DE2262411A1 - ANTIVIRAL COMPLEX, PROCESS FOR ITS MANUFACTURING AND MEDICINAL PREPARATIONS CONTAINING THIS COMPLEX - Google Patents

Description

"Antiviral complex, process for its production and medicinal preparations containing this complex"

Priority: December 21, 1971, Great Britain, No. 59 460/71

It is known per se that the double-stranded complex of Polyriboinosinic acid and polyribocytidylic acid, hereinafter referred to as Poly I: Abbreviated as Poly C, a highly effective interferon inducer and therefore of great importance for the broad spectrum prophylaxis of viral infections and to a lesser extent Extensively it can also be used to treat such infections.

However, there is evidence that the double-stranded complex Poly I: Poly C is too toxic in humans and animals

3 0Ö0 277r 1 7 5

- 2- 2 26 2 41!

Side effect lint,;> an application in human and veterinary medicine is therefore limited.

There is therefore a need for an antiviral agent that is less More toxic than Poly I: Poly C alone is, and its tintiviral Activity is comparable or better.

So far, polybases, such as spermine, spermidine, cadaver , polylysine, protamine and diethylaminoethyl alcohol, have been used to stabilize the nucleic acids, especially some synthetic double-stranded muscles, against thermal denaturation and nuclease degradation. When synthetic double-stranded ribonucleic acids were discovered to be inkerferon inducers, it was believed that treatment of double-stranded ribonucleic acid with such polybases resulted in stabilization against degradation by ribonuclease and thus improved or prolonged antiviral activity in vivo. Most of the work dealing with interferon has so far investigated the separate addition of the polybase to synthetic double-stranded ribonucleic acids, such as polyinosinic acid: polycytidylic acid (poly I: poly C). However, the results of this work are not very encouraging. It is true that increased interferon levels were obtained in tissue cultures (cf. GP Lampson, AA Ty tell, A. Kirck Field, MM Nemes and MR Iliileman, Proc. Soc. Exptl. Biol. Med., 132 (1969) p. 212; F Dianzani, S. Baron, CE. Buckler and HB Levy, Proc. Soc.Exptl. BioL. Med., 136 (1971) p. 1111; JY Richmond, Arch, for the whole of VLrusforschung, XJ. (197L) p. 242; JG Tilles, Proc. Soc. ExptL. Med., 133 (4) (1970)

') Oil BT / 7 1175

P. 1334; Λ. Billiau, CE, Buckler, F. Dianzani, C. Uhlendorf and S. Baron, Ann. N.Y. Acad. Sci., 17-3 (1970) p. 657; B, D. Rosenquist, Am. J. Vet.Res., 3_2! (1) (1971) p. 35), yes where the activities of the polybase-treated synthetic ribonucleic acids were tested in animals (see the authors mentioned above), were neither the protection against viruses nor the toxicity changed significantly.

Gabbay et al. (Ann. N.Y. Acad. Sci., 171 (3) (1970) p. 810 and Biochemistry, K) (9) (1971) p. 1665) have the interaction of some monomeric quaternary ammonium compounds with (inter alia) the double stranded synthetic ribonucleic acid polyadenylic acid: Polyuridylic acid (Poly A: Poly U) investigated. This work, however describe only the physico-chemical properties and the structure of these complexes, moreover they do not have polyquaternary Ammonium compounds, worked.

Surprisingly, it has now been found that polymeric polycations form strong complexes of polyriboinosinic acid and polyribocytidylic acid with a large number of quaternary nitrogen atoms, which are generally less toxic than Poly I: Poly C at least at intraperitoneal administration and are a very good antivira-Ie Have activity, at least in small mammals.

The invention thus provides an antiviral complex, which is characterized in that the cations in the ionic Complex organic polymer polycations with a variety of

309827V-1175

-A-

quaternary nitrogen atoms along the polymer chains and the Anions

a) Polyanions of a complex of polyriboinosinic acid and polyribocytidylic acid or

b) polyanions of a double-stranded derivative of a complex von Polyriboinosinsäure'und Polyribocytidylsaure are.

The term "double-stranded" refers to the fact that one molecule of polyriboinosinic acid and one molecule of polyribocytidylic acid through hydrogen bridge bond between the complementary Bases are associated along the molecule. These. Ribonucleic acids can be "double-stranded" to different degrees.

The term "double-stranded derivative of the complex of polyriboinosinic acid and polyribocytidylic acid "refers to any poly I: poly C complex that is chemical or biochemical (e.g. enzymatic) reaction, which is the primary and / or secondary and / or tertiary structure changed (e.g. the N-oxides according to OS 2 122 644). The prerequisite is that the resulting Derivative still has a substantial part of the base pairs of the complementary strands.

The double-stranded nature of poly I: poly C or its derivative can be determined by two parameters, the hyperchromicity and the Tm value, be characterized. These parameters are obtained by recording the UV absorbance of the material at 258 nm while the Temperature is gradually increased. The UV absorption of a

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double-stranded RNA at this wavelength increases with increasing Temperature until a constant value is reached, that of the absorption of the thermally denatured (e.g. single-stranded) ribonucleic acid is equivalent to. The difference between the two limits of absorption, expressed as a percentage of the absorption of the double stranded material ·, is called the "hyperchromicity" of this Material designated.

The UV absorption at 258 nm of a double-stranded material Plotted against the temperature, it is found that the absorption is greater at high temperatures than at low temperatures is. The temperature at which the absorption is halfway between the absorption of the double stranded material and the of the thermally denatured (e.g. single-stranded) material is referred to as the Tm value of this material.

The cations of the complex according to the invention are organic Polymer cations with a large number of quaternary nitrogen atoms along the polyra chain. Suitable organic polymer polycations have a structure according to formula (I)

(ca) IT.—C. cn Jl-

CII.

CH.,

CH.

CH

CH,

CIL

in which a and b are identical or different integer values from 2 to 10, X is an integer greater than or equal to 2 or a fraction of which mean, depending on the chain length.

3Ό-9 & 2ΤΤΤΤ7-5

Polycations of the general formula (I), in are also suitable which is the carbon chain between the quaternary nitrogen atoms Carries methyl groups.

The antiviral complex of the present invention is essentially a ionic complex created by a strong electrostatic interaction between the polymeric cationic part and the anionic portion of the ribonucleic acid is characterized. However, other types of interactions are also possible, e.g., there is believed to be some sort of "hydrophobic" bond between the two components. Know the exact nature of this bond but not yet.

Preferred complexes according to the invention are those in which all or almost all anionic sites of poly I: poly C anions with quaternary cationic sites of the quaternary polymer are neutralized. Such complexes are called "1: 1 complexes" or "highly neutralized complexes" referred to.

The invention also relates to a process for the preparation of the antiviral complexes, which is characterized in that in Solution either with organic polymer polycations with a large number of quaternary nitrogen atoms along the polymer chains

a) Polyanions of a complex of polyriboinosinic acid and polyribocytidylic acid or

b) polyanions of a double-stranded derivative of a complex of polyriboinosinic acid and polyribocytidylic acid are converted.

309-277-175

Although all complexes according to the invention by this method can be produced, the physical properties of the complexes depend to a certain extent on the type, with which the polycations and polyanions are brought into contact., The complexes according to the invention can be divided into two groups divide, namely those in 0.15 m sodium chloride solution are soluble (hereinafter referred to as "soluble complexes") and those which are insoluble in 0.15 M sodium chloride solution (hereinafter referred to as "insoluble complexes").

In general, insoluble complexes are

put a solution of polyquaternary compound to a dilute solution of Poly I: Poly C or its derivative (e.g. in a Concentration of about 0.5 mg / ml). For example, one can use a solution of the organic containing the desired polycation Polymer easily -in an aqueous solution of an inorganic Make a salt such as sodium chloride. A corresponding; Appropriate solution of Poly I: Poly C can be used in an aqueous solution,!

containing an inorganic salt. The poly-

Quaternary solution is then taken under the solution of Poly I: Poly C Stir added. If the molarity of the resulting saline solution:

is not too high, the desired complex precipitates directly. If no precipitation takes place, the solution can be diluted to reduce the molarity below the critical point, the the desired precipitate then precipitates out.

TB

On the other hand, a device can be the polycation and poly I: Poly C or its derivative containing neutral polymer are added to a salt solution. If necessary, the resulting solution diluted to precipitate the desired complex, preferably in both processes for the preparation of the insoluble Complex a molar excess of organic polymer polycations used, the molar excess being based on the number of basic reaction sites with the phosphoric acid the ribonucleic acid polyanions can react.

For the preparation of the soluble complexes according to the invention a solution of the polyquaternary compound slowly with stirring to a solution of poly I: poly C or its derivative in aqueous 0.15 m sodium chloride solution until precipitation begins or until a small amount of the antiviral complex has precipitated added. Any precipitate that has separated out is removed, the desired complex remains in solution. Generally should extensive precipitation can be avoided, since then the homogeneity of the complex remaining in solution is not guaranteed. The solution of the polyquaternary compound is preferably a solution, the poly I: poly C or its derivative in a Concentration of at least about 5 mg / ml, e.g. 5 to 20 mg / ml, is added, since at higher dilutions almost all poly I. : Poly C precipitates as an insoluble complex.

As described above, such complexes are preferred whose charges, preferably _f more than 60 percent over 75 percent of newly

are centralized. In addition, complexes that are in isotonic salt solutions are soluble, because they - compared to the insoluble complexes - are more suitable for administration and in some cases have more favorable biological properties. However, not all polyquaternary compounds are suitable for production of soluble complexes, since in some cases an insoluble complex is precipitated before sufficiently polyquaternary Compound has been added to provide a high level of charge neutralization to reach. Although one can only determine empirically Whether a soluble complex with a particular polyquaternary compound can be prepared can be given a few guidelines. When using a polyquaternary compound according to the general Formula (I) seems to have some relationship between the equivalent weight of the polyquaternary compound and that before Precipitation of the insoluble complex to exist achievable degree of neutralization. (The equivalent weight is determined as that Molecular weight of the polycation divided by the number of basic nitrogen atoms per molecule). When using quaternary Polycations according to the general formula (I) with a low equivalent weight can before the precipitation of the insoluble Complex more polycations form a complex with the ribonucleic acid than when using quaternary polycations general formula (I) with a higher equivalent weight. For this reason it has not previously been possible to use "soluble complexes" with polycations of the general formula (I) with a higher equivalent weight than the compound (I) (a = 3, b = 4, 2 χ = 7.8).

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Most, if not all, of the insoluble compounds of the present invention Complexes, i.e. complexes that are insoluble in 0.15 M aqueous sodium chloride solution, can be used in concentrated electrolyte solutions but dissociate. This is in contrast to the soluble complexes that exist in 0 »15 m Dissociated sodium chloride solution practically does not dissociate.

The complexes of the present invention (both soluble and insoluble) have broad spectrum antiviral activity against a number of deoxyribonucleic acid and ribonucleic acid viruses such as encephalomyocarditis virus, Semliki Forest virus, foot-and-mouth disease virus and against herpes simplex virus. The complexes according to the invention presumably induce interferon production in the host cells and thus protect against attack by the viruses. Therefore, the complexes according to the invention are probably more suitable for the prophylaxis of viral infections than for the treatment of existing infections. The complexes according to the invention are im ^; generally more resistant to degradation by ribonuclease than Poly I: Poly C itself.

The invention therefore also relates to medicinal preparations which contain an antiviral complex according to the invention as an active ingredient, optionally in combination with one or more pharmacologically acceptable carriers and / or diluents Marked are.

09827 ¹ ATITS

The choice of carrier depends on the preferred one Mode of administration. You can use the medicinal products s.B. Inject subcutaneously intravenously or intramuscularly.

The complex according to the invention is then in the diluent, either dissolved or suspended as a fine dispersion. However, even the soluble complexes of the present invention are after isolation (e.g. by freeze drying) sometimes difficult to dissolve again. It is therefore preferable to place the complex in the diluent, e.g. in an isotonic saline solution. When used locally, e.g. on the mucous membrane, the carrier is a diluent,

The pharmaceutical preparations according to the invention can be used alone or in grain · bination with other agents used for the treatment of viral infections (e.g. vaccines) are used.

The examples illustrate the invention.

cytidylic acid.

Example 1 · '

Preparation of the complex of poly I; Poly C and HexadimethrIn bromide.

To a stirred solution of 100 mg Poly I: Poly C in 200 ml an aqueous 0.15 M sodium chloride solution is a solution of 200 mg of hexadimethrine bromide in 200 ml of a at room temperature aqueous 0.15 M sodium chloride solution was added. A precipitation occurs. That. Reaction mixture is 16 hours at

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Stirred at room temperature and then centrifuged «The UV spectrum of the supernatant solution indicates that the solution does not contain any poly I: poly C. The precipitate is first mixed with 200 ml of water and then washed with 200 ml of methanol and thereafter dried under reduced pressure at room temperature. Yield: 158 mg.

Feature, Transparent and characterization of this complex aften

1) The compound is soluble in aqueous saline solution with a molarity of 0.6 and higher.

2) The UV spectrum shows, with weighed amounts of the complex, that it contains 68-10 percent Poly I: Poly C. A neutral one Complex (IN per phosphate) would contain 76 percent Poly I: Poly ς.

The compound obtained is likely the neutral 1: 1 complex, however, incomplete drying due to a strong bond of the solvent can give a low poly I: poly C analysis.

3) When dissolved in sodium chloride solutions of high molarity, the complex appears to be dissociated.

The addition of an equal volume of ethanol to a solution of the complex in aqueous 1.5 M sodium chloride solution provides a quantitative precipitation of poly I: poly C.

^{3 0 98 27 1/1 1} 7 5

The physical characteristics, such as UV spectrum, hypochromicity, Tm value, of the poly I: poly C obtained in this way are the same as those of the starting complex. Poly I: 'Poly C. In addition, gel penetration chromatography of a solution of the complex in aqueous 1.5 in sodium chloride solution on a "Biogel 150 IT" column provides the same UV spectrum as the starting complex Poly I: Poly C. ·

4) If the molar quantity of the solution of the complex is reduced to an aqueous sodium chloride solution below 0.6 m, the complex will precipitate.

Antiviral activity of the complex

The compound to be investigated is injected intraperitoneally into mice of the CDI strain weighing 16 to 20 g. 24 or 72 hours later, these mice are inoculated with encephalomyocarditis virus, again intraperitoneally. The animals are observed for 12 days and the mortality ratios and the mean survival time of the treated mice are compared with those of untreated control mice. The average service life is calculated as follows:

N
η
χ

ST =

where N is the number of animals in a group and η is the number of animals on day χ.

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Table I.

link Time between
administration
the connection
and the viruses
(Hours) Dose a)
(SchweTn /
Mouse) Virus vaccination virus vaccination
material . material
-4 -5
10 10
Morta- upper Morta- ber-
lity, life, life
duration duration 4.9
5.6 8/10
8/10
4/10 6.9
7.6
13.0 Poly I: _bJ
Poly C ^s '
-Hexadim-
ethrin-
complex 72 1
10
100 9/10
10/10
3/10 6.6
20.7
20.0 2/10
1/10
4/10 42.7
59.9
23.1 24 1
10
100 8/10
3/9
3/10 4.9
6.3
8.4 9/10
7/10
5/10 5.3
7.9
11.4 Poly ls _£)
Poly c "" 72 1
10
100 10/10
9/10
7/10 6 _f 3
8.3
21.4 0/10
0.10
0.10 0.0
0.0
0.0 24 1
10
100 9/10
6/10
3/10. 4.7 19/20 5.2 untreated
delt Ll / 10

a) relates to the respective amount of Poly I: Poly C,

b) administered as a 1.5 M NaCl solution,

c) administered as 0.15 M NaCl solution.

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- '15 ■ -

Toxicity of poly I: poly C-hexadimethrin complex

The toxicity of Poly I: Poly C parent compound and that of the poly I: poly C-hexadimethrin: complex are at 16 to 20 g heavy mice of the strain CDI were compared. The connections are injected intraperitoneally. The animals are 10 days observed for a long time.

Table II

link Dose a)
(mg / kg) mortality entry
of
Death ^LD 50
(mg / kg) Poly I: _b)
Poly C.
-Hexadimeth-
rin-
complex 20th
40
80
160 0/10
0/10
0/10
0/10 160 Poly I: _£)
Poly D 20,
40
80
160 0/10
4/10 j
10/10 y
7/7 ^} 12-17 hours
according to the ver
submission 40,

a) relates to Poly I: Poly C in every preparation,

b) administered as a 1.5 m NaCl solution, ^Λ

c) administered as 0.15 M NaCl solution.

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Example 2

a) Production of polyquaternary ammonium compounds as starting material.

0.1 mol of N, N, N ¹ , N'-tetramethylpropane-1,3-diamine and 0.08 mol of 1,4-dibromobutane are refluxed in 300 ml of methanol for 5 hours. The solution is cooled and evaporated under reduced pressure. The residue is dissolved in 250 ml of water. The solution is extracted three times with 150 ml of ethyl acetate each time.

After extracting with ethyl acetate, the aqueous solution is concentrated under reduced pressure. The residue is three times treated with 500 ml of boiling isopropanol, filtered and dried. A fine catfish powder is obtained, which as "Compound II" is designated.

b) Characterization of the polyquaternary ammonium compounds used as starting compounds .

In a work on the macromolecular properties of Hexadimethrin bromide suggest Barlow et al. (G.H. Barlow, L.J. Coen, E.T. Kimura and S. Keresztes-Nagy in Proc. Soc.Expl. Biol. Med., Ri3_ (1963) p. 884) suggest that the reactions that the Can terminate polymerization, cyclization and dehydrobromination are.

The NMR spectra (determined in D_O) of hexadimethrine bromide and the other saturated polyquaternary ammonium compounds according to the invention do not indicate the presence of vinyl protons

30 98 2771175

which, however, would have to be present if the chain had been terminated by dehydrobromination. In any case, however, there is a singlet at 6 - 2.2 to 3 ppm, which can be ascribed to the -N (CH- ^ protons. This indicates that the polymer chain ends with dimethylamine groups, provided that these Assumption is correct, it is possible to calculate the average molecular weight of these polymers from the ratio of the resonance intensities assigned to the -N (CH ₃ ) ,, protons (chain extension) to the resonance intensities assigned to the -N (CH ₃ ) protons (chain end). Unfortunately, these bands cannot be determined precisely because they overlap with other resonances. However, since both bands represent sharp singlets, the relative peak height can be regarded as a first approximation.

For example, is for hexadimethrin bromide. ("Connection I", a - 6; b ~ 3) the intensity:

+ N (CH) _ 20 * 0

Intensity·. ——— * - * - = - = 11.8 (= x)

N (CH ₃ ) ₂ 1.7

This means that hexadimethrine bromide contains 2 chain end groups per 23.6 chain extension groups. ^Ί

Hence: mean Μοΐ, weight = 116 + (23.6 χ 187.1) + 44 = 4590 »

309 8277Ϊ V75

This value roughly corresponds to the values of Barlow and coworkers (see above.) for a standard sample of hexadimethrine bromide after measuring the sedimentation equilibrium and the sedimentation velocity, give values of 3800 and 4100.

The analytical and structural data of the polyquaternary "Compound II" are given below. The polymer is extremely hygroscopic, making precise elemental analyzes difficult to obtain.

"Connection II":

Br

N ⁺ - (CH ₈ ) _b - N ⁺ -

I I

CH, CH -3-3

Br

N (CH-X

a = 3, b = 4
Yield: 51.3%
Analysis: - C

II

Br

ber.
found 40,
37, 5
7th 8th,
8th, Il +
-N ( 1 9.3
0 8.3 42.1
43.3 24 , 6 ktrum in D ₂ 0; 3.23
-N ( 6th , 3 2.48 CH ₃ J ₂ - 0 ppm = Maximum, Height = (f ppm = Maximum, Height =

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Total number of quaternary nitrogen atoms (2 Jc) = 7.8 molecular weight = 1480 ■
Equivalent weight = 151

( MW )
(2x + 2)

c) Production of complexes of poly I which are soluble in isotonic physiological saline solution: 'poly C and der. Connection I I

1) 90 mg of a solution of Poly I: Poly C in 6 ml of an aqueous 0.15 M sodium chloride solution are kept at one temperature for 2 days kept at 37 C. To this solution is under constant Stirring 3 ml of a solution of 24 mg of the "compound II" in aqueous 0.15 M sodium chloride solution · added dropwise. It kicks a very little precipitation. The precipitate is centrifuged off. Ih the remaining solution is based on the UV spectrum found the concentration of Poly I: Poly C to be 9.8 mg / ml.

This complex is referred to as "C ^ c",

Thinnings of this solution are used for biological investigations used.

2) The process according to (1) is repeated, with the exception that 32 mg of "Compound II" are used. In this case, greater precipitation is observed and the final concentration of the poly I: poly C in the supernatant solution is 8.5 mg / ml. This complex is denoted by ' ^{c i6'}

30 9827/1175

designated. Dilutions of this LösringKiT are used for biological studies used.

The percentage neutralization of the charges based on the average molecular weight of the sodium salt of a nucleotide 3 ^; 10.7 dal tons for both nucleic acids, is _{60 percent for the complex 'C 1} P and 80 percent for the complex C ^. The percentage of precipitation of poly I: poly C during the production of complex C _{] t} - is 2 percent and that of complex C, <13 percent.

d) Biological properties of the complexes Cj ^ and C ^.

1) Antiviral Activity

Mice weighing 18 to 22 g of the CDI strain become the investigating compounds intraperito-

neal 24 hours before infection with encephalomyocarditis viruses (KMC viruses), also by intraperitoneal injection * administered. The dead animals are recorded daily for 13 days .

complex Dose _N
(rng / kg) ^a) Number of dead animals / number of animals one
group Virus Dosi.'i 1O-5 c 15 0.5
0.05 Virus dose 10-4 0/10
4/10 C 16 0.5
0.05 VlO
8/10 2/10
6/10 Poly I.
Poly C. 0.5
0.05 Vio
8/10 3/10
2/10 Untreated
JeIt 7/10
10/10 19/10 19/10

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ORIGINAL INSPECTED

<i) relates to the respective nucleic acid component

2) toxicity

The acute toxicity is measured in mice weighing 18 to 22 g from
Strain CDl determined. The animals are 7 days after a
observed intraperitoneal administration and noted the dead animals.

complex Number of dead animals / number of animals
a group
regular dose &) mg / kg 100 80 50 40 25th '20 LD ^ ₀ (approximate)
(mg / kg) 400 2/5 0/5 C15 0/5 1/5 80 C16 72

a.) relates to the respective nucleic acid component

Ribonuclease Sensitivity

The rate of degradation of the complexes -C ₁ , - and C ₁ ^ -.

. "pancreatic ribonuclease is used with
compared to that of Poly I: Poly C. 10 pi of a solution containing 1 mg / rnl contains the enzyme in aqueous 0.15 M sodium chloride solution to a solution of 100 μ & Nucleinsäüre in 2.5 ml of an aqueous 0.15M sodium chloride solution added. The optical density at 2βθ nm is determined at intervals of 5 minutes;

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Time after
Addition dor
Ribonuclease
(Min.) Hyperchromicity % (260 nm) ^C l5 ^C 16 5 Poly I: Poly C 0 2.2 10 29.0 1.0 15th % ^ 2.0 4.4 20th 58.7 5.0 · 4.4 25th 58.7 4.0 4.4 50 58.7 5.0 4.4 60 58.7 16.0 10.9 120 58.7 58.0 54.8 58.7

After 2 hours, _{a precipitate occurs in the batches with C, r} and Cig. As a result, both complexes are in the middle.

Ribonuelease slower than poly I: poly C degraded.

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Claims (17)

Claims 1. Antiviral complex, characterized thereby net that the cations in the ionic complex are organic Polymer polycations with a large number of quaternary nitrogen atoms along the polymer chains and the anions either a) Polyanions of a complex of polyriboinosinic acid and polyribocytidylic acid or b) are polyanions of a double-stranded derivative of a complex of polyriboinosinic acid and polyribocytidylic acid. 2. Antiviral complex according to claim 1, characterized by an organic polymer polykatiana chain of the general formula (I). CH 'a (-CH 2 " ³ T) CH CH ι! N ⁺ (CH, CH " (D in which a and b are the same or different whole values from 2 to 10, X denote an integer greater than or equal to 2 or a fraction thereof, depending on the chain length. 3. Antiviral complex according to claim 1 and 2, characterized in that that in formula (I) the carbon chain between the 3.09027 / 1176 quaternary nitrogen atoms, double or triple bonds holds or carries methyl groups. 4. Antiviral complex according to claim 1 to 3, characterized in that that it is insoluble in aqueous 0.15 M sodium chloride solution. 5. Antiviral complex according to claim 1 to 3, characterized in that that it is soluble in aqueous 0.15 M sodium chloride solution. 6. Antiviral complex according to claim 1 to 5, characterized in that that over 60 percent of the original charges are neutralized. 7. Process for the preparation of the antiviral complexes according to claim 1 to 6, characterized in that one is in solution organic polymer polycations with a large number of quaternary nitrogen atoms along the polymer chains with either a) Polyanions of a complex of polyriboinosinic acid and polyribocytidylic acid or b) polyanions of a double-stranded derivative of a complex of polyriboinosinic acid and polyribocytidylic acid. 8. The method according to claim 7, characterized in that the reaction with polymer polycations of the general formula (I), 3 0 9827/1 17b (cn) ΐί _i. cn 4__ I 4-CIL CIL CLL. χ. in which a and b are the same or different whole values from 2 to 10, X is an integer greater than or equal to 2 or a fraction thereof, depending on the chain length. 9 * Method according to claim 7 or 8, characterized in that that one can implement the reaction with polymer polycations of the general Formula (I) carries out, wherein the carbon chain between the quaternary nitrogen atoms contains double or triple bonds or carries methyl groups. 10. The method according to claim 7 to 9 ", characterized in that that the insoluble in aqueous 0.15 M sodium chloride solution Complex by reacting a molar excess of organic Polymer polycations with polyanions of the complex of polyriboinosinic acid and polyribocytidylic acid, the molar excess is related to the number of basic centers associated with the phosphoric acid of the polyanions of the complex of Pölyribö ~ inosinic acid and polyribocytidylic acid can react » 11 »The method according to claim 10, characterized in that a mixture of the complex and the polyquaternary compound an aqueous 0.15 M sodium chloride solution is added with stirring. 30 9 8 27/117 5 12. The method according to claim 10, characterized in that an aqueous electrolyte solution of the polyquaternary compound slowly added to a dilute aqueous electrolyte solution of the complex. 13. The method according to claim 12, characterized in that to dissolve the two substances in each case an aqueous 0.15 m Sodium chloride solution used. 14. The method according to claim 7 to 9, characterized in that the soluble in aqueous 0.15 M sodium chloride solution antiviral complex by slowly adding while stirring an aqueous 0.15 M sodium chloride solution of the polyquaternary compound to an aqueous 0.15 M sodium chloride solution of the complex of polyriboinosinic acid and polyribocytidylic acid to the beginning Precipitation or until a small amount of the antiviral complex has precipitated. 15. The method according to claim 14, characterized in that the complex of polyriboinosinic acid and polyribocytidylic acid added at a concentration of 5 to 20 mg / ml. 16. The method according to claim 8 to 15, characterized in that the by the polyquaternary compound and the complex of Polyriboinosinic acid and polyribocytidylic acid formed antiviral complex up to 60 percent of the charges is neutralized. 77T17 17. Medicinal preparations, characterized by ein'Gehalt an an antiviral complex according to claim 1 to 6 as active ingredient, optionally in combination with one or more pharmacologically compatible · carriers and / or diluents. 30 9 827/1176