41. (New) An agricultural formulation comprising:
a) a liposomal encapsulated agricultural pesticide effective for an agricultural use, b) said encapsulated agricultural pesticide including a lipid vesicle having phospholipid materials derived from plant lecithin as its lipid source.
a) a liposomal encapsulated agricultural pesticide effective for an agricultural use, b) said encapsulated agricultural pesticide including a lipid vesicle having phospholipid materials derived from plant lecithin as its lipid source.
42. (New) A formulation as defined in Claim 41 wherein the pesticide is an agricultural herbicide.
43. (New) A formulation as defined in Claim 42 wherein the herbicide is selected from the group of alachlor, atrazine, S-ethyl dipropylthiocarbamate, fluometuron, and trifluralin.
44. (New) A formulation as defined in Claim 41 wherein the pesticide is atrazine.
45. (New) A formulation as defined in Claim 41 wherein the pesticide is an agricultural insecticide.
46. (New) A formulation as defined in Claim 45 wherein the insecticide is selected from the group of alphamethrin, carbaryl, cymiazole, cypermethrin, lambda cyhalothrin, permethrin, piperonyl butoxide, and malathion.
47. (New) A formulation as defined in Claim 41 wherein the pesticide is permethrin.
48. (New) A formulation as defined in Claim 41 wherein the pesticide is an agricultural bactericide.
49. (New) A formulation as defined in Claim 41 wherein the pesticide is streptomycin.
50. (New) A formulation as defined in Claim 41 wherein the pesticide is an agricultural fungicide.
51. (New) A formulation as defined in Claim 41 wherein the pesticide is chlorothalonil.
52. (New) A stock formulation as defined in any one of Claims 32, 33, or 41 wherein said agricultural pesticide is selected from the group of alachlor, alphamethrin, atrazine, carbaryl, chlorothalonil, cymiazole, cupric hydroxide, cypermethrin, S-ethyl dipropylthiocarbamate, fluometuron, lambda cyhalothrin, permethrin, piperonyl butoxide, streptomycin, malathion, and trifluralin.
53. (New) A stock formulation as defined in any one of Claims 27, 32, 33 or 41 wherein said plant lecithin is obtained from a lecithin source selected from the group of soybean oil, cottonseed oil, canola oil, wheat oil, kelp, peanuts, and sunflower seeds.
54. (New) A stock formulation as defined in any one of Claims 27, 32, 33, or 41 wherein said plant lecithin has a phosphotidylcholine content in the range of from about 5% to about 50%.
55. (New) A stock formulation as defined in any one of Claims 27, 32, or 33 wherein the plant lecithin is in a form selected from the group of liquid, granular, powder, gel, and paste.
56. (New) A method for controlling the growth of agricultural pests including weeds, insects, fungi, and bacteria comprising the step of bringing into contact with the agricultural pests an effective amount of the agricultural formulation of claim 41 to control said growth of agricultural pests.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24848094A | 1994-05-24 | 1994-05-24 | |
| US08/248,480 | 1994-05-24 |
Publications (1)
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|---|---|
| CA2190852A1 true CA2190852A1 (en) | 1995-11-30 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2190852 Abandoned CA2190852A1 (en) | 1994-05-24 | 1995-05-24 | Method of preparing a predetermined active agent stock solution for liposomal microencapsulation of active agents for agricultural uses |
Country Status (4)
| Country | Link |
|---|---|
| AU (1) | AU701022B2 (en) |
| CA (1) | CA2190852A1 (en) |
| GB (1) | GB2303791B (en) |
| WO (1) | WO1995031970A1 (en) |
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|---|---|---|---|---|
| NL1001620C2 (en) * | 1995-06-22 | 1996-12-24 | Instituut Voor Agrobiologisch | Improvement in activity of plant growth regulators |
| HUP9903889A3 (en) * | 1996-10-25 | 2004-07-28 | Monsanto Technology Llc St Louis | Composition and method for treating plants with exogenous chemicals |
| JP4155601B2 (en) * | 1996-10-25 | 2008-09-24 | モンサント・テクノロジー・エルエルシー | Compositions and methods for treating plants with exogenous chemicals |
| PT102197A (en) * | 1998-08-21 | 2000-02-29 | Ineti Inst Biotec Q F E Tecnol | LIPOSOMAL FORMULATIONS OF DINITROANILINS AND PROCESS FOR THEIR PREPARATION |
| IL144561A0 (en) * | 1999-01-25 | 2002-05-23 | Optime Therapeutics Inc | Liposome compositions and methods for treating pests utilizing the same |
| US10070649B2 (en) | 2013-01-30 | 2018-09-11 | Agrofresh Inc. | Volatile applications against pathogens |
| US11039617B2 (en) | 2013-01-30 | 2021-06-22 | Agrofresh Inc. | Large scale methods of uniformly coating packaging surfaces with a volatile antimicrobial to preserve food freshness |
| TW201735792A (en) | 2016-03-07 | 2017-10-16 | 農業保鮮股份有限公司 | Synergistic methods of using benzoxaborole compounds and preservative gases as an antimicrobial for crops |
| PL244203B1 (en) * | 2021-07-22 | 2023-12-18 | Syvento Spolka Z Ograniczona Odpowiedzialnoscia | Liquid proliposome composition of plant protection products and method of manufacturing the composition |
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| US5269979A (en) * | 1988-06-08 | 1993-12-14 | Fountain Pharmaceuticals, Inc. | Method for making solvent dilution microcarriers |
| US5277914A (en) * | 1989-03-31 | 1994-01-11 | The Regents Of The University Of California | Preparation of liposome and lipid complex compositions |
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1995
- 1995-05-24 CA CA 2190852 patent/CA2190852A1/en not_active Abandoned
- 1995-05-24 WO PCT/US1995/006572 patent/WO1995031970A1/en active Application Filing
- 1995-05-24 AU AU26480/95A patent/AU701022B2/en not_active Ceased
- 1995-05-24 GB GB9624479A patent/GB2303791B/en not_active Expired - Fee Related
Also Published As
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| AU701022B2 (en) | 1999-01-21 |
| AU2648095A (en) | 1995-12-18 |
| GB2303791B (en) | 1999-02-10 |
| WO1995031970A1 (en) | 1995-11-30 |
| GB2303791A (en) | 1997-03-05 |
| GB9624479D0 (en) | 1997-01-15 |
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