LU86868A1 - SYSTEM FOR REFRENED DOSING OF A BIOLOGICALLY ACTIVE SUBSTANCE - Google Patents

Description

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Patent Application cPInveniioiî I. Request 1 '_ .. _ .._ ._ .. RIJKSONIVERSITEIT ...... GEN T (RUG), -Si.-Pietersnieuwstraat, ....... 25 ... ...-...... B-9000 ....... GENTf Belgium, represented by Monsieur Jacques de Muyser, acting deposition! Nti ce .... sept _mai ..... 1.9 0 0 .. ...eighty seven..............................__ -" " , .......- ·> ** · at ------------- î? ........ hours, at the Ministers of Economy and the Middle Classes, at I uxembours: 1. i present request for obtaining a patent for an invention concerning · "System for the controlled dosage of a biologically active substance." ’Z. sa ûrstnrcor. er. anpe irança ise ........................ of the rinse in three evcmr'uires; . · - - plates or drawing in triplicate: t üifîtance these Utes verseesaiBureau de '"Registration at LuxemV-urc on May 1987 5. ia delegation of re. Vouvoir. Dated, ...... ..... .... .................... ie

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declare »nt · er assuming responsibility for this declaration. that Des? r.er‘caris, is -som:. f · 1 «.. Etienne SCHACHE, .. Rysseyeldstraat, 98 -E-814C ETE DEN, Belgium 2. Walter STEUEBAUT, ..... Ginstberaf 2 -B-9258 0CSTEP2ELE, Belgium ......... .- .......................-........................ . ................................................- xMKgâssacaa ^ g:> ............................................. ....................................._ tSêtSK ........... ........................ ........ ................. ' .................................................. ....................... .................._........ .....

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elected home for) ui feile i and. if appointed, for its representative, in Luxembourg __ „. . . _______ 25, boulevard Royal ............ ........ s 12, requests its issue c a patent for invention for: the object described and represented in the appendices1 mentioned above .

aves ^ pumemen: from this delivery to ..................... 18 months, f 13 "

This depositor, riardctairs: ^ f ........ Π4; -— · —-C ~ '- ‘w *’ · Π. Trial »erba! no above patent application g, pvention has been filed with the Ministry of Etc n <mie e * des Casses Moyennes. Service èeia Pror-ri? '? latebecTsslie in Luxembourg, er. date: 7 - £ i 1987 _ ‘“ i,; . -f '’' -> y - -.? y 5 '·· Er ie Mts :: - ο,: Ξ .. v. ·: L e: oes C, = - es Morcrmes.

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The head of the department ôe l / rr; : -r.eîé rue ’rcruelie.

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> ’! . , i i Brief Description filed in support of a request for

PATENT

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Luxembourg formed by: rijksuniversiteit gent (rug)] 9000 GENT (Belgium) for: "system for the controlled dosing of a biologically active substance." "SYSTEM FOR THE REFRENED DOSING OF A _BIOLOGICALLY ACTIVE_ SUBSTANCE

The present invention relates to a process for carrying out the restrained and continuous dosage of a biological active material or composition in a medium, by means of said active material or composition in a closed envelope which is at least partly formed by a membrane. based on a permeable polymer.

It is intended to distribute the regular and continuous release of chemical materials, including pesticides 10 over several weeks.

In various agricultural applications it is necessary to have available pesticide formulations capable of achieving for a sufficiently long period a release adjusted to the needs.

US Pat. No. 3,577,515 describes a process for the preparation of microcapsules prepared by an interfacial condensation of polymers into a membrane around droplets of liquid in which the active biological products are dissolved.

Thanks to the small size of approximately 250 microns of the microcapsules, the surface between the pesticide contained and the membrane is very large so that the rate of release of the pesticide is maintained only for a short period, i.e. a period of less than a few days.

The dispersion of the product is not “homogeneous but is rather limited at the point of contact of the spray.

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2

A U.S. pesticide formulation is known from U.S. Patent 3,318,769 in which said pesticide is absorbed into an organic, hydrophobic and thermoplastic resin.

5 For domestic use, for example for the care of decorative plants, this type of formulation has advantages in terms of safety and ease of use. However, it is not suitable for agricultural and horticultural operations because too large quantities of resin are necessary during the preparation.

Another system which allows controlled release of pesticides consists of granules in which an active ingredient is contained or suspended.

In most granules, the release rate is only maintained for a short time.

20

A recent development is the so-called "Nutrient Film Technic" - film nutrition technique - in which the plants are cultivated in a medium with slow circulation of water. In this culture method, the formation of mold or algae or attack by insects can be a serious problem. This problem can be overcome by administering pesticides to circulating water. These pesticides are often mixed in the circulation system.

Such manipulation causes local concentrations of active product greater than the desired dose or the desired concentration. This can lead to plant growth problems. In addition, it is very difficult, if not impossible, to dispose of pesticides once they have been added.

On the other hand, when adding a conventional formulation, the content of active product decreases too rapidly to inactive concentrations because of decomposition and absorption at the wall. If the last treatment is carried out just before harvest, it may result in too much residual pesticide content in the harvested fruit. The present invention aims to remedy these drawbacks by mixing the pesticide in a dosage form from which the active product is released for the desired period in controllable and acceptable amounts.

The present invention relates to a method for slowly and constantly releasing a biological active material or composition in a medium by placing said active material or composition in a closed envelope which is at least partially formed by a membrane based on a permeable polymer.

It is mainly characterized by the fact that the active material or composition is enclosed in a container which is at least partly made of a permeable synthetic material, which is placed in an aqueous medium or in contact with air.

In a particular embodiment, the container is suspended in a slow water circulation system.

H

* 4

According to a feature of the invention, the speed as well as the period of release can be varied by adapting the permeability and the surface of the membrane of permeable synthetic material.

5 Other possibilities for fixing the speed and the duration of the release consist in judiciously choosing the quantity and the nature of the composition of the active material as well as the dimensions and the geometric shape of the container.

The present invention also relates to a system for the slow release of a biologically active material or composition, said composition being contained in a closed envelope which is at least partly closed by a membrane based on a semi-permeable polymer , which slows the release of the active material or composition, essentially characterized in that the envelope consists of a container which is directly suspended with the material or composition contained therein in an aqueous medium or in contact with air .

The active ingredient, for example the pesticide, can be added to the container as a pure product or mixed with filler materials, surfactants and other additives. In a particular embodiment, the membrane is in the form of a thermosplastic monomolecular film based on a polymer insoluble in water, a copolymer or a mixture of polymers and / or copolymers and to which various adjuvants can be added.

# 5

These adjuvants can be inert materials which influence the transformation of the polymeric materials, their stability or the permeability of the polymeric material for various chemicals.

5

A microporous polymer film can also be used as the membrane. The polymer, copolymer or mixture of polymers used is preferably chosen from the group comprising vinyl polymers, poly-urethanes, cellulose and cellulose derivatives. The membrane can also contain various additives such as plasticizers, stabilizers, lubricants.

The vinyl polymers are for example poly-ethylene, polypropylene, polyvinyl acetate, polyacrylates and polymethacrylates.

The cellulose derivatives are, for example, cellophane, cellulose acetate.

Other features of the invention will emerge from the following description in which reference is made to the accompanying drawings which schematically and without limitation show a possible embodiment of a slow release system according to the invention.

In these drawings: - Figure 1 schematically shows a system in the form of a bag consisting of an outer part based on polymer and optional additives and an inner part based on a biologically active material under the form of a product of technical purity or of a formulation 6 with or without the addition of additives; FIG. 2 schematically and comparatively represents the evolution of the concentration of active material as a function of time in a system according to the invention and in a system with repeated dosing; - Figure 3 shows a cylinder whose upper and lower surfaces consist of a membrane 10 and the side wall is made of an impermeable material; FIG. 4 represents a bundle of hollow tubes, each hollow tube being closed at its ends and containing an active material.

In these figures, the same reference notations designate identical elements.

The active material 2 contained in a container 1 is released by diffusion in a membrane of permeable synthetic material consisting of a polymer film. This diffusion process takes place in the micropores of the membrane 3 and / or in the polymeric material in which the membrane 3 is made.

The active ingredient 2 contained in the container compartment diffuses into the membrane and dissolves on the outer surface of the membrane in a medium in which a reservoir system is placed.

The force allowing this release is due to the difference in concentration of the active material 2 on either side of the wall of the membrane 3.

If the active ingredient 2 is introduced inside the container 1 in the form of a powder, suspension or emulsion, the concentration gradient will remain constant on either side of the membrane limiting the release until the reserve active ingredient is exhausted in container 1, that is to say at the moment when the concentration (inside the container) is smaller than the saturation concentration.

The speed and duration of the release are limited by the thickness and the surface of the synthetic membrane 3 through which the active product is released, the chemical composition of the membrane 3, i.e. the structure of the polymer or polymers and the nature of the additives which may be present. Other parameters for the release are the parasite of the membrane, the nature of the active product 2, the presence of additives of the active product 2 and also contained in the container 1, as well as the medium 4 in which the container is exposed. .

As shown in Figure 1, the container 1 which contains the active material 2 in powder form consists of a plastic bag made from a permeable synthetic membrane. The bag is suspended in a water circulation system 10, towards said film nutrition technique (Nutrient Film Technic).

The release of the active product has been studied in a static, dynamic system and under practical conditions.

8 EXAMPLE 1

The release of metalaxyl in water has been tested in a static system for different polymers.

5

1 g of Ridomil Special (10% metalaxyl in 48% mancoreb) was placed in a container having a surface area of 2 25 cm and this container was placed in a sealed container containing 800 ml of water. The amount of metalaxyl released into the water was determined at regular intervals using H P L C. After each measurement the water was removed and replaced. The release rates are given in Table I.

15 TABLE I: quantity of metalaxyl released into water as a function of time (in% of the initial quantity in the tank) *

Movie material 20

Duration PP.l PP.2 PP.3 PP.4 PP.5 PP.6 PP.7 E / VA

(hours) 4 4 4.4 4.4 4.6 4.4 3.6 3.6 3.6 25 24 8.8 8.8 21.4 14.6 14.0 15.3 18.0 7.8 48 41.6 17.2 38.4 39.2 23.4 44.6 29.2 16.6 75 72.2 23.6 44.3 52.7 28.4 52.6 34.0 19.8 * PP.l to PP.7: films commercial of 30 microporous polypropylene of the type = celguard 2400 (PP.l), 2402 (PP.2), 2500 (PP.3), 2502 (PP.4) and 3501 (PP.5), 4410 (PP.6) and 4510 (PP.7).

9

E-VA type polymeric materials are copolymers of ethylene and vinyl acetate. They are in contrast to non-micro porous Celguard films.

5 E-VA films (or sheets) can be obtained commercially with different contents of vinyl acetate and with different thicknesses. The percentage of vinyl acetate in the copolymer as indicated in the examples is expressed in% by weight. E-VA polymer films can be obtained, among others, from U.C.B. Sidac, Ottergemsesteenweg Gent.

The content of vinyl acetate in E-VA films modifies the permeability of these films for biologically active products. From Table 2, Example 2, it is clear that the permeability of the E-VA film for metalaxyl increases for increasing contents of vinyl acetate in this film.

The purpose of this test was to check whether diffusion was possible and whether the containers were sufficiently resistant and if they did not show any cracks when they were brought into contact with water.

25 EXAMPLE 2

In a dynamic system, the concentration of pesticide that was released in a given quantity of water was measured as a function of time. The container system containing pesticides was suspended in a filter bottle containing 100 ml of water. Water was added dropwise at a constant rate (20 to 30 ml / hour) using a peristaltic pump. The water in the filter flask was continuously agitated using a low speed magnetic stirrer. The excess water was collected by a side tube in an Erlenmeyer flask and the concentration of active product in this collected water was measured daily.

The release of the metalaxyl composition (see example 1) is given in table 2.

TABLE 2: quantity of metalaxyl as a function of time (in 10% of the total initial quantity present in the container)

Time PP.l PP.4 PP.6 E / VA E / VA E / VA E / VA

(days) 15 1 62.3 12.1 30.0 0.8 0.1 2.2 1.4 2 89.3 41.7 56.3 1.1 0.1 2.5 3.2 4 97.9 80.-8 81.1 1.9 0.3 3.0 5.7 8 99.0 83.4 83.3 4.7 0.7 4.6 14.9 12 99.3 84.0 82.5 5.5 1.0 6.5 24.5 20

The release of an etridiazol (Aaterra) composition is given in the following table.

TABLE 3: quantity of etridiazol released as a function of time (as a% of the total initial quantity in the container) 11

PP.l time PP. 4 PP. 6 E / VA

(days) 1 6.9 5.3 2.7 1.5 2 13.1 8.3 4.6 3.8 5 4 24.9 15.2 9.6 9.9 8 38.2 28.3 17.9 18.8 12 45.7 38.6 22.9 23.7 15 50.2 40.2 26.3 27.7 10 It appears from these results that for metalaxyl there is very widespread rapid fungicide through the pores of the Celguard film membranes. Inward water diffusion also took place, so that the container swelled after some time with water. The release for E / VA films is much slower because the diffusion takes place in the polymer matrix and not by pores. The release curves are almost linear so that the release rate is roughly constant for a long time. It also becomes larger when the vinyl acetate content of the synthetic membrane is increased. The thickness of the membrane must also be taken into account.

Unlike metalaxyl, the release of etridiazol (Table 3) is much slower. This may be due to the poor solubility of etridiazol in water.

The easy diffusion to etridiazol in the E / VA membrane is also surprising. This can be attributed to the good compromise of the solubility parameters of the E / VA and etridiazol polymer chains.

12

Diffusion in Celguard films is very low. Etidiazol must in fact diffuse in the pores filled with water.

5 EXAMPLE 3

The mode of release and working in practice has been studied in a hydroculture system of tomato plants. The container systems were tested in an NFT 10 culture (film nutrition technique) on healthy fruit bearing tomato plants. There were 12 plants in each conduit 11 (6 m long) and the tank capacity was 50 liters of nutrient solution.

15

The following manipulations were carried out in three channels or conduits: channel 1: 30 g of Ridomil containing 10% of metalaxyl were distributed in three container systems in E / VA polymer having a total surface for release 2 (exchange) 150 cm; channel 2: 60 g of Rodomil (10% of

25 metalaxyl) in six E / VA polymer container systems

2 with a total release surface of 300 cm; channel 3: Ridomil was added in a known manner in a single operation to the tank solution so as to obtain there a calculated concentration of metalaxyl of 10 ppm.

The results are given in * Table 4.

13 TABLE 4: metalaxyl content (ppm) in the nutrition water as a function of time.

Time Channel 1 Channel 2 Channel 3 5 (days) 1 0.1 0.1 6.3 2 0.2 0.2 6.2 4 0.2 0.3 5.1 7 0.3 0.4 3, 3 10 11 0.6 1.1 3.1 16 0.5 0.7 2.5 21 0.4 0.5 2.0

The residual contents in the plants are given in Table 5.

TABLEAU5: metalaxyl content (in ppm) in the plant after 1 week.

2Q Channel 1 Channel 2 Channel 3 leaves n / a n / a 0.3 roots n / a 0.3 4.7 tomatoes 0.2 0.2 0.3 25 n / a = not detectable.

During a usual treatment, the content of metalaxyl in the nutritive solution decreases quickly but it allows to obtain important residues in the plant. In the second case of container systems, the concentration gradually increases to a maximum content after 11 to 16 days. This leads to a significant decrease in the initial starting concentration and to a content compared to the direct treatment, but significant in the plant. At the end of the test period, the concentrations in the channels of the reservoir systems 5 were still very high while the concentration during direct treatment was rapidly decreasing.

EXAMPLE 4 10

The mode of release and working in practice was followed (studied) on a hydroculture of strawberries.

The NFT system consisted of twelve channels (length 1.8 m and width 0.2 m) each provided with a tank of a 10-liter capa-15. The nutrient solution was recycled at a rate of 0.4 liters per minute.

Three kinds of strawberries were used, namely: 20 - Fragaria vesca (Alpina variety), used as a control plant due to its sensitivity to Pytophtora fragariae; - healthy "Primella" plants, and - "Primella" plants from multiplication tanks infected with Pytophthora fragariae.

The plants were sorted before use according to their weight so as to obtain, for all the comparisons, an identical distribution of the plants according to their weight. In each channel, a Fragarie vesca plant, ten infected Primella were placed and at the entrance as well as at the exit a healthy plan.

A conventional metalaxyl treatment was compared to a container treatment.

5

Channel 1 s not treated

Channel 2: an aqueous solution containing 0.4 ppm of Pridomil (25% by weight) was regularly applied (Disc Disc curve of FIG. 2) • ^ g Channel 3: 400 mg of Ridomil (25 % by weight) in an E / VA container system with a total release surface of 25 cm (curve SR 1)

Channel 4: 1600 mg of Ridomil (25% by weight) were distributed ^ 5 in four E / VA container systems having a total release surface of 100 cm

Channel 5: 6400 mg of Ridomil (25% by weight) were distributed in sixteen E / VA container systems having a total release surface of 400 cm 20 (curve SR 16).

Direct application (channel 2) was repeated after 11, 28 and 51 days. The metalaxyl content in the nutrient solution was measured regularly. The results are plotted in the graph of Figure 2.

In slow release formulation systems a substantially constant level has been reached after a transitional phase. For the release areas of 25, 2 100 100 and 400 cm the plateau (or constant level) was respectively 0.1 + 0.05, 0.35 + 0.05 and 1.0 + 0.1 ppm. It can therefore be seen that an increase in the total release surface 16 gives rise to an increase in release. Fractional direct application gives rise to higher concentrations after each application and rapidly decreasing to 5 inactive residual levels. The plateau reached in the 2nd channel 3 (25 cm of release surface) did not allow sufficient fungicidal concentrations to be obtained.

The container systems were removed after 84 days and the amount of metalaxyl remaining was determined there. On average, there were still 45 mg of metalaxyl.

The results of the root attack are given in Table 6. The root formation index is a parameter which assigns a value to the root formation varying from 0 for no new formation of f roots to 9 for the formation total (100%) of new roots greater than 5 cm in length.

20 TABLE 6: strawberry root formation index

Treatment after after after 6 weeks 12 weeks 20 weeks

Channel 1 1.0 1.3 7.6 25 Channel 2 1.6 1.8 8.9

Channel 3 1.8 2.5 8.9

Channel 4 1.4 1.5 8.8

Channel 5 1.6 1.1 9.0 30 If weeks after planting only the old roots of the control plants (channel 1) showed signs of root rot.

17

For all other treatments there was only one attack by Phytophthora fragariae. After 12 weeks, the control plants (channel 1) showed serious signs of root rot. The plants in the other 5 channels are healthy.

After 20 weeks, the attack was quantitatively measured. The degree of attack is given in table 7 (scale varying from 0 for the complete destruction of the 10 roots to 9 for healthy roots).

TABLE 7: degree of attack, increase in weight and total production of strawberries after 20 weeks 15

Subject Degree Increase Production in attack of the weight% compared to the control strawberries 20 (or witnesses)

Channel 1 1.5 a * 42 a 100

Channel 2 3.8 b 212 b 157

Channel 3 4.2 b 188 b 157

Channel 4 3.7 b 211 b 184 25 Channel 5 3.4 b 176 b 144 * Duncan's test î the same letter does not give rise to significant differences (p = 0.05).

30 It appears that the results of the strawberry plants treated are much better than those of the control strawberries, although they are not significantly different.

* 18 The increase in weight of the plants was also not significantly different.

Maximum yields were obtained for channel 5 and for direct fractional application (channel 2).

It thus appears from this test that the treatment with a container system with slow release of active product 20 makes it possible to obtain a fight against the disease and a production as good as those during the treatment by direct but fractional addition of the active product. The slow release formulation has the great advantage that a single treatment is sufficient to maintain the concentration at a constant level for 12 weeks.

The release systems described above can also be applied for the release of other pesticides, for example algicides, limacids, microbi-20 cides, molluscids, insecticides, but also for pheromones, antiseptics, disinfectants, minerals and nutrients. This concept is also suitable for designing systems for releasing materials which are sufficiently soluble in water as well as for those which are poorly soluble in water. The release may take place by contact of the container with an aqueous medium or, in the case of phenomena, by contact with air.

The release is constant and continuous for a long time. The reservoir can, if desired, be removed from the medium so as to stop the supply of active product.

t 19

The amount of active product and optional additives which is contained in the container according to the invention can be modified according to the aim pursued or the requirements required.

5

Many changes can be made in the shape of the container and the composition of the active ingredient.

The container may, for example, have various geometric shapes as well as variable dimensions as required, without thereby departing from the scope of the invention.

As shown in FIGS. 3 and 4, the container can, for example, consist of a cylinder, the upper 5 and lower 6 walls of which consist of a membrane and the side wall of which is made of an impermeable material 8 or of a bundle of fine hollow tubes 9, each of these tubes being closed at these ends and containing the active product.

Claims (13)

1. Method for slowly and constantly releasing a biologically active material or composition (2) in a medium (4), said biologically active material or composition (2) being in an envelope which is at least partially constituted by a membrane (3) based on a permeable polymer, characterized in that the active material or composition is enclosed in a container (1) which is at least partially formed from a permeable synthetic membrane (3) which is placed in an aqueous medium (4) 10 or which is brought into contact with air. 2. Method according to claim 1, characterized in that the synthetic membrane is immersed in a slow circulation system of water (5) such as in said film feeding technique. 3. Method according to any one of claims 1 and 2, characterized in that the speed and the duration of the release are modified by adjusting the permeability and the surface of the permeable synthetic membrane (3). 4. Method according to any one of the preceding claims, characterized in that the permeability of the synthetic membrane (3) is modified by adjusting the thickness, the polymerization means, the plasticizer, the stabilizers, the additives and synthetic membrane lubricants (3). ▼ 'Λ 21 5. Method according to any one of the preceding claims, characterized in that the speed and duration of the release are determined by choosing the quantity and the nature of the active material or composition (2). 6. Method according to any one of the preceding claims, characterized in that the speed and duration of the release are determined by choosing the dimensions and the geometric shape of the container (1). 7. System for the slow supply of a biologically active material or composition (2), consisting of a closed envelope surrounding said active composition, which is at least partially composed of a membrane (3) based on a semi polymer -permeable, which slows the release of the active material or composition, characterized in that the envelope consists of a container (1) which, with the active material or composition which is enclosed therein, 2o is directly suspended in a medium aqueous or is contacted with air. 8. System according to claim 7, characterized in that the container is a plastic bag, pocket or box. 9. System according to any one of claims 7 and 8, characterized in that the membrane (3) is a permeable thermoplastic polymer film, consisting of a polymer, copolymer or mixture of polymers insoluble in water. 10. System according to any one of # t 22 claims 7 to 9, characterized in that the polymer, copolymer or mixture of polymers is a vinyl polymer, a polyurethane, a cellulose or a cellulose derivative. 5 11. System according to claim 10, characterized in that the vinyl polymer is a polyethylene, a polyvinyl acetate, a polyacrylate or a polymethacrylate. 10 12. System according to claim 10, characterized in that the cellulose derivative is cellophane or a cellulose acetate. 13. System according to any one of Claims 7 to 12, characterized in that the biologically active material or composition is a pure chemical product, of technical quality or a mixture of chemicals in the form of a composition with or without addition of additives.