FR2558728A1 - ANTI-MALARIA PHARMACEUTICAL COMPOSITION BASED ON QUININE, QUINIDINE AND CINCHONINE - Google Patents

Abstract

THE INVENTION RELATES TO A PHARMACEUTICAL COMPOSITION HAVING ANTI-MALARIA ACTIVITY, COMPOSITION CONTAINING, AS ACTIVE INGREDIENT, FROM 20 TO 2000MG OF A MIXTURE CONSISTING OF: 30 TO 60 OF QUININE; 20 TO 40 OF QUINIDINE; 20 TO 40 OF CINCHONIN, EACH OF THESE CONSTITUENTS BEING IN BASE OR PHARMACEUTICALLY ACCEPTABLE SALT.

Description

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  Pharmaceutical composition intended to combat malaria.

  The present invention relates, in general, to a pharmaceutical composition and more particularly to a pharmaceutical composition

having an antimalarial action.

  Malaria is probably the most common of all human diseases. It has been estimated that some 300 million people are afflicted by it

  each year, the disease being fatal in 1% of them.

  It is therefore imperative to have effective means to combat this

  scourge and any improvement to existing treatments could be considered

  derived as a beneficial contribution to therapy.

  Quinine is still one of the most common agents today.

  pandus and the most indicated in the fight against malaria.

  This alkaloid is effective both in suppressing and controlling overt attacks of malaria due to Plasmodium falciparum, Plasmodium

vivax and Plasmodium malariae.

  Other alkaloids strongly related to quinine, such as quinidine, cinchonine and cinchonidine have shown efficacy quite similar to that of quinine in this treatment [L.H. SCHMIDT, Alkaloids, 1955, vol. V, p. 141 and sq (1956)] and certain associations of quinine with

  such cinchona alkaloids have been described and used.

  In these associations, the alkaloids are mixed for example with the resor-

  cine to improve solubility.

  However, quinine has not yet been surpassed for the treatment of

  severe fections due to P.falciparum.

  We have now found that certain drug combinations including quinine, quinidine and cinchonine, in defined weight ratios, have a higher rate of antimalarial activity than that recorded

with quinine alone.

  It has also surprisingly been found that such associations present

  not only try an improved activity compared to quinine, but 2 -

  also good activity on quinine resistant strains.

  Thus, the present invention relates to an anti-pharmaceutical composition.

  malaria, in the form of a dosage unit, composition comprising from 20 to 2000 mg of a mixture consisting of: 30 to 60% of quinine to 40% of quinidine to 40% of cinchonine

  each of these constituents being in the form of a base or a pharmaceutical salt

  only acceptable, in combination with a pharmaceutical vehicle or

suitable excipient.

  Preferred compositions according to the invention will comprise from 50 to 1000 mg of a mixture of quinine, quinidine and cinchonine in a ratio of 1: 1: 1, each of the components of these mixtures being in the form of the base or of salt

pharmaceutically acceptable.

  Other preferred compositions according to the invention may contain from 50 to

  1000 mg of a mixture of 50% quinine, 20% quinidine and 30% cincho-

  nine, each of these components being in the form of a base or a pharmaceutical salt

ceutically acceptable.

  As pharmaceutically acceptable salts, mention may be made, for example, of the hydrochloride, the hydrobromide, the sulphate, the maleate, the formate, the fumarate,

  benzoate, methanesulfonate, carbonate, gluconate or resorcinate.

  Pharmacological studies carried out with compositions according to the invention

  revealed significant antiparasitic activity in vitro as well as in vivo.

  The results of tests carried out to demonstrate this activity are mentioned below: 1) In vitro a) Ex vivo tests were carried out on cultures of P. falciparum from

  of 20 infested Thai patients.

  Following these tests, the cultures in question are subjected for three days to the action of the composition to be studied, then the proliferation of the

  parasitic by incorporation of a radio-labeled precursor.

  According to this experimental protocol, a test was carried out with a mixture of quinine-resorcin monohydrochloride / quinidineresorcin monohydrochloride /

  cinchonine-resorcin monohydrochloride in a ratio of 1: 1: 1.

  For comparison, a similar test was carried out with different concentrations

  trations of quinine-resorcin monohydrochloride used alone.

  The results show that on the cultures from the 20 patients in question

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  tion the ID50, that is to say the dose of therapeutic agent studied necessary to reduce the parasitosis by 50%, is 49.8.10 -9g in the case of

  composition of the invention and 161.10-9g in the case of quinine salt alone.

  The composition of the invention therefore has an activity rate 3.2 times greater than that of the quinine salt.

  b) Trials of P. falciparum were also carried out.

  held in continuous culture in R.P.M.I. 1640 (Roswell Park Membrial Institute) supplemented with 35mMi of H.E.P.E.S. (N-hydroxy-2 ethyl piperazino acid

  N'-ethanesulfonique-2) and 10% human umbilical cord serum.

  At the time of the test, the parasitaemia is reduced to 0.2% by the addition of human red blood cells ORh + previously stored for 8 to 20 days at +4 C.

  removes the top of the red blood cell pellet during 3 la-

  so as to reduce white blood cells and platelets to negligible amounts. Each composition to be tested is distributed in decouoisaantes concentrations so as to obtain final concentrations ranging from 8,000 to, u / L: -J. In the wells of a culture microplate. We put the globules o.'e. '"- ;? p: azasite suspension in culture medium supplemented ly.:-.n.,,n, -;,. from one to obtain, in each culture well, a

  -, oJe de 2, 'p! d - place 6 μl of globular base and 0.8 pCi of H3-hypo-

  J: *: = i- in cbe.ça;: s ies plates for 3 days at 37 C in atmosphere: '..., -, -: z ::. Iep ga, -e -' 5% d ' carbon dioxide, 18% oxygen and fP.- = - :: -: - 9 v; _1 --... ceil: - es by suction on a fiber -filter, :: ':.: {S.-.- o-.ure' ds.ns a scintillation counter, the

<..? - = ^ .......: -.

  -.,: es: d; pou.? roa each concentration of omposition :: -, - f- T .. '- L .. end and following indicators * red blood cells

  :., s -.:.] '', -s --sa: 's;: without antimalarial agent.

  -. gvz-_u- ^: ..- s far.; o. graphi.qua the inhibitory doses and the slope of

  --.:e '9' kills it- we recorded results similar to.

  to'-zt :, 3.-u ': e, .....-' l7é tude ex- vivo i.;:. we have i.-rua -_.- tests similar to those described above in? t -._ i.- t.'o: --- .; Ci. f'inCvertion contains 0q .- [. e,! e -no "rh! orLyd a ': d: 14 quinidine hydrochloride and cinchonine monohydrochloride

  in a r-.ippo'rt of i:!: and this, compared to quinine monohydrochloride.

  In the ex vivo as in vitro tests, results similar to those mentioned above have been recorded. 2) In vivo The following test was carried out in vivo using a strain of Plasmodium.

berghei as an infestant.

  Male white mice (Swiss Albino F1) weighing 18 to 22 grams are injected intravenously, 107 red blood cells parasitized with a strain of Plasmodium berghei N. The infested red blood cells come from a donor mouse which is killed by inhalation chloroform when its parasitaemia reaches 20%. The red blood cells are collected in a slightly heparinized syringe and the blood is then diluted in NCTC medium 199 (National Cancer Tissue Culture) so that 0.2 ml contains approximately 107 red blood cells. The composition to be studied is dissolved or suspended in Tween

  and sterile distilled water and then administered subcutaneously.

  The compositions to be studied are administered once a day for 4 days and parasitaemia is then determined by spreading blood in a thin layer the day after the last treatment. We then determine the DI90, i.e.

  the dose of composition reducing the parasitosis by 90%.

  The following results were obtained with the compositions below: Composition 1 Quinine-resorcin monohydrochloride / quinidine-resorcin monohydrochloride /

  cinchonine-resorcin monohydrochloride: 1: 1: 1.

  Composition 2 Quinine-resorcin monohydrochloride / quinidine-resorcin monohydrochloride / cinchonine monorchloride-resor-ciae: 50%, 20%, 30, compared to

  quinine-resorcin monohydrochloride used alone.

  Table DI90 (in mg / kg) Quinine salt 380: Composition I 160: Composition 2 165 These results clearly show that the compositions of the invention are

  at least 2.3 times more active than the quinine salt used alone.

  Results similar to those cited above were recorded

  with compositions identical to Compositions 1 and 2 but in the-

which resorcinol is absent.

  The pharmaceutical compositions of the invention may be in any form suitable for administration in human or veterinary therapy

for the treatment of malaria.

  As a form of administration, mention may be made of oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal administration. As regards the administration unit, this may take the form, for example, of a tablet, a dragee, a capsule, a capsule, a powder, a granule, suspension or syrup for oral administration, suppository for rectal administration

  or a sterile solution or suspension for parenteral administration.

  The total amount of active ingredient, namely the mixture of quinine, which

  nidine and cinchonine, or one of their pharmaceutically acceptable salts, is from 20 to 2000 mg per administration unit depending on whether this

  unit is intended for oral, rectal or parenteral administration.

  The unit preferably comprises 50 to 500 mg of active principle in the case of oral administration, from 100 to 150 mg in the case of rectal administration and from 20 to 2000 mg in the case of parenteral administration, per example

by infusion.

  The daily administration of compositions according to the invention depends on the route of administration chosen. Generally, an administration unit will be needed 1 to 4 times a day so that the daily amount of

  above active ingredient can vary from 1 to 30 mg per kg of body weight.

  Preferably, it will be of the order of 25 mg / kg.

  In their most general aspect and taking into account the route of administration

  tration chosen, the pharmaceutical compositions of the invention are pre-

  adorned by combining the active ingredient defined above with a phar-

  maceutical or an appropriate excipient, the latter being selectable from substances such as distilled water, starches, talc, stearate

  magnesium, polyvinylpyrrolidone, alginic acid, coloidal silica, chloro-

  sodium rure, titanium dioxide, cocoa butter, sweetening agents etc ...

  We will describe later, in a more specific but non-limiting manner,

  some embodiments of compositions of the invention.

  A composition of the invention is prepared, for example, in the form of a

  award-winning by forming a pulverulent mixture from the active ingredient above and a diluent or a base such as starch, sucrose, kaolin, bicalcium phosphate etc ... then by granulating or cutting after adding a

  lubricant and finally compressing.

  Granulation of the powder mixture can be done by wetting with a 6 - binder such as syrup, starch paste or acacia mucilage and forcing

through a sieve.

  Another method of granulation is to cut the pulp mixture

  crooked by passing it through a tablet machine and then breaking the resulting tablets imperfectly into fragments (sections)

  trained. The sections can be lubricated to prevent them from sticking by addi-

  tion of a stearate in the form of salt, talc or a mineral oil then

by forming cubes.

  The lubricated mixture is then compressed to form the defi

nitives.

  If necessary, the tablets obtained can be coated, coated with a

  enteric lacquer or coated in such a way that the prin-

  active cipe is gradually released.

  Likewise, a composition of the invention is obtained in the form of capsules by simple mixing of the above active principle with a pharmaceutical vehicle,

  this pulverulent mixture being subsequently introduced into gelatin sheaths

soft or hard.

  Before the filling operation, it is advantageous to add, to the pulverulent mixture, a lubricant such as talc, magnesium stearate or stearate

calcium.

  Powders for oral administration can be prepared by grinding the above active ingredient to a suitable fineness and mixing with a similarly ground diluent which may be a carbohydrate derivative

  edible such as starch. Advantageously, a sweetening agent is incorporated.

  rant or a sugar as well as a flavoring oil.

  In order to obtain an oral liquid composition, granules are formed by wetting the above active principle and a water-soluble diluent such as sucrose, glucose, etc. with a binder such as acacia mucilage, gelatin. solution, methylcellulose in solution and by forcing through a sieve to form granules which are dried. Preferably, we introduce

  in the composition, a suspending agent such as tragacanth.

  Liquid compositions for oral administration can then be prepared in unit dosage forms such as syrup, in which each teaspoon of such a composition contains a predetermined amount.

  of the above active ingredient to be administered.

  A preparation in the form of syrup or elixir may contain, in addition to the principal

  active ingredient, a sweetener, an antiseptic such as methylparaben or pro-

  pylparaben as well as a suitable coloring and sweetening agent.

  A composition can also be prepared for administration by the

  rectal in the form of a suppository by pouring, in a suitable mold, a -

  mixture formed of the above active principle and of a binding agent which melts at the rectal temperature, for example cocoa butter, polyethylene glycols or

$ lanolin.

  For side administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing the above active principle and a solubilizing agent are produced.

  if necessary, for example polysorbate 80, suitable wetting agents

  0 required for example propylene glycol or butylene glycol and a

  storage such as benzyl alcohol.

  The following nonlimiting examples illustrate pharmaceutical compositions.

according to the invention:

EXAMPLE 1

  Compositions which can be administered orally I. Tablets Tablets are prepared with the composition below: -! Quinine onochlorohydrate, 2H O 25.2 mg Quinidine hydrochloride, 1H20 24.8 mg 0 onocbilorhydrcate ad cinclhonine ,. 2H20 256 mg don e rais 5624 mg Poly. id-on, excipient: 5.0 mg Csr: yt'ylamid! on sodiquoe 7.5 mg Tae l. 4.5 mg Magnet.um stearate 1.0 mg e; t ee, as follows: One s.! Age imtimei ent in a mialngeuse-kneader all the ingredients auf ie lu ri. -nL (talc, magnesium st-arate), for 15 minutes. The mixture is graded by graduation. It is drilled and the mass is passed through a sieve of 1.25 m. We know the granule obtained in a fan oven.

  Xorce lation until a relatively low residual humidity is obtained.

  <We granulate the granulate and add the lubricant.

  By this ..... re, 511on forms acor-s tablets each weighing 150 mg and ren-

  each closing 75.6 mg of active ingredient! l. G] e tt Capsules having the following composition are prepared: t -8 - Quinine sulfate, 2H20: 49.7 mg Quinidine sulfate, 2H20 51.2 mg Cinchonine sulfate, 2H20 50, 4 mg Lactose: 19, 2 mg Coloidal silica: 0.2 mg Talc: 5.0 mg

EXAMPLE 2

  Composition for parenteral administration A sterile aqueous injection composition has been prepared, corresponding to the following formulation: Quinine monohydrochloride, 2H20 25.2 mg Quinidine monohydrochloride, 1H20: 24.8 mg Cinchonine monohydrochloride, 2H20 25.6 mg Urethane: 75.5 mg Sodium chloride: 7.0 mg

  Hydrochloric acid, water qs. for 1 ml.

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Claims (8)

Claims   1. Pharmaceutical composition, in the form of a dosage unit, having an antimalarial action, characterized in that it comprises from 20 to 2000 mg of a mixture consisting of: 30 to 60% of quinine to 40% of quinidine to 40 % of cinchonine   each of these constituents being in the form of a base or a pharmaceu-   tically acceptable, in combination with a pharmaceutical vehicle or an appropriate excipient.   2. Pharmaceutical composition according to Claim 1, characterized in that it comprises from 50 to 1000 mg of a mixture of quinine, or of a pharmaceutically acceptable salt thereof, of quinidine, or of a salt thereof   pharmaceutically acceptable and cinchonine, or a phar-   maceutically acceptable, in a ratio of 1: 1: 1.   3. Pharmaceutical composition according to Claim 1 characterized in that it comprises from 50 to 1000 mg of a mixture of 50% quinine, or of a pharmaceutically acceptable salt thereof, 20% of quinidine, or of a its pharmaceutically acceptable salts and 30% cinchonine, or one of   its pharmaceutically acceptable salts.   4. Pharmaceutical composition according to any one of Claims 1 to   3 characterized in that it is in the form of an administrative unit tion for oral administration.   5. Pharmaceutical composition according to any one of Claims 1 to   3 characterized in that it is in the form of an administrative unit tion for rectal administration.   6. Pharmaceutical composition according to any one of Claims 1 to   3 characterized in that it is in the form of an administrative unit   - tion for parenteral administration.   7. Pharmaceutical composition according to Claim 4, characterized in that   it comes in the form of tablets, dragees, capsules, capsules, dre, granulated, suspension or syrup.   8. Pharmaceutical composition according to Claim 5, characterized in that   that it comes in the form of a suppository.   9th Pharmaceutical composition according to Claim 6 characterized in that   whether in the form of a solution or suspension.