Solid pharmaceutical composition for oral administration in the treatment of leishmaniasis and method of its manufacture, pharmaceutical combination for the treatment of leishmaniasis in mammals and treatment (options)

 

(57) Abstract:

The invention relates to medicine, in particular to novel solid pharmaceutical compositions containing hexadecylphosphocholine (miltefosine) for oral administration in the treatment of leishmaniasis, to a method for the production of specified pharmaceutical compositions for the treatment of leishmaniasis specified pharmaceutical composition to a combination that includes the specified solid pharmaceutical composition, an antiemetic and/or antidiarrheal agent. Compositions allow to cure patients with advanced problem visceral infection, are not sensitive to treatment with antimony. 5 C. and 13 C.p. f-crystals.

The technical field to which the invention relates

The present invention relates to new solid pharmaceutical compositions containing hexadecylphosphocholine (miltefosine), for oral administration in the treatment of leishmaniasis, to a method for the production of specified pharmaceutical compositions, to use for oral administration of a specified pharmaceutical composition for the treatment of leishmaniasis and, finally, to the combination, including the specified solid pharmaceutical composition, an antiemetic is the cue of the disease, which are called flagellates of the genus Leishmania and transmitted to various blood-sucking insects. Manifestations of leishmaniasis can be visceral (Kala-Azar), cutaneous-mucous (American leishmaniasis) or skin (Halep furuncle or diffuse cutaneous leishmaniasis). The incubation period of weeks or months. If untreated, there is a very high mortality, especially in Cala azure and American leishmaniasis.

Prior to the present invention in the prior art lacked a drug for oral treatment of leishmaniasis. Known means in the standard therapy in the treatment of leishmaniasis, i.e. compounds of pentavalent antimony (for example, stibogluconate sodium) and aromatic diamidine had to apply by intravenous injection, thereby causing not only serious side effects, due to their high toxicity, but also increasing the risk of infection.

Leishmaniasis is a parasitic disease that often occurs in geographic areas with a pronounced tropical climate and where medical care is complicated by lack of transport. Therefore, any drug medium spans the overall environment.

The suitability of miltefosine in oral and local treatment of leishmaniasis was first described by Eibl et al. in a pending patent application in Germany for a number R 4132344, filed September 27, 1991.

Although it is produced in a dry form in the form of crystalline wafers with a specific melting point above 200oWith miltefosine is difficult to process because of its high hygroscopicity. Attaching molecules of water can lead to an increase in mass up to 30 wt.%, the decrease of the melting temperature and sintering and agglutination crystals. Water-containing miltefosine becomes unsuitable for further processing in the solid pharmaceutical compositions such as tablets, capsules or sachets. In particular, is the lack of fluidity of the water-containing miltefosine. Satisfactory fluidity, however, is one of the essential properties for the production of solid pharmaceutical compositions on an industrial scale.

In addition, anhydrous miltefosine has a significant tendency to accumulate an electrostatic charge, especially when it is ground in a dry condition. Electrostatically charged miltefosine also shows nakoplenie electrostatic charge raises important security issues due to the associated risk of explosion, and damage to sensitive electronic parts.

In an attempt to overcome the above-mentioned problem in the preparation of solid pharmaceutical compositions containing miltefosine, Eibl et al. proposed to apply miltefosine on the surface of particles of silicon dioxide by evaporation to dryness suspension 1 weight part of silica in a solution containing 1 weight part of miltefosine. The resulting solid dispersion, according to the proposal Eibl et al., indeed exhibits sufficient fluidity to fill the capsules, at least in laboratory scale. However, the process as it is described Eibl et al., associated with the use of vysokoletuchih, and non-flammable (due to the accumulation of electrostatic charge) of the solvent. For all practical purposes there are only two solvent that is acceptable in this area, which 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 accumulate in fatty tissues and are only slowly metabolized. Thus, rastorgaetsya the competent authorities in the field of medicine, at least if you keep in mind the people and animals that are part of the consumer link.

From the above it follows that for a long time there was a need for solid pharmaceutical composition for oral administration in the treatment of leishmaniasis. The solution to this problem was the aim of the present invention.

The invention

Suddenly and unexpectedly, at the present time has been set, according to one aspect of the present invention that the foregoing problems can be solved by simple physical mixing of hexadecylphosphocholine at least one agent controlling the flow and/or lubricating material selected from 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 object of the present invention is novel and not obvious in relation to the prior art, so as no longer need any particle of the medium or granulating solvent to obtain a solid pharmaceutical composition containing miltefosine is Osina, agent, controlling the flow and/or lubricating material, and at least one filler can provide a solid pharmaceutical mixture, which has sufficient fluidity for further processing, for example, in capsules, tablets or sachets.

In contrast, according to the proposal Eibl et al., specialists in this field may attempt to achieve the desired fluidity or with granules using different granulating solvent than water (due to the hygroscopicity of miltefosine), or by using solid dispersions. The latter requires a large excess of silica gel.

Therefore, an object of the present invention is new and corresponds to inventive step compared with the prior art.

In a preferred embodiment, the solid pharmaceutical composition according to the present invention, can be used as a filler capsules, preferably of hard gelatin capsules, or compressed into tablets or foaming tablets, or to fill the sachet as drinking water mixture or foaming the mixture.

The content of miltefosine on the standard dose is in the range 10-800 mg, preferably in the limits of 50-150 mg.

Suitable agents that control the fluidity, for example, are finely dispersed or colloidal silicon dioxide (e.g., Aerosilsuch as AerosilV200; DEGUSSA AG, Germany), magnesium stearate, talc, siliconisation talc, archinet calcium cetyl alcohol, ministerului alcohol and mixtures thereof. Lubricating materials that can be used are, for example, magnesium stearate or other stearates such as calcium stearate, D,L-leucine, talc, stearic acid, lauric acid, polyglycols (average molecular weight 3000-35000), fatty alcohols or waxes.

The preferred ratio between miltefosine and agent, controlling the flow and/or lubricating material is 1 weight part of miltefosine and 0.01 to 0.6 weight part of the agent that controls the flow.

Protivogaznymi agents who, for example, you can use are: glycols, starch, talc, siliconisation talc, aluminum stearate, stearic acid, magnesium stearate, calcium stearate or D,L-leucine.

Suitable controlling fluidity agents, lubricants and protivorededivne agents are, for example, the following guides:

W. A. Ritschel, Tabled g. Thieme Verlag, Stuttgart, pp. 334-336, 1st edition, 1978;

Munzel, Buchi, Schultz, Guide Galenika (GALENISCHES PRAKTIKUM), Wissenschaftliche VerlagsanstaIt, Stuttgart, page 731, 1st edition, 1959;

R. Voigt, the Textbook of pharmaceutical technology (LEHRBUCH DER PHARMAZEUTISCHEN TECHNOLOGIE), 4th edition, Verlag Chemie, Weinheim, PP 195, 1st edition, 1982;

R. N. List, Manual on medicines (ARZNEIMITTELLEHRE), Wissenschaftliche Verlagsanstalt, Stuttgart, page 86, 1st edition, 1976.

Solid pharmaceutical compositions according to the invention may also contain binders, such as gelatin, cellulose, esters of cellulose, amylose, dextrose, polyglycols, tragakant, pectins, alginates, polyvinylpyrrolidone.

Solid pharmaceutical compositions according to the invention may also contain dezintegriruetsja agents, such as, for example: starches (e.g. corn starch), modified starch (e.g., sodium glycolate derived starch, starch 1500), pectin, bentonite, cellulose, derivatives of cellulose (such as carboxymethyl cellulose), alginates, polyvinylpyrrolidone, ultramylonite, transversely crosslinked polyvinylpyrrolidone or transversely crosslinked carboxymethylcellulose (Ac-Di-Sol/FMC).

Suitable fillers are, for example, lactose (e.g., deficieny starch, sugar alcohols such as sorbitol or mannitol, cellulose derivatives, sucrose, microcrystalline cellulose and mixtures thereof. The preferred ratio between miltefosine and filler is 1 weight part of miltefosine for 0.1 to 120 parts by weight of filler.

According to the next object of the invention proposes a method of manufacturing the pharmaceutical composition according to the present invention, which includes stages

(a) mixing miltefosine, agent, controlling fluidity, and filler, optionally together with other auxiliary agents, obtaining a pharmaceutical composition having sufficient fluidity, and

(b) filling the mixture of capsules or sachets or, alternatively, pressing the mixture into tablets.

The production of pharmaceutical compositions for oral administration according to the present invention can be performed by mixing or homogenization of miltefosine with conventional physiologically tolerant excipient, carrier, diluent or/and auxiliary substances at temperatures between 20 and 120oAnd, if desirable, for the preparation of compositions containing 10-800 mg miltefosine in one standard to the s of the appropriate size, or granularit and then pressed into tablets, if desired, with the addition of other conventional auxiliary substances. The active substance can, for example, be mixed with one or more of the following excipients: starch, cellulose, lactose, formaldehyde-casein, modified starch, magnesium stearate, calcium phosphate, highly dispersed silicic acid, talc and Phenoxyethanol. The resulting mixture granularit, if desirable, with a water solution containing, for example, gelatin, starch, polyvinylpyrrolidone, a product of copolymerization of vinylpyrrolidone with vinyl acetate and/or polyoxyethylene servicemanual as an integral part, and the granulate is homogenized, if desirable, one or more of the abovementioned excipients. Then this mixture can be pressed into tablets or filled her capsules, with each tablet or capsule contains 10-800 mg miltefosine in one standard dose.

Manufacture of capsules and tablets carried out, for example, at a temperature between 15oAnd the 26oWith, preferably between 18oAnd the 22oC. relative humidity in the premises preferably should not exceed 40%.

According to the invention, a method of manufacturing the pharmaceutical compositions can also include stage granulating composition having sufficient fluidity, which is obtained according to stage (a) before stage (b) is known, essentially, ways. The granulation can be carried out according to methods in the entity known in this field (see, for example, Hagers, Guidance on pharmacy practice (Handbuch der Pharmazeutischen Praxis), 5th edition, Springer Verlag, 1991, pp. 722-742). The mixture can be diluted with liquid and, if you want a wet connection, you can then pass through a strainer. Further processing stages are drying, sieving, mixing with other fillers and filling sachets or capsules or pressed into tablets. The mixture can also or compound, or be subjected to extrusion according to the prior art to obtain a granulate.

Carriers and fillers, which, for example, can be taken into consideration, recommended or described in the following literature surveys as auxiliary substances dleep Chemie"), volume 4 (1953), pp. 1-39; Journal of Pharmaceutical Sciences, volume 52 (1963), page 918 and forth; H. v. Czetsch-Lindenwald, excipients for the pharmaceutical industry and related fields "Hilfsstoffe fur Pharmazie und angrenzende Gebiete"; Pharm. Ind., issue 2 (1961), pp. 72 FF; Dr. H. P. Fiedler, "the Names of auxiliary substances for pharmacy, cosmetics and related fields" "(Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete") cantor KG, Aulendorf in Wurttemberg, 1981.

Examples of these include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin starches (e.g. corn starch), cyclodextrins and cyclodextrin derivatives, polyvinylpyrrolidone, polyvinyl acetate, gelatin, Arabic gum, alginic acid, tylose, talc, lycopodine, silica gel (e.g., colloidal), cellulose, cellulose derivatives (for example, a simple ester of cellulose in which a hydroxyl group of cellulose is partially tarifitsirovana lower saturated aliphatic alcohols and/or lower saturated aliphatic oxapentane, such as methoxypropylacetate, methylcellulose, hypromellose, phthalate of hydroxypropylmethylcellulose), fatty acids, as well as magnesium, calcium or aluminum salts of fatty acids with 12-22 carbon atoms, in particular,isovue oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower oil, fish oil), in each case also hydrogenated; mono-, di - and triglycerides of saturated fatty acids from the C12H24O2to C18H36ABOUT2and mixtures thereof, pharmaceutically acceptable one - or polyhydric alcohols and polyglycols such as polyethylene glycol and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2-22 carbon atoms, in particular 10-18 carbon atoms) with monohydroxy aliphatic alcohols (1 to 20 carbon atoms) or polyhydric alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, sorbitol, mannitol, and so on, which can also be optionally etherified, esters of citric acid with primary alcohols, acetic acid, benzoylbenzoate, dioxolane, glycerin, formal, tetrahydrofurfuryl alcohol, polyglycolic broadcast with1-C12-alcohols, dimethylacetamide, lactamide, lactate, ethyl carbonate, silicones (in particular, the average level of viscosity polydimethylsiloxane), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like.

The powders are made as follows: miltefosine at least one agent controlling the flow and/or lubricating substance, at least one filler and optionally a flavoring agent and/or sweetener mix and fill them sachets (packets) corresponding to the standard dose. When using all the contents of the package or, alternatively, part of it is mixed with water or fruit juice and swallow. This method makes it easier to obtain any level of dose of the oral method of drug administration.

For the preparation of foaming tablets or foaming mixture miltefosine at least one agent controlling the flow and/or lubricating substance and at least one filler is mixed in the traditional way with carbonate or acid component and the resulting mixture is pressed into tablets or filled her packages, optionally after addition of flavouring substances, and even in the absence of acid components or carbonate, as well as other agents controlling fluid/P> Solid pharmaceutical compositions according to the invention may also contain a substance that gives taste, podslushivaet and/or aromatic substances. Aromatic substances are: pineapple, Apple, apricot, raspberry, cherry, Cola nut, orange, fruit edible passion flower, lemon, grapefruit, vanilla, chocolate. As a sweetener, you can use the following substances: saccharin and its sodium salt, ciclamino acid and its sodium salt, glycerinate ammonium, fructose, xylitol, sorbitol, mannitol, aspartame, Acesulfame-K.

Foaming powder or chewable or foaming tablets are prepared by using conventional methods, as described in the literature (for example in standard reference Sucker, Fuchs and Speiser (editor), Pharmaceutical technology (Pharmazeutische Technologie), Thieme Verlag, Stuttgart). Preparation of (all stages except drying) is carried out, for example, at temperatures between 10oWith 80oWith, preferably 18oC-50oWith, in particular 20oS-30oC.

Production of miltefosine detail in the examples for hexadecylphosphocholine, which are presented in the pending patent application in Germany for a number R 4132344. Other methods of production and A 3641379, DE-A 3641491, DE-A 4013632, DE-A 3641377, the literature cited in these or the earlier patent applications or descriptions to patents, introduced here as references.

According to further aspect of the present invention, provided is a method of treatment in the treatment of leishmaniasis in humans in oral introduction pharmaceutical composition according to the present invention.

In a preferred embodiment of the invention is suitable for the following treatment method for the treatment of leishmaniasis in humans in oral introduction:

the total daily dose: 10-250 mg, preferably 50 to 150 mg a.i. miltefosine (a.i. - the active ingredient);

single or multiple daily dosage: total daily dose of 10-50 mg a.i. preferably administered as a single daily dose; the dose of between 50-250 mg a. i., preferably between 50-150 mg a.i. administered orally as multiple daily dose, preferably daily, twice a day (total daily dose of 100 mg a. i. ) daily or three times daily (total daily dose of 150 mg a.i.). In relation to the patient is divided into 4 to 5 times the daily dose is usually considered as the upper limit. However, in the interest of the treatment can be applied differently than divided into 1-5 receptions per diem a.i./day=h mg a.i./day or 150 mg a.i./day=h mg a.i./day).

The period of treatment time: 2-6 weeks, preferably 4 weeks.

According to further aspect of the invention provides a method of treatment in the treatment of leishmaniasis in mammals, other than humans, in oral introduction pharmaceutical composition according to the present invention.

All mammalian animals can be treated using the invention, for example, animals from the category of little friends, such as, for example, dogs, all rodents and hamsters. The treatment can be carried out in vivo in animals or in isolated conditions, such hospitals for animals or veterinary institutions, and the former are more preferred. According to the method of treatment according to the invention can be treated from all leishmania species, especially from leishmania major and leishmania infantum. According to the method of ecene of the invention, the total daily dose for the treatment by oral administration is within 1 to 15 mg a.i. miltefosine per kg of body weight of the animal (mg a. i. /kg). In a preferred embodiment of the invention, therapy is started with initial total unit (loading dose) in the range of 3-15, preferably 5-10 mg and.i/kg, and then continue with the total daily dose (maintenance dose) 1-10, preference is according to the following object of the invention, provides a combination pharmaceutical composition according to the invention with antiemetic agent and/or anti-diarrhoeal agent for oral administration in the treatment of leishmaniasis.

In a preferred embodiment of the invention the pharmaceutical composition according to the invention is used in combination with an antiemetic agent and/or anti-diarrhoeal agent. The introduction can be carried out simultaneously or sequentially. An antiemetic and antidiarrheal agent can be entered independently of each other. An antiemetic and/or antidiarrheal agent may be, or in pharmaceutical compositions according to the invention, or contained in the pharmaceutical means, independent of the pharmaceutical composition.

Suitable antiemetic means are, for example, antagonists of 5-NTZ-receptor, substituted benzamide, corticosteroids, antigistaminny tools, neuroleptics type fenotiasine, neuroleptics type butyrophenones, benzodiazepines and cannabinoids. The preferred antiemetic means are, among others, metoclopramide, domperidone and alizapride.

Suitable protivodiareynoe compositions according to the invention are preferred for the treatment of leishmaniasis. Other protozoal diseases that can be treated by means according to the present invention are, for example, malaria, trypanosomiasis, toxoplasmosis, babesiosis, amoebic dysentery and giardiasis. The means according to the present invention are particularly suitable for such diseases in which the pathogen is present in the internal organs such as the liver, spleen or kidney, lymph nodes, bone marrow and blood.

Information confirming the possibility of carrying out the invention

It is supposed to illustrate the invention the following examples without limiting the invention to these examples.

1. Examples of the preparation of solid pharmaceutical compositions according to the invention

Example 1: Hard gelatin capsule (contents: 10 mg miltefosine). 100 g of hexadecylphosphocholine, 808,50 g of lactose, 448,50 g microcrystalline cellulose, 26 g of talc and 13 g of highly dispersed silicon dioxide are passed through a sieve with apertures of 0.8 mm and then homogenized in an appropriate mixer for 30 minutes. Then add 4 g of magnesium stearate (0.8 mm sieve) and the components are mixed in the next 5 minutes. The mixture is filled known of pic is polerowanie. Each capsule (total weight: 190 mg) contains 10 mg of hexadecylphosphocholine.

The ratio between hexadecylphosphocholine:agent controlling the fluidity/surface-active agent:filling in the filling mixture is 1:0,4:12,4 (weight part).

Example 2: Hard gelatin capsule (content: 50 mg miltefosine). 258 g of hexadecylphosphocholine, 430 g of lactose, 241 g of microcrystalline cellulose, 14 g of talc, 7 g of highly dispersed silicon dioxide and 2 g of magnesium stearate are mixed according to the method described in Example 1. Thus obtained mixture to fill in portions of 185 mg fill gelatin hard capsules weight 59 mg in a known manner using a suitable apparatus for encapsulation. Each capsule (total weight: 244 mg) contains 50 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine:agents, controlling fluidity, and lubricating materials:fillers fill in the mixture is 1:0,09:2,6 (weight part).

Example 3: Hard gelatin capsule (contents: 100 mg miltefosine). 1000 g of hexadecylphosphocholine, 584 g of lactose, 345 g of microcrystalline cellulose, 50 g of talc, 15 g of highly dispersed m the mixture to fill in portions of 200 mg fill gelatin hard capsules weight 76 mg in a known manner using a suitable apparatus for encapsulation. Each capsule (total weight: 276 mg) contains 100 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine:agent controlling the fluidity,:filling in the filling mixture is 1:0.07 to:0,9 (weight part).

Example 4: Hard gelatin capsule (contents: 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 are mixed according to the method described in Example 1. Thus obtained mixture to fill in portions of 201 mg fill gelatin hard capsules weight 76 mg in a known manner using a suitable apparatus for encapsulation. Each capsule (total weight: 277 mg) contains 150 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine:agent controlling the fluidity,:filling in the filling mixture is 1:0.04 to:0,3 (weight part).

Example 5: Hard gelatin capsule (contents: 200 mg miltefosine). 200 g of hexadecylphosphocholine, 80 g of lactose, 50 g of microcrystalline cellulose, 4 g of talc, 5 g of highly dispersed silicon dioxide and 10 g of magnesium stearate are mixed according to the way that OPI is e capsules weight 97 mg in a known manner using a suitable apparatus for encapsulation. Each capsule has a total weight of 446 mg contains 200 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agent controlling the fluidity,:filling in the filling mixture is 1:0,095:0,65 (weight part).

Example 6: Hard gelatin capsule (contents: 250 mg miltefosine). 250 g of hexadecylphosphocholine, 80 g of lactose, 50 g of microcrystalline cellulose, 5 g of talc, 5 g of highly dispersed silicon dioxide and 15 g of magnesium stearate are mixed according to the method described in Example 1. Thus obtained mixture to fill fill portions 405 mg gelatin hard capsules weight 97 mg in a known manner using a suitable apparatus for encapsulation. Each capsule has a total weight of 502 mg and contains 250 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agent controlling the fluidity,:filling in the filling mixture is 1:0,1:0,52 (weight part).

Example 7: Tablets (contents: 250 mg hexadecylphosphocholine). 50 g of hexadecylphosphocholine, of 24.25 g of microcrystalline cellulose and 22,00 g anhydrous acidic phosphate dicalcium sift and mix. 3.75 g of magnesium stearate is screened and added to with the 500 mg One tablet contains 250 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agent controlling the fluidity/surface - active agent:fillers in the tablet is 1:0.07 to:0,925 (weight part).

Example 8: Tablets (content: 30 mg hexadecylphosphocholine). 23 g of hexadecylphosphocholine, 23 g of microcrystalline cellulose and 52 g of spray dried lactose sift and mix. Add 1 g of colloidal silicon dioxide and 1 g of magnesium stearate. The mixture is then mixed again. The resulting mixture is pressed into tablets, each of which weighs 130,5 mg One tablet contains 30 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine:agent controlling the fluidity/surface-active agent:fillers in the tablet is 1:0,087:0,31 (weight part).

Example 9: Foaming tablets and mixture (contents of hexadecylphosphocholine: 250 mg). 1700 g of granulated sodium bicarbonate loaded into an oven and heated at 100oC for 60 min After cooling to room temperature converted bicarbonate mixed with 160 g of granulated monobasic calcium phosphate, 1030 g granular anhydrous citric keys mixed for 10 minutes. The resulting foaming mixture is pressed into tablets, each of which weighs 278 mg. One foaming tablet contains 250 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine:agent controlling the fluidity /surface-active agent: fillers in the tablet is 1:0,50:0,53 (weight part).

Alternatively, foaming the mixture in an amount of 278 mg you can fill the sachet, thus obtaining the foaming mixture.

Example 10: Foaming tablets and mixture (content: 50 mg hexadecylphosphocholine). 1600 g of granulated sodium bicarbonate loaded into an oven and heated at 100oC for 60 min After cooling to room temperature converted bicarbonate mixed with 150 g of granulated monobasic calcium phosphate, 900 g of granular anhydrous citric acid, 80 g of talc and 30 g of magnesium stearate. To the resulting mixture is added 200 g of hexadecylphosphocholine and mixed for 10 minutes. The resulting mixture is pressed into tablets, each of which weighs 740 mg. One foaming tablet contains 50 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agent control Studio strobe, flash is.

Alternatively, foaming the mixture in an amount of 740 mg you can fill the sachet, thus obtaining the foaming mixture.

Example 11: Drinking water mix (sachet) (content: 50 mg hexadecylphosphocholine). Mix 5 g of hexadecylphosphocholine, 308 g of lactose, 280 g of microcrystalline cellulose, 5 g of saccharin and 2 g of colloidal silicon dioxide. The mixture is filled sachet. Each sachet weighs 6 grams and contains 50 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine: agent controlling the fluidity /surface-active agent:fillers in the mixture is 1:0,4:117,5 (weight part).

Example 12: Drinking water mix (sachet) (content: 100 mg hexadecylphosphocholine). Mix 10 g of hexadecylphosphocholine, 200 g of lactose, 250 g of microcrystalline cellulose, 7 g of saccharin and 3 g of colloidal silicon dioxide. The mixture is filled sachet. Each sachet weighs 4.7 grams and contains 100 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine:agent controlling the fluidity /surface-active agent:fillers in the mixture is 1:0,3:45 (weight part).

Example 13: Drinking water mix (sachet) (contents: 200 mg hexadecylphosphocholine). Mix 20 g of hexadecylphosphocholine, 306 g of lactose, which each sachet weighs 7,4 g and contains 200 mg of hexadecylphosphocholine. The ratio between hexadecylphosphocholine:agent controlling the fluidity /surface-active agent:fillers in the mixture is 1:0,3:35,5 (weight part).

The results of clinical trials of treatment of leishmaniasis oral administration of capsules according to the present invention.

Further abbreviations mean:

once qod - one introduction through the day;

BID qod two insertion through the day;

BID - two daily;

TID - three infusions daily;

QID - four injections daily.

Miltefosine (MILT, hexadecylphosphocholine, ASTA Medica), the antineoplastic alkylphosphoric is active in experimental visceral leishmaniasis (VL). For testing oral MILT when VL in humans 30 patients presented men Hindus from Bihar (age >14 years; 18 of the 30 unsuccessfully treated with antimony (Sb)) with positive VL spleen obtained by aspiration, is subjected to treatment in 6 groups of 5 patients each (groups A-F) within 28 days of increasing doses by oral administration of capsules according to example 1: (A) 50 mg once qod (qod - number in a day), (C) 50 mg BID qod (BID - twice a day) and then daily, using 50 mg (S) BID (100 mg/day), (D) TID (150 mg/su the 14 day had the following results in 30 patients: 25 without fever, 25 with the reduced size of the spleen, 28 negative VL spleen, obtained by aspiration (explicit parasitological treatment); 21 out of 30 showed all 3 reactions were considered, thus, as clearly cured rate. 1 patient from group F died on the 21st day (medication was discontinued on day 19) with severe vomiting and diarrhea (possibly related to drug or intercurrent gastrointestinal disturbance), dehydration and renal failure. Weak vomiting and diarrhea, lasting 3-7 days, appeared in most of the patients in groups B-E.

One patient in group E and three in group F were removed at 7, 7, 8, and 10 days from vomiting. Therefore, 200 mg/day was the maximum allowable daily dose. Hematological toxicity was observed.

One patient from group F showed increased hepatic transaminases (enabled).

28 day 29 of 29 patients (100%) showed a clear recovery, including 4 who received <10 days of therapy and were not subjected to further treatment.

Within 6 months, 7 out of 29 clearly cured suffered a relapse (A-3/5, 3/5, D-1/5); thus, 6 out of 7 after relapse were from groups with low doses, qod-dosing (a, b). Within 6 Masaze of 26 patients (A-2/5, In-2/5, 5/5, D-4/5, E-5/5); 1 patient is on the path of healing; of the first 21 patients with a certain cure 14 refused to continue therapy with antimony.

The results obtained demonstrate that the solid pharmaceutical composition and the use according to the present invention are effective in the treatment of leishmaniasis by oral administration. The obvious cure was observed even in patients with increased problem visceral infection, not insensitive to treatment with antimony.

1. Solid pharmaceutical composition for oral administration in the treatment of leishmaniasis, containing miltefosine, agent, controlling the flow and/or lubricating material selected from the group comprising silicon dioxide, talc, magnesium stearate and mixtures thereof, and a filler selected from the group comprising cellulose, lactose, mannitol, calcium phosphate and mixtures thereof, characterized in that it contains these components in the following ratio, wt. including :

Miltefosine/agent controlling the fluidity and/or lubricant - 1: 0,01-0,6

Miltefosine/filler - 1: 0,1-120

moreover, the composition has sufficient fluidity and obtained by simple physical mixing meteosensitivity composition p. 1, characterized in that it is obtained in the form of a dosage form selected from the group consisting of capsules, tablets, foaming tablets, foaming mixture and Sasha (clean mix).

3. Solid pharmaceutical composition under item 1 or 2, characterized in that before being processed into tablets, capsules or sachets obtained pharmaceutical composition having sufficient fluidity can be granulated.

4. Solid pharmaceutical composition according to any one of paragraphs. 1-3, characterized in that it further comprises at least one auxiliary agent selected from the group consisting of dezintegriruetsja agents, binding agents, antiemetic agents, carriers, diluents, foaming compounds, such as carbonate component and acid component, flavoring agents, sweeteners, aromatics.

5. The method of manufacturing the solid pharmaceutical composition by mixing miltefosine, agent, controlling fluidity, and optional filler, together with other auxiliary agents, characterized in that the mixing is a simple physical mixing with obtaining pharmaceutical HDMI is actively pressed the mixture into tablets.

6. The method according to p. 5, characterized in that prior to filling capsules or compressing a composition having sufficient fluidity, granularit by known methods.

7. A method of treatment of leishmaniasis by oral administration of miltefosine, characterized in that miltefosine is administered for a time period of 2-6 weeks in total daily dose in the range 10-250 mg

8. The method according to p. 7, characterized in that choose the total daily dose of from about 50 to about 150 mg miltefosine.

9. The method according to p. 7 or 8, characterized in that the introduction of a daily for a period of time around 4 weeks.

10. The method according to any of paragraphs. 7-9, characterized in that the oral introduction of a once, twice or three times a day, for a total daily dose of 50, 100 and 150 mg miltefosine, respectively.

11. The method according to p. 10, characterized in that the multiple doses are administered in equal portions, such as 100 mg/day= 250 mg/day, 150 mg/day= 350 mg/day.

12. A method of treatment of leishmaniasis in mammals other than humans by oral administration of miltefosine, characterized in that the total daily dose in the range 1-15 mg miltefosine per kg of body weight of the mammal (bgcolour initial single daily dose (loading dose) in the range of 3-15 mg/kg and then the following daily dose (maintenance dose) in the range 1-10 mg/kg

14. The method according to p. 13, characterized in that as a loading dose chosen by 5-10 mg/kg

15. The method according to p. 13, characterized in that as a maintenance dose pick 3-5 mg/kg

16. The method according to any of paragraphs. 12-15, characterized in that the introduction continue for 4 weeks.

17. The method according to any of paragraphs. 12-16, characterized in that as mammals choose animals, such as dogs, all rodents and hamsters.

18. Pharmaceutical combination for the treatment of leishmaniasis in mammals, characterized in that it includes a pharmaceutical composition according to any one of paragraphs. 1-4, an antiemetic and/or antidiarrheal agent, while the pharmaceutical composition according to any one of paragraphs. 1-4, an antiemetic and/or antidiarrheal agent, you can enter together or independently of each other.

 

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