DD233075A5 - METHOD FOR PRODUCING PREPARATIONS OF HEAVY WATER-SOLUBLE ANTHELMINTHICA - Google Patents

Abstract

Preparations with increased bioavailability and efficacy of poorly water-soluble anthelmintics and methods for the preparation of these preparations are described. The active ingredients have a large specific surface area.

Description

Phenylsulfonyloxybenzimidazole, as described in DE-OS 3132167 [= European Patent Application with the publication number 72532]) or anthelmintically effective, so-called benzimidazole prodrugs (benzimidazole precursors) (eg 8 Febantel, thiophanate, substituted phenylguanidines [cf .. eg DE -OS 2608238,2653766 or 2836385], nitro compounds, for example, according to DE-PS 2541742 or ureido compounds according to DE patent application P 3232959.8).

The preparations according to the invention contain the said anthelmintics alone or in combination with each other or with other active ingredients. A preferred combination is z. B. fenbendazole with triclabendazole.

The production of anthelmintic with increased surface area is achieved by precipitation processes, whereby precipitation processes are understood as meaning both precipitation and crystallization processes. For this purpose, in principle all combinations of the active ingredient dissolving with the active ingredient not dissolving solvents or solvent mixtures can be used.

By way of example, some preferred combinations of solvents for the crystallization of anthelmintics may be mentioned:

Dimethylformamide, dimethyl sulfoxide, acetonitrile or dioxane in each case in conjunction with water or alcohols, such as. B.

Methanol, ethanol, isopropanol, amyl alcohol, methyl glycol, or organic acids such as glacial acetic acid, propionic acid or trifluoroacetic acid, each in combination with water or alcohols such as methanol, ethanol, isopropanol, amyl alcohol, methyl glycol. Depending on the circumstances, these solvents can also be used alone for crystallization.

It is also possible to dissolve the anthelmintics by salt formation in a suitable solvent and then reprecipitate by neutralization in the desired surface finish.

Here you proceed z. B. as follows: Dissolve the substance in water or an alcohol such. As methanol, ethanol, isopropanol, amyl alcohol, methyl glycol, or in acetone or butanone.

a) with the addition of acids, such as. For example, aqueous hydrochloric acid, HCl gas, sulfuric acid, nitric acid, phosphoric acid, glacial acetic acid, propionic acid, trifluoroacetic acid, or

b) with the addition of bases such as sodium, potassium, calcium, barium hydroxide, sodium methoxide, sodium ethylate, sodium hydride, triethylamine, pyridine, ammonia.

Then neutralized in the case of a) z. B. with a b) base mentioned; in the case of b) z. B. with one of the acids mentioned under a).

The acids or bases used can be either in pure gaseous, liquid or solid form or in a mixture or solution with a suitable solvent, such as. As water, methanol, ethanol, isopropanol, amyl alcohol, methyl glycol, acetone, butanone, are used.

The selection of the optimal method depends on the physical and chemical conditions of the active ingredient used which are known to the person skilled in the art. One works z. B. at low or high temperatures, at a well-defined stirring rate or even without stirring and with certain proportions of the solvents used with each other and in relation to the amount of active ingredient used.

The dry grinding is known and occurs z. B. with hammer, fly cross, pen or air jet mills. In the wet grinding suspensions of the sparingly soluble active ingredient z. B. in ball mills that rotate about a horizontal or vertical axis, in ball mills that vibrate on a vibrating table or ground in ball mills, the so-called bead or sand mills, with a vertical or horizontal axis. The mills can be made of different materials, such as hard glass, hard porcelain or hard metals, and can be operated in a batch or flow-through process.

Suitable suspension medium are all liquids in which the substance to be ground is sparingly soluble. For practical reasons, water is preferred.

The wet grinding can be carried out in suspensions which contain only the suspending medium apart from the active substance or the active ingredient mixture. Conveniently, these suspensions already contain one or more auxiliaries, such as the following:

Buffer substances, such as acetates, phosphates or citrates, suspension stabilizers, such as cellulose, cellulose ethers, polyvinylpyrrolidone or fumed silica, wetting agents, such as polyethylene glycol ethers or alkanesulfonates, preservatives, such as parabens, sorbic acid or benzyl alcohol.

The suspension medium during wet milling may be identical to the application medium, especially if the active ingredient is to be administered in the form of a suspension. However, it is also possible to mill the active substance (s) for example in a fluorohydrocarbon suspension and then to exchange the suspending agent for water by evaporation and resuspension.

The preparations preferably have a liquid or paste-like consistency. However, solid preparations such as powders, granules, capsules or tablets are also possible. For this purpose, the suspensions obtained by wet grinding suspensions medium by suitable drying methods, such. B. withdrawn evaporation. The suspensions may also be grown on solids such as silica, corn starch, cellulose or lactose, followed by drying. The solid preparations obtained in this way and containing the anthelmintics in the form according to the invention and optionally auxiliaries can be applied either directly or after further process steps, such as granulation or tabletting, in which further customary auxiliaries are optionally added.

The preparations according to the invention are valuable chemotherapeutic agents with high bioavailability and efficacy and are suitable for combating parasitic diseases of humans and animals.

They are particularly effective against a large number of helminths, e.g. B. Haemonchus, Trichostrongylus, Ostertagia, Cooperia, Metastrongyliden, Chabertia, Strongyloides, Oesophagostomum, Hyostrongylus, Ancylostoma, ascarids and Heterakis, but also z. B. Fasciola and Moniezia. Particularly pronounced is the effectiveness against gastrointestinal enemas, lungworms, tapeworms and liver flukes, which mainly affect domestic animals and livestock.

Therefore, the preparations according to the invention are used except in humans especially in veterinary medicines.

Because of their greater effectiveness, the preparations according to the invention are administered in smaller dosages of the active ingredient than preparations prepared by conventional methods.

The concentrations of the active compounds in the form according to the invention in the preparations prepared therewith are preferably between 0.5 and 22% by weight for use as veterinary medicinal products; for use as a human medicament, the concentrations of the active ingredients are preferably between 20 and 80% by weight.

The process products are not only excellently effective in oral administration, but can also be administered parenterally.

The combination of the two process steps has the following significant advantages over the individual steps:

1. Due to the upstream precipitation or dry grinding the wet grinding time is considerably shortened. The risk that abrasion of the grinding media enters the preparation is thereby negligible.

2. The active ingredient particles show no irreversible agglomeration.

3. The result is an unexpectedly high level of effectiveness.

embodiment

The following examples describe the invention without limiting it.

example 1

630 g of fenbendazole are dissolved at room temperature in a mixture of 2000 g of methanol and 288 g of 37% strength hydrochloric acid. With vigorous stirring (®Ultra-Turrax), 354 g of 33% strength sodium hydroxide solution are added to the resulting solution. The thereby precipitated fenbendazole is filtered off, washed chloride-free with deionized water and dried at 70 ° in vacuo.

Yield: 625g. Specific surface 18.7m ² / g.

Example 2

a) Preparation of the suspension

a) 25 g fenbendazole (taken from a batch of 550 kg fenbendazole, which was obtained by precipitation according to Example 1, specific surface 12.6 m ² / g) and 30 g fumed silica were dissolved in an aqueous solution of 15 g Natriumcarboxymethy! 19 g of polyvinylpyrrolidone 25 000.33 g of sodium citrate χ 2H ₂ 0.1 g of citric acid χ H20.1.7 g of methyl 4-hydroxybenzoate, 0.2 g of propyl 4-hydroxybenzoate and 5 g of benzyl alcohol are suspended. With water was made up to a final volume of 1.01.

ß) Fenbendazole according to Example 1 was used in the preparation of the suspension.

b) wet grinding:

325 ml of suspension α or β were filled in a porcelain ball mill of 11 content. There were added 0.51 porcelain spheres with a diameter of 8-10 mm.

The porcelain ball mill was clamped on a vibrating mill and ground for 150 hours. The amplitude of the vibrations was about 3-4 mm and their frequency, due to the speed of the electric motor, about 1 350th

Example 3

Instead of fenbendazole, 25 g of methyl 5- (4-fluorophenyl-sulfonyloxy) benzimidazole-2-carbamate were used

a) recovered by precipitation, specific surface area 5.4 m ² / g; (The precipitation was carried out as follows: 7.3 kg of anthelmintic were dissolved with stirring in 80 l of methanol and 1.95 l of hydrochloric acid [conc.] The solution was between 10-20 ° C with 30% aqueous sodium hydroxide solution to pH 7 to 7.5 The precipitated product was separated, washed with a methanol-water mixture and dried 25 g of the product was taken to make the suspension.)

ß) obtained by dry grinding (air jet milling) of 3 α, specific surface 8.2 m ² / g; γ) obtained by dry grinding (pin mill grinding) of 3 α, specific surface area 6.9 m ² / g; δ) recovered by precipitation, specific surface area 2.5 m ² / g;

(The precipitation was carried out as follows: 75 g of anthelmintic were dissolved hot in 300 ml of dimethylformamide and 1 000 ml of methanol were added, the product precipitated on cooling, washed with a mixture of methanol and diisopropyl ether, and 25 g of the product were added Preparation of the suspension taken.) And

ε) obtained by precipitation, specific surface 24.8 m ² / g; (The precipitation was carried out as follows:

25 g of anthelmintic were dissolved in 250 ml of dioxane with heating and vigorous stirring. Thereafter, 2,000 ml of water was added dropwise. The precipitated product was separated and washed with a mixture of water and methanol.)

used. Otherwise, as in Example 2 a) α or 2 a) α + 2 b) specified, proceed.

Example 4 animal experiments Treatment:

In each case 3 sheep, one of the formulations A, B, C and D were administered orally. The active ingredient concentration of the preparation was 2.5 wt .-% and the dosage 1 χ 6mg fenbendazole / kg body mass.

preparations:

A: Suspension according to Example 2 a) α specific surface area of fenbendazole: 12.6 m ² / g, without wet grinding).

B: suspension according to Example 2 a) α) with N aßmahlung according to Example 2 b).

C: Suspension according to Example 2 a) ß), specific surface of fenbendazole 18.7 m ² / g, without wet grinding

D: suspension according to Example 2 a) ß) with wet grinding according to Example 2 b).

Evaluation:

The blood was drawn from the jugular vein before administration of the preparation as well as 1, 2,4,6,8, 24, 30,48, 54, 72,96,120, 144,168, 240 and 336 hours post-application;

The samples were stored frozen at -237-24 ° C until assayed.

High pressure liquid chromatographic examination of serum levels was performed on fenbendazole and the metabolites SO-fenbendazole, SO2-fenbendazole and p-HO-fenbendazole.

The measured data are listed in Table 1. They were arithmetically averaged in groups. Before application, serum levels were O.

Table 1

Serum levels of fenbendazole, SO- and SO ₂ -fenbendazole after oral administration of formulations A, B, C and D in ng / ml

time in fenbendazole B C D SO-fenbendazole B C D SO ₂ - fenbendazole C D hours 15.3 0 15 0 0 0 0 0 p.appl. A 61 19 77.3 A 15.3 0 14.3 A B 0 0 1 0 127.6 64.6 204.3 0 57.3 19.3 81.3 0 0 3.3 0 2 14 199.6 110.3 265.6 0 148.6 72.3 174.6 0 0 5.6 6.3 4 36 197.6 107.6 249 8.3 106 102.3 235 0 0 11.6 19.3 6 60 203.3 142 285.6 34.6 350 257.6 454 0 4.3 63.3 100.6 8th 53 164.3 115.6 254. 52.6 358.3 261 477 0 9 82 126.3 24 86.6 82 66.3 121.6 140.3 170 130.6 227.6 27.3 81.3 76 113 30 90.6 62.3 65.6 103.6 165.6 144 112.3 191 39 106.6 75 · 103.6 48 49.6 30.3 22.6 50.6 91.3 69 52 98.3 43.6 103.3 60 79.6 54 45.3 8.3 4 11 86.3 20.3 11.3 26.6 44 104.3 39 49.6 72 20.6 3.6 0 0 46.3 5 0 4.3 35.6 70.6 22.3 31.3 96 0 0 0 0 10.3 0 0 0 25.6 49.6 20.3 18.6 120 0 0 0 0 0 0 0 0 15.6 32 9 10.3 144 0 0 9.3 17.6 3.6 0 168 0 0 4 11 0 0 240 0 0 336 0 0

The (arithmetically averaged) serum levels in ng / ml measured for fenbendazole (curve 1), SO-fenbendazole (curve 2) and SO-fenbendazole (curve 3) are shown in FIGS. 1-4. (Figure 1 represents serum levels after administration of Preparation A, Figure 2 of Preparation B, Figure 3 of Preparation C and Figure 4 of Preparation D). The metabolite p-HO-fenbendazole could not be detected in any of the samples.

Result:

The advantage of the higher specific surface area of the active substance results from the comparison C with respect to A, the unexpectedly high influence of the wet grinding from the comparison B / D against A / C. Also, the metabolites of fenbendazole are subject to an analogous behavior of absorption and absorption rate.

Example 5 animal experiments Treatment:

In each case 3 sheep were one of the formulations A, B, C, D, E or fin a dosage of 1 χ 6 mg of 5- (4-fluorophenylsulfonyloxy) benzimidazole-2-carbamic acid methyl ester per kg of body mass p.o. administered. Preparations G and H were administered in dosages of 1 × 4.5 and 1 × 3.0 mg / kg BW. The drug concentration was in all cases 2.5 wt .-%.

preparations:

A: Suspension according to Example 3a) or 2a); specific surface area of the active substance 5.4m ² / g, without wet grinding. B: Suspension with wet grinding according to Example 3a) or 2a) + b).

Suspension according to Example 3/3) or 2 a); specific surface area of the active substance 8.2m ² / g, without wet grinding.

Suspension according to Example 3y) or 2a); specific surface area of the active ingredient 6.9 m ² / g, without wet grinding.

Suspension according to Example 38 or 2a), specific surface area of the active ingredient 2.5m ² / g, without wet grinding.

Suspension with wet grinding according to Example 3/3 or 2a) + b).

Suspension according to Example 3ε) or 2a); specific surface area of the active ingredient 24.8 m ² / g, without wet grinding.

Suspension with wet grinding according to Example 3ε) or 2a) + b).

Evaluation:

The blood was drawn from the jugular vein prior to administration as well as 2,4,6,8,24,30,48,54,72,96,120,144 and 168 hours post-application;

Samples were stored frozen at -237-24 ° C until assayed and serum levels of 5- (4-fluorophenylsulfonyloxy) benzimidazole-2-carbamic acid methyl ester were determined by high pressure liquid chromatographic analysis.

The measured data (arithmetic mean) are it. Table 2 listed. Before application, the values were 0.

The respective serum level (arithmetic mean in ng / ml) is shown in FIGS. 5-9. The assignment of the figures to the preparations A to H is as follows:

FIG. 5 Suspension A - curve A

Suspension B - Curve B Figure 6 Suspension C - Curve C

Suspension F-curve F Figure 7 Suspension D - curve D

Suspension Ε-curve E Figure 8 Suspension G, dose 3 mg - curve G *

Suspension H, dose 3mg - curve H * Figure 9 Suspension G, dose 4,5mg - curve G **

Suspension H, dose 4.5 mg - curve H **

Result:

The preparations containing the active ingredient with a higher specific surface area also show higher blood levels, as is evident from the series of formulations E, A, D, and G. Significant increase in blood levels was observed in comparison to preparations A, C and G after administration of preparations B, F and H, which had additionally been wet-milled.

Table 2

Serum level of methyl 5- (4-fluorophenylsulphonyloxy) benzimidazole-2-carbamate after oral administration of formulations A to H in ng / ml

time in A B C D e F G* H* G** H** hours p.appl. 2 17.3 114.7 19.7 23.0 7.0 125 43 83 56 117 4 76.0 268.3 87.7 105.3 22.7 347 146 207 179 358 6 165.0 452.3 179.7 200.0 56.3 599 350 400 389 624 8th 189.0 507.3 209.3 233.7 71.0 744 453 454 503 709 24 365.0 950.0 434.0 461.3 196.3 865 640 776 751 1007 30 372.7 813.0 455.7 450.3 203.3 722 600 775 742 1018 48 292.7 654.0 388.0 357.0 228.0 428 412 457 390 593 54 301.0 623.0 392.3 386.3 224.0 354 274 396 335 521 72 171.3 314.7 240.7 227.7 139.7 160 156 195 170 257 96 152.0 164.0 162.0 142.3 96.3 57 64 87 87 121 120 53.0 70.7 93.0 81.7 62.0 17 27 38 25 56 144 19.3 26.7 42.3 43.3 30.3 7 12 15 8th 26 168 7.7 9.7 17.7 15.0 17.3 2 5 8th 4 13

* Dosage: 3mg / kg KM ** Dosage: 4.5mg / kg KM

Claims (5)

claims: 1. A process for the preparation of preparations of poorly water-soluble anthelminthics, characterized in that one converts heavy water-soluble anthelminthics into those with high specific surface by subjecting them to a precipitation and / or dry grinding, in water or a liquid which dissolve the active ingredients difficult, and the suspensions are additionally wet-milled and, if appropriate, subsequently dried. 2. The method according to item 1, characterized in that the suspending agent is water and contains other auxiliary substances. 3. The method according to item 1, characterized in that are used as anthelminthic benzimidazole-2-carbamates, benzothiazole-2-carbamates, benzimidazoles or benzimidazole prodrugs with high specific surface area. 4. Method according to item 3, characterized in that one or more anthelmintics with a large specific surface are used. 5. The method according to item 3, characterized in that one uses fenbendazole, 5- (4-fluorophenylsulfonyloxy) benzimidazole-2-carbamic acid methyl ester and / or triclabendazole. For this 9 pages drawings Field of application of the invention The application relates to preparations of poorly soluble anthelmintics with increased bioavailability and efficacy and to processes for preparing these preparations. Characteristic of the known technical solutions It is known that orally administered anthelminthics are absorbed in the digestive tract, in the bloodstream and from this into organs and develop there over longer periods of their effectiveness. Anthelmintics are usually poorly water-soluble substances known to increase their biological activity by increasing their specific surface area. The larger specific surface area causes a higher dissolution rate. The rate of dissolution, however, is often that of the absorption and, in consequence, the effectiveness determining step. The relationship between particle size and effectiveness has already been described (W. A. Ritschel, Angewandte Biopharmazie, p. 293 ff., Wissenschaftliche Verlagsgesellschaft, Stuttgart [1973]). Specific surfaces up to about 10m ² / g can be prepared by dry grinding, wie z. B. air jet milling, produce coarser material. Another method for achieving large specific surface areas is the precipitation of the substance, which is z. B. in a water-miscible solvent in solution, by addition of water, separation of the sediment and optionally drying. Does a z. B. obtained by precipitation substance has a specific surface area of about 5 to 10m ² / g, it can be increased only slightly by dry grinding. Experiments have shown that aqueous suspensions containing fenbendazole type anthelmintics with a large specific surface area obtained by dry grinding (5-10m ² / g as determined by a BET gas adsorption method) are more effective than those containing the active substance with a specific one Surface of about 1 m ² / g. The visually detectable drug particles in the former suspension were larger than expected due to the specific surface area. Increasing the specific surface area of poorly water-soluble anthelmintics by modified precipitation methods to about 25 m ² / g resulted in a further increase in activity towards substances with a lower specific surface area. The solvents used for the precipitation must be removed quantitatively after precipitation. According to the information in the literature, the possibilities of increasing the efficiency of poorly water-soluble drugs are exhausted with specific surfaces of this size. Furthermore, according to the information in the literature, the decrease of the particle size is technically limited. Smaller particle sizes than about 10μΓΠ are difficult to handle. However, a particle size of 10 μm corresponds only to a specific surface area of the order of magnitude of 1 m ² / g (cf., for example, the abovementioned publication by WA Ritschel). Object of the invention The aim of the invention is to provide preparations of sparingly soluble anthelminthics with increased bioavailability and greater efficacy. Explanation of the essence of the invention _φ The invention has for its object to further increase the surface of poorly soluble, obtained by precipitation and / or dry grinding anthelmintic. It has surprisingly been found that by additional wet milling, the biological effectiveness of the poorly water-soluble anthelmintic can be maximized, even if these anthelmintics have a high specific surface area produced by dry grinding or precipitation. The invention therefore relates to preparations of poorly water-soluble anthelmintics with a large specific surface, obtained by precipitation and / or dry grinding and additional wet grinding. They are characterized by maximum bioavailability and efficacy. The invention further relates to a process for the preparation of these preparations, which is characterized in that sparingly water-soluble anthelmintic substances are converted into those with high specific surface area by subjecting them to a precipitation and / or dry grinding, in water or a liquid in which the Active ingredients difficult to solve, suspended and the suspensions additionally wet-milled and optionally subsequently dried. The Naßmahleffekt is determined by comparative grain size analysis z. B. controlled with the Coulter counter device. According to the invention, particularly poorly soluble anthelmintics of the following classes of substances are suitable: benzimidazole and benzothiazole-2-carbamates (examples include: fenbendazole, albendazole, oxibendazole, oxfendazole, parbendazole, mebendazole, flubendazole, ciclobendazole, tioxidazole or substituted phenylsulfonyloxybenzimidazole-2-carbaminates, as z. B. in DE-OS 2,441,201 (= US-PS 3996368) or DE Patent Application P 3247615.9 described), other anthelmintic benzimidazoles (ζ B. triclabendazole, cambendazole, thiabendazole or substituted