DE2602363A1 - LIQUID INJECTABLE NICLOFOLAN FORMULATIONS - Google Patents

Description

Liquid, injectable Niclofolan formulations

The present invention relates to new liquid formulations of the known, effective against liver fluke Substance Niclofοlan (5,5-dichloro-2,2-dihydroxy-3,3-dinitrodiphenyl), which are better tolerated and easier to administer.

Formulations of the substance niclofolan, which is effective against liver fluke, have already become known the formulation as a tablet for oral application «The active ingredient Niclofolan becomes this Purpose wrapped rumen-resistant, as described for example in the German Offenlegungsschrift 21 07 917 will.

However, these formulations for oral administration have a number of disadvantages. In addition, the oral Application quite cumbersome and associated with considerable difficulties, especially with larger animals. It There is therefore no lack of attempts to develop an injection formulation that is easier for the veterinarian to apply and dose.

When injecting the active ingredient Niclofolan in the form of up to

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previous injection formulations turned out to be very tissue toxic and necroses develop. At the Injecting aqueous suspensions of the nielofolans the drug depot at the injection site was also not degraded When injecting solutions of the active ingredient Niclofolan in organic solvents fell the active ingredient was also released at the injection site and was not broken down there. Such an active ingredient depot can but now not be tolerated, since there is once the danger that such an active ingredient depot with the meat is consumed, on the other hand, too high a Niclofolan for too long. with the result that the animal cannot be released for slaughter during this time. The addition of Emulsifiers with solubilizing properties, such as. B. polyoxyethylated castor oil for injection formulations of Niclofolan in organic solvents The active substance niclofolan reduces the tendency to crystallize out at the injection site However, it turned out to be so tissue toxic that these attempts did not result in a usable preparation could lead "

It has been found that liquid, injectable formulations of Niclofolan, which in addition to the active ingredient one or several physiologically suitable bases, polyvinylpyrrolidone and water and optionally another one with water Contain miscible organic solvents, very good compatibility in animal experiments (especially Tissue compatibility) on white ^

Furthermore, it has been found that two factors are essential for achieving a usable and well-tolerated injection formulation of Niclofolan, namely

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Salt formation and addition of polyvinylpyrrolidone (hereinafter often referred to as "PVP" for short) _o

It can be described as extremely surprising that the injectable formulations according to the invention des Niclofolans are so well tolerated by animals as this in the previously known injection formulations des Niclofolans was not the case.

Injectable niclofolan formulations according to the invention represent a real enrichment of veterinary medicine.

As already mentioned above, the formation of a water-soluble salt of the phenolic group - can be used The active ingredient Niclofolan with a pharmaceutically suitable base surprisingly clearly shows the tissue compatibility to enhance.

Only one of the two phenolic hydroxyl groups of Niclofolan can be used for salt formation if the solution produced with it is to have a pH value that is physiologically acceptable. This can be seen from the titration curve of the active ingredient with sodium hydroxide solution. (see "Fig. 1). In this case, the range from pH k to pH 10 is to be regarded as a physiologically acceptable pH value range.

1 shows the titration of 6.9g Niclofolan-active agent is dissolved dimethylformamide _(2/100 mol) titrate with 1 N NaOH imaged. The ordinate indicates the amount of NaoH in g, the abscissa the pH value of the solution.

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The salt is preferably not prepared separately and then dissolved, but in the solution to be injected by adding the base to the active ingredient suspension or vice versa, immediately brought into the dissolved form. The isolated salt dissolves very slowly because it has a "jelly effect" which complicates the solution,

In principle, all physiologically harmless inorganic and organic bases can be used to form phenolates can be used. However, preference is given to those which are soluble in water and which are at a pH below 10 give a soluble salt.

For example, the active ingredient dissolves when adding Sodium hydroxide solution or triaethylamine - only at a pH ^> 10 clear on. With other bases, however, a clear solution is created at pH 8 - 9.

Bases of this type are preferably organic bases, e.g. B .: basic amino acids like L- or "D, L-arginine or" L- or D, L-Lysine, Methylglucamine, Glucosamine, Triaethanolamine, Diaethanolamine, monoaethanolamine or 2-amino-2-hydroxymethyl propanediol (1.3). Salts with diamine are also suitable, so ζ forms. Β «, Ν, Ν, Ν ', N'-tetrakis (2-hydroxypropyl) -ethylenediamine a soluble salt at pH 8.3 also forms, for example, a polyether tetrol on the base Ethylenediamine (molar weight 480-520, OH index 432 467) is also a soluble salt in the physiologically acceptable range pH range.

In the case of salt formation, a jelly develops with all bases used in the weakly alkaline medium. The gelatinization decreases with increasing pH. Therefore, in general, some base will be in excess of the 1/2 molar ratio

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1 used to achieve a physiologically acceptable pH value between 8 and 10 «, It is therefore useful water-soluble To use bases.

This can be demonstrated by the following experiment:

Niclofolan suspension is converted into N-methylglucamine Niclofolan salt solutions (active ingredient content 596) of pH 9.3, 9.4, 9.5, 9.6, 9.7, 9.8. The solutions up to pH 9.6 form stiff gels, at pH 9.7 one forms soft gel and at 9.8 the gel formation is canceled in favor of a viscous solution »at pH values up to pH 9.7, the active ingredient crystallizes out of the gels after a while »

Injectable niclofolan formulations according to the invention generally contain 1 to 10 percent by weight, preferably 2 to 7 percent by weight, Niclofοlan active ingredient and 3 to 25 percent by weight, preferably 5 to 20 percent by weight of a physiologically compatible, preferably organic base, with the combination of niclofolan active ingredient and base the corresponding Salt is created.

The polyvinylpyrrolidone (PVP) used is PVP with a molecular weight between 10,000 and 160,000, preferably between 10,000 and 40,000 in a concentration between 5 and percent, preferably between 10 and 20 percent (w / w) used »

As could be established according to the invention, the addition of PVP is essential for the following reasons:

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a) After the addition of PVP, the previously gelatinous mass surprisingly liquefies, which occurs at a lower pH value. Thus, by adding 5% PVP to the jelly described above, clear solutions without gel formation and without precipitations are obtained "

b) Thickening of a solution with a higher pH value is prevented by adding PVP.

c) Crystallization of the salts in the formulation is prevented.

d) The addition of PVP also improves tissue compatibility the Niclofolan - saline solution.

The injectable Niclofolan formulations according to the invention furthermore contain water in a concentration from 40 to 90, preferably 55 to 80 percent by weight. Furthermore, the injectable niclofolan formulations according to the invention optionally contain further ones Water-miscible organic solvents, preferably monohydric and / or polyhydric alcohols, for example be ethanol, n-propanol, i-propanol and polyethylene glycols These are water-miscible organic solvents called from molecular weight 200 to 400 optionally added in concentrations of 1 to 30, preferably 5 to 20 percent by weight.

The salt formation of Niclofolan thus leads, as described above, to a water-soluble product, which

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surprisingly more tolerable than the pure Niclofolan active ingredient.

For a practical Niclofolan injection formulation a pure salt solution would be not tolerated enough and too viscous · You would have a high pH, d _e h _e a region outside of the physiologically acceptable pH-range pH or in excessive dilution will.

By adding PVP, it is now possible, surprisingly, as described above to continue to reduce the viscosity sufficiently and at the same time the tissue compatibility in addition to increase. The combination of salt formation and the addition of PVP surprisingly results a very well injectable Niclofolan formulation, which in sufficient concentration of 1 to 10, preferably 2 to 7 percent by weight of Niclofolan active ingredient is to be produced. A failure of the active ingredient Niclofolan is prevented here, also in such a way that there is none in the animal's CSF after the injection Niclofolan - active ingredient secretes. The importance of this question is generally recognized in the professional world, (see z. B. H.G. Schroeder and P.P. des Luca, Bull. Par. Drug i Assoc. 28 (1), 1 (1974) j

The active ingredient used according to the invention niclofolan (5.5 ^L dichloro-2,2-dihydroxy-3,3'-dinitrodiphenyl) is already known (see e.g. US Pat. No. 3,082,151)

Injectable Niclofolan Formulations According to the Invention can be done by any order of the mixing steps, i. H. by any order

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the addition of Niclofolan, the pharmaceutically suitable base, of polyvinylpyrrolidone in aqueous solution optionally prepared with the addition of a water-miscible organic solvent, Preferably, an active ingredient suspension of Niclofolan in water is first used, optionally with the addition of a prepared with water-miscible organic solvent and then with constant stirring the other Components of the niclofolan injection formulations according to the invention, d. ho the organic base and the polyvinylpyrrolidone admitted.

The resulting solution is preferably stirred with a high-speed stirrer, then filtered, bottled and sterilized in a known manner under water or steam «(e.g. at 120 C, 1 at. at least 20 min. Long)

The tests which follow are intended to determine the compatibility, applicability and the plasma level values (blood level values) of the niclofolan injection formulations described in the preparation examples below document",

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1 “Compatibility Tests

Compatibility tests on cattle with the injectable Niclofolan formulations were carried out analogously the preparation examples 1 and 2 carried out pro injectione. applied subcutaneously on the left side of the neck of the test animals. The single subcutaneous application only led to few animals to slight swellings up to Days after treatment.

Differences in terms of their local tolerance could not be found in the tested formulations will. General symptoms of intolerance · were not determined,

The results' should be documented by the following table 1 »

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Table 1

Niclofolan - formulations pro injectione:

Test of tolerance in cattle after three times

subcutaneous application

Animal formula dose counting in

according to mg / kg positional example no.

Application tolerance in days cation after treatment *

2 2 0.75 S.Cο 0/2/2 0/2/2 / 0/2/2 0/2/2

2 2 1.00 S _e C. 1/1/2 1/1/2 0/2/2 0/2/2

2 1 0.70 S.Cο 0/2/2 0/2/2 0/2/2 0/2/2

2 1 1.00 S.C. 1/1/2 1/1/2 0/2/2 0/2/2

* The sequence of numbers x / y / z means

χ = number of swellings

y = number of injection sites without findings ζ = total number of injection sites

After just 5 days, no swelling whatsoever could be detected in the individual test animals.

When using a niclofolan formulation consisting of 2% active ingredient in N-methylpyrrolidone w / v, swellings and necroses were found at the respective injection site 14 days after the treatment.

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Applicability i

All tested formulations could be applied very well.

Blood level determination

Comparative plasma level studies on cattle with the injectable niclofolan formulations were carried out carried out according to example 1 and 2 after subcutaneous and intramuscular injection and with niclofolan tablets. Here, the niclofolan formulations according to the invention showed clearly higher blood level values than the Tablets - formulations.

The highest blood level values were reached after intramuscular injection. (See the following for more details Table 2).

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Table 2

Niclofolan / blood level determination / plasma concentrations in cattle

Formulation beef
No. body
weight
kg dose
mg / kg application Solution according to mean values: 364
360 0.75
0.75 subcutaneous
Il Mean values: 360
373 1
1 subcutaneous
Il Percentage _Μ ^ _β1νίβ ^ _θ : 404
370 0.75
0.75 subcutaneous
Il Mean values: 302 1 in the. ä 300 mg mean values: µg of niclofolan per ml of plasma 6 ^h 24 ^h 48 ^h 72 ^h 96 ^h 952
Nicolofolan 953
5 percent 954 354
344
350 1
1
1 subcutaneous
Il
Il Example 2 _g55
956 948
Niclofolan _g4g Example 1 ^
951 Niclofolan _g73
5% solution
according to example 2 364 1 in the. 4.5
6.1
5.8 5.5
7.3
6.2 3.3
4.2
3.7 2.5
3.3
2.6 2.1
2.4
«2.0 Niclofolan _g47
5% solution
according to example 1 347
365 3
3 per os
■ 1 Il 5.5 6.3 3.7 2.8 2.1 Niclofolan-945
Tablets 946 4.7
6.5 4.0
5.0 2.5
3.4 <2.0
2.6 <2.0
<2.0 5.6 4.5 3.0 2.3 <2.0 5.5
4.5 5.1
6.6 3.4
4.1 2.5
2.8 <2.0
2.5 5.0 5.9 3.8 2.7 2.2 3.5
4.8 3.2
6.0 2.6
3.0 <2.0
2.4 <2.0
<2.0 4.2 4.6 2.8 2.0 <2.0 6.8 8.8 5.4 3.9 3.4 5.7 7.6 4.7 3.3 2.8 <2.0
2.3 . 3.3
6.3 2.9
4.9 2.1
3.6 <2.0
2.3 <2.0 4.8 3.9 2.9 2.0

VO

vo

The manufacture of the injectables according to the invention Injection formulations are intended by the following preparation examples documented, but not restricted.

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example 1

10g of 96% pure ethyl alcohol and 64.08 g of water are used placed in the reaction vessel and then the solids, d. H. here 5.00 g Niclofolan (5,5'-dichloro-2,2'-dihydroxy-3,3'-dinitrodiphenyl) and 7.5 g of N-methylglucamine and 20 g of polyvinylpyrrolidone with a molecular weight of approx. 25,000 are stirred in addition. The resulting solution is filtered, bottled and sterilized under water.

This creates a dark red solution with a pH of 9.4. The viscosity of the solution is 100 cps (centipoise)

In Examples 2 to 5 below, the individual components were combined as described in Example 1. The components contained in the individual examples were combined in the following amounts:

Example 2

Niclofolan active ingredient DL-Lysine-Base 5096 in water

PVP 25 (molecular weight approx. 25,000)

Pure alcohol 9696 water per inj «,

104.7 g = 100 ml dark red solution, pH 9.4, viscosity approx. 125 cps.

5.0 G 10.0 G 20.0 G 5.0 G 64.7

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Example 5

Niclofolan active ingredient 5.0 g

DL-lysine base 50% in water 10.0 g

PVP 17 (molecular weight approx. 11,500) 2o, o g

Water per inj. 71.3 g

106.3 g = 100 ml

Dark red solution, pH 9.2, viscosity 18 cps. Example 4

Niclofolan active ingredient 4.0g

N-methyl glucamine 6.0 g

PVP 25 (molecular weight approx. 25,000) 16.0 g

Alcohol pure 96% 10.0 g

Water per inj. 67.0 g

103.0 g = 100 ml

Dark red solution, pH 9.7, viscosity 55 cps. Example 5

Niclofolan active ingredient 5.0 g

Triethanolamine 15.0 g

PVP 25 (molecular weight approx. 25,000) 17.5 g

Aqua pro inj. 69.5 g

107.0 g = 100 ml dark red solution, pH 8.8, viscosity 66 cps.

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Claims (3)

Claims Liquid, injectable formulations of Niclofolan (5,5'-dichloro-2,2'-dihydroxy-3,3'-dinitrodiphenyl), characterized in that it contains one or more physiologically suitable bases, polyvinylpyrrolidone and Water and optionally also contain a water-miscible organic solvent. 2. Formulations according to claim 1, characterized in that they _{contain 2 to 7 percent by weight:} Niclofοlan active ingredient, 2 to 20 percent by weight of a polyvinylpyrrοlidons 55 to 80 percent by weight of water and 5 to 20 percent by weight of a water-miscible organic solvent » 3. Process for the preparation of liquid, injectable formulations of Niclofolan (5,5'-dichloro-2,2'-dihydroxy-3,3'-dinitrοdiphenyl), characterized in that 2 to 7 percent by weight of the Niclofοlan active ingredient it with 55 to 80 percent by weight of water, optionally with the addition of 5 to 20 percent by weight of a water-miscible organic solvent and then stirred for 2 to 20 Weight percent of a physiologically suitable organic base and 5 to 20 weight percent of one Polyvinylpyrrοlidons and the resulting solution then sterilized according to methods known per se, Le A 16 694 - 16 - 70 983 1/083 3 ORIGINAL! NSPeCTED