Process for making avermectin/zein compositions

• US 5,436,355 A
• Filed: 02/03/1994
• Issued: 07/25/1995
• Est. Priority Date: 02/03/1994
• Status: Expired due to Term

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Demchak, Richard J.
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): OWENS, AMELIA A
• Application Number:
  US08/191,824
• Time in Patent Office: 537 Days
• Field of Search: 549/267, 514/450
• US Class Current: 549/264
• CPC Class Codes: A01N 2300/00 Combinations or mixtures of active ingredients covered by classes A01N27/00 - A01N65/48 with other active or formulation relevant ingredients, e.g. specific carrier materials or surfactants, covered by classes A01N25/00 - A01N65/48
• CPC Class Codes: A01N 25/04 Dispersions, emulsions, suspoemulsions, suspension concentrates or gels foams A01N25/16
• CPC Class Codes: A01N 25/28 Microcapsules or nanocapsules
• CPC Class Codes: A01N 49/00 Biocides, pest repellants or attractants, or plant growth regulators, containing compounds containing the group , wherein m+n>=1, both X together may also mean —Y— or a direct carbon-to-carbon bond, and the carbon atoms marked with an asterisk are not part of any ring system other than that which may be formed by the atoms X, the carbon atoms in square brackets being part of any acyclic or cyclic structure, or the group , wherein A means a carbon atom or Y, n>=0, and not more than one of these carbon atoms being a member of the same ring system, e.g. juvenile insect hormones or mimics thereof containing hydrocarbons A01N27/00
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/10 Anthelmintics

Abstract

Their is disclosed a novel solvent-depletion process for making an avermectin/zein composition and the composition itself, which has excellent photostability and unexpected bioavailability to foliar-feeding insects. The process consists of depleting a dilute acidic, basic or alcoholic solvent from an emulsified solution of avermectin, zein, and dilute solvent.

Claims

1. A solvent-depleted avermectin/zein composition useful for treating plants or animals infected with parasites which comprises avermectin or a pharmaceutically acceptable salt thereof and zein in suspension with a ratio from about 1 to 1 to about 100 to 1 of zein to avermectin and an inert ingredient.

2. The composition of claim 1, wherein the avermectin compound has the structural formula:

##STR5## where the broken line indicates a single or a double bond at the 22,23-positions;

R₁ is hydrogen or hydroxy, and is hydroxy only when the broken line indicates a single bond;

R₂ is alkyl of from 1 to 6 carbon atoms or alkenyl of from 3 to 6 carbon atoms or cycloalkyl of from 3 to 6 carbon atoms;

R₃ is hydroxy, methoxy, or=NOR₅ ;

R₅ is hydrogen or C₁ -C₃ alkyl; and

R₄ is hydrogen, hydroxy, (C₁ -C₃ alkoxy)(--C₀ -C₃ alkoxy)methoxy, ##STR6## where R₆ and R₇ is=O, hydroxy, or R₈ R₉ -amino, and R8 and R9 are independently hydrogen, C₁ -C₃ alkyl, C₂ -C₃ alkanoyl, substituted benzenesulfonyl wherein the substituent is halogen or C1-C₃ sulfonyl.

3. The composition of claim 2 wherein R4 is:

##STR7## R₆ is as above, the avermectin and zein is suspended in mineral oil and the zein to avermectin ratio is from about 3 to 1 to about 25 to 1.

4. A solvent-depletion process for making avermectin/zein compositions which comprises contacting avermectin or a pharmaceutically acceptable salt thereof and zein with a dilute acidic, basic, or alcoholic solvent, emulsifying the avermectin/zein/solvent solution in a mineral oil with an emulsifier to form a dispersed phase consisting of the avermectin/zein and solvent and a continuous phase consisting of the mineral oil and emulsifier, saturating the continuous phase with the solvent before or during emulsification, pumping and recycling the resulting emulsion through a semi-permeable membrane which retains the dispersed phase and releases the solvent-saturated continous phase as permeate and adding additional continuous phase which is not saturated with solvent, resulting in depletion of the solvent from the dispersed phase, thereby making the avermectin/zein composition suspended in the mineral oil solution.

5. The process of claim 4, wherein the avermectin compound has the structural formula:

##STR8## where the broken line indicates a single or a double bond at the 22,23-positions;

R₁ is hydrogen or hydroxy, and is hydroxy only when the broken line indicates a single bond;

R₂ is alkyl of from 1 to 6 carbon atoms or alkenyl of from 3 to 6 carbon atoms or cycloalkyl of from 3 to 6 carbon atoms;

R₃ is hydroxy, methoxy, or=NOR₅ ;

R₅ is hydrogen or C₁ -C₃ alkyl; and

R₄ is hydrogen, hydroxy, (C₁ -C₃ alkoxy)(--C₀ -C₃ alkoxy)methoxy, ##STR9## where R₆ and R₇ is=O, hydroxy, or R₈ R₉ -amino, and R8 and R9 are independently hydrogen, C₁ -C₃ alkyl, C₂ -C₃ alkanoyl, substituted benzenesulfonyl wherein the substituent is halogen or C₁ -C₃ sulfonyl.

6. The process of claim 4 wherein R4 is:

##STR10## and R₆ is as above.

7. The process of claim 4 wherein the dilute acidic, basic or alcoholic solvent belongs to the group consisting of acetic acid, propionic acid, lactic acid, ethylene glycol, propylene glycol, diethylene glycol, methyl alcohol, formamide, monoethanolamine, and water, the semi-permeable membrane has a pore size of about 0.1 to about 0.8 microns and the mineral oil has a specific gravity of about 0.83 to about 0.88 at 25°

C.

8. The process of claim 7 wherein the dilute acidic, basic or alcoholic solvent is acetic acid and the semi-permeable membrane has a pore size of about 0.1 to about 0.3 microns.

9. The process of claim 4 wherein dodecylamine can be optionally added to the permeate to form insoluble dodecylamine acetate, which allows the mineral oil to be recycled.

10. The process of claim 4 wherein the emulsifier is food-grade lecithin or fractionated lecithin.

11. The process of claim 4 wherein the emulsifier is fractionated lecithin.

12. A solvent-depletion process for making avermectin/zein compositions which comprises contacting avermectin and zein with acetic acid, emulsifying the avermectin/zein/acetic acid solution in a mineral oil with a specific gravity of about 0.83 to about 0.88 at 25°

C. and fractionated lecithin to form a dispersed phase consisting of the avermectin/zein and acetic acid and a continuous phase consisting of the mineral oil and fractionated lecithin, saturating the continuous phase with acetic acid before or during emulsification, pumping and recycling the resulting emulsion through a semi-permeable membrane which retains the dispersed phase and releases the solvent-saturated continous phase as permeate and which has a pore size of about 0.1 to about 0.8 microns, and adding additional continuous phase which is not saturated with acetic acid, resulting in depletion of the acetic acid from the dispersed phase, thereby making the avermectin/zein composition suspended in a mineral oil solution.

13. The process of claim 12, wherein the avermectin compound has the structural formula:

##STR11## where the broken line indicates a single or a double bond at the 22,23-positions;

R₁ is hydrogen or hydroxy, and is hydroxy only when the broken line indicates a single bond;

R₂ is alkyl of from 1 to 6 carbon atoms or alkenyl of from 3 to 6 carbon atoms or cycloalkyl of from 3 to 6 carbon atoms;

R₃ is hydroxy, methoxy, or=NOR₅ ;

R₅ is hydrogen or C₁ -C₃ alkyl; and

R₄ is hydrogen, hydroxy, (C₁ -C₃ alkoxy)(--C₀ -C₃ alkoxy)methoxy, ##STR12## where R₆ and R₇ is=O, hydroxy, or R₈ R₉ -amino, and R8 and R9 are independently hydrogen, C₁ -C₃ alkyl, C₂ -C₃ alkanoyl, substituted benzenesulfonyl wherein the substituent is halogen or C₁ -C₃ sulfonyl.