Formulations of Indoxacarb and use of Indoxacarb for Indoor Residual Spray

Background of the invention

Indoxacarb is also known as DPX-KN128 S-enantiomer and is chemically (S)-7-chloro-3-[methoxycarbonyl-(4-trifluoromethoxy-phenyl)-carbamoyl]-2,5-dihydro-indeno[l,2-e][l,3,4] oxadiazine-4a(3H)- carboxylic acid methyl ester. The compound belongs to a chemical class known as oxadiazines and has the following chemical structure:

Indoxacarb is permitted by many countries in several food commodities, including Apple, Brassica, Cattle, Corn, Cotton, Goat, Hog, Horse, Lettuce (head & leaf), Milk, Milk fat, Pear, Sheep and Vegetables (fruiting group). Indoxacarb is considered to be a broad spectrum insecticide with proven efficacy against a wide range of vectors.

Vector control is an important part of the current global strategy for controlling major vector-borne diseases. Indoor Residual Spraying (IRS) is the application of long-acting chemical insecticides on the walls and roofs of all houses and domestic animal shelters in a given area, for example, to kill the adult vector mosquitoes and sand flies that land and rest on these surfaces.

The primary effects of IRS towards curtailing disease transmission transmission are:

i) to reduce the life span of vector mosquitoes so that they can no longer transmit disease causing parasites from one person to another, and ii) to reduce the density of the vector mosquitoes. In some situations, IRS can lead to the elimination of locally important disease causing vectors, iii) Some insecticides also repel mosquitoes and by so doing reduce the number of
mosquitoes entering the sprayed room, and thus human-vector contact.

The efforts of the Malaria Eradication Programme (1955-1969) contributed to significantly reducing the global malaria burden, particularly in Asia, Latin America and Southern Africa. The eradication programme was based on IRS against the vector mosquitoes, as endorsed by the WHO combined with other measures, led to malaria eradication from Europe, the former USSR, and several countries in Asia and the Caribbean.

Despite its initial widespread use and contribution to the success of malaria eradication and control efforts, in recent years, the use of IRS has declined.
There exists a need for novel formulations of Indoxacarb that can reduce the levels of exposure to the environment, the handlers and the food products and at the same time improve vector control by means of applying them as IRS.

Summary of the invention

It is an object of the invention to provide formulations of Indoxacarb in the form of Suspension Concentrates (SC).

It is another object of the invention to provide formulations of Indoxacarb in the form of Emulsion Concentrates.

It is another object of the invention to provide formulations of Indoxacarb in the form of Wettable Powders (WP).

It is yet another object of the invention to provide formulations of Indoxacarb in the form of water soluble granules (WG) and Water Dispersible Granules (WDG).

It is yet another object of the invention to provide formulations of Indoxacarb in the form of Capsulated suspensions

It is yet another object of the invention to provide microemulsions of Indoxacarb.

It is yet another object of the invention to provide Indoxacarb for IRS (Indoor Residual spray) application.

Detailed description of the invention

In the inventor's investigations, it was found that certain formulations of Indoxacarb have better efficacy, better tolerance and stability as compared to the active ingredient or application thereof.

Generally, all insecticides are poisons and can be harmful if improperly used. They can enter the body by three different routes: the skin (dermal absorption), the mouth (ingestion), and the lungs (inhalation). Poisoning may occur while preparing, spraying, storing, or transporting insecticides. Taking special safety precautions minimizes the risk of poisoning that insecticides not only pose to users, but to other people, non-target organisms, and the environment (including drinking water, food, and soil).
Insecticides are seldom used at full strength but are formulated with other substances. Thus, a marketed insecticide product is composed not only of a toxic part (either called the toxicant or the active ingredient), but of a toxic part and one or more non-toxic parts (often referred to as inert materials). The typical ingredients of a formulation include an active ingredient, solvents, carriers, surface active agents, and special additives. The inert materials may serve to dissolve the active ingredient, act as carriers, disperse the active ingredient, improve effectiveness, reduce toxicity, or break the active ingredient down into smaller parts, making the resulting formulation diluted, extended, and easier to apply. Formulation has great influence on the effectiveness of an insecticide. Toxicity measures the degree to which a substance may cause harm to human, animal, or insect. It is usually expressed in terms of Lethal Dosage (LD). To compare the toxicity of various insecticides, the value of Lethal Dose 50 (LD50) is used. Acute oral and acute dermal toxicity is measured by observing test animals' responses to single doses of toxin. Toxin doses are measured in milligrams of active ingredient per kilogram weight of test animal (e.g. rat, rabbit).

LD50 refers to the dose, measured in PPM, of a chemical that kills 50% of a population of test animals. Insecticides are divided into various hazard classes according to their LD50 values. The toxicity of an insecticide is determined by the concentration of its active ingredient and its formulation. For any insecticide, a granule formulation is safer to use than a spray, and a coarse spray is safer to use than an aerosol. The most highly toxic chemicals are applied as granules since fine powders are too easily inhaled.
Suspension Concentrates (SC)

Indoxacarb can be formulated as a suspension concentrate.

Suspension concentrates are stable suspensions of pesticide particles in water. Suspension concentrates were developed as means for overcoming dust problems associated with WP formulations. Suspension concentrates are usually made by premixing the active powder in an aqueous solution of a wetting agent and a dispersing agent. This is followed by a wet grinding process in a bead mill, to give a particle size distribution of about 1 - 10 u. with an average particle size of about 2 - 3 u..

The suspension concentrate of this invention demonstrates many favourable attributes like rapid and complete dispersion in the spray tank with minimal agitation in hard or soft water, lack of breakdown or dust formation, good re-suspension after settling and stable shelf life; enhanced biological activity; low cost of production.

The formulation may have wetting and dispersing like Sodium lignosulfonates, Aliphatic alcohol ethoxylates, EO/PO co-polymers, Sodium naphthalene sulfonates - formaldehyde condensates, Tristyryl phenol ethoxylates phosphate esters, graft co-polymers and antisettling agents like Xanthum gum, Cellulose derivatives, Polyvinyl alcohols, Modified starches, Natural gums, Polyethylene oxide. The formulation may further contain dispersed phases like Bentonite clay, Atapulgite, Precipitated silica and fumed silica. Antifungal agents like formaldehyde solution and Proxel GXL may also be used.

Wettable Powders (WP) and Water-Dispersible Powders (WDP)
Powders consist of active ingredients, wetting agents and inert carriers. Wettable powders are finely divided solid pesticide formulations which are applied after dilution and suspension in water. WP formulations are usually made from solid active ingredients which are suitable for fine grounding through a hammer or pin type mill or air jet milling for wettable powder. The formulation contains dry surfactants as powder wetting, dispersing agents and inert carriers or fillers. Average particle size of wet table powders 5u..

Wettable powders are finely divided solid pesticide formulations which are applied after dilution and suspension in water. WP formulations are usually made from solid active ingredients which are suitable for fine grounding through a hammer or pin type mill or air-jet mill.

The WP/ WDG formulation may contain wetting agents such as Benzene sulfonates, Naphthalene sulfonates, Aliphatic sulfosuccinates, Aliphatic alcohol ethoxylates and the like; dispersing agents like Lignosulfonates, Naphthalene sulfonate - formaldehyde condensates and antifoaming agents like Silicone oil based polymers.

Water Dispersible / soluble granules (WG)

Water dispersible granules contain wetting agent and dispersing agents similar to those used in WP & SC formulation. They may also contain disintegrants to assist granule break up in the spray tank. WG are essentially non dusty, free flowing granules which should disperse or dissolve quickly when added to water in the spray tank. They have added convenience in handling and use over the conventional liquid and powder formulations. They can be packed into simple bags or cartons to minimize the pack disposable problems.

The granules may contain wetting agents like Benzene sulfonates, Naphthalene sulfonates, Aliphatic sulfosuccinates, Aliphatic alcohol ethoxylates etc and dispersing agents like Lignosulfonates and Naphthalene sulfonate - formaldehyde condensates. The formulations may further contain antifoaming agents such as Silicone oil based polymers.

Emulsifiable Concentrates (EC)

Emulsifiable concentrates consist of an active ingredient, a solvent, and an emulsifier. The formulation is economical as it may be shipped in high concentrations and diluted later with water. The solvent may be chosen with respect to the solubility of the active ingredient and the emulsifier may be chosen as per its HLB (Hydrophilic Lipophilic Balance) value. Since Indoxacarb has negligible solubility in water, appropriate solvent system may be chosen to make an emulsion concentrate.

The EC formulations have the advantages of good chemical stability, high biological activity, easy pourability.

Oil in water emulsions (EW)

EW formulations contains active ingredient dissolved in solvent and surfactants. This oil is mixed with water under high shear stirring to form droplets of about 0.5|i. This oil in water emulsions has reduced VOC (volatile organic compounds) than EC formulations.

The emulsions may contain solvents like Solvosso 100, 150 , 200 or equivalent solvents, Aromatic heavy naphtha, Solvent C-IX, Vegetable oils, Glycols and glycol esters, Aliphatic and aromatic esters, Aliphatic ketones, alcohols etc and emulsifiers like aliphatic alcohol sulfates as sodium salts, alkyl benzene sulfonates as sodium and calcium salts, alkyl naphthalene sulfonates as sodium salts , naphthalene sulfonate formaldehyde condensates as sodium salt, lignosulfonates as sodium and calcium salts, Dioctyl-sulfosuccinates as sodium salts, Alkanol / propylene oxide / ethylene oxide copolymers, Quartanery ammonium salts with alkyl chain ranging from C3 - C18 etc. The formulations may also contain antifoaming agents, thickeners, antifreezing agents and antifungal agents.

Micro emulsions (ME)

Micro emulsions are water based formulations that are thermodynamically stable over a wide temperature range due to their very fine droplet size usually 0.05 - O.lu. in size. Micro emulsions consist of liquid or solid active ingredient dissolved in a solvent, surfactant solubilisers and water.

Capsulated Suspensions

Capsulated suspensions consist of either wettable powder and water or suspension concentrate and water held in a capsule. Microcapsule suspensions are small spherical particles (typically 1 - 20 urn in diameter) composed of a core material containing active ingredient and an outer shell wall of polymeric material, which is designed to release the core in a controlled way, as appropriate for the biologically active material. Suspensions are produced normally as aqueous concentrates that are diluted in water and sprayed conventionally.

The capsulated suspensions may contain wetting and dispersing, antisettling agents, dispersed phases and antifungal agents.

Solutions

Solutions are made up of an active ingredient and a solvent. An appropriate solvent system may be chosen based on the solubility and stability of Indoxacarb in the solvent system.

The formulation may contain wetting / bio-enhancing agents like sorbitol, solvents like alcohols, ketones and glycols, anti freezing agents like Propylene glycol, Ethylene glycol, Inorganic salts such as sodium chloride, Urea, Sorbitals

Indoxacarb for IRS application.

The inventors have surprisingly found that Indoxacarb is effective against malaria vector control, kala-azar vector control, flea control, Nuisance fly control, Tsetse fly control and others when applied using IRS technique. Indoxacarb IRS is good for prolonged persistence and long lasting residual effect against vectors. More specifically Indoxacarb IRS demonstrated a prolonged knock down effect on mosquitoes and also on those vectors which show resistance to other insecticides.

While the WHO guidelines specify the dosage and duration of effective action for various insecticides when applied as IRS, they do not disclose the use of Indoxacarb for IRS. The guideline specifically mentions the use of DDT, Malathion, Fenitrothion, Bendiocarb, Propoxur, Bifenthrin, Cyfluthrin etc for IRS in different formulations. But the inventors do not know of any reported study of application of Indoxacarb for IRS. Examples

1. SC FORMULATION

Procedure for SC formulations:

Suspension concentrates are made by premixing the active ingredient powder in an aqueous solution of a wetting agent and a dispersing agent. This is followed by a wet grinding process in a bead mill, to give a particle size distribution of about 1 - 10 u with an average particle size of about 2 - 3 p..

2. WP / WDP FORMULATION

Procedure for WP/ WDP formulations

Wettable powder (WP) / Water dispersible powder (WDP) formulations are made by blending active ingredient with surfactant wetting and dispersing agents and inert fillers, followed by grinding to the required particle size.

3. MICROEMULSION

Procedure for Micro emulsions (ME) formulations

Micro emulsion formulations are prepared by blending the oily active ingredient and the surfactants together and pouring the blend into water with a gentle stirring motion until a transparent mixture is obtained.

4. EMULSIFIABLE CONCENTRATE

Procedure for EC formulations

Active ingredient is dissolved in suitable solvents, emulsifiers to form a clear oily stable liquid, which on dilution with water forms milky emulsion.

5. SOLUTIONS

Procedure for Soluble concentrates / liquids (SL) formulations
Active ingredient is dissolved in water / water miscible solvents, wetting /bio-enhancing agents and antifreezing agents to form a homogeneous liquid.

6. WATER DISPERSIBLE GRANULES (WDG) / SOLUBLE GRANULES (WG)

Procedure for WG formulations

Water dispersible / soluble granules (WG) formulations are made by blending active ingredient with surfactant wetting and dispersing agents and inert fillers, followed by grinding to the required particle size. The powdered formulation is wetted with water and extruded to a particle size of 0.8 to 1.2mm diameter and 5-10 mm in length. The wet granules are dried in a hot air chamber.

7. OIL IN WATER EMULSION (EW)

Procedure for Oil in Water emulsions (EW) formulations

Oil of active ingredient prepared by dissolving active ingredient in suitable solvent and surfactants is mixed with water under high shear stirring. Thickener is used to prevent the separation of oil droplets.

Claims

1. An insecticidal composition of Indoxacarb in the form of a suspension concentrate, emulsifiable concentrate, capsulated suspension, wettable powder, water dispersible granule or solution.

2. A composition of Indoxacarb for application as Indoor Residual Spray

a. The composition of claim 2 wherein Indoxacarb is formulated as a suspension concentrate.

b. The composition of claim 2 wherein Indoxacarb is formulated as an emulsifiable concentrate.

c. The composition of claim 2 wherein Indoxacarb is formulated as a capsulated suspension.

d. The composition of claim 2 wherein Indoxacarb is formulated as a wettable
powder.

e. The composition of claim 2 wherein Indoxacarb is formulated as water dispersible granules.

f. The composition of claim 2 wherein Indoxacarb is formulated as a solution.

g. The composition of claim 2 wherein Indoxacarb is formulated as oil in water emulsion (EW).

3. The composition of Indoxacarb as outdoor spray / fogging

4. A resistance management composition for fighting resistance against vectors resistant to existing Indoor residual spray insecticides.

5. A composition of indoxacarb for the application as a paint additive.