OA10057A - Synergistic anti-malarial compositions containing benflumetol - Google Patents

Abstract

FIELD: chemical-pharmaceutical industry. SUBSTANCE: invention relates to pharmaceutical composition showing activity with respect to malaria. Composition has SYNERGISTIC ANTIMALARIAL component containing ANTIMALARIAL agent benflulatol and ANTIMALARIAL agent from quinine group, for example, quinine. EFFECT: enhanced effectiveness of composition. 3 cl, 2 tbl, 6 dwg

Description

010057

Synergistic anti-malarial compositions containing benflumetol

The present invention relates to a synergistic anti-malarial composition, methods of treating malaria by administering these compositions, and a method for the preparation of said synergistic anti-malarial composition.

Drug-resistant malaria is a serious clinical and public health problem. The parasite malaria Plasmodium falciparum has developed the ability to escape the effects of standardized drugs such as chloroquine either by genetic mutation or by non-genetic adaptation methods. Proliferation of chloroquine-resistant Plasmodium falciparum and other antimalarial drugs is a major concern of health programs in tropical and subtropical countries.

As a result, newpharmaceutical compositions that decrease resistance to malaria parasites are needed for successful therapy. The anti-malarial effect of the compositions containing the benflumetol agent has been disclosed in ChemicalAbstracts 97: 28538h and 101: 136941u. Othercompositions contain combinations of known anti-malarial agents. For example, the combination of amodiaquine and tetracycline has been used in conjunction [Suphat Noeypatimanond et al. (1983), malaria treatment due to Plasmodium falciparum with a combination of amodiaquine and tetracycline 2 010057 in central Thailand, Trans. R. Soc. Too much. Med. etHyg. 73 (3), 338-3401. Another anti-malarial combination (FANSIMED, mefloguine, pyrimethamine and sulphaloxine) has been launched on the market [Tropical Diseases Research, Seventh Program Report, Chapter 2; Malaria, UNDP World Bank / WHO. Published by WHO 1985], The use of combination artemisinin, its derivatives and other anti-malarial compounds, such as quinine, has been published in the German patent application P 37 15 378. Similarly, the synergistic effect of a combination of artemisinin and primaquine is known (Wan Yaode, Cang Qizhong, Pharmacy Bulletin, Vol.16, No.1, 1981).

Combinations of the anti-malarial agents: artemether, arteether, artemisinin, dihydroartemisinin, or artesunate with quinidine or with lametfloquine have been described in the European patent application 362,810.

The motivation for the present invention stems from the need in therapy for an improved anti-malarial composition of higher activity and lower resistance to malaria parasites such as Plasmodium falciparum.

It has now been discovered that pharmaceutical compositions comprising the benflumetol agent in combination with the quinine agent or a derivative thereof have improved anti-malarial activity and are more active than compositions containing only the individual ingredient benflumetol, or, alternatively, derivatives of quinine.

The present invention relates to a pharmaceutical composition suitable for energetic action of the active components against malaria, comprising an energetically effective amount of a compound of the formula:

Cl 010057

Cl

(I), CH (OH) CH2NBu2 combined with a synergistically effective amount of at least one compound selected from group (II) consisting of quinine, mefloquine, halofantrine, chloroquine, primaquine and pyronaridine or a salt or a pharmaceutically acceptable derivative thereof having an effective anti-malarial action.

The definitions and general terms used in the specification of the invention preferably have the following meanings: The term "pharmaceutical composition" defines a mixture comprising the combination of a compound of Formula I with at least one compound of the group (II). This mixture consists of a dry preparation of active components (I) and (II) such as a lyophilizate or preferably contains suitable additives for the manufacture of a dosage form such as tablets, capsules or suppositories. . The term "synergistic action" refers to the enhancement of the effectiveness of the composition above the level of effectiveness of at least one activeindividual component (I) or (II) for the given dose. Preferably, the effectiveness of all the active components present in the pharmaceutical composition is increased. The synergistic effect is highly desirable since it allows the use of a weaker individual component dosage and / or activity enhancement above the activity levels of the individual components. The synergism of the claimed composition is proven by experimental results from in vitro and in vivo models. The results show that the activity of the component according to formula I is increased by comparison with the activity of benflumetol (I) in an individual dosage form and that the activity of component (II) is also increased. The synergistic action against malaria of the composition according to the present invention allows the combined application of different drug prescriptions during therapy by the administration of a single dosage form, such as one or two tablets per day. The application of a dosage form comprising the active ingredient benflumetol (I) allows for permanent action against malaria. This is evident from trials conducted on different, standardized, in vitro and invivo pharmacological models. The presence in the same dosage form of the second active component (II) allows immediate and rapid action against the protozoa after the event of the disease.

The active ingredient (I) mentioned above, in which Bu means n-butyl, is known under the name benflumetol, see C.A.R.N. 82186-77-4. Pharmaceutical compositions containing benflumetol and their activity against malaria are also known, see the abbreviations according to C.A. 97: 28538 hrs and 101: 136941. The preparation of benflumetol has been described in published Chinese patent application 010057 88 / 076666.X.

The active components selected from the group (II) consisting of quinine, mefloquine, halo-fantrine, primaquine and pyronaridine are known active agents for use in malaria therapy.

A pharmaceutically acceptable salt of quinine is, for example, the acid addition salt with one or two equivalents of a monobasic, inorganic or organic acid or the acid addition salt with a dibasic acid, inorganic or organic. Such an acid addition salt is, for example, a hydrohalogenated salt, for example a hydrochloride, a hydrobromide or a hydroiodide, the dihydrolalogenated salt, for example the dihydrochloride, the dihydrobromide or the dihydrochloride, the hydrogen sulfate or the sulphate, the hydrogen carbonate or carbonate, ethylcarbonate, formate, acetate, gluconate or quinine tannate.

A pharmaceutically acceptable derivative of laquinin is, for example, one of its structurally useful derivatives to quinidine, cinchonine or cinchonidine. These derivatives are preferably present in the composition as an acid addition salt, such as, for example, a hydrogen halogenated or dihydrogenohalogenated salt, for example a hydrochloride or a dihydrochloride salt.

Quinine and the salts mentioned above and their derivatives are known anti-malarial agents. We will refer to the Merck Index published by Merck & Co., Inc. 1Oth Edition (1983), and the variousarticles pages 1164-1166.

Mefloquine (CAS reg RN53230-10-7) is preferably present in the composition in the form of a hydrochloric acid addition salt (CAS Reg 010057).

No.51 773-92-3). Reference is made to Martindale's article N) .1381-vpage 513, The Extra Pharmacopoeia, 29th Ed., The Pharmaceutical Press London, 1989. Halofantrine (CAS Reg. Nos. 69756-53-2 and 66051-63). 6) is preferably present in the composition in the form of an acid addition salt of hydrochloric acid (CAS Reg No. 361 67-63-2). Reference is made to Martindale article No.16829-p, TheExtra Pharmacopoeia (loc.cit.).

Chloroquine, 7-chloro-4- [4-diethylamino-1-methyl-n-butylamino] -quinoline, is an anti-malarial agent known from the 4-aminoquinoline group and is preferably present in the composition in the form of diphosphate or sulphate. Reference No.2163, page 334 of the Merck Index, 11th Edition.

Primaquine, 8- (4-amino-1-methyl-n-butylamino) -6-methoxy-quinoline, is an anti-malarial agent known from the 8-aminoquinoline group and is represented by the following structural formula:

this compound is 34, ParasitePrinciples of The anti-malarial efficacy also disclosed in ChapterChemotherapy, E.B. Roche et al., Medicinal Chemistry, W.O. Foye (Editor), Lea & Febiger, Philadelphia / London, 1989.

Pyronaridine is an anti-malarial agent with the following structural formula: 010057

Pharmaceutica Sinica 15: 630-632 (1980). The anti-malarial efficacy of this compound is also discussed in Pratical Chemotherapy of Malaria, Report of a WHOScientific Group, Technical Report Series 805, Geneva 1990, see Chapter 8.5, pages 122-124. A pharmaceutical composition, suitable for the synergistic action of the active components, against malaria, which comprises the combination of an effective amount, of the energy point of benflumetol (I) with an effective amount, from the point of view, is preferred. synergistically, at least one compound selected from the group (II) consisting of laquinine, mefloquine and halofantrine, or a pharmaceutically acceptable compound or derivative thereof having an anti-malarial efficacy. Especially preferred is a pharmaceutical composition, suitable for a synergistic action of the active ingredients against malaria, which comprises combining an effective, point-of-view compound of energy, benflumetol (I) with a synergetically effective amount. of a pharmaceutically acceptable quinine acid addition salt.

Pharmaceutically acceptable additives are preferably present in the composition according to the present invention. The additives are used for the determination, preferably, according to the oral methods, additives diluents or preparation of forms deenteral or parenteralformulation.

Suitable administration includes inert fillers, thereby forming solid or liquid dosage forms, such as tablets, powders, capsules, syrups and the like. The pharmaceutical compositions may, if desired, include additional ingredients such as flavoring agents, binding agents, excipients and the like.

For example, tablets which contain variousextrin, complexed, solid additives such as starch, and some silicates alginic acid together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricating agents such as magnesium ettearate, sodium lauryl sulphate and talc are often used for purposes of tableting. Solid compositions of similar type can also be used, such as fillers in soft and hard gelatine capsules, preferred products for this purpose include lactose or galactose as well as high molecular weight polyethylene glycols.

For other dosage forms, the mixture of compounds may, for example, be administered in a gelatin capsule. Such a formulation could be based on a suitable refined edible oil, such as sunflower oil, demais oil, peanut oil, coconut oil or tall oil.

In a preferred embodiment of the present invention, the active components (I) and (II) 01005? are formulated in a unit dosage form such as tablets or capsules.

The active components (I) and (II) can also be formulated into two individual dosage forms, enclosed in an administration system (set of elements), which are simultaneously or consecutively administered. The same route of administration is possible, for example an administration of two individual dosage forms contained in a set of elements. A tablet or capsule containing the component. (I) and, subsequently, a second dosage form containing component (II) are administered. An individual dose prescription may be specially developed during clinical treatment, for example, by administering after the first occurrence of malaria, a tablet or a capsule containing a high dose of an active component (I) or, correspondingly, multiplying lower doses at the beginning of the malaria attacks, then also administering a tablet or capsule containing a lower dose of the active component (II). During the course of treatment, dosage forms containing a lower dose of components (I) and a higher dose of components (II) are administered. Different dosage forms present in a set of elements may also be administered, simultaneously or consecutively, for example by administration of a tablet containing component (I) and a suppository containing component (II). The dosage range can also be adjusted according to the dose requirements specified above. The utility of the pharmaceutical composition of the present invention in malaria therapy is evident from in-vitro and in-vivo results from experiments conducted on specific test models. The ability of the composition to act as a long-acting, effective anti-malarial agent even against P.berghei's blisters known to be extremely resistant against other antimalarial agents demonstrates the utility of the present invention. .

The present invention also relates to a method of treating malaria, which comprisesadministration to a patient after the manifestation of malaria of the pharmaceutical composition mentioned above, comprising the combined active components (I) and (II). The composition is administered to the patient for a period of at least 4 days, preferably five days or more. The term "method of treatment" also includes the prophylactic administration of the composition to healthy patients to prevent manifestation of the disease in areas of high risk of contamination, especially in areas between the Tropics of Capricorn and Cancer. .

The dose of active ingredient benflumetol (I) as contained in the pharmaceutical composition may vary within wide limits and depends on the condition of the patient and the period of time elapsed after onset of the disease. Based on in vivo data from model experiments as specified below in the examples, it has been established that the daily dose of benflumetol is between about 0.2 to 50.0 mg / kg, preferably 0.2 to 10.0 mg / kg and especially about 0.2 to 5.0 mg / kg. This daily dose may increase in a considerable amount if necessary depending on the high low toxicity and high tolerance of benflumetol. It has also been estimated that the daily dose of component 010057 (II) in the composition is between 0.2 and 50 mg / kg, preferably from 0.3 to 5.0 mg / kg and especially between about 0.4 and 3.0. mg / kg.

The dose ratio between the component (I) and the component (II) can also vary within wide limits. The synergism will be especially effective if the albuminol is administered in equal amounts or preferably in excessive amounts as compared with the weight amounts of the administered component (II). Accordingly, the weight amount of debenflumetol may vary from one to ten parts for each part of component (II) administered. Preferably, from 3 to 7 parts and especially from 5 to 7 parts of benflumetol are administered for each part of component (II). The quantities of the specified doses and the dose ratios refer to daily dosages. The invention also relates to a process for the preparation of a pharmaceutical composition, suitable for a synergistic action of the active components against malaria, in which an effective amount of a compound of formula (I) is combined with an effective amount of the component (II) after which this combination of active components is formulated with the optional addition of pharmaceutically acceptable additives to a suitable dosage form.

The novel pharmaceutical compositions contain, for example from 10 to 80%, preferably from 20 to 60%, of the combination of active components. Pharmaceutical compositions according to the invention are suitable for enteral administration and are, for example formulated in unit dosage form, such as tablets, tablets, capsules or suppositories. These are made in a manner known per se, for example by conventional methods of mixing, granulating, deconditioning, dissolving or lyophilizing. For example, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and entraining the mixture or granule, if desired, or if necessary, after the addition of suitable adjuvants to form tablets or dragee cores.

In a preferred embodiment of the method, the active components (I) and (II) are ground either individually or together in a particle size of from about 10 μ to about 400 μ, preferably from 20 μ to 200 μ. At least 90% of the crystals of the active components are within these ranges.

Particles of this size are obtained by conventional powder reduction methods, for example by grinding in an air jet mill, a ball mill or vibratory mill. Lamicronization is preferably carried out by known techniques employing a ultrasonic disintegrator, for example of the Branson Sonifier type as described, for example in J.Pharm. Sci. 53 (9), 1040-1045 (1965), or by stirring a suspension with a high speed stirrer, for example with a Homorex type stirrer (distributed by Brogli & Co., Basel). In these preferred techniques, the micronization is carried out at about 500 to 10,000 rpm by dissolving or suspending the combination of active components in an organic solvent, for example methanol, ethanol or propylene glycol, and precipitating it under its microcrystalline form at about 0.degree.-5.degree. C. in water or an aqueous solution of salt, for example a 2% sodium chloride solution which may additionally contain a protective colloid such as gelatin or a cellulose ether, for example methylcellulose or hydroxypropyl methylcellulose at low concentration (0.1 to 1%), and filtering the resulting stirred suspension. The filter cake is dried at low temperature, for example in the vicinity of 0 to 5 ° C. underwater (for example under 50 mbar, preferably at 0.5 mbar). Subsequent drying can be carried out in the range of 50 to 90 ° C.

The crystals thus obtained are then formulated into granules, preferably by wet granulation which is carried out according to standard techniques.

The pharmaceutical composition is preferablyprepared by compressing a granular formulation which is obtained, for example, by sieving and, if desired, by powdering the drug, either in the excipient, by compacting with another solvent such as ethanol or methanol. water, by removing the solvent or by drying, with or without the addition of lubricant or slip agent such as magnesium stearate or TWEEN, by powdering the granules and sieving them once again.

The granules can be compressed into cores decompressed in a conventional machine to manufacture tablets, for example an eccentric compression machine, EKO Korsch, at a pressure of about 10 kN. The coating can be carried out by applying an aqueous ethanolic solution in which, for example, polyethylene glycol and deducrose are dissolved or dispersed.

Dredge cores are provided with suitable coatings which may be resistant to gastric juice, using here, inter alia, concentrated solutions of sugar which may contain gum arabic, talc, polyvinylpyrrolidone or polyethylene glycol. The dyes, the desiccants or the pigments can be added to syrups, tablets or dragee coatings, for example for identification purposes, to mask the effect or to indicate the different doses of active ingredients.

In addition, pharmaceutical compositions, which can be administered orally, are dry filled capsules consisting of gelatin, and also sealed soft capsules consisting of gelatin and a plasticizer, such as glycerin or sorbitol. The dry filled capsules may contain the active components in the form of a granule, for example in admixture with fillers, such as lactose, binding agents such as starches, and / or slip agents, such as talc or lataarate. magnesium and, where appropriate, stabilizing agents. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols, to which stabilizers may also be added.

Also suitable for administration are suppositories which consist of the combination of active ingredients and a suppository base. Examples of suitable bases are synthetic glycerides, paraffins, polyethylene glycols or high derang alkanols. It is also possible to use rectal gelatin capsules which contain a combination of the active ingredient and a base material, suitable base materials are, for example, triglycerides, lipids, polyethylene, and the like. glycols or paraffinic hydrocarbons.

Following examples illustrate the invention described above; however, they are not intended to limit the scope of the invention in any way. Example: Preparation of Tablets Benflumetol 120 mg Quinine Dihydrochloride 20 mg Corn Starch 100 mg Dextrin 40 mg Tween-80 0.6 mg Paste at 15% cornstarch q. s. Mg stearate 3 mg

Dequinine dihydrochloride crystals are passed through a 100 mesh size sieve. Benflumetol crystals were passed through a 60 mesh mesh and then mixed with solid quinine, starch and dextrin. This mixture is passed three times through a 40 mesh sieve. TWEEN -30 is added to the starch paste which is mixed with the above formulations. This mixture is granulated by means of a wet granulation, then passed through a 40 mesh sieve, and dried under reduced pressure at 50-60 ° C. The magnesium stearate is added and the tablets are pressed.

Claims (8)

010057 1 6 CLAIMS '. A pharmaceutical composition suitable for synergistic action of malaria active components comprising a synergistically effective amount of a compound of the formula: In combination with a synergistically effective amount of at least one compound selected from group (II) consisting of quinine, mefloquine, halofantrine, chloroquine, primaquine, and pyronaridine or a salt or a pharmaceutically acceptable derivative thereof, havingeffective anti-malarial action. 2. A pharmaceutical composition according to claim 1 comprising a synergetically effective amount of benflumetol (I) combined with an energy-efficient amount of at least one compound selected from group (II) consisting of quinine, mefloquine and halofantrine, or a pharmaceutically acceptable salt or derivative thereof having anti-malarial efficacy. 3. A pharmaceutical composition according to claim 1, comprising a synergetically effective amount of benflumetol (I) combined with a synergistically effective amount of a pharmaceutically acceptable salt of quinine ( II). 4. A process for the preparation of a pharmaceutical composition according to claim 1, wherein a synergistically effective amount of benflumetol (I) is combined with a synergetically effective amount of at least one compound selected from the group (II) consisting of laquinine, mefloquine, halofantrine, lachloroquine, primaquine and pyronandine or a pharmaceutically acceptable salt or derivative thereof, after which this combination of active compounds with optional addition is formulated pharmaceutically acceptable additives to a suitable dosage form. 5. A process according to claim 4 wherein an effective amount of benflumetol (I) is combined with a synergistically effective amount of a pharmaceutically acceptable dequinine salt. A process for the preparation of a pharmaceutical composition according to claim 4 which comprises a combination formulation of active components with the addition of solid tablet additives. 7. The use of the combination comprising an effective synergistic amount of benflumetol (I) with an effective synergistic amount of at least one compound selected from the group (II) consisting of laquinine, mefloquine, halofantrine, chloroquine, primaquine and pyronaridine or a pharmaceutically acceptable salt or a derivative thereof for the preparation of a pharmaceutical composition. 8. A pharmaceutical composition according to claim 1 for use in the therapy of malaria.