AP827A

AP827A - Pharmaceutical preparation with trypanocidal qualities for veterinary use.

Info

Publication number: AP827A
Application number: APAP/P/1998/001196A
Authority: AP
Inventors: Alain Jacques Bourdichon
Original assignee: Atarost Allgemeine Tierarzneimittel Fabrik Dr Ulrich Bohmer Nachf Gmbh & Co
Priority date: 1995-08-21
Filing date: 1996-08-20
Publication date: 2000-04-28
Also published as: AP9801196A0; DE19530708C2; DE19530708A1; EP0845983A2; WO1997006769A3; AU6875096A; WO1997006769A2; EA199800218A1; OA10665A

Abstract

A pharmaceutical composition with oypanccidal properties useful in veterinary medicine in' the form of an aqueous solution contain; diminazen-diacerurate. pentamidine, phenazon, glycerine and a water-soluble cellulose ether.

Description

Pharmaceutical preparation with trypanocidal qualities

Feld of application

The invention refers to a pharmaceutical preparation with trypanocidal qualities for veterinary medical use, in the form of an aqueous solution, which contains diminazen-di-aceturate (4.4’ diamidinediazobenzenediacelamidoacetate) and pentamidine (4.4’ - (pentamethyienedioxy) dibenzamidine) as trypanocidal drugs, phenazone (1.2- dihydro-1,5-dimethyi-2-phenyl-3Hpyrazo(e-3-one) as fever-reducing and pain-relieving components, as well as glycerol.

In countries with a tropica! climate, infectious diseases caused by protozoa are widely spread, such as the so-called sleeping sickness (trypanosomiasis), which damages the central nervous system and leads to death if not treated. The disease concerns humans and animals equally and has to be treated by chemotherapy.

In the field of agriculture, veterinary medicine is in great need of effective preparations to fight such infectious diseases. Permanent consideration needs to be paid to the fact that conditions in regard to sanitary measures as they can be found in Africa, for example, are oftentimes poor.

Prior art

Arsenic preparations and trypan dyes are known as chemotherapeutical drugs, which are, however, disadvantageous due io their content of arsenic respectively their carcinogenicity. A weH known preparation which has long been used for the treatment of such infections in animals in many cases is a trypanosome on the basis of diminazene powder. Other commercial trypanosomes are aiso available in a powdered form only. But especially the powdered form of the drug is extremely disadvantageous, due to the fact that the powdered drugs cannot be mixed into the fodder and thus need to be mixed with water to make an injectable solution. It Is not possible to produce a sterile solution from the powdered preparations, since the active substances form crystals in the solution after a short time, so that the effectiveness of the preparation gets lost quickly. Thus, such solutions cannot be stored and transported well enough. For this reason the injectable solution has to be produced a short time before the injection. This is very dangerous due to the fact that the water which is available, usually contains bacteria, viruses and causative organisms, which can causa additional

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AP 0 0 0 8 2 7 diseases in the animals and would thus put great strain on the animals. Also, no complete solution of the solids can be reached, due to poor solubility of these powdered drugs. This leads to an insufficient effectiveness of the injectable solution.

The powdered trypanosomes which are known today, thus pose a danger of additional infections respectively contamination. At the same time there is the danger of underdosage of the therapeutic drug, so that the chemotherapeutic treatment may have to be repeated, which naturally involves an increased risk of infections and the like.

In order to avoid the disadvantages of powdered trypanosomes, aqueous solutions of diminazen-di-aceturate have been developed, which contain caster oil as a solubiliser.

The manufacturing process is, however, relatively time-consuming and the stability of the resuiting solution of the preparation can only be assured up to a temperature of about 25*C.

This may be sufficient under normal circumstances; in tropical countries, however, storage conditions cannot always be observed, so that the preparation will spoil.

Problem, solution, advantages

The object of the invention is to provide a solution of a pharmaceutical preparation of the abovedescribed kind which remains stable, even in high temperatures.

in order to solve this problem, the plan according to the invention is to provide a \ pharmaceutical preparation with trypanocidal qualities in the form of an aqueous solution which contains the following agents:

(Ix » diminazen-di-aceturate (4.4’ diamidine-diazoaminobenzene-diacetamido-acetate) • pentamidine (4.4’-(pentamethylenedioxy)-dibenzamidine) • phenazone (1,2-dihydro-1,5-dimethyl-2-phenyl-3H-pyrazole-3-one) • glycerol • water-soluble cellulose ether.

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Diminazen-di-aceturats and pentamidine are trypanocidal drugs with different activity spectrums which therefore complement each ether in regard to their area of effectiveness, so that almost ail kinds of blood parasites can be treated. Additionally, this combination has the advantage of avoiding resistance.

An advantage of the combination of the two trypanocidal agents according to the invention is that the diminazen-di-aceturate’s poor water solubility is compensated by the pentamidine which is water-soluble and acts as a'solubiiiser.

Also, the phenazorse brings about a better solubility of the diminazen-di-aceturate besides its effectiveness as an analgesic with the advantage of alleviating pains and fevers in animals, caused by the injection respectively infection.

Glycerol and the water-soluble cellulose ether serve as emulsifiers; however, a stable aqueous solution can only be reached by a combination of all above mentioned agents, according to the invention.

Advantageously, the preparation according to the invention is stable enough to allow for the preparation to be heated up to 7Q°C for an extended period without showing any signs of disintegration.

Preferably, the water-soluble cellulose ether used is methyl cellulose, even though other cellulose ethers, such as hydroxy-ethyl-cellulbse or hydroxy-propyl-celiulose or any of their mixtures can also be used.

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The water is preferably a water which is physiologically, i.e. with regard to its pH and Its osmolarity, adapted. The water is pH-neutral and isotonic. Also, it contains 0.9 ± 0.3¾ of sodium chloride.

The result is an aqueous solution as a preparation, which keeps without problems, since the drug cannot crystallise. Moreover, there is no danger of an additional infection, since the preparation can be manufactured under sterile conditions.

The preparation according to the invention assures the effectiveness of the preparation against the following protozoa:

AP 0 0 0 8 2 7 • Trypanosomes congolense, Tryp. vivax, Tryp. Sruccei and T. Evartsi • Piroplasmosis (piroplasma motasi, piroplasma caballi) • Babesiosis (babesia bigemina, babesia motasi, babesia canis and other babesias) • Thaileria annulate.

According to another preferred embodiment, the preparation according to the invention is combined with another fever-reducing substance and/or a painkiller. This combination has the above-mentioned advantage of reducing the mortality rate of tha treated animals significantly by lowering the high fever which occurs together with a protozoal infection respectively reducing the strong pain in connection with the injection, which can lead to a fatal state of shock.

Lidocaine, procaine or any of their derivatives are preferably U3ed. If required, acetyl» licylic add can additionally be used against fever and as a painkiller.

According to another embodiment, the preparation according to the invention comprises isometadium-hydrochloride from the group of phenathridines as a further biocidal agent.

A preferred embodiment of the preparation according to the invention shows the following composition.

Active agents: diminazen-di-aceturate pentamidine phenazone lidocaine 33.5 % by volume

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Mixture of emulsifying agent and water: glycerol methyl cellulose physiologically adapted water 66.5 % by volume

The composition of active agents in % by weight is preferably the following:

diminazen-di-aceturate	20.9%
pentamidine	11.9%
phenazone	37.3 %
iidocaine	29.9 %

APOΟ Ο 8 2 7 and that of the mixture of emulsifier and water is the foilowing, in % by volume:

gtycerol 20.0 % methyi cellulose 1.6% physiologically adapted water 78.4 %

The preparation according to the invention offers the advantage that in relation to volume, the content of active agents can be doubled in comparison to the prior art.

Further advantages can be seen in the fact that by using the preparation according to tha invention, an extremely fast and complete cure wili be reached within 8 to 12 hours. At the same time, the preparation shows an increased effectiveness in comparison to other preparations, since ail protozoa can be effectively fought. Moreover, application can be carried out effortlessly, since the prescribed doses are smaller than those of other trypanocidal preparations, so that fewer treatments, sometimes one single injection of 15 mi, will be sufficient.

The fact that one single injection which is necessary for chemotherapy also provides protection from reinfection for three months has to be seen as a special advantage.

Another major advantage is to be seen in the fact that the required time for manufacturing can be drastically reduced in comparison to other preparations, since the components can simply be mixed by stirring, without being heated.

Further advantageous embodiments will be characterised in the dependent claims.

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Detailed description of the invention and best wav of carrying out the invention

Below, the invention will be more closely explained by means of an example.

A preferred embodiment of the pharmaceutical preparation can be prepared by mixing the biocidal agents, the intended further components which improve the effectiveness and the mixture of water and emulsifier.

in order to provide 3,35 grams of a mixture of biocidal agent and components which improve the effectiveness, the following will be mixed;

0.7 g	dimina2»n-di-aceturate
0.4 g	pentamidine
1.25g	phenazone and
1.0 g	lidocain.

Subsequently, the mixture of emulsifier and water, which consists of glycerol 20 % by volume, methyl cellulose 1.6 % by volume and physiological water 78,4 % by volume, will, be added to the active substances. The ready-for-use preparation can be filtered in a sterile way and drawn off.

The above-mentioned quantitative ratio has proved to be the most suitable, even though different ratios are also possible for the combination of substances according to the invention, so that an adaptation to the respective conditions is possible.

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AP000827

International Application PCT/EP 56/03657

Applicant: BOURDICHON, Aiain Jaques

Η.ινί,ιΰ now particularly described and ;_fseeri;iined.niy/our said invention and in v luu manner the same is to be pertonneJ • /we declare that what J/we claim is-·

Claims

Claims

1. A pharmaceutical preparation with trypanocidal qualities for veterinary medical use in the form of an aqueous solution, containing diminazen-die-aceturate (4,4'-pentadiacetamidoacetate) as trypanocidai drug, phenazone ft ,2-dihydro-1,5-dimetbyS-2-phenyl3H-pyrazole-3-one) as a fever-reducing and painkilling component as well as glycerol, characterised in that the preparation contains pentamidine (4.4'-(pentamethylendioxy)dibenzamidlne and a water soluble cellulose ether as a solubiliser.
2. A pharmaceutical preparation according to claim 1, characterised in that methyl cellulose is used as cellulose ether.
3. A pharmaceutical preparation according to claim 1 or 2, characterised in that the water that is used is physiologically adapted water, which has been adapted with regard to its pH and/or its osmolarity.
4. A pharmaceutical preparation according to claim 3, characterised in that the pH of the water is neutral.
5. Pharmaceutical preparation according to claim 3 or 4, characterised in that the water is isotonic and contains 0.9 ± 0.3 % of sodium chloride.

5. A pharmaceutical preparation according to any of the claims 1 to 5, characterised in that it contains a local anaesthetic.
7. A pharmaceutical preparation according to claim 6, characterised in that lidocain or a lidocain derivative is used as local anaesthetic.

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8.

8.
9.

9.
10.

10.
11.

11.

A pharmaceutical preparation according to claim 6, characterised in that procaine or a procaine derivative is used as local anaesthetic.

A pharmaceutical preparation according to any of the claims 1 to 7, characterised in that it contains 15 to 40 % by volume - preferably 33.5 % by volume - of a trypanocidal drug and a painkilling and fever-reducing component, wherein 15 to 25 % by volume preferably 20.9 % by volume - of diminazen-di-aceturate, 7 to 20 % by volume preferably 11.9 % by volume - of pentamidine, 20 to 45 % by volume - preferably 37.3 % by volume - of phenazone and 15 to 45 % by volume - preferably 29.9 %' by volume - of lidocain are contained, and 60 to 85 % by volume - preferably 66.5 % by volume - of glycerol, cellulose polymer and water, wherein 15 to 30 % by volume - preferably 20 % by volume - of glycerol, 1 to 3 % by volume - preferably 1.6 % by volume - of cellulose polymer and 70 to 80 % by volume - preferably 78.4 % by volume - of water are contained.

A pharmaceutical preparation according to any of the claims 1 to 9, characterised in that the,pharmaceutical preparation contains acetylsalicylic acid.

Pharmaceutical preparation according to any of the claims 1 to 10, characterised in that isometadium-hydrochloride from the group of phenathridines is contained.