OA10665A - Pharmaceutical preparation with trypanocidal properties containing diminazene pentamidine and phenazone - Google Patents

Abstract

A pharmaceutical composition with trypanocidal properties useful in veterinary medicine in the form of an aqueous solution contains diminazen-diaceturate, pentamidine, phenazon, glycerine and a water-soluble cellulose ether.

Description

1 010665

Field of application

The invention refers to a pharmaceutical préparation with trypanocidal qualities for veterinarymedical use, in the form of an aqueous solution, which contains diminazen-di-aceturate (4.4' -diamidinediazobenzenediacetamidoacetate) and pentamidine (4.4’ - (pentamethylenedioxy) -dibenzamidine) as trypanocidal drugs, phenazone (1.2- dihydro-1.5-dimethyl-2-phenyl-3H-pyrazole-3-one) as fever-reducing and pain-relieving components, as well as glycerol.

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

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

Prior art

Arsenic préparations and trypan dyes are known as chemotherapeutical drugs, which are,however, disadvantageous due to their content of arsenic respectively their carcinogenicity. Awell known préparation which has long been used for the treatment of such infections inanimais in many cases is a trypanosome on the basis of diminazene powder. Othercommercial trypanosomes are also available in a powdered form only. But especially thepowdered form of the drug is extremely disadvantageous, due to the fact that the powdereddrugs cannot be mixed into the fodder and thus need to be mixed with water to make aninjectable solution. It is not possible to produce a stérile solution from the powderedpréparations, since the active substances form crystals in the solution after a short time, so thatthe effectiveness of the préparation gets lost quickly. Thus, such solutions cannot be stored andtransported well enough. For this reason the injectable solution has to be produced a short timebefore 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 cause additional 2 010665 diseases in the animais and would thus put great strain on the animais. Also, no complétésolution of the solids can be reached, due to poor solubility of these powdered drugs. This leadsto an insufficient effectiveness of the injectable solution.

The powdered trypanosomes which are known today, thus pose a danger of additional5 infections respectively contamination. At the same time there is the danger of underdosage of the therapeutic drug, so that the chemotherapeutic treatment may hâve to be repeated, whichnaturally involves an increased risk of infections and the like.

In order to avoid the disadvantages of powdered trypanosomes, aqueous solutions ofdiminazen-di-aceturate hâve been developed, which contain caster oil as a solubiliser. 10 The manufacturing process is, however, relatively time-consuming and the stability of theresulting solution of the préparation can only be assured up to a température of about 25°C.

This may be sufficient under normal circumstances; in tropical countries, however, storageconditions cannot always be observed, so that the préparation will spoil. 15 Problem, solution, advantaqes

The object of the invention is to provide a solution of a pharmaceutical préparation of the above-described kind which remains stable, even in high températures.

In order to solve this problem, the plan according to the invention is to provide apharmaceutical préparation with trypanocidal qualifies in the form of an aqueous solution which 20 contains the following agents: • diminiazen-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) 25 · glycerol • water-soluble cellulose ether. 3 010665

Diminazen-di-aceturate and pentamidine are trypanocidai drugs with different activityspectrums which therefore complément each other in regard to their area of effectiveness, sothat almost ail kinds of blood parasites can be treated. Additionally, this combination has theadvantage of avoiding résistance. 5 An advantage of the combination of the two trypanocidai agents according to the invention isthat the diminazen-di-aceturate’s poor water solubility is compensated by the pentamidinewhich is water-soluble and acts as a solubiliser.

Also, the phanazone brings about a better solubility of the diminazen-di-aceturate besides itseffectiveness as an analgésie with the advantage of alleviating pains and fevers in animais, 10 caused by the injection respectively infection.

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

Advantageously, the préparation according to the invention is stable enough to allow for the 15 préparation to be heated up to 70°C for an extended period without showing any signs ofdisintegration.

Preferably, the water-soluble cellulose ether used is methyl cellulose, even though othercellulose ethers, such as hydroxy-ethyl-cellulose or hydroxy-propyl-cellulose or any of theirmixtures can also be used. 20 The water is preferably a water which is physiologically, i.e. with regard to its pH and itsosmolarity, adapted. The water is pH-neutral and isotonie. Also, it contains 0.9 ± 0.3% ofsodium chloride.

The resuit is an aqueous solution as a préparation, which keeps without problème, since thedrug cannot crystallise. Moreover, there is no danger of an additional infection, since the 25 préparation can be manufactured under stérile conditions.

The préparation according to the invention assures the effectiveness of the préparation against the following protozoa: 4 010665 • Trypanosomes congolense, Tryp. vivax, Tryp. Bruccei and T. Evansi • Piroplasmosis (piroplasma motasi, piroplasma caballi) • Babesiosis (babesia bigemina, babesia motasi, babesia canis and other babesias) • Theileria annulata.

According to another preferred embodiment, the préparation according to the invention iscombined with another fever-reducing substance and/'or a painkiiier. This combination has theabove-mentioned advantage of reducing the mortality rate of the treated animais significantly bylowering the high fever which occurs together with a protozoal infection respectively reducingthe strong pain in connection with the injection, which can lead to a fatal State of shock.

Lidocaine, procaine or any of their dérivatives are preferably used. If required, acetylsalicylicacid can additionally be used against fever and as a painkiiier.

According to another embodiment, the préparation according to the invention comprisesisometadium-hydrochloride from the group of phenathridines as a further biocidal agent. A preferred embodiment of the préparation according to the invention shows the followingcomposition:

Active agents: diminazen-di-aceturate

Mixture of emulsifying agent and water: pentamidine phenazone lidocaine 33.5 % by volume glycerol methyl cellulosephysiologically adapted water 66.5 % by volume

The composition of active agents in % by weight is preferably the following: diminazen-di-aceturate pentamidine phenazone lidocaine 20.9 %11.9%37.3 % 29.9 % 5 010665 and that of the mixture of emulsifierand water is the following, in % by volume: glycerol methyl cellulosephysiologically adapted water 20.0 %1.6%78.4 %

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

Further advantages can be seen in trie fact that by usîng the préparation according to the10 invention, an extremely fast and complété cure will be reached within 8 to 12 hours. At the same time, the préparation shows an increased effectiveness in comparison to otherpréparations, since ail protozoa can be effectively fought. Moreover, application can be carriedout effortlessly, since the prescribed doses are smaller than those of other trypanocidalpréparations, so that fewer treatments, sometimes one single injection of 15 ml, will be 15 sufficient.

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

Another major advantage is to be seen in the fact that the required time for manufacturing canbe drastically reduced in comparison to other préparations, since the components can simply 20 be mixed by stirring, without being heated.

Further advantageous embodiments will be characterised in the dépendent daims. 6 010665

Detailed description of the invention and best way of carryinq out the invention

Below, the invention will be more closely explained by means of an example. A preferred embodiment of the pharmaceutical préparation can be prepared by mixing thebiocidal agents, the intended further components which improve the effectiveness and the 5 mixture of the water and emulsifier.

In order to provide 3.35 grams of a mixture of biocidal agent and components which improvethe effectiveness, the following will be mixed: 10 0.7 g diminazen-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 tothe active substances. The ready-for-use préparation can be filtered in a stérile way and drawn 15 off.

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

Claims (9)

1. 7 010665 B 96357 14048 6th August, 1997International application PCT/EP 96Z03657 Applicant: BOURDICHON, Alain Jaques Claims

   1. A pharmaceutical préparation with trypanocidal qualities for veterinary medical use in theform of an aqueous solution, containing diminazen-di-aceturate (4.4'-penta-diacetamidoacetate) as trypanocidal drug, phenazone (1.2-dihydro-1.5-dimethyl-2-phenyl-3H-pyrazole-3-one) as a fever-reducing and painkilling component as well asglycerol, characterised in that the préparation contains pentamidine (4.4’-(pentamethylendioxy)-dibenzamidine and a water soluble cellulose ether as a solubiliser.
2. 2. A pharmaceutical préparation according to claim 1,characterised in that methyl cellulose is used as cellulose ether.
3. 3. A pharmaceutical préparation according to claim 1 or 2,characterised in that the water that is used is physiologically adapted water, which has been adapted withregard to its pH and/or its osmolarity.
4. 4. A pharmaceutical préparation according to claim 3,characterised in that the pH of the water is neutral.
5. 5. Pharmaceutical préparation according to claim 3 or 4,characterised in that the water is isotonie and contains 0.9 ± 0.3 % of sodium chloride.
6. 6. A pharmaceutical préparation according to any of the claims 1 to 5,characterised in that it contains a local anaesthetic.
7. 7. A pharmaceutical préparation according to claim 6,characterised in that lidocain or a iidocain dérivative is used as local anaesthetic. δ 8. 9. 5 ΙΟ 15 A pharmaceutical préparation according to claim 6, characterised in that procaine or a procaine dérivative is used as local anaesthetic. A pharmaceutical préparation according to any of the daims 1 to 7, characterised in that it contains 15 to 40 % by volume - preferably 33.5 % by volume - of a trypanocidal drugand 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 - oflidocain are contained, and 60 to 85 % by volume - preferably 66.5% by volume - ofglycerol, 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 cellulosepolymer and 70 to 80 % by volume - preferably 78.4 % by volume - of water arecontained.
8. 10. A pharmaceutical préparation according to any of the daims 1 to 9,characterised in that the pharmaceutical préparation contains acetylsalicylic acid.
9. 11. Pharmaceutical préparation according to any of the daims 1 to 10, 20 characterised in that isometadium-hydrochloride from the group of phenathridines is contained.