MXPA00001768A - Dosage device - Google Patents

Abstract

A method of making a dosage device comprises mixing a suspension concentrate comprising at least one active ingredient which is in solid form at 25°C, and which has an average particle size of less than 10 microns, in a carrier liquid in which the active ingredient is non-soluble or sparingly soluble, and a drying agent for the carrier liquid. The drying agent takes up at least some of the carrier liquid of the suspension concentrate, thereby to dry the active ingredient at least partly and to obtain a mixture comprising the active ingredient and the drying agent. The mixture is compressed into at least one unitary dosage device.

Description

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DOSING DEVICE DESCRIPTION OF THE INVENTION This invention relates to a dosing device. This also relates to a method for forming a dosing device, and to a method for treating an article or site. EP 0 777 964 A discloses a method for making a dosing device comprising mixing at least one active ingredient which is a pesticide which is in the form of a solid at 25 ° C, is poorly soluble in water, and which has a size of average particle of less than 5 microns, with a disintegrating agent, to provide a compressible mixture in a unit dosing device capable of disintegration in water to form a suspension of such an active ingredient in water. Neither suspension preparation techniques nor drying agents are used. DE 25 12 247 A discloses making stabilized tablets containing sensitive moisture ingredients, but in which the particle size is relatively large. US 4 172 714 A describes the preparation of a herbicidal composition in which the particle size is also relatively large, the herbicide is applied in the form of relatively large granules so much that the herbicide is applied in concentrated form to relatively few loci. WO 93 13658 A describes pesticidal tablets with an internal desiccant. DE 41 09 921 Cl describes the preparation of a solid product, but without a compaction stage and particle sizes of the components are relatively large. According to a first aspect of the invention, there is provided a method of making a dosing device, which method comprises mixing a concentrated suspension comprising at least one active ingredient which is in the solid form at 25 ° C, and which has an average particle size of less than 10 microns, in a liquid carrier in which the active ingredient is insoluble or sparingly soluble, and a drying agent for the liquid carrier, such that the drying agent takes up less some of the liquid carrier of the concentrated suspension, thereby to dry the active ingredient at least partially and to obtain a mixture comprising the active ingredient and the drying agent; and compressing the mixture in at least one unit dosing device. The method can include forming the concentrated suspension by mixing the active ingredient and the liquid carrier. The method can include communicating the active ingredient in solid form and having an average particle size greater than 10 microns, to have an average particle size of less than 10 microns. The active ingredient can be pulverized sufficiently to have an average particle size of less than 5 microns, and even less than 3 microns, for example, less than 1 micron. The pulverization can be effected by wet milling, to obtain the particle size of the desired active ingredient. Meanwhile, at least in principle, any liquid carrier in which the active ingredient is insoluble or sparingly soluble, can be used, the liquid carrier is preferably water. The drying agent or desiccant may be in at least one partially anhydrous substance. The at least partially anhydrous substance may be an anhydrous salt which takes the aqueous carrier as water of hydration. The anhydrous salt can be selected from the group comprising anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium acetate, and anhydrous calcium chloride. A molar excess of the anhydrous salt on the aqueous carrier present in the concentrated suspension can be used. For example, the molar ratio of anhydrous salt to carry water can be from about 2: 1 to 2.5: 1. However, it is conceived that in some instances the proportion of the anhydrous salt used does not necessarily need to be a molar excess on the aqueous carrier present. For example, certain anhydrous salts can take more than an equimolar amount of water of hydration. The method may include adding an additional substance capable of reacting with some of the water present in the concentrated suspension to the concentrated suspension and / or mixture., as well as to dry the ingredient. The additional substance may be an oxide that is capable of reacting with water to form a hydroxide. The additional substance may be magnesium oxide and / or calcium oxide. The magnesium oxide and / or calcium oxide can thus replace some of the anhydrous substance that is used. For example, when used, it can typically replace in the order of 25% to 50% by mass of the anhydrous substance that is used. The method may include adding the dispersing agent for the active ingredient and / or an anti-foaming agent and / or anti-settling agent to the concentrated suspension before and / or after spraying thereof. Thus, the concentrated suspension may comprise the active ingredient, the release agent, the antifoaming agent, the anti-settling agent, and water as a carrier for the other components. More preferably, the concentrated suspension may comprise Component% (m / m) active ingredient approximately 40 to 50 dispersing agent approximately 7 anti-foaming agent <; 1 anti-sedimentation agent < 1 water balance The dispersing agent can be a surfactant such as that conventionally used in a wettable powder or concentrated suspension formulation, for example a lignosulfonate such as sodium lignosulfonate or that available from Borregaard under the trademark Borresperse CA; Naphthalenesulfonic acid / condensed formaldehyde; sodium alkylarylsulfonate; a nonylphenolyalkylene oxide, such as nonylphenoletylene oxide, condensate or nonylphenoletylene / propylene oxide such as SYNPERONIC NPE 1800 (trademark), available from ICI; ethylene alcohol / condensed propylene oxide; a laurylsodium sulfate which also acts as a wetting agent, such as that available under the trademark EMPICOL LZ from Lankro; a sodium diisopropylnaphthalene sulfonate which also acts as a wetting agent, such as that available under the trademark AEROSOL OS from Cyanamid; a sodium salt of formaldehyde condensate of naphthalenesulfonic acid, such as that available under the trademark TAMOL NNO or TAMOL DN from BASF; oxyethylated polyarylphenol phosphate, which is a dispersing agent in aqueous medium, and an example which is obtainable under the trademark SOPROPHOR FL from Rhone-Poulenc; or the similar ones. While the active ingredient can be any suitable active ingredient, such as a therapeutic agent, anthelmintic, pigment or dye, or the like, the Applicant believes that the method will find particular, but not necessarily exclusive, application in performing dosing devices wherein the active ingredient is a pesticide, for example an insecticide, herbicide, fungicide, acaricide, or the like. The active ingredient can thus be a pesticide that is poorly soluble in water, with water therefore being the liquid carrier for use in forming the concentrated suspension, as described hereinbefore. The pesticide may have an aqueous solubility of less than 1000 mg / L at 25 ° C, preferably less than 50 mg / L at 25 ° C. Preferably the pesticide should have a melting point exceeding 70 ° c. The pesticide may be a herbicide such as atrazine, simazine, cyanazine, terbutylazine, diuron, chlorsulfuron, metsulfuron, tralkoxidin, or 2- (2-chloro-4-mesylbenzoyl) cyclohexane-1,3-dione; an insecticide such as deltamethrin, lindane, carbaryl, endosulfan, or carbofuran; a fungicide such as methyl thiophanate, carbendazim, flutriafol, hexaconazole, chlorothalonil, copper oxychloride, captan or thiram; or an acaricide such as hexitiazox, cyhexatin, amitraz or acrinatrin. The method may include adding a disintegrating agent to the mixture prior to compression in the unit dosing device. The disintegrating agent may be capable of disintegration and effervescence or entrapment in contact with water. When it is capable of swelling in contact with water, it may be a cross-linked polyvinyl pyrrolidone which also acts as a binder. For example, the crosslinked polyvinylpyrrolidone may then be that available under the trademark POLYPLASDONE XL from GAF Corp., or that available under the trademark KOLLIDON CL from BASF. However, this may instead be any other suitable disintegrating agent capable of swelling in contact with water such as a modified cellulose gum, for example, that available under the trademark AC-DI-SOL from FMC Corporation; a sodium starch glycolate such as that available under the trademark EXPLOTAB from Protea Chemical Services; or a microcrystalline cellulose binder such as that available under the trademark Avicel PH101 from FMC Corp. When it is capable of effervescence in contact with water, it may be an acid and base combination such as tartaric acid and an alkali metal carbonate or bicarbonate, for example, sodium bicarbonate. The method may also include adding one or more of the following mixtures to the mixture or to the concentrated suspension before mixing the anhydrous salt with it: an additional surfactant, such as that described hereinbefore, to inhibit the recompaction of the active ingredient. an absorbent carrier such as a colloidal silica, for example AEROSOL 200 (trademark), diatomaceous earth, or a clay such as attapulgite; - a binder such as a microfine cellulose, for example, that obtainable under the trademark ELCEMA P100 from Degussa, and which also acts as a filler and disintegrating agent; or lactose monohydrate for example, that obtainable under the trademark LUDIPRESS from BASF, and which is also an adjunct in direct tablet formation; - a lubricant such as magnesium stearate; - a flow improver agent such as an absorbent silica, for example SIPERNAT 22S (trademark) of Degussa, which is a spray-dried ground silica, and acts as an anti-binder flow free agent; and - a water soluble filler such as a soluble starch, urea, or sodium chloride. The mixture can thus comprise the concentrated suspension, the additional surfactant, the anhydrous salt, and the disintegrating agent. More particularly, the mixture may comprise Component% m / m) concentrated suspension 25 to 40 filler / surfactant / dispersant approx. 8 anhydrous salt 30 to 40 binder / disintegrating agent 12 to 37 The mixture is, if necessary, converted into a compressible form. The mixture can be allowed to settle for a sufficient period of time until the salt hydration, ie the water absorption, has been completed, so that it also becomes compressible. The water absorption or hydration period will depend on the anhydrous salt used, but can typically range from about 12 hours to about 72 hours. If necessary, the mixture can be pulverized, for example ground, before being compressed. The method is, however, characterized in that drying the mixture at an elevated temperature before compressing it is not required.

The invention also extends to a metered device when made in accordance with the method of the first aspect of the invention. According to a second aspect of the invention, a dosing device is provided which is in a compressed unitary form and which comprises a mixture of an active ingredient which is in solid form at 25 ° C and which has an average particle size of less than 10 microns, and a substance that is capable of being anhydrous, and that is at least partially hydrated in the dosing device. The dosing device can be as described hereinabove. According to a third aspect of the invention, there is provided a method for treating an article or site, which comprises introducing a dosing device according to any of claims 13 to 19 inclusive, in a predetermined volume of water, with the volume of water being such that the concentration of the active ingredient in the water is greater than the limit solubility of the active ingredient in the water; allowing the dosing device to be disintegrated in that way to form a suspension of the active ingredient in the water; and apply the suspension to an article or site to be treated. The invention will now be described by way of the following non-limiting examples. EXAMPLE 1 A) Preparation of Concentrated Suspension A concentrated suspension containing 50% (m / m) deltamethrin was made by mixing, in a Dyno mill (registered trademark), the following components in the proportions of mass indicated. The Dyno mill is a ball mill comprising a static case inside that rotates to the rotor such that the rotor has a peripheral speed of 10-15 m / sec. The mill is filled above a level of approximately 85% by volume with 1 mm glass beads. 15 Component% (m / m) Deltamethrin tech 98.5% as active ingredient 50.76 Synperonic NPE 1800 (registered trademark), 20 available from ICI, as dispersing agent 6.60 Silcolapse 5000 A (registered trademark), an anti-foaming agent 25 available from Rhone -Poulenc 0.10 Kelzan D (registered trademark), an anti-sedimentation agent, available from Kelco Inc. 0.04 Water 42.50 'B) Preparation of Tblets according to the invention A tablet was formulated, using the procedure set forth below, to have the following composition: Component % (m / m) Deltamethrin 50% (m / m) concentrated suspension, obtained in (A) 40.00 Tamol DN (trademark), a surfactant available from BASF 8.00 Anhydrous magnesium sulfate 40.00 Kodillon CL (trademark) an available disintegrant of BASF 12.00 Tamol DN was dissolved in the concentrated suspension under agitation in a planetary mixer. Thereafter, the anhydrous magnesium sulfate was added as a single addition. The mixture was stirred to dryness in crumbled granules. The mixer was disconnected, covered and left overnight for the hydration reaction of the magnesium sulfate to proceed with the termination, that is, for the absorption of water to be carried out. The period of water absorption was thus about 12 hours. After this, the mixture was briefly stirred to discard the dry granules agglutinated in small pieces sufficient to be introduced in a mill. The total dry granules were milled in a hammer-type mill having a sieve of 1-2 mm. The Kollidon CL was added to the pulverized concentrate, and mixed therewith in the mill. The resulting homogenous mixture was introduced into a tabletting machine, and pressed into 2 g of boards at about 5 MPa pressure. The resulting tablets thus had the following composition: Component% (m / m) Active Deltamethrin 20.00 Impurities 0.30 Synperonic NPE 1800 2.64 Silcolapse 5000 A 0.04 Kelzan D 0.02 Magnesium sulphate anhydrous 40.00 Tamol DN 8.00 Kollidon CL 12.00 Water 17.00 Magnesium sulfate anhydrous can drink water, to form water of hydration thereof, in a molar ratio of above 7 moles of water per 1 mole of magnesium sulfate. Thus, the anhydrous magnesium sulfate used is in a theoretical excess, on a mass basis, of about 2: 1. This is to ensure that all the water present in the concentrated suspension is taken up by the anhydrous magnesium sulfate. The use of anhydrous magnesium sulfate thus dried the concentrate suspension sufficiently to compress the same into tablets to be viable without further drying thereof at elevated temperature being required. The tablets, when they are introduced into the water to the ratio of one tablet in 5 liters of water, disintegrated for 1 minute. Microscopic examination revealed that most of the particles in the suspension were in the 0.5-2 micron range. Examples 2, 3 and 4 below were prepared in identical form to Example 1, apart from the deferred constituents of those of Example 1, as given in the examples. Additionally, in Examples 2 and 3 the water absorption period was 72 hours. EXAMPLE 2 Component% (m / m) Concentrated suspension of Deltametrin 50% (m / m) 40.00 Tamol DN 8.00 Anhydrous sodium sulfate 40.00 Kollidon C L 12.00 One 25 g tablet was pressed at a pressure of approximately 5 MPa. This tablet was harder than the tablet of Example 1, ie, the tablet containing magnesium sulfate. When the ratio of one tablet in 5 liters of water was introduced into the water, the disintegration time was approximately 4 minutes. Microscopic examination revealed that most of the particles in the suspension were in the 0.5-2 micron range. EXAMPLE 3 Component% (m / m) Concentrated suspension of Deltametrin 50% (m / m) 40.00 Tamol DN 8.00 Acetate of sodium anhydrous 40.00 Kollidon C L 12.00 A tablet of 2.5 g was pressed at approximately a pressure of 5 MPa. The tablet was softer than the tablet of Example 2, i.e., the tablet containing sodium sulfate. When the ratio of one tablet in 5 liters of water was introduced into the water, the disintegration time was about 2 minutes. Microscopic examination revealed that most of the particles in the suspension were in the 0.5-2 micron range.

EXAMPLE 4 A 2.0 g tablet was also prepared using a proprietary acaricidal product. Component% (m / m) Concentrated suspension of Acrinatrin 40% (m / m) obtainable from Hoechst Schering AgrEvo Sa and containing 50% (m / m) of water 25.0 borresperse CA, a dispersible lingosulphate obtainable from borregaard 8.0 Magnesium Sulphate anhydrous 30.0 Kollidon CL 5.0 Avicel PH 101, a microcrystalline cellulose binder obtainable from FMC Corp 32.0 The resulting tablet has satisfactory properties when diluted or dispersed in water. The Applicant has found that with active pesticides requiring a very low application rate, typically for a few grams per hectare, very small particles of pesticide, typically having an average particle size of less than 5 microns, and even less than 1 miera. , dispersed in the prescribed liquid carrier, usually water, are highly desirable because they are effective, true, and even distribution of the pesticide in application. In addition, the smallest particle size, the largest surface area thereof, which promotes effective release of the pesticide after application to the -site or substrate. However, it is hitherto a problem when pesticides are provided in the form of tablets, that if the pesticide particles are smaller, unsatisfactory dispersion ratios of the tablet in the result of the liquid carrier. However, it has surprisingly been found that in the method and dosing device of the present invention in which the average pesticide particle size is less than 5 microns, and typically in the order of 1 to 3 microns, or even less than 1 micron. miera, rapid disintegration and dispersion relationships are achieved. In addition, the resulting tablets have adequate hardness that allows handling in the field, and the boards in the dispersion have excellent suspension properties. The dosing devices of the present invention thus provide a good vehicle for such pesticides, since they are compact and therefore are easily transported and stored, and are also in a form in which they are handled safely. In addition, there is no problem of having to dispose of long-term pesticide containers. They are also easy to disperse and apply effectively and truthfully as they are here before, that is, with small losses. In addition, the Applicant was also surprised to find that the average pesticide particle size resulting from the active ingredient, then the tablets have been dispersed in water, made of the desired order of less than 3 microns in waste from the fact that the active ingredient, then being ground to less than 5 microns, it was then compressed with the disintegrating agent in the tablet form during which agglomeration in large particle sizes could have been expected. However, as established, it is surprisingly found that the average particle size of the active ingredient, in the resulting suspensions, as it is distilled in the range of 0.5-3 microns. The Applicant believes that the method of the invention, which does not require drying of the formulation in a drying oven before being tabletted, has advantages over tablets formulated using such a drying step, particularly with respect to capital and operating costs. Thus, the need to provide a furnace is avoided. The operating costs associated with such a furnace, such as heating costs and labor costs for loading and not loading the furnace, are also avoided.

Claims (20)

1. CLAIMS 1. A method for making a dosing device, the method is characterized in that it comprises: mixing a suspension concentrate comprising at least one active ingredient which is in a solid form at 25 ° C, and which has a size of average particle of less than 10 microns, in a liquid carrier in which the active ingredient is non-soluble or sparingly soluble, and a drying agent for the liquid carrier, such that the drying agent takes at least some of the liquid carrier from the liquid carrier. suspension concentrate, whereby to dry the active ingredient at least partially and to obtain a mixture comprising the active ingredient and the drying agent; and compressing the mixture in at least one unit dosing device. The method according to claim 1, characterized in that it includes forming the suspension concentrate by mixing the active ingredient in a solid articulated form and having an average particle size greater than 10 microns, and the liquid carrier, and grinding the concentrate of wet suspension to spray the active ingredient since it has an average particle size of less than 10 microns. 3. The method in accordance with the claim 2, characterized in that the liquid carrier is water, and wherein the drying agent is in at least one partially anhydrous substance. 4. The method of compliance with the claim 3, characterized in that at least the partially anhydrous substance is an anhydrous salt which takes the aqueous carrier as water of hydration, and which is selected from the group comprising anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium acetate, and calcium chloride anhydrous. The method according to claim 3 or claim 4, characterized in that it includes adding to the suspension concentrate and / or to the mixture an additional substance capable of reacting with some of the water present in the suspension concentrate, thereby also for Dry the active ingredient. 6. The method of compliance with the claim 5, characterized in that the additional substance is an oxide which is capable of reacting with water to form a hydroxide. 7. The method of compliance with the claim 6, characterized in that the additional substance is magnesium oxide and / or calcium oxide. The method according to any of claims 3 to 7 inclusive, characterized in that it includes adding a dispersing agent for the active ingredient and / or an anti-foaming agent and / or an anti-settling agent to the suspension concentrate before and / or after spraying it. The method according to any of claims 3 to 8 inclusive, characterized in that the active ingredient is a pesticide having an aqueous solubility of less than 1000 mg / l at 25 ° C, and a melting point exceeding 70 ° C . The method according to any one of claims 3 to 9 inclusive, characterized in that it includes, if necessary, rendering the mixture compressible, and including adding a disintegrating agent to the mixture before being compressed in the unit dosing device. . The method according to claim 10, characterized in that the mixture comprises: Component% (m / m) suspension concentrate 25 to 40 filler / surfactant / dispersant approx. 8 anhydrous substance 30 to 40 disintegrating agent 12 to 37 12. The method according to claim 10 or claim 11, characterized in that it includes allowing the mixture to be placed for a sufficient period of time until the hydration of the salt has been completed , in that way also to become compressible, and, if necessary, to pulverize the previous mixture to compress it. 13. A dosing device when made according to the method according to any of claims 1 to 12 inclusive. 14. A dosing device that is in a compressed unitary form and that comprises a mixture of an active ingredient that is in a solid form at 25 ° C and that has an average particle size of less than 10 microns, and a substance that is capable of being in anhydrous form, and that is at least partially hydrated in the dosing device. 15. The dosing device according to claim 14, characterized in that the substance is an anhydrous salt and is selected from the group comprising anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium acetate, and anhydrous calcium chloride. 16. The dosing device according to claim 14 or claim 15, characterized in that it includes an oxide which is capable of reacting with water to form a hydroxide. 17. The dosing device according to claim 16, characterized in that the oxide is magnesium oxide and / or calcium oxide. 18. The dosing device according to any of claims 14 to 17 inclusive, characterized in that it includes a dispersing agent for the active ingredient and / or an anti-foaming agent and / or an anti-sedimentation agent and / or a disintegrating agent. The dosing device according to any of claims 14 to 18 inclusive, characterized in that the active ingredient is a pesticide having an aqueous solubility of less than 1000 mg / l at 25 ° C, and a melting point which exceeds 70 ° C. ° C. 20. A method for treating an article or site, characterized in that it comprises introducing a dosing device according to any of claims 13 to 19 inclusive, in a predetermined volume of water, with the volume of water being such that the concentration of the active ingredient in water it is greater than the limit solubility of the active ingredient in water; allowing the dosing device to disintegrate, thereby to form a suspension of the active ingredient in the water; and apply the suspension to an article or site to be treated.