MXPA00005298A - Solid pharmaceutical compositions containing miltefosine for oral administration in the treatment of leishmaniasis - Google Patents

Abstract

The present invention relates to new solid pharmaceutical compositions containing hexadecylphosphocholine (miltefosine) for oral administration in the treatment of leishmaniasis, a process for the manufacture of said pharmaceutical composition, a dosage scheme for oral administration of said pharmaceutical composition in the treatment of leishmaniasis, and finally a combination comprising said solid pharmaceutical composition, an antiemeticum, and/or an antidiarrhoeal.

Description

SOLID PHARMACEUTICAL COMPOSITIONS CONTAINING MILTEFOSIN FOR ORAL ADMINISTRATION IN THE TREATMENT OF LEISHMANIAS IS Description of the invention The present invention relates to the new solid pharmaceutical compositions containing hexadecylphos focholine (miltefosine) for oral administration in the treatment of leishmaniasis, a process for the manufacture of said pharmaceutical composition, a dosage scheme for the oral administration of the pharmaceutical composition in the treatment of LA leishmaniasis, and finally a combination comprising the solid pharmaceutical composition, an antiemetic and / or an antidiarrheal. Leishmaniasis is a name for various tropical diseases that are caused by flagellates of the genus Lei shmani a and is transmitted by various insects that suck blood. The manifestations of leishmaniasis can be visceral (ala-azar), mucocutaneous (American leishmaniasis) or cutaneous (Aleppo boil or diffuse cutaneous leishmaniasis). The incubation period is weeks or months. A very high mortality rate is observed in untreated cases, in particular with kala-azar and American leishmaniasis. Before the present invention there was no medication available in the state of the art for the oral therapy of leishmaniasis. The known agents in the standard therapy for the treatment of leishmaniasis, for example pentavalent antimony compounds (for example sodium stibogluconate) and aromatic diamidines, had to be administered for example by intravenous injection, whereby not only side effects are caused severe due to its high toxicity, but also supporting the risk of infections. Leishmaniasis is a parasitic disease that is frequently found in geographic areas with an extreme tropical climate and where medical care is complicated by insufficient communication channels. Any medicine that contains miltefosine for the treatment of leishmaniasis, therefore, has to take into account these severe environmental conditions. The ability to use miltefosine in the oral and topical treatment of leishmaniasis was first described by Eibl et al. In the Unexamined German Patent Application No. P 41 32 344 filed on September 27, 1991. Although it is obtainable It is anhydrous form as crystalline plates with a defined melting point higher than 200 ° C, miltefosine is difficult to handle due to its high hygroscopicity. The incorporation of molecules can result in an increase in weight of up to 30% by weight, melting point depression and agglomeration and agglutination of the crystals. Miltefosine containing water shows insufficient handling capacity to be further processed into solid pharmaceutical compositions, such as tablets, capsules or sacks. In particular, the flow capacity of miltefosine containing water is insufficient. The satisfactory flow capacity, however, is one of the essential prerequisites for the manufacture of solid pharmaceutical compositions on an industrial scale. In addition, anhydrous miltefosine shows a significant tendency for electrostatic charging, particularly when agitated in the anhydrous state. The electrostatically charged miltefosine, too, shows insufficient flow capacity to be further processed in solid pharmaceutical compositions. In addition, any electrostatic charge gives rise to significant safety problems due to the accompanying risk of explosion and that the sensitive electronic parts are damaged. In an attempt to overcome the aforementioned problem in the preparation of solid pharmaceutical compositions containing miltefosine. Eibl et al. Suggested coating the miltefosine on the surface of silicon dioxide particles by evaporating to dryness a suspension of one part by weight of silicon dioxide in a solution containing one part by weight of miltefosine. The resulting solid dispersion as suggested by Eibl et al. Truly shows sufficient flow capacity to be filled in capsules, at least as far as the laboratory scale is concerned. However, the process as described by Eibl et al. Is committed to the use of a highly volatile solvent as well as non-flammable (due to electrostatic charge). For all practical purposes, there are only two solvents available in the state of the art that meet these requirements, namely methylene chloride and chloroform. However, halogenated hydrocarbons, in particular chloroform, are classified as toxic and carcinogenic compounds. In addition, halogenated hydrocarbons are enriched in fatty tissues and are only slowly metabolized. In this way, a development of a solid pharmaceutical composition according to the description by Eibl et al. Has only little opportunity to be approved by the competent health authorities, at least as regards humans and animals that are part of the food chain. From the above it follows that there was a long-detected need for a solid pharmaceutical composition for oral administration in the treatment of leishmaniasis. Solving this problem was the objective of the present invention. Surprisingly and unexpectedly, it has now been found, according to one aspect of the present invention, that the aforementioned problems can be solved simply by physically mixing the hexadecyl phosphocholine, at least one agent for flow control and / or a selected lubricant of the group consisting of highly dispersed silicon dioxide, talc, magnesium stearate and mixtures thereof, and at least one filler selected from the group consisting of lactose, microcrystalline cellulose and mixtures thereof. The subject of interest of the present invention is novel and not obvious from the relevant prior art, since carrier particles or granulation solvent are no longer necessary to obtain a solid pharmaceutical composition containing miltefosine with sufficient flowability. According to the present invention, simply by physically mixing the miltefosine, an agent for flow control and / or a lubricant, and at least one filler, a solid pharmaceutical mixture having sufficient flow capacity for further processing can be provided. for example in the form of capsules, tablets or sacks. In contrast, according to the teaching of Eibl et al., The expert person would have tried to achieve a desired flow capacity, either as granules by using a granulation solvent different from water (due to the hygroscopicity of miltefosine ) or as solid dispersions. In the latter case a large excess of silica gel is necessary. Therefore, the subject matter of the present invention is novel and inventive on the pertinent prior art. In a preferred embodiment, the solid pharmaceutical composition according to the present invention can be filled into capsules, preferably hard gelatin capsules, or pressed into effervescent tablets or tablets, or filled into bags or sacks as a drinkable mixture or effervescent mixture. . The content of miltefosine per unit dose is in the range of 10 to 800 mg, preferably in the range of 10 to 500 mg, more preferably in the range of 50 to 250 mg. The most preferred content is in the range of 50 to 150 mg. Suitable agents for flow control are, for example, highly dispersed or colloidal silicon dioxide (for example Aerosil® such as Aerosil ® V200; DEGUSSA AG. Germany), magnesium stearate, talcum, talc siliconisate, calcium araquinate, cetyl alcohol, myristyl alcohol and mixtures thereof. The lubricants which may for example be used are magnesium stearate or other stearates such as calcium stearate, D, L-leucine, talc, stearic acid, lauric acid, polyglycols (average molecular weight 3000 to 35000), fatty alcohols or waxes . The preferred ratio between the miltefosine and the agent for the flow control and / or the lubricant is 1 part by weight of miltefosine to 0.01-0.6 parts by weight of the flow controller. Anti-adhesion agents which can be used, for example, are: glycols, starch, talc, talc siliconisate, aluminum stearate, stearic acid, magnesium stearate, calcium stearate or D, L-leucine. Suitable agents for flow control, lubricants and anti-adhesion agents are for example listed in the following textbooks: W.A. Ritschel, DIE TABLETTE, Editio Cantor Verlag, page 125, edition 1966; Sucker, Fuchs, Speiser, PHARMAZEUTISCHE TECHNOLOGIE, g. Thieme Verlag, Stuttgart, pages 334 to 336, 1st edition 1978; Münzel, Büchi, Schultz, GALENISCHES PRAKTIKUM, issenschaflitche Verlagsantalt, Stuttgart, page 731, edition 1959; R. Voight, LEHRBUCH DER PHARMAZEU ISCHEN TECHNOLOGIE, 4th edition, Verlag, Chemie, Weinheim, page 195, edition 1982; P.H. List, ARZNEIMITTELLEHRE, Wissenchafliche Verlagsantalt, Stuttgart, page 86, the 1976 edition. The solid pharmaceutical compositions according to the invention may also contain binding agents such as gelatin, cellulose, cellulose ethers, amyloses, dextrose, polyglycols, tragacanth, pectins, alginates, polyvinylpyrrolidone. The solid pharmaceutical compositions according to the invention may also contain disintegrating agents, such as for example: starch (for example, corn starch), modified starch (for example sodium starch glycolate, starch 1500), pectins, bentonite, cellulose , cellulose derivatives (for example carboxymethylcellulose), alginates, polyvinylpyrrolidones, ultraamylopectin, crosslinked polyvinylpyrrolidone or crosslinked carboxymethylcellulose (Ac-Di-Sol / FMC). Suitable fillers, for example, lactose (eg, spray dried), glucose, fructose, calcium phosphates, calcium sulfates, calcium carbonates, starch, modified starch, sugar alcohols such as sorbitol, cellulose derivatives, sucrose , microcrystalline cellulose, and mixtures thereof. The preferred ratio between the miltefosine and the filler is 1 part by weight of the miltefosine at 0.1-120 parts by weight of the filler. According to a further aspect of the invention, there is provided a process for the manufacture of the pharmaceutical composition according to the present invention, which comprises the steps of: (a) mixing the miltefosine, the agent for the flow control and the filler, optionally with each other with additional auxiliary agents, whereby a pharmaceutical composition having sufficient flowability is obtained, and (b) filling the obtained mixture into capsules or bags, or alternatively, compressing the obtained mixture to form tablets .

The production of an oral pharmaceutical composition according to the present invention can be carried out by mixing or homogenizing miltefosine with the usual physiologically tolerated fillers, carriers, dilution and / or auxiliaries, at temperatures between 20 and 120 ° C and, if desired, in order to prepare formulations containing 10 to 800 mg of miltefosine in a unit dose, the mixture obtained in this way is poured into hollow cells of an appropriate size or filled into capsules of an appropriate size or granulated and then pressed to form tablets, if desired, with the addition of additional, common auxiliary substances. The active substance can be, for example, mixed with one or more of the following auxiliary substances: starch, cellulose, lactose, formalin-casein, modified starch, magnesium stearate, calcium acid phosphate, highly disperse silicic acid, talc and phenoxyethanol. The obtained mixture is granulated, if desired, with an aqueous solution containing for example gelatin, starch, polyvinylpyrrolidone, copolymerized vinylpyrrolidone-vinyl acetate and / or polyoxyethylene sobianmonooleate, as a constituent and the granulate is homogenized, if desired, with one or more of the auxiliary substances mentioned above. Subsequently this mixture can be pressed into tablets or refilled into capsules whereby the tablets or capsules each contain from 10 to 800 mg of miltefosine in a unit dose. The manufacture of the capsules and tablets occurs for example between 15 ° C and 26 ° C, preferably between 18 ° C and 22 ° C. The relative humidity in the production room should preferably not exceed 40%. The preparation of the solid pharmaceutical compositions according to the invention is carried out in a conventional manner, it being also possible to use auxiliary pharmaceutical substances, conventional and customary, and other conventional carriers and diluents. According to the invention, the process for the manufacture of the pharmaceutical compositions may further comprise the step of granulating the composition having sufficient flowability, as obtained according to step (a) before step (b) by the methods known per se. The granulation can be carried out according to the methods known per se in the art (see for example Hagers Handbush der pharmazeutischen Praxis, 5th edition, Springer Verlag, 1991, pages 722-742). The mixture can be melted with a liquid and if the wet compound is required it can then be passed through a screen. Additional processing steps are drying, screening, mixing with additional excipients and filling into bags or capsules, or compression to form tablets. The mixture can also be compounded or extruded according to the prior art in order to obtain a granulate. The carrier and the excipients can for example be considered those that are recommended or cited in the following literature references as auxiliary substances for pharmacy, and the cosmetic fields and related fields: "Ullmanns Encyklopadie der technischen Chemie", Volume 4 (1953) , pages 1 to 39; Journal Pharmaceutical Sciences, Volume 52 (1963), page 918 et seq; H. v. Czetsch-Lindenwald, "Hilfsstoffe für Pharmazie und angrenzende Gebiete"; Pharm. Ind. Issue 2 (1961), page 72 and seq, M -dr, G, O, Fuedker, Lexikon der Hilsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, cantor KG, Aulendorf in ürttemberg 1981. Examples of these are gelatine, natural sugars, such as unrefined sugar or lactose, lecithin, pectin starches (for example corn starch), cyclodextrins and cyclodextrin derivatives, polyvinylpyrrolidone, polyvinyl acetate, gelatin, gum arabic, alginic acid, tylose, talcum, licopodium, silica gel (for example colloidal), cellulose, cellulose derivatives (for example cellulose ether in which the hydroxyl groups of the cellulose are partially etherified with saturated, lower aliphatic alcohols, and / or lower saturated aliphatic oxyalcohols, for example ethyloxypropylcellulose , methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate); fatty acids such as magnesium, calcium, aluminum, fatty acids with 12 to 22 carbon atoms, in particular those which are saturated (for example stearates), emulsifiers, oils and fats, in particular vegetable fats (for example peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in each case also hydrogenated; mono- or di- and triglycerides of saturated fatty acid C? 2H24? 2 to C? sH3602 and their mixtures, alcohols and polyalcohols simple or multivalent, pharmaceutically acceptable such as polyethylene glycols, as well as derivatives thereof, saturated fatty acid esters or unsaturated aliphatics (from 2 to 22 carbon atoms, in particular from 10 to 18 carbon atoms) with monovalent aliphatic alcohols (from 1 to 20 carbon atoms) or multivalent alcohols such as glycols, glycerin, diethylene glycol, pentaeri tri tol, sorbitol, mannitol, and so on, which may optionally also be etherified, ethers of citric acid with primary alcohols, acetic acid, benzyl benzoate, dioxolanes, glycerin formates, tetrahydrofurfuryl alcohol, polyglycol with alcohols of 1 to 12 carbon atoms, dimethylacetamide, lactamides, lactates, ethyl carbonates, silicones (in particular medium viscosity polydimethylsiloxanes), calcium carbonate of sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and Similar.

Other excipients that can be used are disintegration-assisting substances (so-called disintegrators) such as: cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethylcellulose or microcrystalline cellulose. The powders are manufactured in the following manner: miltefosine, at least one agent for flow control and / or a lubricant, at least one filler, and optionally a flavoring and / or sweetening agent are mixed and filled into sacks ( bags) of the appropriate dose unit. In use, in the total contents of a bag, or alternatively a part of it, they are stirred in water or fruit juice and swallowed. This method makes it easy to apply any dose level via the peroral route. To prepare an effervescent tablet or an effervescent mixture, miltefosine, at least one agent for flow control and / or a lubricant, and at least one filler are mixed in a conventional manner with a carbonate or an acid component and the mixture obtained it is pressed into a tablet or filled into bags, optionally after the addition of flavorings, of missing acid or carbonate components as well as other agents for flow control, and lubricants. In the same way, the administration is carried out by placing the tablet or the mixture in water. The solid pharmaceutical compositions according to the invention may also contain flavoring, sweetening and / or aromatic substances. The aromatic substances are: pineapple, apple, apricot, raspberry, cherry, cola, orange, passion fruit, lemon, grapefruit, vanilla, chocolate. The following substances can be used as sweeteners: saccharin and its sodium salt, cyclamic acid, and its sodium salt, ammonium glycyrrhizinate, fructose, xylitol, sorbitol, mannitol, aspartame, acesulfame-K. The effervescent or chewable powder or the effervescent tablets are prepared using conventional processes as described in the literature (for example in the standard reference work by Sucker, Fuchs, and Speiser (ed.), Pharmazeutische Technologie, Thieme Verlag, Stuttgart). The preparation (all steps other than drying) is carried out, for example, at temperatures between 10 ° C and 80 ° C, preferably 18 ° C to 50 ° C, in particular 20 ° C to 30 ° C.

The production of miltefosine is described in detail in the examples for hexadecylphosphocholine as described in the German patent application not examined No .. P 41 32 344. Additional methods for the production and purification of miltefosine are described for example in the German patent applications not examined Nos. DE-A 27 52 125, DE-A 36 41 379, DE-A 36 41 491, DE-A 40 13 632, DE-A 36 41 377, the literature cited in these or in Previous patent applications or patent specifications are incorporated by reference herein. According to a further aspect of the present invention, a dosage scheme for the treatment of leishmaniasis in humans by administration is provided. of the pharmaceutical composition according to the present invention. In a preferred embodiment of the invention, the following dosage scheme is suitable in the treatment of leishmaniasis in humans, by oral administration: Total daily dose: 10-250 mg, preferably 50-150 mg of i. to. miltefosine (i.a. = active ingredient); Single or multiple daily dose: a total daily dose of 10 to 50 mg of i. to. it is preferably administered as a simple daily dose; a dose between 50-250 mg of i. a., preferably between 50-150 mg of i. a., is administered orally as a multiple daily dose, preferably as a twice daily dose (100 mg of total daily dose) or a dosage of three times a day (150 mg of total daily dose); With respect to patient compliance, a divided daily dose of 4 to 5 times is generally considered to be an upper limit. For reasons of healing, however, daily doses divided in another way from 1 to 5 times can also be applied. In a preferred embodiment, multiple daily doses are administered in equal portions (for example 100 mg ai / day = 2 x 50 mg ai / day or 150 mg ai / day = 3 x 50 mg ai. day) . Period of therapy: 2-6 weeks, preferably 4 weeks. According to a further aspect of the invention, a dosage scheme is provided for the treatment of leishmaniasis in mammals other than humans, by oral administration of the pharmaceutical composition according to the present invention. All mammalian animals can be treated by the invention, for example, small companion animals such as for example dogs, all rodents and hamsters. The treatment can be carried out in the natural surroundings of the animals or in selected surroundings such as hospitals for animals or veterinary offices, with the first ones being the preferred ones. All Leishmania species can be treated by the dosage scheme of the invention, especially Lei shmani a major and Lei shmani a i nfan t um. According to the dosage scheme of the invention, the total daily dose in the treatment by oral administration is in the range of 1-15 mg of i. to. miltefosine per kg body weight of the animal (mg of i.a./kg). In a preferred embodiment, the therapy is initiated with an initial total simple dose (loading dose) in the range of 3-15, preferably 5 to 10 mg ai / kg, and thereafter continued with a total daily dose ( maintenance dose) in the range of 1 to 10, preferably 3 to 5 mg ai / kg. The period of time for the treatment is in the range of 2 to 8, preferably 4 to 5 weeks. According to a further aspect of the invention, a combination of the pharmaceutical composition according to the invention with an antiemetic and / or antidiarrheal is provided. for oral administration in the treatment of leishmaniasis. In a preferred embodiment of the invention, the pharmaceutical composition according to the invention is administered in combination with an antiemetic and / or an antidiarrheal. The administration can be carried out simultaneously or sequentially. The antiemetic and the antidiarrheic can be administered independently of each other. The antiemetic and / or the antidiarrhoeic can be either contained in the pharmaceutical composition according to the invention or contained in a pharmaceutical formulation independent thereof. Suitable antiemetics with, for example, 5-HT3 receptor antagonists, substituted benzamides, corticosteroids, antihistamines, neuroleptics of the phenothiazine type, neuroleptics of the butophenone type, benzodiazepines and cannabinoids. Preferred antiemetics are, among others, metoclopramide, domperidon and alizaprid. Suitable antidiarrheals are, among others, opioids, such as loperamide. The oral solid pharmaceutical compositions, according to the invention, are preferably useful in the treatment of leishmaniasis. Other diseases by protozoa that can be treated by the agent according to the present invention are for example malaria, trypanosomiasis, toxoplasmosis, babesiosis, amoebic dysentery and lambliasis. The agents according to the present invention are in particular suitable for those diseases in which the pathogen is present in the internal organs such as the liver, spleen and kidney, in the lymph nodes, the bone marrow and in the blood. The invention is further elucidated by the following examples without the invention being restricted by these examples.

I. Examples for oral solid pharmaceutical formulations according to the invention Example 1: hard gelatin capsule (content: 10 mg of miltefosine) 100 g of hexadecylphosphocholine, 808.50 g of lactose, 448.50 g of microcrystalline cellulose, 26 g of talc and 13 g of highly dispersed silicon dioxide are passed through a sieve with a mesh number of 0.8 mm and then homogenized in a suitable mixer in 30 minutes. Then add 4 g of magnesium stearate (0.8 mm sieve) and the components are mixed for an additional 5 minutes. The obtained mixture is filled in the known manner in portions of 140 mg into hard gelatin capsules of 50 mg in weight, by the use of a suitable encapsulating machine. Each capsule, as obtained (total weight: 190 mg), contains 10 mg of hexadecyl focholine. The ratio between hexadecylphosphocholine: agent for flux control / surfactant: fillers in the filler mixture is 1: 0.4: 12.4 (parts by weight).

Example 2: hard gelatin capsule (content: 50 mg of miltefosine) 258 g of hexadecylphosphocholine, 430 g of lactose, 241 g of microcrystalline cellulose, 14 g of talc, 7 g of highly disperse silicon dioxide and 2 g of magnesium stearate are mixed according to the process as described in Example 1. The filling mixture obtained in this way is filled in portions of 185 mg into hard gelatin capsules of 59 mg in weight, in a known manner by the use of a suitable encapsulating machine. Each capsule, as obtained (total weight: 244 g), contains 50 mg of hexadecylphosphocholine. The proportion between hexadecylphosphocholine: agents for flow control and lubricants: fillers in the filler mixture is 1: 0.09: 2.6 (parts by weight).

Example 3: hard gelatin capsule (content: 100 mg of miltefosine) 1000 g of hexadecylphosphocholine, 584 g of lactose, 345 g of microcrystalline cellulose, 50 g of talc, 15 g of highly disperse silicon dioxide and 6 g of magnesium stearate were mixed according to the process as described in Example 1. The filling mixture obtained in this way is filled in portions of 200 mg into hard gelatin capsules of 76 mg in weight, in a known manner by the use of a suitable encapsulating machine. Each capsule as obtained (total weight: 276 mg) contains 100 mg of hexadecyl focholine. The ratio between hexadecylphosphocholine: agents for flow control: fillers in the filling mixture is 1: 0.07: 0.9 (parts by weight).

Example 4: hard gelatin capsule (content: 150 mg miltefosine) 150 g of hexadecylphosphocholine, 30 g of lactose, 15 g of microcrystalline cellulose, 3 g of talc, 2 g of highly dispersed silicon dioxide and 1 g of magnesium stearate were mixed according to the process as described in Example 1. The filling mixture obtained in this way is filled in portions of 201 mg into hard gelatin capsules of 76 mg in weight, in a known manner by the use of a suitable encapsulating machine. Each capsule, as obtained (total weight: 277 mg), contains 150 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agents for flow control: fillers in the filling mixture is 1: 0.04: 0.3 (parts by weight).

Example 5: Hard gelatin capsule (content: 200 mg miltefosine) 200 g of hexadecylphosphocholine, 80 g of lactose, 50 g of microcrystalline cellulose, 4 g of talc, 5 g of highly disperse silicon dioxide and 10 g of magnesium stearate were mixed according to the process as described in Example 1. The filling mixture obtained in this way is filled in portions of 349 mg into hard gelatin capsules of 97 mg weight, in a known manner, by the use of a suitable encapsulating machine. Each capsule, as obtained (total weight: 446 mg), contains 200 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agents for flow control: fillers in the filling mixture is 1: 0.095: 0.65 (parts by weight).

Example 6: hard gelatin capsule (content: 250 mg of miltefosine) 250 g of hexadecylphosphocholine, 80 g of lactose, 50 g of microcrystalline cellulose, 5 g of talc, 5 g of highly disperse silicon dioxide and 15 g of magnesium stearate were mixed according to the process as described in Example 1. The filling mixture obtained in this way is filled in portions of 405 mg into hard gelatin capsules of 97 mg in weight, in a known manner, by the use of a suitable encapsulating machine. Each capsule, as obtained (total weight: 502 mg), contains 250 mg of hexadecyl focholine. The ratio between hexadecylphosphocholine: agents for flow control: fillers in the filling mixture is 1: 0.1: 0.52 (parts by weight).

Example 7: Tablets (content: 250 mg of hexadecylphosphocholine) 50 g of hexadecylphosphocholine, 24.25 g of microcrystalline cellulose and 22.00 g of anhydrous dicalcium phosphate are sieved and mixed. 3.75 g of magnesium stearate are sieved and added to the mixture. Then the mixture is homogenized again. The resulting mixture is compressed into tablets each weighing 500 mg. One tablet contains 250 mg of hexadecylphosphocholine. The ratio between the hexadecyl focholine: agent for flow control / surfactant: fillers in the tablet is 1: 0.07: 0.925 (parts by weight).

Example 8: Tablets (content: 30 mg hexadecylphosphocholine) 23 g of hexadecylphosphocholine, 23 g of microcrystalline cellulose, 52 g of spray-dried lactose are sieved and mixed. 1 g of colloidal silicon dioxide and 1 g of magnesium stearate are added. The mixture is then homogenized again. The resulting mixture is compressed into tablets each weighing 130.5 mg. One tablet contains 30 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agent for flow control / surfactant: tablet fillers .is 1: 0.087: 0.31 (parts by weight).

Example 9: Mixture and effervescent tablets (content of hexadecylphosphocholine: 250 mg) 1700 g of granular sodium bicarbonate are placed in an oven and heated at 100 ° C for 60 minutes. After cooling to room temperature the converted bicarbonate is mixed with 160 g of monobasic, granular calcium phosphate, 1030 g of granular anhydrous citric acid, 100 g of talc and 50 g of magnesium stearate. To the resulting mixture, 300 g of hexadecylphosphocholine are added and mixed for 10 minutes. The resulting effervescent mixture is compressed into tablets each weighing 278 mg. An effervescent tablet contains 250 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agent for flux control / surfactant: fillers in the tablet is 1: 0.50: 0.53 (parts by weight). Alternatively, the effervescent mixture can be filled in an amount of 278 mg in sacks, thereby obtaining a special effervescent mixture.

Example 10: Mixture and effervescent tablets (content: 50 mg hexadecylphosphocholine) 1600 g of granular sodium bicarbonate are placed in an oven and heated to 100 ° C for 60 minutes. After cooling to room temperature the converted bicarbonate is mixed with 150 g of granular monobasic calcium phosphate, 900 g of granular anhydrous citric acid, 80 g of talc and 30 g of magnesium stearate. To the resulting mixture, add 200 g of hexadecylphosphocholine and mix for 10 minutes. The resulting mixture is compressed into tablets each weighing 740 mg. An effervescent tablet contains 50 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agent for flux control / surfactant: fillers in the tablet is 1: 0.55: 0.75 (parts by weight). Alternatively, the effervescent mixture can be filled in an amount of 740 mg in sacks, thereby obtaining an effervescent mixture.

Example 11: Drinkable mixture (sacks) (content: 50 mg hexadecylphosphocholine) g of hexadecylphosphocholine, 308 g of lactose, 280 g of microcrystalline cellulose, 5 g of saccharin and 2 g of colloidal silicon dioxide are mixed. The mixture is filled into sacks. One sack weighs 6 g and contains 50 mg of hexadecyl focholine. The ratio between hexadecylphosphocholine: agent for flux control / surfactant: fillers in the mixture is 1: 0.4: 117.5 (parts by weight).

Example 12: Drinkable mixture (sacks) (content: 100 mg hexadecylphosphocholine) g of hexadecylphosphocholine, 200 g of lactose, 250 g of microcrystalline cellulose, 7 g of saccharin and 3 g of colloidal silicon dioxide are mixed. The mixture is filled into sacks. One sack weighs 4.7 g and contains 100 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agent for flux control / surfactant: fillers in the mixture is 1: 0.3: 45 (parts by weight).

Example 13: Drinkable mixture (sacks) (content: 200 mg of hexadecylphosphocholine) g of hexadecylphosphocholine, 306 g of lactose, 403 g of microcrystalline cellulose, 5 g of saccharin and 6 g of colloidal silicon dioxide are mixed. The mixture is filled into sacks. One sack weighs 7.4 g and contains 200 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agent for flux control / surfactant: fillers in the mixture is 1: 0.3: 35.5 (parts by weight).

II. Results of clinical studies in the treatment of 1eishmaniasis where capsules according to the present invention were perorally administered In the subsequent, the abbreviations mean: once qod = one administration every third day IDB qod = two administrations every third day IDB = two administrations per day; TID = three daily administrations; QID = four daily administrations; Miltefosine (MILT, hexadecylphosphocholine, ASTA Medical), an alkyl phospholipid antineoplastic, is active in experimental visceral leishmaniasis (VL). To test oral MILT in human VL, 30 male Indian patients from Bihar (age> 14 years; 18 out of 30 failed antimony (Sb)) with positive VL to splenic aspirate were treated in 6 groups of 5 patients each one (AF groups) for 28 days with increasing doses by oral administration of capsules according to example 1: (A) 50 mg once qod (qod = quantity every third day), (B) 50 mg BID qod (IDB = twice a day), and then daily using 50 mg (C) IDB (100 mg / day), (D) TID (150 mg / day), (E) QID (200 mg / day), and (F) 5x per day (250 mg / day). 16 patients were afebrile on day 7. Results on day 14 in 30 patients: 25 afebriles, 25 decreased the size of the spleen, 28 with negative splenic aspirates (apparent parasitological cure); 21 of 30 showed all 3 responses and were thus considered apparently cured. One patient in group F died on day 21 (the drug was stopped on day 19) with severe vomiting and diarrhea (possibly associated with drug or interactive gastroenteritis), dehydration and renal failure. Mild vomiting or diarrhea that lasted 3 to 7 days developed in the majority of patients in Groups B-E. 1 patient in Group E and 3 more in Group F were withdrawn on days 7, 7, 8 and 10 due to vomiting. 200 mg / day was therefore the maximum daily dose tolerated. There was no haematological toxicity. 1 patient in Group F developed increased hepatic transaminases (resolved). On day 28, 29 of 29 patients (100%) were apparently cured including the 4 who received < of 10 days of therapy and were no longer treated. Within 6 months 7 of 29 seemingly cured relapsed (A-3/5, B3 / 5, D-l / 5); thus, 6 of 7 relapses were in the low dose, in the qod dosage groups (A, B). Within 6 months, apparent cure (no relapse, bone marrow aspirate free of parasites) has been achieved in 21 of 26 patients (A-2/5, B-2/5, C-5/5, D-4 / 5, E-5/5); 1 patient is still in follow-up; Of the first 21 patients with definitive cure, 14 have failed prior antimony therapy. The results found demonstrate that the solid pharmaceutical compositions and the dosage scheme according to the present invention are effective in the treatment of leishmaniasis by peroral administration. Apparent cures were even observed in patients with the increasing problem of visceral infection without antimony response.

Claims (23)

1. A solid pharmaceutical composition for oral administration in the treatment of leishmaniasis, comprising miltefosine, an agent for flow control and / or a lubricant, and a filler.

2. The solid pharmaceutical composition according to claim 1, characterized in that the solid composition is selected from the group consisting of capsules, tablets, effervescent tablets, effervescent mixture and sacks (drinkable mixture).

3. The solid pharmaceutical composition according to claim 1 or 2, characterized in that the agent for controlling the flow is selected from the group consisting of silicon dioxide, talc, magnesium stearate and mixtures thereof.

4. The solid pharmaceutical composition according to any of claims 1 to 3, characterized in that the filler is selected from the group consisting of a cellulose, lactose, mannitol, a calcium phosphate and mixtures thereof.

5. The solid pharmaceutical composition according to any of claims 1 to 4, characterized in that the ratio between the hexadecylphosphocholine (HPC) and the agent for flow control and / or lubricant is one part by weight of HPC and 0.01 - 0.6 parts by weight. weight of the agent for flow control and / or lubricant.

6. The solid pharmaceutical composition according to any of claims 1 to 4, characterized in that the ratio between the hexadecylphosphocholine (HPC) and the filler is 1 part by weight of HPC and 0.1-120 parts by weight of filler.

7. The solid pharmaceutical composition according to any of claims 1 to 6, characterized in that a solid pharmaceutical composition having sufficient flow capacity is obtained by simply physically mixing the miltefosine, an agent for flow control and / or lubricant, and a filler.

8. The solid pharmaceutical composition according to any of claims 1 to 7, characterized in that optionally the obtained pharmaceutical composition having sufficient flow capacity can be granulated before processing into tablets, capsules or sacks.

9. The solid pharmaceutical composition according to any of claims 1 to 8, characterized in that it may further comprise one or more excipients (auxiliary agents) selected from the group consisting of disintegrating agents, a binder (binders), anti-adhesion agents, carriers, diluents, effervescent mixtures (for example a carbonate component and an acid component), flavoring agents, sweeteners, aromatic agents.

10. A process for the manufacture of a solid pharmaceutical composition according to any of claims 1 to 9, comprising the steps of: (a) mixing the miltefosine, the agent for flow control and the filler, optionally together with auxiliary agents additional, thereby obtaining a pharmaceutical composition having sufficient flow capacity, and (b) filling the mixture obtained inside capsules or bags, or alternatively, compressing the obtained mixture to tablets.

11. The process according to claim 10, characterized in that the composition having sufficient flow capacity, as obtained according to step (a), can be granulated by methods known per se before step (b).

12. The use of miltefosine for the preparation of a medicament for the treatment of leishmaniasis in humans by oral administration, whereby a total daily dose in the range of 10 to 250 mg of the active ingredient of i. to. of miltefosine is administered orally in a period of time of 2 to 6 weeks.

13. The use according to claim 12, characterized in that the total daily dose is from about 50 to about 150 mg of the active ingredient miltefosine.

14. The use according to claims 12 or 13, characterized in that the administration is continued on a daily basis for a period of time of approximately 4 weeks.

15. The use according to any of claims 12 to 14, characterized in that the oral administration takes place once, twice or three times per day when the total daily dose is 50, 100 and 150 mg of miltefosine active ingredient, respectively .

16. The use according to claim 15, characterized in that multiple daily doses are administered in equal portions (for example 100 mg ai / day = 2 x 50 mg ai / day, 150 mg ai / day = 3 x 50 mg a i.a./day).

17. The use of miltefosine for the preparation of a medicament for the treatment of leishmaniasis in mammals other than humans by oral administration, whereby a total daily dose in the range of 1 to 15 mg of the active ingredient of miltefosine per kg of weight mammalian body (mg ai / kg) is administered over a period of time in the range of 2 to 8 weeks.

18. The use according to claim 17, characterized in that the initial simple daily dose (loading dose) is in the range of 3 to 15 mg ai / kg and the following daily doses (maintenance dose) is in the range of 1. to 10 mg ai / kg.

19. The use according to claim 18, characterized in that the loading dose is in the range of 5 to 10 mg of i.a./kg.

20. The use according to claim 18, characterized in that the maintenance dose is in the range of 3 to 5 mg of i. a / kg.

21. The use according to claims 17 to 20, characterized in that the period of time for oral administration is 4 weeks.

22. The use according to claims 17 to 21, characterized in that small companion animals such as dogs, all rodents and hamsters, are treated with this composition.

23. The pharmaceutical combination for the treatment of leishmaniasis in mammals, comprising a pharmaceutical composition according to any of claims 1 to 9, an antiemetic and / or an antidheal, whereby the pharmaceutical composition according to claims 1 to 9 , the antiemetic and / or the antidhoeic can be administered either jointly or independently of one another.