JPH07506376A - Microencapsulation - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Microencapsulation The present invention relates to the microencapsulation of biologically active materials within polymer particles; This is useful for delayed release of biologically active materials.

Handjanj et al., U.S. Pat. No. 5,139,783 Cosmetic active agents such as physical compounds gen t) and can be enclosed in an external gel phase. Discloses nin capsules. The composition of the present invention is characterized in that the biologically active material is a microorganism. 1randjani Ct in that it is introduced during, but not after, the formation of the cells. al, different from that of.

Outline of the invention The present invention has low equipment costs and power requirements (and effectively encapsulates insoluble biologically active materials). It is possible to obtain long-term stable microcapsule dispersions, and A method of encapsulating biologically active materials is provided, in which a dispersion system can be advantageously used.

One embodiment of the invention is essentially non-flowing but non-destructively agitated. non-mixable, curable with biologically active materials, forming thixotropic gels that can forming a substantially uniform carrier composition of a compatible organic liquid; - Droplets of the carrier composition into the gel without appreciable disruption to the gel. While stirring the gel to finely disperse the mixture, They are mixed in such a proportion that the gel becomes a continuous phase and the homogeneous carrier composition becomes a dispersed phase. , the droplets are cured, resulting in a stable dispersion of the biologically active material in the microcapsules. A method of microencapsulation of biologically active materials comprising obtaining a system.

Another embodiment of the invention provides a continuous phase of an essentially non-flowing aqueous thixotropic gel. , and fine microcapsules of a polymer stably dispersed therein. and the microcapsules contain a pest control agent (pestic 1de). include.

Detailed description of the invention In the case of the methods and products of the present invention, an aqueous gel is prepared by mixing water with sufficient water-soluble gelling agent. , to form a gel in the viscous, essentially non-flowing form desired in the present invention. Made from more. Insufficient amount of gelling agent can cause problems, e.g. due to the formation of colloids. merely increases the viscosity of the resulting solution, which can still flow easily (pourable). Unlike gels, such thickened solutions have suspended When a droplet or suspended solid is left for a period of time, e.g. a day or a month, Eventually it will settle.

To describe in more detail, the basic non-flowing state of the gel desired in the present invention is , has been determined regarding the flow characteristics of gel when placed in a cylindrical glass container with an inner diameter of approximately 5 cm. can be justified. After standing undisturbed for at least 1/2 hour, invert the container. If the basic non-flowing gel is allowed to run for at least 3 seconds, preferably at least 5 seconds It does not flow during the time. The gel contents of the container can be dynamic. directly from such disturbances. Even after the gel remains non-flowing, i.e. if the container containing the gel is inverted Preferably, it is essentially stiff for at least 5 seconds.

Although gels are essentially non-flowing, they can also be stirred without destroying the gel. That is, the gel can be stirred without being broken into pieces. Destruction is a book Impair the gel's ability to disperse curable organic liquids, as described later in the specification. .

The non-flowability and stirrability of the gel of the invention exist at room temperature, e.g. 15-25°C. is preferred.

Although the gel of the present invention is hard and non-flowing and has a somewhat low viscosity when stirred, It is thixotropic in that it becomes hard and non-flowing again when left undisturbed.

Examples of gelling agents include clay, cellulose derivatives, polyacrylic acid, polysaccharides, gelatin, Rubber, starch, arginine, polyvinyl alcohol, sodium stearate poly Includes ethylene glycol and ethylene maleic anhydride copolymers. preferred A strong gelling agent includes carboxymethyl cellulose and copolymer salts. Ethylene anhydride after treatment (hydrolysis) with an aqueous base solution such as NaOH Contains phosphoric acid copolymers. Without treatment with an aqueous base, e.g. Unless used in very large amounts, such as 25% by weight based on the weight of the water, the polymer will increases the viscosity but tends not to gel.

Basically to the weight of the gelling agent required for the formation of a fluid stirrable gel It will be within 1-15% based on When the reagent is carboxymethylcellulose salt , the preferred amount is 8-12% by weight, and when the copolymer salt is the reagent, the preferred amount is 1 to 5% by weight.

A preferred aqueous gel is a 10% by weight aqueous solution of a metal salt of carboxymethylcellulose; and gels derived from hydrolysis of crosslinked ethylene-maleic anhydride copolymers ( EMA”-91 and EMA”-61, Mon5anto Chemical C o, ).

A dispersion or solution of biologically active material in a curable organic liquid can be used as a powder or liquid active material. formed by mixing a curable material with a curable liquid.

If the material is soluble in the liquid, the carrier composition is a solution; if the material is insoluble in the liquid, the carrier composition is a solution. In this case, the carrier composition is a dispersion. In the latter case, a dispersant can be used. most Materials capable of forming microcapsules that ultimately encapsulate biologically active materials The proportions of materials and curable liquids can vary widely.

The choice of organic liquid depends on which embodiment of curing is used.

The organic liquid includes a dissolved polymer or polymer precursor. liquid curing (1) Precipitating the polymer from the solution, e.g. by removing the solvent, and releasing the active ingredient into the polymer. (2) polymer precursor as described below; Polymerize the body to form polymeric microcapsules containing biologically active materials in a gel Including any of the following:

The carrier composition is liquid due to the presence of a curable organic liquid and is mixed with the gel. Forming a fine dispersion of droplets of carrier composition within the gel. Biology with fine dispersion speed The result is microdroplets containing the chemically active material. The curable liquid is not a solution of biologically active material. In the case of dispersions, stirring does not force the active material out of the curable liquid. stomach. Gels are much more viscous than liquid carrier compositions, with the latter having a viscosity of about 1 to 1 at 25°C. Preferably it is in the range of 600 centipoise (cpS). used in the present invention The viscosity of the gel is at least about twice that of the liquid composition (i.e. at 25°C). (approximately 2 to 1200 cps), the viscosities described herein are Brookfield Measure using a viscometer.

Stirring for the formation of the gel composition is carried out at low rotational speeds, e.g. 60 rpm and generally 15 This is preferably carried out by operating a simple paddle-shaped stirring impeller at a speed not higher than 0 rpm. Delicious. Higher speeds can also be used, but do not provide any advantage, increase power consumption, or reduce foam. formation and, if present, of the dispersed biologically active material in the curable organic liquid. The disadvantage is the risk of separation from the drops. For small batches, droplet dispersion is usually sputtering. It can be obtained by manual mixing using a vacuum cleaner.

The proportion of homogeneous carrier composition and aqueous gel is sufficient for the gel to form a continuous phase. present and in proportion such that the carrier composition forms a dispersed phase.

Generally, this requires that the dispersed phase account for at least 50% of the total composition (continuous and dispersed phases). It is necessary that it is not more than % by weight. Distribution of homogeneous carrier compositions present as droplets The amount depends on the desired concentration of biologically active material. Based on the weight of the entire composition Generally at least 0.5% and preferably at least 1% of biologically active material is desired. Yes. The high viscosity of the gel (as low as 1000 centipoise) causes the droplets to separate and prevent coagulation. It does not aggregate and remains well dispersed in the gel. Hardening of organic liquids in drops by dispersion Drop microphone by, 1 0 capsules becomes easy.

The level of microcapsules obtained by the method of the invention and present in the products of the invention The average particle size is approximately 1-1000 microns in average diameter, with a range of 1-200 microns. Preferably. A preferred method of application is dilution of the gel/microcapsule composition and its For later sprays, smaller capsule sizes are desirable. Biologically active materials are Exists as a core within a microcapsule, i.e. surrounded by a polymer shell The active material is first present as a dispersion in a curable organic liquid. Happens if you do. If the active material is present as a solution in an organic liquid, the polymer Hardening of the liquid by precipitation results in a homogeneous distribution of the active material within the polymer matrix. Microcapsules are often given. For example, interfacial polymerization, solvent evaporation, etc. The method of curing the liquid can also affect the physical properties of the microcapsules. world Microcapsules formed by surface polymerization are typically polymers that encapsulate the active ingredient. It has a shell. On the other hand, microcapsules formed by solvent evaporation are There tends to be a homogeneous dispersion of active ingredients.

Can you explain more about curable liquids? In a preferred embodiment, Curing is performed by interfacial polymerization. In this embodiment, the organic liquid is at least two at least one water-insoluble polyfunctional group containing isocyanate or acid chloride groups of Polycondensation monomers, or mixtures of such polyfunctional compounds, as well as cases Contains water-insoluble organic solvents. The organic liquid/active material composition is then added to the water described above. microencapsulated active material mixed with a synthetic gel and suspended in a gel matrix Get a drop of material. A water-soluble compound that can perform interfacial polymerization with the monomer system in the droplet. A gender-complementary monomer or mixture of monomers is added to the gel by stirring. The distributed system Continuing to stir the gel after it is formed and during the interfacial polymerization reaction surprisingly No agglomeration of dispersed droplets occurs. A preferred water soluble complementary amine is diethylene chloride. It's Liamin. Examples of polyfunctional monomers include toluene diisonanate and seba. Coil chloride, hexamethylene diisocyanate and terephthaloyl chloride is included. A preferred polyisocyanate is PAPI” (Dow Chemical It is polymethylene polyphenylisocyanate available as al　Co,). Ru.

In another embodiment of interfacial polymerization, the liquid monomers present in the dispersed droplets of the gel are cured. , using at least one polyfunctional isocyanate followed by a complementary water-soluble monomer. The interfacial polymerization method is carried out without adding a mer system. In this case, some of the isocyanate groups are water It is hydrolyzed in a polyurethane gel to give an amino group, which self-condenses to form polyurea. to be accomplished.

In yet another embodiment, the organic liquid is a solution of a polymer in a water-insoluble solvent. , the active material is dissolved or dispersed therein. Dispersing liquid that disperses this organic liquid into a gel The body forms discrete droplets containing solvent, polymer and active material suspended in a gel. Take. The drops are hardened by evaporation of the solvent by heating the gel composition, forming a hard micro- Form a capsule. The preferred polymer for this method is polymethyl methacrylate. polylactic acid or lactic acid/glycolic acid copolymers. Preferred polymer The solvent is methylene chloride.

No. 3,523,906. this References to Gel Dispersion Compositions of the Invention, Methods for Their Preparation, or Dispersion as Described herein Does not disclose the advantages of the invention.

Other embodiments of hardening of organic liquids in dispersed drops by precipitation of dissolved polymers organic solvents for polymers can slowly dissolve in water, thereby This allows the solvent to slowly move into the gel matrix without being heated at the same time (activation Microcapsules containing the material are selected to be liberated. water-soluble solvents such as Examples include ethyl acetate, tetrahydrofuran and cyclohexanone. child These solvents are miscible in water and therefore in aqueous gels. droplets are immiscible with aqueous gels when present in solution with water-insoluble polymers properties, thereby allowing the active/organic liquid carrier composition to form dispersed droplets in an aqueous gel. It becomes possible to form Use fast dissolving solvents that are miscible with water in all proportions. (e.g. methanol, acetone, etc.) tends to cause droplet agglomeration during stirring. There is.

If the droplets are hardened into microcapsules, the stability of the droplet dispersion in the aqueous gel is Retained. The resulting product of the invention, i.e. biologically active material in an aqueous gel. A dispersion of microcapsules containing It is very stable as shown by the determined lack of sedimentation. Traditional aqueous dispersion If a thickener is not used, sedimentation will generally occur overnight immediately after production; Even when used, sedimentation often occurs when stored for a long period of time.

The biological, active materials added to the gel, whether monomers or polymers, are mutually exclusive. It must be extremely inert. The active material is sufficiently inert (non-reactive) towards water. the active material in the form of dispersed droplets or microcapsules formed therefrom. Preferably, there is no appreciable reaction between the active material and the surrounding gel even on the surface.

Within this non-reactive nature, a variety of biologically active materials can be used in the present invention to Therapeutic benefits can be conferred on subjects who come into contact with the psel. biologically active materials Examples of chemicals include herbicides, bactericides, fungicides, insecticides, nematicides, and acaricides (acari). cides), acaricides, virucides, aldicides ( a1gicidesL bactericides, plant growth regulators, and mixtures thereof. This includes any pesticides, as well as pharmaceuticals.

The gel composition product of the present invention provides pesticide protection in that it minimizes leakage from the outer packaging. This is particularly useful as a treatment method. The gel composition is available in cartridges and toothpaste-type chips. Can be packaged in tubes and bags and can be applied directly from these containers Ru. When applied neat, the gel composition has several advantages over conventional agricultural preparations. has advantages. These are located directly in the wood or leaves, or in cracks through which insects can enter. The thixotropic nature of the gel allows it to be applied directly to conventional agricultural sprays. is expected to remain in place for a long period of time. These gels can be injected directly into the crevices. Can be applied. These preparations may be mixed with water for dilution before application by spraying. It can also be mechanically injected or mixed.

The polymeric component controls the release of the active material present in the microcapsules. advance As in the case of controlled release technology microcapsules, to adjust the openness of the release can be adjusted over a wide range by optionally using adjuvants. .

Advantages cited in the literature regarding conventional controlled release systems, such as reduced mammalian toxicity, Reduced operator exposure and long-term activity are also true for the gel compositions of the present invention.

The present invention provides a low cost controlled release system comprising controlled release microcapsules suspended in a gel. A composition is provided. The preparation of these compositions is extremely simple and requires no traditional seed-type stirring. Use low-force mixing equipment such as stirrers and kneaders. Low shear mixing allows for active ingredient solution Dispersions of active ingredients can also be used without providing unencapsulated active ingredients. become capable.

Example 1 A low viscosity food grade carboxymethyl cellulose with a degree of substitution of 0.7. Non-flowable but stirrable aqueous gel of 10% by weight of lithium salt (CMCLF-7) Add 6g of PAPI"901 and 013g of powdered pensulfuron methyl to 50g. Add the herb mixture with manual agitation for approximately 30 seconds to ensure PAPI' and removal in the gel. A fine dispersion of drops of herbal medicine mixture was prepared. Followed by constant manual stirring (with a spatula). Add 0.2 g of diethylenetriamine (using cross-linked polyurea microcapsules. PAPI” and weeding in gel The mixture of agents was left overnight. Aged microcapsule-gel in excess water A sample of the mixture contained only about 20% biologically active material (hereinafter referred to as “active material”) in 40 hours. 75% released in 120 hours.Release rates are expressed as percentages at the indicated times. The activity was measured by high pressure liquid chromatography (HPLC).

50 g of the 10 wt% CMC aqueous gel defined in Example 1 was manually stirred for about 15 seconds. While stirring, add 6 g of polymethylene containing 1% dibutyltin dilaurate catalyst. Polyphenylisocyanate (PAPI”901, Dow Chemical Co, ) and 13 g of powder N-(((4゜6-cymethoxypyrimidin-2-yl )aminocarbonyl)-1-methyl-4-(2-methyl-2H-tetrazole- 5-yl)-1H-pyrazole-5-sulfonamide herbicide mixture and A fine dispersion of droplets of the mixture was formed in the tube. The mixture was left in the gel overnight, The drops thereby converted into a polyurea shell around 6 drops of PAP I'' mixture.

5% by weight of N-(((4,6-cymethoxypyrimidin-2-yl)aminocarboxylic acid) nyl)-1-methyl-4-(2-methyl-2H-tetrazol-5-yl)-1 Capsules containing H-pyrazole-5-sulfonamide are an unencapsulated powder compound standard. 41% of the activity was released in water in 24 hours compared to 100% for the case. release rate The degree was obtained in the same manner as in Example 1. Standard samples are PAPI' and dibutyltin dilaure. Prepared as described in Example 2 without the addition of salt.

Example 3 6 g of PAPl”901 to 40 g of 10 wt% CMC aqueous gel defined above. , ■, 0,0-diethyl O-(1,2,2,2 -tetrachloroethyl) phosphorothioate and left overnight in 0°C. The droplets polymerize by reaction with the water in the gel, resulting in a cross-section with an average particle size (diameter) of approximately 25 microns. The bridge became polyurea microcapsules. It becomes active when aged for 24 hours in a 45℃ oven. Sexual loss was 29%.

Standard dispersions of unencapsulated activity in the same gel under the same conditions as determined by HPLC. There was a loss of activity of 51%. Standard samples are dibutyltin dilaurate and PAP. Produced as described in Example 3 except that I' was omitted.

Example 4 5.0 g of EMA”91 polymer was mixed with 500 g of water and 2.3 g (50 wt. %) of sodium hydroxide to form a non-flowing but stirrable ethylene A maleic anhydride/maleic anhydride copolymer gel was prepared.

0.2 g of powdered N-(((4,6-cymethoxypyrimidin-2-yl)aminoca) (2-methyl-2H-tetrazol-5-yl)-1-methyl-4-(2-methyl-2H-tetrazol-5-yl) -18-pyrazole-5-sulfonamide herbicide and dibutyltin dilaurate Catalyzed 1, Og P to I) 1″901 mixture to 7, Og EMA’ gel was added with stirring to form droplets of the mixture finely dispersed in the gel. The above street 0.2 g of diethylene trichloride dispersed in 8.6 g of HMA' gel prepared by Other gel mixtures containing amines were prepared. Manually blend the two gel mixtures The mixture was left to stand for 20 minutes to form microcapsules by interfacial polymerization. My from gel To recover the black capsules, the gel was treated with 50 g of sodium chloride solution. -yl)-1H-pyrazole-5-sulfonamide was released.

To 75 g of 10 wt% CMC aqueous gel defined in Example 1 was added methylene chloride. 10% Elvac i te’2008 poly(methyl methacrylate) (D 15 g of solution of U Pon t Company) and 0.3 g of powder N-((( 4,6-Simethoxypyrimidin-2-yl)aminocarbonyl)-1-methyl- 4-(2-methyl-2H-tetrazol-5-yl)-1H-pyrazole-5- The sulfonamide herbicide was added for 15 seconds with medium mechanical agitation. methylene After a good dispersion of the chloride solution was obtained, the mixture was further heated at 30-35°C for 3. Stir for 0 hours and remove the solvent to obtain hard 5-60 micron microcapsules. . Next, water (500 g) was added with stirring, and the capsules were separated from the gel by centrifugation. It was separated and dried at 40-50°C. The microcapsules contain 16.6% activity by weight. I did. Microcapsules were incubated at 30°C for 20.5 hours in excess buffered water at pH 7. 15% of the activity as defined in Example 1 in the water discharge, as determined by HPLC. 60 g of gel containing 10 wt% CMC was added with 10% Elvac in ethyl acetate. iteR2008 poly(methyl methacrylate length) (((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl)-1-methane Thyl-4-(2-methyl-2H-tetrazol-5-yl)-1H-pyrazole The -5-sulfodiamide herbicide mixture was added with manual stirring. gel and activity A white opaque mass consisting of drops of Elvacite® solution containing the compound is homogenized in the gel. Stirring was continued for about 30 seconds until uniformly and finely dispersed. Gel composition for 3.5 hours Upon standing, most of the ethyl acetate migrates to the continuous aqueous gel phase, forming a hard 5-containing active compound. ~45 μm microcapsules remained. Stir the gel composition with 400 mL of water. diluted, filtered using a basket centrifuge, and dried. Capsule is 16.6 Contains % Shigesato activity.

International search report PCT/US 93104215

Claims (9)

[Claims] 1. Thixototro, which is basically non-flowing but can be stirred without destruction. of an immiscible organic liquid that forms a gel and is curable with a biologically active material. A homogeneous carrier composition is formed, and the carrier composition, which is homogeneous with the gel, is recognizable to the gel. to finely disperse the homogeneous carrier composition as droplets in the gel without causing any disruption. While stirring the gel, on average the gel becomes a continuous phase in the resulting combination. The droplets are combined in such a proportion that the uniform carrier composition becomes the dispersed phase. resulting in a stable dispersion of microencapsulated biologically active materials. A method of microencapsulation of biologically active materials, comprising: 2. the biologically active agent in the organic liquid that is curable to the substantially uniform carrier composition; 2. The method according to claim 1, wherein the method is a dispersion of a material. 3. The curable liquid includes a polymerizable monomer, and the curing polymerizes the monomer. The method of claim 1 comprising forming the biologically active material encapsulated. Law. 4. The curable liquid includes a polymer dissolved in an organic solvent, and the curing occurs from the droplets. The solvent is removed to precipitate the polymer and the microencapsulated biology 2. The method of claim 1, comprising forming a therapeutically active material. 5. The gel has a viscosity of 2 to 1200 centipoise (cps). The method according to claim 1. 6. The polymerizable monomer is polymethylene polyphenylisocyanate, and the monomer is 4. The method of claim 3, wherein the polymerization of the mer comprises the addition of diethylenetriamine. 7. The polymer is poly(methyl methacrylate) and the solvent is ethyl acetate. , the removal of the solvent comprises leaving the product to migrate the solvent into an aqueous gel. The method according to claim 4. 8. continuous phase of non-flowing aqueous gel with effective microencapsulation amount, and 3 at room temperature. diameter, as shown to be stably dispersed therein by not settling for months. contains polymeric microcapsules smaller than 1000 microns; A composition in which the capsule comprises a pesticidal agent. 9. The microcapsules containing the pesticidal agent are formed in situ in the aqueous gel. The composition according to claim 8, characterized in that: