NO146974B - MEASURES TO AA REDUCE THE QUANTITY OF A BIOLOGICAL ACTIVE SUBSTANCE WHILE MAINTAINING THE BIOLOGICAL EFFECT - Google Patents

Description

The present invention relates to another method

to reduce the amount of a biologically active substance while maintaining the biological effect. Furthermore, biologically active compositions are described for carrying out the method and the use of such compositions to reduce the necessary amount of biologically active substance involved in the treatment of a biological system.

The term "biologically active substance or substance" (or "biologically active compound") usually, and likewise in the present text, generally denotes compositions containing medicines, pesticides, disinfectants (e.g. phenols, chlorinated phenols such as p-chloro-m-xylenol , tetrabromo o-cresol), biocides and deodorants.

Pesticides (insecticides, herbicides, fungicides, germicides, rodenticides etc.) such as e.g. DDT (dichlorodiphenyltrichloroethane) has been, and still is, in extensive use, but it has been increasingly realized that their use is associated with various risk factors. Many countries have therefore sought to regulate the use of such toxic substances by imposing a maximum permissible limit, or certain particularly dangerous substances are simply prohibited. However, banning a poison must be weighed against the need for the pesticide. In many cases, it seems that the negative effects of not using the poison are at least as great, e.g. in the case of DDT, as the risk that comes with its use.

To illustrate the problems, it can be mentioned that despite poison spraying of vegetables such as tomatoes, insect attacks lead to a large part of the tomatoes being destroyed during transport and storage. Nevertheless, it is proposed to prohibit spraying tomatoes

because of the risk to which users are thereby exposed. This

risk is due to the fact that the pesticide is found in high concentration on the tomatoes, and because it is difficult to remove the poison by washing with water, and further because the poison penetrates to a certain extent into the tomato itself. A ban on spraying tomatoes would significantly reduce production with the following reduced supply and higher tomato prices. The same applies to other fruit and vegetable types that are sprayed, e.g. oranges, apples, pears, lettuce, cauliflower etc.

From the point of view that there is already a shortage of food, it is not desirable that food production, as previously mentioned, be reduced by banning spraying with poison. It is therefore very urgent to find a solution to the problem of the seemingly contradictory requirements, namely that on the one hand attacks from insects and diseases are combated by spraying, and on the other hand the reduction of health and environmental risk factors caused by the spread of these poisons.

In connection with what has been mentioned above with regard to pesticides, it is known for medicines that several of these produce unwanted side effects, e.g. peptic ulcer when using acetylsalicylic acid, due to the stomach's mucosa being locally exposed to high levels

concentrations of the drug. Because of biochemical processes that take place in the body's organs, higher doses of the preparation are often required than are actually necessary to produce the particular effect that is intended. Part of the active compound is broken down or converted into other substances, so-called metabolites, which in many cases produce the unwanted side effects. In special cases, the required dose can be very close to a dose that produces a toxic effect, especially in sensitive people.

It is therefore clear that also in connection with medication, there is often a need to reduce, if possible, the required preparation dose, while retaining the healing effect, in order to thereby be able to reduce or completely remove unwanted side effects. A reduced need for expensive, active preparations will naturally also result in financial savings.

The above with regard to pesticides and medicines also applies to other biologically active substances that are mentioned in the introduction, i.e. that it would be desirable both from an economic and environmental as well as a health point of view if the use and spread of biologically active substances could in one way or another is reduced.

The purpose of the present invention is to provide a solution to the above problem, starting from the basic idea that by increasing the activity of the biologically active substance in a suitable way, it will be possible to reduce the amount required to achieve a certain result , thereby reducing or eliminating unwanted side effects.

According to the method according to the invention, the reduction of the required amount of biologically active substance that is required to achieve a specific effect is achieved by combining a certain amount of biologically active substance with a special carrier medium (carrier) in certain specified quantity ratios. Even when the biologically active compound is used in normal concentrations, but combined with a carrier according to the invention, a reduction of the negative effects is achieved with an increased positive effect (as will be seen from table 5 later, penetration of DDT into fruit will also be significantly reduced when one operates with normal concentrations of DDT in combination with carriers according to the invention).

Common biologically active preparations are often available in the form of liquids or powders, where the biologically active ingredient is mixed with a carrier medium when the preparation is in powder form. The previously known preparations differ from the present invention in that they use a much larger amount of active substance in relation to the amount of carrier substance, compared to the solution of the present invention. Another crucial difference is that the carriers used in previous preparations are only used as fillers, i.e. that the active substance is physically mixed with the carrier medium, and not distributed as an even layer on the carrier as in the present invention. Furthermore, in accordance with previously known technology, the carrier material mostly has a very low specific surface area, substantially below 50 m 2g, although silica gel with a surface area of over 50 m 2 /g has been used. However, it also applies here that the silica gel used has been used as a filler, and not as a real carrier medium.

The invention thus relates to a method for reducing the amount of biologically active substance necessary for a certain biological effect, in which method the biologically active substance, possibly together with further additives, is coated on an inactive, solid, finely divided silica dioxide or silicate carrier in a weight ratio between biologically active substance

and carrier of no more than 1:1, which method is characterized by the carrier having a surface area of at least 200 m 2 /g, and that the biologically active substance is coated on the carrier at a weight ratio between biologically active substance carrier of from 1:10 to 1:1, whereby, calculated per unit weight of biologically active substance and carrier, the amount of biologically active substance coating the carrier amounts to only from 10 -1 to 10 -5 of the amount in a conventional composition with the same biological effect.

(The values for specific surface area in the present text follow the manufacturer's description. Usually the surface area is measured by ^-adsorption according to the BET method).

It should be mentioned that while the present description particularly deals with pesticides and medicines associated with carriers with a specific surface area of more than 200 m 2 /g, it is nevertheless possible to use carrier substances with a smaller surface area than 200 m 2 /g. With such carriers, however, the pesticide/carrier ratio will not be able to be reduced as much as with carriers that have a higher surface area of more than 200 m 2 /g. When carriers have been used in the prior art, the carrier has been physically mixed with the active compound, and only formed a filler, while an important feature of the present invention lies in the fact that the carrier is evenly coated with the absolutely minimal amount of biologically active substance that is necessary for to give the desired effect.

Useful inorganic carriers can be selected from inorganic elements and oxides, acids, salts and polymers. In particular, the following types of inorganic carriers are mentioned: colloidal metal or metalloid oxides, such as aluminum oxide and silicon oxide; various silicates and other siliceous compounds, such as asbestos, talc, vermiculite, diatomaceous earth, diatomaceous earth, mica, expanded mica; and carbonates and phosphates of alkaline earth metals, such as calcium carbonate, magnesium carbonate and calcium phosphate. Particularly preferred are fumed silicon oxide and alkali metal or alkaline earth metal silicates, which will be described in more detail later.

In a preferred embodiment of the invention, the carrier has a particle size of between 1 and 250 µm.

In connection with a biologically active substance to be taken orally, such as medicine, excessively large amounts of inorganic carrier will be unfavorable, and in these cases a weight ratio between biologically active substance and carrier of between 1:1 and 1:20 is chosen, and the amount of biological active substance is from 1/2 to 1/10 of the amount normally used when using the biologically active substance alone.

In other and normal cases, when e.g. uses pesticides, it is possible to use a larger amount of carrier and a reduced amount of biologically active substance, and in these cases the limits are preferably chosen to be between 1:10 and 1:10, and preferably

4 2

1:10 and 1:10 for the weight ratio between biologically active substance and carrier, and between 10 ^ and 10 5 of the amount of biologically active substance that is usually included when the compound is used alone.

The term "inactive" denotes here that the carrier itself does not adversely affect the effect of the biologically active compound. The carrier should therefore not bind the biologically active ingredient so firmly that its effect is reduced or inhibited. However, a certain mutual attraction of binding nature may exist between the carrier and a combination of biologically active substances and optional additives, which will

be described in more detail later.

In a further preferred embodiment of the invention, the inorganic carrier material consists of silicon oxide or a silicate.

In a particularly preferred embodiment, the silicon oxide is precipitated or pyrogenic silicon oxide produced by known precipitation or pyrogenic methods. Precipitated or pyrogenic silicon oxide with a surface area of at least 200 m 2 /g can be obtained commercially.

According to the most preferred embodiment of the invention, the carrier medium is pyrogenic silicon oxide, which can be obtained in different qualities with a surface area of approx. 200 - 1000 m2/g.

It is also important that the carrier is modified so that it does not in itself create any imbalance in the environment, the body or the biological system in which or on which the product is used. You can get or order silicon dioxide or silicates. with different particle size and surface area, but it is often necessary to modify these substances with regard to acidity, alkalinity, hydrophilic or hydrophobic character. Experiments have shown that acidic silicon dioxide can be neutralized by adding ammonia or ammonium hydroxide, other alkaline substances, calcium hydroxide, magnesium or barium hydroxides as well as other metal oxides. In a similar way, alkaline silicon dioxide can be neutralized by adding nitric acid, other mineral acids such as phosphoric acid, organic acids, etc. In this way, the carrier substance can be carefully modified to suit, and even enrich, the particular biological system under consideration, e.g. .ex. a certain soil. The main aim is to reduce the amount of biologically active substance, but according to the invention, the natural balance of the environment is also made more favourable. When using pesticides, it is thus possible to add nitrogen-fixing organisms.

In its simplest form, the invention comprises a combination of biologically active substance and a carrier, but as previously mentioned, it is possible to add different substances without thereby going beyond the idea and scope of the invention. However, such additions or additives only form secondary components, the main components being the biologically active substance and the selected carrier medium. Various additives can consist of coloring matter and flavorings (eg hormonal attractants) to give the preparation an attractive colour, smell or taste, which can be of particular importance for pesticides. The additives can also consist of compounds that have an inhibiting or accelerating effect on the release of the biologically active substance. Ion-active substances as well as hydrophobic or hydrophilic substances are examples of such agents. The additives can also be ordinary, more or less "inert" additives, used as a diluent and solvent for the biologically active substance. Common fillers such as kaolin, talc, attapulgite etc. can also be added. Hormone reagents can also be used as additives. Since a person skilled in the art will easily be able to think of further examples of suitable additions, a further enumeration of such possibilities will be redundant.

For the sake of simplicity, the invention will be described in more detail below with reference to pesticides and medicines alone as biologically active substances and silicon oxide as an inorganic carrier medium. The possibility of applying the invention to other categories of biologically active substances and other types of inorganic carriers will be easily realized without it being necessary to burden the present preparation with a special and detailed description for each area of use and carrier medium.

It has surprisingly been found that by combining a pesticidally active ingredient with a carrier of the aforementioned type, and in the aforementioned manner, a pesticidal composition is obtained which has a significantly improved effect compared to ordinary pesticide compositions and preparations. In short, the improved effect of the composition according to the invention can be classified as follows: a) One can achieve the same pesticidal effect as ordinary preparations with a significantly smaller amount of pesticide active ingredient, nem--1 -5

equal from 10 to 10 or less of the usual amount.

b) The effect under a) is greater with a lower poison concentration in the preparation, i.e. with a reduced ratio pesticide/

carries.

c) In some cases, preparations can produce stimulating effects, e.g. in that unwanted growth is prevented in herbicidal compositions at the same time that desired growth is stimulated to an unexpected degree. d) The pesticide compositions obtained mean a minimal risk to health and the environment. The reason for this is on it

on the one hand, that the total amount of pesticide required to achieve the desired effect is very low according to a),

and on the other hand that the composition can be easily removed by washing e.g. sprayed vegetables. Besides, on

due to the low pesticide content in the composition, the risk of the poison penetrating the sprayed fruit or vegetables will be almost completely removed.

Regarding the above-mentioned possibility of being able to easily remove the pesticide composition from the treated object,

it should be mentioned that this property, which is a measure of the adhesion strength between the composition and the object or bond

to the treated material, is important with regard to the pesticide's overall usability and effect. Thus, a very strong adhesion to the sprayed product, which may seem desirable, as the poison will then stay in the desired area without being affected by weather conditions, will be unfavorable since it will be difficult or even impossible to remove the pesticide from the product before use (e.g. when the object is a fruit or vegetable). Furthermore, the pesticide can be so firmly bound to the object that the intended effect is reduced, e.g. in that the pesticide is not transferred to the insects that attack a sprayed fruit.

On the other hand, the adhesion of the pesticide composition to the object should not be too weak either, since then there will be a risk that the preparation will not adhere to the object at all, or that the poison will be completely removed from the surface at the slightest weather influence, e.g. after a rain.

It has been found that the above-mentioned inorganic carriers, and in particular silicon oxide and silicate compounds, provide a very fortunate compromise when it comes to adhesion for the entire pesticide composition to the sprayed object. It is also possible to modify such compositions (by changing the ratio between active substance and carrier) so that the toxins can be removed by washing with water and at the same time adhere sufficiently strongly to the product so that the desired biological effect is maintained over a given period of time. This will prevent unwanted accumulation of active substance on the sprayed object (eg DDT in tomatoes, tables 5 and 6).

In addition to varying the quantity ratio between carrier and active substance as mentioned above, other changes can also be made by choosing carriers with an acidic or basic character.

Preferably, the carrier is silicon dioxide or an alkali metal or alkaline earth metal silicate, including double silicates containing alkali metals or alkaline earth metals, or other metals such as aluminium, boron, zirconium and bismuth (e.g. aluminum silicate, magnesium silicate, magnesium aluminum silicate, calcium silicate), which has a specific surface area of over 200 m 2/g or more. Several of these products are available on the market under different names, e.g.:

"Fluosil" <®>

"Cab-O-Sil"

"Aerosil"

"HiSil" <®>

"Zeosil" <®>

"Brite Sorb"

"Quoso"

"Manosil"

"Failed" <®> etc.

The pharmaceutical preparations can

also include a solid or liquid pharmaceutically acceptable non-toxic substance. Such pharmaceutical compounds can be sterile liquids, such as water or oils, including petroleum, animal, vegetable or synthetic oil, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred suspension medium when the preparation is to be given orally or parenterally. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid additives, particularly for injection solutions. Suitable pharmaceutical thickeners or excipients include starch, glucose, lactose, sucrose, gelatin, agar, malt, rice, flour, chalk, silica gel, magnesium carbonate, magnesium stearate, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skimmed milk, glycerol, propylene glycol, water, ethanol and the like. These compositions can be in the form of suspensions, tablets, pills, capsules, powders, preparations with prolonged action and the like. Suitable preparation methods for pharmaceutical products of the present type are described in Remington's Pharmaceutical Sciences by E.W. Martin, to whom reference is hereby made in its entirety. The preparations contain an effective therapeutic amount of the biologically active compounds together with a suitable amount of admixture which gives the suitable form of administration. Pharmaceutical compositions can be administered orally, parenterally or topically to mammals.

The invention and its advantages will be described in more detail below by means of some examples. The following examples are necessarily limited to just a few illustrative pesticides. However, an exhaustive list of pesticides can be found in an article by D. Armstrong Lowe and A.R. Stiles, "Pesticides, Nomenclature, specifications, analysis, use, and residues in foods" (Pesticides, nomenclature, specifications, analysis, use, and preparation residues in foods), Progress In Standardization: 1 WHO, Geneva, 1974, as hereby in refer to in its entirety. Particularly useful pesticides and the most favorable ratio between pesticide and carrier can be determined by a person skilled in the art by simple experiments.

Further addition of carrier material coated with biologically active material

The biologically active substance can be deposited as a uniform and even layer on the support by dissolving the substance in a solvent, mixing the support with the resulting solution and evaporating the solvent from the mixture. The solvent is chosen so that it is inert to the biologically active substance, i.e. that the solvent must not destroy the substance's biological activity. Furthermore, the solvent must be able to evaporate from the mixture at a temperature significantly lower than the temperature at which the biologically active substance will denature or evaporate or sublime. Evaporation of the solvent should take place during very careful stirring of the mixture, which helps to achieve an even and uniform layer on the carrier material. The rate of evaporation can advantageously be controlled by regulating the temperature of the mixture, the vacuum applied to the apparatus containing the mixture and the evaporation time. These factors will naturally depend on the amount of solvent to be removed, and are chosen so as to avoid decomposition or evaporation of the biologically active substance. In the following examples, methylene chloride is used as solvent, and the evaporation time, temperature and vacuum are listed. Other solvents may be used, and the optimum conditions are determined with a minimum of experimentation.

In the following examples, a carrier coated with biologically active substance has been used. In all the cases mentioned, the carrier consisted of silica airgel with a large specific surface area, while the biologically active substance was varied and chosen from insecticides, herbicides and medicines. The carrier and the biologically active substance will be described in more detail in the various examples. The same general method of coating the carrier with biologically active compound was used in all examples, namely as follows:

A certain amount of carrier substance according to the invention

(300 g) was mixed with methylene chloride (6 liters) or other suitable solvent for the biologically active substance while stirring. The amount in grams of biologically active substance required to arrive at the prescribed weight ratio of between 1:10 and 1:1, biologically active substance/carrier, was then added. Suitable additives such as those previously mentioned can be used. The mixture was then stripped of solvent by evaporation under low pressure and temperature (about 20 mm Hg and 25°C for methylene chloride) for the time necessary (about 20 hours) to completely remove the solvent. The dry product was then carefully ground to a powder with a preferred particle size of approx. 1 - 250 ^.m. If such paint were to change the product's properties, methods such as e.g. such as are used in gas chromatography for the coating of stationary phases on solid supports are used. In principle, the evaporation can be carried out in any suitable evaporation apparatus which allows control of pressure and temperature in the desired manner. A particularly suitable apparatus is a rotary flask evaporator of the "Rotavapor" type. The evaporation should be carried out as gently as possible so that the carrier will be completely coated with biologically active substance, i.e. both on the outside and the inner surfaces of the carrier. In the event that the evaporation is too strong, e.g. if the temperature is raised to approx. 35°C in connection with methylene chloride as solvent, an uneven concentration of biologically active substance is obtained on the surface of the carrier.

Although in the following examples the above-mentioned method is used for coating from solution, followed by evaporation of the solvent, other methods can be used for coating the support with biologically active compound. Instead of a solution of the biologically active substance, an emulsion of this can thus be used, the biologically active substance being emulsified in a medium that is not a solvent for the substance. The method of emulsifying the biologically active substance is particularly suitable when this is poorly soluble in common solvents.

Another method, however, is not as good

consists of coating the carrier directly with the biologically active substance. In this case, the active substance is sprayed directly onto the carrier under vigorous stirring, e.g. by means of ultrasound or a fluidized bed to keep the carrier suspended during the application of the active substance.

Yet another method consists in evaporating the active substance and condensing the vapor on the carrier substance into a smooth and uniform coating.

Regardless of the coating method chosen

of the biologically active substance on the carrier, the decisive condition for obtaining a satisfactory end product is that the biologically active substance is coated as an even and uniform layer on the carrier.

Example 1

The above-mentioned method is used for the production of a carrier material with coating, making three different batches of carrier material ("Fluosil" ® , 200 m 2 /g) coated with the insecticide "Malathion" (S-[1,2-bis(ethoxycarboxyl )-ethyl]-o,o-dimethyl phosphorodithioate) in varying concentrations. The first batch consisted of a mixture of 1% "Malathion"/99% carrier, the second of 0.1% "Malathion"/99.9% carrier, and the third contained 0.01% "Malathion"/99.99 % carrier.

Twelve open boxes made of PVC plastic were used to test the prepared preparations, and the inside of the boxes were coated with coarse sandpaper. The surface of each box that was thus coated with sandpaper was 0.05 m 2. The rough sandpaper-coated surfaces in the boxes were sprayed with 15 ml suspension in distilled water of the above preparations in different coating quantities, as will be seen from table 1. A not -sprayed thirteenth box was used as a comparison box.

Twenty live ants were placed in each box sprayed with insecticide and in the control box, and the top sides of the boxes were covered with a fine-mesh net to prevent the ants from escaping. The boxes were examined once a day for a week to count dead ants in each box. The results appear in table 1.

Table 1 shows that pesticide t according to the invention is very effective even at very low concentrations.

Example 2

In order to show the superior effect of the pesticide according to the invention, comparison tests were carried out with the insecticide "Propoxur" (2-isopropoxyphenyl-N-methylcarbamate) which is sold under the trade name "Baygon", applied to a carrier substance with a high surface area (Fluosil, 200 m<2> /g. The different preparations were the following: 1) Usual composition of 1% "Propoxur" on a carrier substance ("Baygon"®),

2) 0.1% "Propoxur" on "Fluosil" ® carrier, and

3) 0.01% "Propoxur" on "Fluosil" ® carrier.

Suspensions were made of all preparations in distilled water with three different concentrations as shown below.

1. Common Composition ("Baygon")

500 mg was crushed in a mortar and suspended in 50 ml of distilled water. The suspension was divided into the following portions:

a) 14 ml without further dilution,

b) 7 ml suspension + 7 ml distilled water, and

c) 1.4 ml suspension + 12.6 ml distilled water.

2. 0.1% " Propoxur" on " Fluosil" ® carrier

5 g of "Propoxur" coated carrier was crushed in a mortar and suspended in 100 ml of distilled water. The suspension was divided into the following portions:

a) 28 ml suspension without further dilution,

b) 14 ml suspension + 14 ml distilled water,

c) 2.8 ml suspension + 25.2 ml distilled water.

3. 0.01% " Propoxur" on " Fluosil" ®carrier

5 g of "Propoxur" coated carrier was crushed in a mortar and suspended in 100 ml of distilled water. The suspension was divided into the following portions:

a) 28 ml suspension without further dilution,

b) 14 ml suspension + 14 ml distilled water,

c) 2.8 ml suspension + 25.2 ml distilled water. The above nine different suspensions were used for interior spraying of nine plastic boxes whose walls and bottom had a total surface of 0.07 m 2. Coarse sandpaper was glued to both walls and bottom so that the sprayed insecticide suspension would not run off. A tenth box was not sprayed, but used as a control box. 30 ants were placed in each of the ten boxes, and the percentage of dead ants in the boxes was observed after 20 hours, 44 hours and 72 hours.

The test results appear in table 2, which shows that the preparation produced according to the invention was more effective than the usual preparation, and that compared to the usual preparation, an equally good or better effect was obtained with a smaller amount of preparation according to the invention. It should be emphasized in particular that with the same total amount of sprayed active substance of the preparation manufactured according to the invention, increased effectiveness can be achieved with a lower content of active substance. Thus, the total amount of active substance sprayed on was the same in boxes 1, 4 and 9, but for box 9 which was sprayed with a suspension of 0.01% "Propoxur" on a carrier, twice as many could be counted relatively dead ants after 20 hours compared to box 4 and box 1. After 72 hours, 90% of the ants in box 9 were dead, while in box 4 80% were dead, and in box 1 only 50%.

Example 3

In this example, experiments were carried out to ensure adhesion and penetration of the insecticide DDT (dichloro-diphenyltrichloroethane) on tomatoes when they were sprayed respectively with pure DDT (100%), i.e. not applied as a coating on a carrier substance, and DDT applied in varying amounts as a layer on carrier material. As in the previous examples, the carrier material consisted of silicon oxide airgel with a specific surface area of approx. 200 m 2 /g, and this carrier was coated with DDT (in the same way as previously described and used for coating carrier material in the previous examples)

for the production of preparations with a composition of 10% DDT/90% carrier and 1% DDT/99% carrier respectively. The three DDT preparations were suspended in distilled water, and the suspension was sprayed on untreated green tomatoes in boxes 2X2 dm. The sprayed quantities will appear in table 3.

The tomatoes thus treated were analyzed for DDT before and after the tomatoes were rinsed under the tap to remove the sprayed insecticide preparation. The analysis results appear in tables 4 and 5.

It appears from table 4 that the insecticide was most strongly washed out with the preparation prepared according to the invention compared to DDT alone. It appears from table 5 that the <p>sprayed preparation produced according to the invention is completely removed by washing with water, while significant quantities remain with ordinary spraying with only DDT.

Example 4

This example shall show the effect of the invention when the pesticide is a herbicide. "Simazine" is used as herbicide

(N,N'-diethyl-6-chloro-S-triazine-2,4-diamine) on the one hand, as a powder containing 50% active substance (this preparation is marketed under the trademark "Gesatop <®> "), and on

on the other hand, the same compound applied as a coating in different concentration on silica airgel as carrier

with a specific surface of approx. 300 m2/g. The "simazine"/carrier preparations with large surfaces were made in the same manner as previously described and used as the insecticide/carrier preparations in the previous examples. Experiments were made with three different "Simazin" preparations, namely: y

A. "Gesatop" ® (50% active substance)

B. 20% "Gesatop" <®> on 80% carrier material with a large surface area, i.e.

active substance content = 10%

(R)

C. 2% "Gesatop" w on 98% carrier with a large surface area, i.e. the content of active substance = 1%.

In addition to the above herbicidal preparations, 13 boxes with a bottom surface of approx. 0.25 m 2 capacity when filling with soil and sowing radish, spinach, lettuce and grass seed in each box.

The boxes were then sprayed with different amounts of water suspensions of the aforementioned preparations as indicated in Table 6. One of the boxes (box no. 13) was not sprayed to serve as a control sample. The various boxes were in the course of approx. two months observed with regard to growth, both of weeds and vegetables.

It was found that, apart from box no. 13 (the control sample), all boxes were weed-free, and that the vegetables in the sprayed boxes showed greatly varying growth. The growth state of the vegetables appears in table 6. As a supplement to the growth figures in table 6, it should be mentioned that after a general visual assessment of the growth in the boxes, there was practically no growth in boxes no. 2, 3, 4, 5, 6 and 12, and the growth in boxes no. 7 and 11 was insignificant, while the growth in the other boxes was much more abundant. Furthermore, it was surprisingly found that the growth in box no. 9 was strongest in comparison. Apart from the absence of weeds in this box, the desired growth was stimulated, which was unexpected. This stimulation also took place, albeit to a lesser extent, in box no. 10 which had been sprayed with a larger amount of active substance (0.031 g/m 2 ). However, it should be noted that the increased growth stimulation was not only achieved by reduce the content of active substance that had been sprayed, since box no. 8 whose content of active substance (0.015 g/m ) was between the contents of box no. 10 and box no. 9, and showed weaker growth than both box no. 10 and box no. 9. The growth stimulation also seems to depend on the total amount of active substance and carrier substance, i.e. the concentration of active substance in the preparation where a preparation with a lower concentration of active substance provides better growth stimulation than a preparation with a higher concentration.

Another important conclusion that can be drawn from table 6 is that with a herbicidal preparation produced according to the invention, one can use a smaller amount of active substance than with normal herbicidal preparations, while at the same time achieving equally good or better results. On the one hand, this means economic benefits since a smaller amount of expensive herbicide is required, and on the other hand benefits from a pollution point of view through reduced spraying of herbicide poison. Since, according to the invention, very small amounts of active substance can be used, it will be assumed that it will also be possible to use such pesticides which have previously been prohibited, or where the concentration used has been set so low that the compound became ineffective.

As previously mentioned, the method according to the invention can also be used to reduce the required dose of various medicines, and in some cases, make it possible to use medicines that have previously been considered ineffective. E.g. experiments have recently been carried out with different penicillin esters on rats in order to, if possible, produce enzymatic breakdown of the ester in the digestive system and thus release the penicillin in active form. These experiments were successful on rats, but not on humans, and it was assumed that humans lack the ability to enzymatically break down the esters in question. However, by

combine the drug esters with a carrier substance

of the type in question and in the indicated amounts and ratios, good results could also be achieved on humans, as can be seen from the following examples. This can be attributed partly to the fact that the medicinal compound occupies a larger surface area, and partly to the fact that a significant increase in the enzymatic reaction rate is achieved when using the combination of ester substrate and the various carrier substances with a large specific surface area. As examples of antibiotic esters of the above type, chloramphenicol esters, penicillin esters and cephalosporin esters can be mentioned. Two concrete examples follow below.

Example 5

Chloramphenicol palmitate (2 mg/ml) and chloramphenicol palmitate as a coating on a carrier ("Fluosil")<®>, 200 m /g) in the weight ratio 50/50 (4 mg/ml) were suspended in a solution of

1 ml of 1.0 M CaCl2

0.1ml "Tween" 80"

Distilled H20 ad 100 ml

5 ml IM Tris + HCl to pH 8.0

Each suspension was mixed with an equal volume of pancreatic lipase enzyme solution (from the company Sigma) (5 mg/ml) in a buffer at pH 8.0: The preparations were tested against Escherichia coli K 12 after the enzymatic reaction had stopped when heated to 50°C

for 3 minutes. The results appear in table 7.

It appears from table 7 that while no antibiotic effect was obtained at all with the amounts of chloramphenicol palmitate used when this antibiotic was not applied as a coating on a carrier substance, a good antibiotic effect was obtained when the chloramphenicol palmitate was applied as a layer on a carrier substance with a large specific surface area. As mentioned

above, this can be explained by the fact that the enzymatic reaction rate is significantly increased by this method. In order to achieve the same antibiotic effect as with the method of the invention, it will therefore be necessary to use a significantly larger amount of chloramphenicol palmitate when the antibiotic is not applied as a coating on the carrier substance according to the invention.

Example 6

The experiment was repeated according to example 5, but used resp. benzylpenicillin phenacyl ester and cephalosporin phenacyl ester as antibiotic instead of chloramphenicol palmitate and Sarcina lutea ATCC 9341 as test organism. An inhibition zone of 12 - 16 mm was then obtained for an antibiotic that had not been applied as a coating on a carrier substance, while the inhibition zone for an antibiotic applied as a carrier substance coating was 16 - 2 4 mm, i.e.

a clearly improved antibiotic effect. The explanation that a certain inhibition zone was also developed for uncoated antibiotics is probably that free benzylpenicillin is formed by spontaneous hydrolysis of the phenacyl ester. Despite this side effect, however, the increased effect of the method of the invention is clear.

Also many other medicines, vitamins, pain relievers, antibiotics, parasiticides, diabetic preparations, hormones, sedatives, anesthetics, antihistamines, mineral supplements (eg iron and iron compounds), antipyretics, preventives such as anti-malarial preparations .

Especially when a biologically active compound such as a medicine, a carrier substance is applied, the substance is more evenly distributed and distributed over a larger area and does not build up unwanted high local concentrations that can cause adverse side effects such as e.g. peptic ulcer for acetylsalicylic acid.

In other cases, a more uniform and more extensive distribution of the active compound bound to a carrier substance can be achieved than without such binding. This can be particularly important when treating stomach infections.

Furthermore, when the invention is used in connection with

a substance that undergoes enzyme reactions during the formation of biologically active compounds, e.g. a precursor for biologically active substances (for example the above esters from examples 5

and 6) an increased release of the biologically active substance is achieved compared to using the compound without a carrier.

Finally, it should be mentioned once again that although the invention is described in particular in connection with insecticides, herbicides and medicines, it can not only be used in connection with groups, but can be thought of as being used together with biologically active substances in general to produce a specific biological effect with smaller amounts of biologically active substance than usual, or vice versa to induce an increased biological effect compared to the effect that is usually obtained with the same amount of biologically active substance without a carrier. Thus, the idea of the invention is not based on a special type of biologically active substance, but on the fundamental discovery that one can achieve the same effect as previously with smaller amounts of biologically active substance if this is applied, as described, to a carrier substance with a large specific surface area.

Claims (4)

1. Method for reducing the amount of biologically active substance required for a certain biological effect, by which method the biologically active substance, possibly together with additional additives, is coated on an inactive, solid, finely divided silica dioxide or silicate carrier in a weight ratio of biologically active substance and carrier at most 1:1, characterized in that the carrier has a surface of at least 200 m/g, and that the biologically active substance is coated on the carrier to a weight ratio between biologically active substance:carrier of from 1:10 to 1:1 , whereby, calculated per weight unit of biologically active substance and carrier, the amount of biologically active substance that is coated on the carrier amounts to -1 -5 only from 10 to 10 of the amount in a conventional composition with the same biological effect. 2. Method according to claim 1, characterized in that the biologically active substance is coated on the carrier in a weight ratio of from 1:10 to 1:10<2>. 3. Method according to claim 1 or 2, characterized in that the carrier has a particle size of 1-250 ym. 4. Method according to any one of claims 1-3, characterized in that pyrogenic silica dioxydaerogel is used as the carrier.