FI61637B - SAETT ATT MINSKA DOSEN AV EN BIOLOGISKT AKTIV SUBSTANS UNDER BIBEHAOLLANDE AV DEN BIOLOGISKA EFFEKTEN - Google Patents

Description

RSF ^ l M (NOTICE OF PUBLICATION ¢ 1637 JB | lJ utlAconingsskhift di (Sä Patent cny ^ netty 10 09 1932

Patent patent

Vs— ^ (51) Kv.ik.Va.3 B 01 P 3/12 // A 01 N 17/08 FINLAND —FINLAND (M) P * MnttHwl »mu · - PtMntaM5kitln | 763304 (22) H * k «ml« pUvt — AiM6knlngfda (16.11.76 (13) Alkuptiv * —GlHIghatsdag l8.ll.76 (41) Tullut lulkteukal - Mlvlt offuntHg 30.12.77

Patent · and r.ki.taHhallltu. Nthavtoip ^ |. the date of the month

Patent · oeh registentyreleen Ansök * n utbgdodi utUkrtfUn pubikund 31.05.82 (32) (33) (31) Pyy ^ «« y «tuolkuu * —Ugird prlorlMC 29.06.76 Sweden-Sweden (SE) 7607389“ 9 (71) Kockums Chemical Aktiebolag, Nya Agnesfridsvägen lll, Malmö, Sweden-Sweden (SE) (72) Kjell Gunnar Blixt, Malmö, Rolf Juhlin, Akers Styckebruk,

Mandayam Tiru, Järfälla, Sweden-Sverige (SE) (74) Leitzinger Oy (54) The present invention relates to a method of reducing the dose of a biologically active substance while maintaining its biological potency - Sätt att minska dosen av en biologiskt is a way of reducing the amount of biologically active substance required to produce a particular biological effect, wherein the biologically active substance or its precursor is uniformly distributed together with a possible additive over an inactive, solid, finely divided, inorganic carrier, preferably having an area of at least 50 m 2 / g.

2 61 637

The term "biologically active substance" generally and also in the context of the present invention means, in general terms, mixtures containing drugs, lethal substances, pesticides, disinfectants (for example phenols, chlorinated phenols such as p-chloro-m-xylenol, tetrabromo-o-cresol), biocides and deodorants.

For example, the use of pesticides (infecticides, herbicides, fungicides, germicides, rodenticides, etc.), such as DDT (dichlorodiphenyltrichloroethane), has been and still is very widespread, but there is a growing awareness that there are various dangers associated with their use. Several countries have therefore regulated the use of pesticides by setting a maximum level for them or simply banning the use of certain pesticides that are considered to be particularly dangerous. However, the ban on the use of pesticides must be assessed in the light of the remaining need for the pesticide. In many cases, for example with regard to DDT, the negative effects of not using a pesticide appear to be at least as undesirable as the risks associated with their use.

To clarify the problems in question, it can be mentioned that, despite the pesticide spraying of vegetables such as tomatoes, a large proportion of the tomatoes are damaged by insects during distribution. However, a ban on spraying tomatoes is planned because of the dangers it poses to the consumer. These dangers are due to the high concentration of the pesticide on the tomatoes, the difficulty in removing the pesticide by washing with water and also the fact that the pesticide penetrates to a certain extent into the tomato itself. Banning the spraying of tomatoes will, of course, mean much lower production, which will result in lower stocks and higher tomato prices. The same goes for other fruits and vegetables that are sprayed, such as oranges, apples, pears, lettuce, cauliflower, etc.

Given that there is already a shortage of food, it is not at all acceptable for food production, as mentioned above, to be further reduced by banning spraying with moths. Thus, it is highly desirable to find a solution to the problem of two seemingly opposite claims, i. on the one hand, spraying should be able to control insect nuisances and diseases, and on the other hand, the health and environmental hazards of spraying pesticides should be reduced.

As mentioned above for pesticides, it is also known from drugs that many of them cause undesirable side effects, for example when acetylsalicylic acid is used in the gastrointestinal bleeding due to the local abrasion of the gastric mucosa exposed to high concentrations of the substance. Due to the biochemical processes in the body's organs, a higher dose of the drug in question is often required than is actually needed to produce a particular, desired effect. Some drugs are broken down or converted into other compounds, so-called "metabolites", which in many cases cause unwanted side effects. In some special cases, the required dose may be very close to a dose that is toxic, especially in sensitive individuals.

Thus, it is obvious that in the case of drugs, too, in many cases there is a need for a method which, if possible, can reduce the required dose of the preparation while maintaining a curative effect, thereby reducing or eliminating undesirable side effects. For hedgehogs, the need for a smaller amount of expensive, active drug is, of course, also associated with economic benefits.

As mentioned above with regard to pesticides and drugs, the other biologically active substances mentioned in the introduction also apply, i.e. it is valuable in both economic, environmental and health terms if the use and distribution of the biologically active substance could be reduced.

It is an object of the present invention to provide a solution to the problem outlined above by deviating from the basic idea that by increasing the activity of a biologically active substance in a suitable manner it is possible to reduce the amount required to achieve the desired result and thus reduce or eliminate undesirable side effects.

According to the method of the invention, the reduction of the amount of biologically active agent required to produce a particular effect is accomplished by combining a certain amount of the biologically active agent with a particular carrier in certain specified proportions. Also, when the biologically active substance is used at the concentration normally used, but in combination with the carrier according to the present invention, the negative effects can be reduced and a pronounced positive effect can be obtained (as shown in Table 5 by maintaining the normally used DDT concentration, DDT The penetration of DDT into the fruit is significantly reduced when DDT is used in combination with carriers according to the invention).

Conventional biologically active preparations are available as liquids or powders, in which case the biologically active ingredient, when the active preparation is in powder form, is mixed with a carrier. Prior art formulations differ from the present invention in that they use a much higher amount of active ingredient relative to the amount of carrier compared to the present invention. Another critical difference is that "carriers" previously used in the art are used only as fillers, i. the active substance is physically mixed with the carrier and not distributed in a uniform layer on the carrier, as in the present invention. Furthermore, prior art carriers have a very low specific surface area, substantially less than 50 m 2 / g, although silica gel with a surface area of more than 50 m 2 / g has also been used. In this case, however, silica gel has been used as a filler and not as an actual carrier.

In contrast to the prior art, the biologically active substance, possibly in combination with other additives, is uniformly distributed in the present invention over an inactive, solid, finely divided inorganic carrier, preferably having a surface area of at least 50 m 2 / g. The invention is characterized in that the biologically active substance is distributed on the carrier in a weight ratio of 1:10 to 1: 1, preferably 1:10 to 1:10, the amount of biologically active substance per unit weight of the mixture being 1/2 to 10 times the amount. per unit weight required to achieve the same effect when using a conventional mixture of biologically active substance.

(The area values given in this specification correspond to the data provided by the manufacturer. The area is usually determined by N2 adsorption by the BET method).

It should be noted that, although the specification below applies in particular to pesticides and drugs applied to carriers with a specific surface area of more than 50 m2 / g, it is nevertheless possible to rope with carriers with an area of less than 50 m2 / g. However, when using such 5 616 3 7 carriers, the ratio of pesticides to the carrier may not be as low as when using carriers with a higher surface area, more than 50 m / g. In addition, where carriers have previously been used in the art, they have been physically mixed with the active agent and used only as excipients, whereas in the present invention it is important that the carrier be uniformly deposited with the minimum amount of biologically active agent required to achieve the desired effect.

Useful inorganic carriers can be selected from inorganic elements and their oxides, acids, salts and polymers. Particular mention may be made of the following types of inorganic supports: Colloidal metal or metalloid oxides, such as alumina and silica; various silicates and other silicon-containing compounds such as asbestos, talc, vermiculite, kieselguhr, diatomaceous earth, mica, expanded mica; and alkaline earth metal carbonates and phosphates such as calcium carbonate, magnesium carbonate and calcium phosphate. Particularly preferred are fumed silicas and alkali metal and alkaline earth metal silicates, as will be explained in more detail later.

In a preferred embodiment of the present invention, the carrier has a particle size of about 1 to 250.

In the case of a biologically active substance for oral use, such as drugs, excessive amounts of inorganic carrier are unsuitable, and in these cases the weight ratio of biologically active substance to carrier is chosen to be 1: 1 to 1:20, whereby the amount of biologically active substance is 1/2 - 1/10 times the amount normally required for the use of the biologically active substance alone.

In other normal cases, for example when pesticides are used, it is possible to use a larger amount and a smaller amount of biologically active substance in the carrier, and in these cases the limits are appropriately selected so that the weight ratio of biologically active substance to carrier is 1:10 to 1:10 and preferably 1 : 10 λ -1-5 1:10, in which case the biologically active substance is 10 to 10 times the amount normally required.

In this context, "inactive" means that the carrier itself does not adversely affect the biologically active substance, so that the carrier should not bind the biologically active ingredient so tightly that it inhibits its action. however, between the carrier and the biologically active agent and the combination of optional additives, as described in more detail below.

In a preferred embodiment of the invention, the surface area of the inorganic carrier 2 is at least 200 m / g.

In another preferred embodiment of the invention, the inorganic support is silica or silicate.

In a particularly preferred embodiment of this invention, the silica is precipitated silica or pyrogenic silica prepared by known precipitation or pyrogenic methods. Doped or pyrogenic silicas with surfaces of at least about 200 m 2 / g are commercially available.

In the presently most preferred embodiment of the invention, the support is fumed silica, which can be obtained in various grades, with a surface area of about 200 to 1000 m / g.

In accordance with the present invention, it is also important that the carrier used be modified so that it does not itself cause an imbalance in the environment, body, or biological system into which the product is introduced. It is possible to obtain silicas or silicates with different particle sizes and surfaces, but it is often necessary to modify these substances in terms of acidity, alkalinity, hydrophilicity or hydrophobicity. Experiments have shown that acidic silica can be neutralized by the addition of ammonia or ammonium hydroxide, other alkalis, calcium hydroxide, magnesium or barium hydroxides, as well as other metal oxides. Similarly, basic silica can be neutralized by the addition of nitric acid, other mineral acids such as phosphoric acids, organic acids, etc. In this way, the carrier material can be carefully modified to suit and improve a particular type of biological system, e.g., a particular type of soil. Thus, it should be noted that although the present invention is directed to reducing the dose of a biologically active agent, it also contributes to the natural weight of 7,61637. When pesticides are used, it is thus possible to add, for example, nitrogen-absorbing organisms.

In its purest form, the invention is only a combination of a biologically active substance and a carrier, but it can be easily understood, as also mentioned above, that it is of course possible to add various additives if desired without departing from the spirit and scope of the invention. However, such additives are only secondary ingredients, the primary ingredients being a biologically active agent and a specific carrier. The various additives may be colorants and flavoring agents (including hormonal attractants) which impart an attractive color, odor or taste to the preparation, which may be particularly important with pesticides. Additives are further substances which have an inhibitory or accelerating effect on the release of a biologically active substance. Examples of such substances are ionic substances, both hydrophobic and hydrophilic substances. Additives are also the usual, more or less "inert" additives, such as diluents and solvents for the biologically active substance. Conventional fillers such as kaolin, talc, attapulgite can also be added as an additive. Hormone-type substances can also be used as additives. Further examples of suitable additives will be readily available to those skilled in the art and a thorough listing is therefore not necessary.

For the sake of simplicity, the invention will now be described in more detail using only pesticides and drugs as the biologically active substance and silica as the inorganic carrier. The applicability of the invention to other classes of biologically active substances and other types of inorganic carriers can be readily understood without having to burden this application with detailed descriptions of each type of carrier for each separate field of application.

According to the present invention, it has been found, quite surprisingly, that a pesticidally active ingredient of a compound with a carrier of the type outlined above is obtained as described above with a pesticide mixture which has a significantly better potency than the corresponding conventional pesticide mixtures. In short, the superior potency of the composition of the invention can be divided as follows: 61637 a) The same pesticidal potency as in conventional preparations can be obtained by using a significantly lower amount of pesticidally active ingredient - 1 to 5 ingredients; this amount can be as small as 10 to 10 times the amount of a conventional substance or less.

b) The effect of a) is further emphasized by the lower pesticide concentration of the mixture, i. with a lower ratio of pesticide component to carrier.

c) In some cases, the mixture according to the invention may have accelerating effects, for example in herbicidal mixtures the undesired growth is inhibited while the desired growth is stimulated unexpectedly.

d) The pesticide mixture obtained by the method according to the invention involves the lowest possible risks to health and the environment. This is due, on the one hand, to the very low total amount of pesticide required to achieve the desired effect according to a) above and, on the other hand, to the fact that the mixture can be easily removed by washing, for example from sprayed vegetables. Due to the low amount of pesticide in the pesticide mixture, the risk of the pesticide penetrating the sprayed fruits or vegetables is almost completely eliminated.

With regard to the above-mentioned possibility of easily removing the pesticide composition according to the invention from a treated object, it should be noted that this property, which measures the adhesion of the mixture or its binding to the treated substance, is important for the overall usefulness and efficacy of the pesticide. Thus, very strong adhesion to the sprayed product, which may appear advantageous because the pesticide remains at the intended location without being affected by weather conditions, is inappropriate because the pesticide is difficult and even impossible to remove from the target before consumption (e.g. when the fruit or vegetable is targeted). In addition, the pesticide may be so strongly bound to the target that its intended potency is reduced, for example, the pesticide does not migrate to insects attacking the sprayed fruit.

On the other hand, the adhesion of the pesticide mixture to the target should also not be too weak, since in this case there is a risk that the mixture will not adhere at all or, if it adheres, will disappear completely from the surface for as little reason as possible.

9 61 O 3 7

In accordance with the present invention, it has been found that the above-mentioned inorganic carriers, and in particular the silica and silicate carriers, constitute a very successful compromise for the adhesion of the entire pesticide mixture to the sprayed target. It is also possible to modify such mixtures according to the invention (by changing the ratio of the mixture containing the active ingredient to the carrier) so that they can be removed by washing with water while adhering to the subject so tightly that the desired biological effect is maintained for the desired time. This prevents undesired accumulation of the active ingredient in the sprayed product (e.g. DDT in tomatoes, Tables 5 and 6).

In addition to being able to vary the ratio of carrier to active ingredient as described above, other changes may be made by selecting carriers which are acidic or basic in nature.

The support is preferably silica or alkali metal or alkaline earth metal silicate - including double silicates containing alkali metals or alkaline earth metals or other metals such as aluminum, boron, zirconium and bismuth (e.g. aluminum silicate, magnesium silicate, magnesium aluminosilicate) - with a specific surface area of more than 50 m / g or more.

Several of these products are available in the market under different trade names, for example

Fluosil Cab-O-Sil ^

Aerosil ^

HiSil ®

Zeosil ® <r)

Brite Sorb **

Quso ®

Manosil ^

Fellte 3ne.

The pharmaceutical compositions of this invention may also contain a solid or liquid pharmaceutically acceptable non-toxic agent. Such pharmaceuticals may be sterile liquids, such as water and oils, including oils derived from petroleum, animals, plants, or synthetic, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is the preferred suspending medium when the pharmaceutical composition is administered orally or parenterally. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid additives, especially for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, agar, malt, rice, wheat flour, lime, silica gel, magnesium carbonate, magnesium stearate, sodium stearate, glycerol monostearate, talc, sodium chloride, dried chloride, sodium chloride, dried ethanol and the like.

These compositions may be in the form of suspensions, tablets, pills, capsules, powders, sustained release formulations, and the like. Formulation methods suitable for the pharmaceutical product of this invention are described in E.W. Martin's Remington's Pharmaceutical Sciences, the information of which is incorporated herein by reference. The compositions contain the biologically active compositions of this invention in an effective therapeutic amount as well as an appropriate amount of a diluent to provide a form suitable for administration to a subject. It is to be understood that the pharmaceutical compositions of this invention may be administered to mammals orally, parenterally or topically.

The invention and its advantages are further illustrated below by means of some examples. When examples of pesticides have been given, these subsequent examples are, by necessity, limited to only a few representative pesticides. A comprehensive list of pesticides is given by D. Amstron Lowe and A.R. In Stiles, "Pesticides, Nomenclature, Specifications, Analysis, Use, and Residences in Foods," Progress In Standardization: 1 WHO, Geneva, 1974, which is relied upon and referred to in this context. One skilled in the art can determine the most useful pesticides and the most effective pesticide and carrier by simple experiments.

Preparation of a carrier coated with a biologically active substance ^ ______________________________________________

The biologically active substance can be deposited as a uniform and even layer on the support by dissolving the biologically active substance in its solvent, mixing the carrier with the resulting solution, and evaporating the solvent from the resulting mixture. The solvent is selected so that i. '*' 11 61637 is inert to the biologically active substance; i.e. the solvent must not destroy the biological activity of the substance. It must also be possible to evaporate the solvent from the mixture at a temperature substantially lower than the temperature at which the biologically active substance would be denatured or evaporated or sublimed. Evaporation of the solvent should be accomplished by mixing the mixture very gently, which promotes an even and uniform layer on top of the support. The evaporation rate can be suitably controlled by adjusting the temperature of the mixture, the vacuum and evaporation time of the device containing the mixture. These factors naturally depend on the volume of solvent to be removed and must be chosen so as to avoid denaturation or evaporation of the biologically active substance. In the following examples, methylene chloride was used as the solvent and the evaporation time, temperature and vacuum are given. Other solvents can be used and the optimum conditions can be determined by a few experiments.

In the following examples, a carrier coated with a biologically active substance was utilized. In all cases, the carrier consisted of a silica aerogel with a high specific surface area. The biologically active agent was varied and selected from insecticides, herbicides and drugs. The carrier and the biologically active substance are described in more detail in various examples. In all examples, the carrier was coated with the biologically active agent by the same general method as follows.

A selected amount of the carrier of the invention (30.0 g) was combined with stirring with methylene chloride (6 liters) or other suitable solvent for the biologically active substance. Thereafter, a gram amount of biologically active substance was added such that the ratio of biologically active substance to carrier was said weight ratio of 1:10 to 1: 1. If desired, suitable additives can be added, for example those mentioned above. The resulting mixture was then stripped of solvent by evaporation under reduced pressure and temperature (about 200 mm Hg and 25 ° C with methylene chloride) until (about 20 hours) that the solvent was completely removed. The dry product was then carefully ground to a powder with a recommended particle size of about 1-250. If such grinding changes the properties of the product.

For example, methods used in gas chromatography to coat stationary phases on solid supports can be used. Evaporation can in principle be carried out in any suitable evaporator which makes it possible to adjust the pressure and temperature as desired. A particularly suitable device is the so-called Rotavapor type rotary evaporator. Evaporation should be performed as carefully as possible so that the biologically active substance completely coats the carrier, i. both the outer surface and the inner part of the carrier. If the evaporation is too strong, for example if the temperature is raised to about 35 ° C when methylene chloride is used as the solvent, an uneven concentration of the biologically active substance on the surface of the support will result.

Although the following examples utilize the method described above in which the coating is performed from a solution and the solvent is evaporated, other methods for coating the carrier with a biologically active agent may be used in accordance with the invention. Instead of a solution of a biologically active substance, it is possible to use an emulsion thereof, in which case the biologically active substance is emulsified in a medium which does not act as a solvent for the substance. A method involving emulsification of a biologically active substance is particularly suitable when the active substance is sparingly soluble in ordinary solvents.

In another method, which is not the preferred method, the carrier is coated directly with the biologically active agent. In this case, the active substance is sprayed directly onto the carrier while stirring vigorously, for example by means of ultrasound or a round bed, so that the carrier remains suspended during the application of the active substance.

In another coating method, the biologically active substance is evaporated and the generated steam is condensed on the carrier, whereby a uniform and uniform coating of the active substance is obtained on the carrier.

Regardless of the method used to coat the biologically active agent on the carrier, it is essential and critical to provide a uniformly finished product to uniformly coat the biologically active agent; and as a uniform layer on the carrier.

61 637 13

Example 1 Using the method described above for preparing the coated carrier according to the invention, three (¾ 2 different batches of carrier (Fluosil200 m / g) coated with different coating amounts of Malathion insecticide (S- / 1,2-bis- (ethoxycarboxylic acid)) were prepared. The first batch had a composition of 1% Malathion / 99% carrier, the second batch had a composition of 0.1% Malathion / 99.9% carrier and the composition of the third batch had 0.01% Malathion / 99.9% carrier. 99.99% carrier.

Twelve open PVC plastic boxes were used to test the obtained preparations. The inside of the side walls of the boxes was coated with coarse sandpaper. The area of each box coated with sandpaper in this way was 0.05 m. The surfaces of the boxes coated with coarse sandpaper were then sprayed with 15 ml of a suspension containing said preparations in different amounts of coating in distilled water, as shown in Table 1. Thirteen, non-sprayed boxes were used as a control box.

Thereafter, 20 live wood ants were placed in each insecticide-sprayed box and control box, and the upper sides of the boxes were covered with a fine-meshed net to prevent the ants from escaping. The number of dead ants in each box was then counted once a day during the week. The results are given in Table 1.

It can be seen from Table 1 that the pesticide according to the invention is very effective even when used in very low concentrations.

Example 2

To demonstrate the superior efficacy of the pesticide of the invention, comparative experiments were performed using Propoxus insecticide (2-isopropoxyphenyl-N-methylcarbamate) marketed under the tradename Baygon® (available from Bayer Agro-Kemi AB, Malmö, Sweden) and the same substance applied to a carrier, has a large surface area R 2 (Fluosil, 200 m / g). The different preparations of the tests were as follows: 14 61637 1) A standard mixture containing 1% Propoxur with carrier R (Ss (Baygon), 2) 0.1% Propoxur with Fluosil t-'carrier and 3) 0.01% p

With Propoxur Fluosil. Each preparation was made into the following suspensions at different concentrations in distilled water as given below.

1. A conventional mixture (Baygon ®) of 500 mg was finely ground in a mortar and suspended in 50 ml of distilled water. The suspension was divided into the following volumes: a) 14 ml, no further dilution; b) 7 ml of suspension + 7 ml of distilled water, and c) 1.4 ml of suspension + 12.6 ml of distilled water.

/ £) 2. 0.1% Propoxur Fluosil with carrier 5 g of Propoxur-coated carrier were finely ground in a mortar and suspended in 100 ml of distilled water. The suspension was divided into the following volumes: a) 28 ml of suspension, no other dilution, b) 14 ml of suspension + 14 ml of distilled water, c) 2.8 ml of suspension + 25.2 ml of distilled water.

3. With 0.01% Propoxur Fluosil ® Carrier 5 g of Propoxur-coated carrier was finely ground in a mortar and suspended in 100 ml of water. The suspension was divided into the following volumes: a) 28 ml of suspension, no other dilution, b) 14 ml of suspension + 14 ml of distilled water, c) 2.8 ml of suspension + 25.2 ml of distilled water.

Said nine differently prepared suspensions were sprayed into the inner parts of nine plastic boxes with a total wall and bottom area of 0.07 m. Coarse sandpaper was attached to both the walls and the bottoms to prevent the sprayed insecticide suspension from draining off. The tenth box was not sprayed but used as a control box.

15 61-637

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Thirty wood ants were placed in each of the ten boxes, and after 20 hours, 44 hours, and 72 hours, the percentage of dead ants in the boxes was calculated.

The experimental results are shown in Table 2, which shows that the preparation according to the invention was much more effective than the conventional preparation, and that an equally good result or a better result compared to the conventional preparation was obtained by using a smaller amount of the preparation according to the invention. In particular, it should be noted that when the sprayed active ingredient of the preparation according to the invention is used in the same total amount, a better result can be obtained by using a preparation containing less active substance. The amount of conia of the active substance thus sprayed was the same in boxes 1, 4 and 9, but in box 9 sprayed with a suspension containing 0.01% Propoxur on a carrier, the number of dead ants after 20 hours was twice as high as in boxes 4 and 9. in box 1. After 72 hours, 90% of the ants in box 9 had died, while 80% of the ants in box 4 had died and only 50% in box 1.

17,616 37

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Example 3 In this example, experiments were performed to confirm the attachment and penetration of the DDT insecticide (dichlorodiphenyltrichloroethane) to tomatoes sprayed with pure (100%) DDT, respectively. without coating on a carrier, and with DDT applied in various amounts as a coating on the carrier according to the invention. As in the previous examples, the carrier according to the invention consisted of a silica aerogel with a specific surface area of 200 m / g. This carrier was coated with DDT (in the same manner as the carriers in the previous examples) to give preparations; with compositions of 10% DDT / 90% vehicle and 1% DDT / 99% vehicle, respectively. The three DDT preparations were suspended in distilled water and then the suspensions were sprayed onto untreated, green tomatoes in boxes measuring 2 dm x 2 dm. The amounts sprayed are shown in Table 3.

Table 3

Box Sprayed total Active substance spray No. Preparation amount total wetted DDT + carrier (mg) (mg,) 1 100% DDT - 80 2 - 8 3 - 0.8 4 10% DDT / 90% carrier 800 80 5 "80 8 6 8 0.8 7 1% DDT / 99% carrier 800 8 8 80 0.8 9 "8 0.08 The tomatoes thus treated were then analyzed for DDT before and after rinsing in tap water to remove the insecticide preparation sprayed on them. The analysis results are shown in Tables 4 and 5.

19 61 637

It can be seen from Table 4 that the penetration of the insecticide was most significantly reduced when the preparation according to the invention was used, compared to the use of DDT alone. It can be seen from Table 5 that the sprayed preparation according to the invention is completely removed when washed with water, while a considerable amount remains when sprayed, usually only DDT.

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Example 4 The purpose of this example is to demonstrate the efficacy of the invention when the pesticide is a herbicide. The herbicide used is Simazin (Ν, Ν'-diethyl-6-chloro-S-triazine-2,4-diamine) on the other hand as a powder containing 50% of the active substance (this mixture is marketed under the trade name Gesatop AB Plantex, Södertälje, Sweden) , and on the other hand, as a coating applied in various amounts on silica aerogel carriers with a high specific surface area, about 300 m / g. Simazin / carrier preparations with large surface areas were prepared in the same manner as described above for the preparation of insecticide / carrier preparations in the previous examples. The experiments were performed with three different Simazin preparations, i.e .: A. Gesatop ® (50% active substance) B. 20% Gesatop®, 80% vehicle with a large surface area, i. amount of active substance = 10% C. 2% Gesatop®, 98% carrier with a large surface area, i.e. amount of active substance = 1%.

In addition to the herbicidal preparations described above, 13 boxes were prepared with a base area of about 0.25 m and filled with earth. Seeds of radish, spinach, lettuce and grass were sown in each box.

After preparation, various amounts of aqueous suspensions of the above preparations were sprayed onto the boxes, as shown in Table 6. One box (Box No. 13) was left unsprayed and used as a control. Different boxes were monitored for about 2 months for both weed and vegetable growth. It was found that, with the exception of box 13 (comparison), there were no weeds in any of the boxes and that the growth of vegetables in the sprayed boxes varied widely. The growth of vegetables is shown in Table 6. In addition to the decreasing values in Table 6, the visual overall impression of the growth of the boxes was that there was essentially no growth in boxes 2, 3, 4, 5, 6 and 12 and that the growth in boxes 7 and 11 was very small, while growth in other boxes was much more abundant. Furthermore, it was quite surprisingly found that the growth in Box No. 9 was relatively strongest. Except that there were no weeds in this box, the desired growth. *. v. V- 23 61637 was stimulated, which was unexpected. This stimulation occurred, albeit less, in Box No. 10, which had been sprayed with a larger amount of active substance (0.031 g / m 2). It should be noted, however, that greater growth stimulation was not achieved by simply reducing the amount of active agent sprayed, as Box 8, which had an increase in active agent content (0.016 g / m2) between Boxes 10 and 9, was weaker than both in box No. 10 and in box No. 9. The stimulation of growth also appears to depend on the total amount of active substance and carrier sprayed, i. the concentration of the active substance in the preparation, wherein the preparation with a lower concentration of the active substance stimulates growth better than the preparation with a higher concentration.

An important conclusion can be drawn from Table 6 that by using the herbicidal preparation according to the invention it is possible to use a smaller amount of active substance compared to conventional herbicidal preparations and at the same time to obtain equally good or even better results. This has economic benefits, on the one hand, because a smaller amount of expensive herbicide is needed, and, on the other hand, environmental benefits, because the spread of herbicide is reduced. Since the invention makes it possible to use extremely small amounts of active substance, it is also conceivable that pesticides which have previously been packaged unused could be used again because it is prohibited or because the upper limit for their use has been considered too low and ineffective.

24 61 637

Table 6

Box- Action- Action- Growth rate ko / Silent vinen „^ ... . _. ... „, ... _,. . , Λ Radishes Spinach Lettuce Grass box ame + substance carrier (g / m2) substance __ (g / m2) ____________________ 1 0.063 0.031 + ++ _ + ++ 2 0.313 0.156 - + 3 A 1,000 0.500 - - + 4 3,000 1,500 - + 5 7.500 0.750 - + 6 2.500 0.250 - + - + 7 B 0.825 0.082 + ++ 8 0.163 0.016 ++ +++ + +++ 9 0.625 0.006 ++++ ++++ ++++ ++ ++ 10 3.125 0.031 +++ - ++++ ++++ +++ - ++++ +++ 11 C 10.000 0.100 + + + 12 25.000 0.250 - - + + 13 0 0 +++ ++ + +++ +++ - = no growth + = weak or poor growth + = irregular but clearly visible growth ++ = relatively good growth +++ = good growth ++++ = excellent growth

As mentioned above, the method of the invention can also be used to reduce the required dose of various drugs. In some cases, it is possible to take advantage of drugs that have previously been considered ineffective. Thus, for example, experiments have been performed in the past in which rats have been administered several penicillin esters in order to cause enzymatic degradation of the ester in the digestive system and thus release penicillin in active form. These experiments were successful when performed in rats but not in humans. This was hypothesized to be due to the inability of man to enzymatically degrade the esters in question. However, by combining the drug esters with the carrier of the type in question in said proportions and amounts according to the method of the present invention, good results may also be obtained in humans, as shown in the following examples. This can be attributed in part to the presence of a larger surface area of the drug and in part to the fact that the rate of the enzymatic reaction is significantly increased when the combination of ester substrates with a corresponding high surface area carrier is used. Examples of antibiotic esters of the above type include chloramphenicol esters, penicillin esters and cephalosporin esters. Two concrete examples of these are given below.

Example 5

Chloramphenicol palmitate (2 mg / ml) and chloramphenicol palmitate applied as a coating on a carrier according to the invention (Fluosil, 200 m / g) in a weight ratio of 50/50 (4 mg / ml) were suspended in each solution containing 1 ml of 1.0 M CaCl 2. , 1 ml Tween 80

Dist. H2O to 100 mL to 5 mL IM Tris + HCl to pH 8.0

An equal volume of pancreatic lipase enzyme solution (from Sigma) (5 mg / ml) in pH 8.0 buffer was mixed with each suspension.

The preparations were tested on Escherichia coli K 12 after the enzymatic reaction was stopped by holding at 50 ° C for 3 minutes. The results are given in Table 7.

Table 7

Reaction time known- Chloramphenicol palmate- Chloramphenicol palmitate, tea biliary lithate (uncoated) coated with carrier passage_ Contraceptive zone, mm_ Contraceptive zone, _mm____________

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It can be seen from Table 7 that although no antibiotic effect was obtained with chloramphenicol palmitate when the antibiotic was not applied as a coating on the carrier, a good antibiotic effect was obtained when chloramphenicol palmitate was applied as a coating on the large surface area of the invention. As mentioned above, this can be explained by the fact that the rate of the enzymatic reaction is considerably increased in the process according to the invention. Thus, in order to obtain the same antibiotic effect as the method according to the invention, it is necessary to use a considerably larger amount of chloramphenicol palmitate when the antibiotic is not applied as a coating on the carriers according to the invention.

Example 6

The experiment of Example 5 was repeated, but instead of chloramphenicol palmitate, benzylpenicillin phenacyl ester and cephalosporin phenacyl ester were used instead of antibiotics, and Sareina lutea ATCC 9341 , the contraceptive zone was 16 - 24 ram, i.e. the antibiotic efficacy was clearly better. The explanation for why a particular contraceptive zone was also obtained with an uncoated antibiotic is probably found in the presence of free benzylpenicillin as a result of spontaneous hydrolysis of the phenacyl ester. Despite this side effect, however, the better effect obtained by the method according to the invention is obvious.

The examples given for the antibiotics set forth above are not to be construed as limiting the invention, but for many drugs, vitamins, anesthetics, antibiotics, parasiticides, diabetic preparations, hormones, sedatives, anesthetics, antihistamines, antioxidants, mineral supplements, e.g. antimalarials, alkaloids, antidotes, expectorants 1, etc. and the like can be better utilized when combined with a carrier having a high specific surface area in accordance with the present invention 61637 27, whereby the active ingredients are present more effectively and have a better effect than is achieved with a normal dose.

In particular, when a biologically active substance, for example a drug, is applied to a carrier according to the invention, it is more evenly distributed and more widely distributed, and the substance is not present in too high local concentrations which can cause adverse side effects such as gastrointestinal bleeding in the case of acetylsalicylic acid. In some cases, the active substance bound to the carrier is distributed more evenly and more widely and at the same time has a greater therapeutic effect than if the active substance has not been absorbed onto the carrier. This may be particularly important in the treatment of enteric infection.

Furthermore, when the invention is used in connection with a substance which reacts enzymatically to form a biologically active substance, i.e. in the case of a precursor of a biologically active substance (such as the esters of Examples 5 and 6), a better release of the biologically active substance is obtained compared to the use of this substance without a carrier.

Finally, it should be emphasized once again that although the invention has been described specifically for insecticides, herbicides and pharmaceuticals, it is not limited to these groups of substances but can generally be applied to biologically active substances so as to obtain a predetermined biological effect using less physiologically active substance than usual. , or conversely, a better biological potency is obtained compared to the potency normally obtained by using the same amount of biologically active substance. The essence of the invention is thus not in a particular type of biologically active substance used but in the fundamental finding that it is possible to achieve the same effect as before using a smaller amount of biologically active substance if the active substance is applied according to the invention to a carrier with a high specific surface area as described above. .

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Claims (12)

28 6 1 6 3 7 A method for reducing the amount of a biologically active substance required to produce a particular biological effect, wherein the biologically active substance or its precursor, together with a possible additive, is uniformly distributed over an inactive, solid, finely divided, inorganic carrier, preferably having an area of at least 50 m 2 that the biologically active substance is distributed on the carrier in a weight ratio of 1: 106 to 1: 1, the amount of biologically active substance per unit weight of the mixture being 1/2 to 10 "times the amount per unit weight required to achieve the same effect when using a conventional biologically active substance mixture. Process according to Claim 1, characterized in that the surface area of the inorganic carrier is at least 200 m 2 / g. Process according to Claim 1 or 2, characterized in that the support is chosen from metals and metalloids, inorganic oxides, acids, salts and polymers. Process according to Claim 3, characterized in that the inorganic support is chosen from silica and silicates. Process according to Claim 4, characterized in that fumed silica is used as the support. Process according to one of the preceding claims, characterized in that the carrier is neutralized by treatment with an acid or an alkali Method according to one of the preceding claims, characterized in that the biologically active substance is distributed on the carrier in a weight ratio of 1:10 to 1:10. Method according to one of the preceding claims, characterized in that the particle size of the carrier is about 1 to 250 μm. 29 61637 Method according to one of the preceding claims, characterized in that the biologically active substance is selected from pesticides, medicaments, disinfectants, biocides and deodorants. A method according to claim 9, characterized in that the pesticide is selected from insecticides, berbicides, fungicides, germicides and rodenticides. A method according to claim 9, characterized in that the medicament is selected from vitamins, analgesics, antibiotics, parasiticides, diabetic preparations, hormones, sedatives, anesthetics, antihistamines, mineral supplements, antipyretics, alkaloids, antidotes and expectorants. A method according to claim 9, characterized in that the drug is selected from penicillin esters, cephalosporin esters and chloramphenicol esters.