WO2003061669A1 - Use of alkylphosphocholines for the preventative treatment of protozoan diseases - Google Patents

Abstract

The invention relates to pharmaceutical compositions containing alkylphosphocholines, especially hexadecylphosphocholine or octadecyl-(1, 1-dimethyl-piperidinio-4-yl)-phosphate for the preventative treatment of protozoan diseases, especially leishmaniasis. The invention also relates to a dosing scheme of said compositions for the preventative treatment of said illnesses.

Description

Use of alkylphosphocholines in the preventive treatment of protozoal diseases

introduction

The present invention relates to alkylphosphocholines, in particular hexadecylphosphocholine (Miltefosine) or octadecyl (1,1-dimethylpiperidino-4-yl) -phosphate (perifosine, D-21266), pharmaceutical compositions for oral administration in the preventive treatment of protozoal diseases , in particular leishmaniasis, and a dosage regimen for the oral administration of said pharmaceutical composition in the preventive treatment of protozoal diseases, in particular leishmaniasis, and a combination comprising said pharmaceutical composition, an antiemetic and / or an antidiarrheal.

State of the art

Leishmaniasis is a term for various tropical diseases, which are caused by flagellates of the genus Leishmania and transmitted by various blood-sucking insects. The manifestations of leishmaniasis may be visceral (Kala-Azar), mucocutaneous (American leishmaniasis) or cutaneous (Aleppo's bump or diffuse cutaneous leishmaniasis). The incubation period is weeks to months. Especially in the case of Kala-Azar and American leishmaniasis a very high mortality rate is observed in untreated cases.

The known agents in standard therapy for the treatment of leishmaniasis, i. Pentavalent antimony compounds (eg sodium stibogluconate) and aromatic diamidines had to be administered by parenteral injection, which not only led to serious side effects due to their high toxicity, but also included a risk of infection.

The use of alkylphosphocholines, in particular hexadecylphosphocholine (miltefosine), for the oral and topical treatment of leishmaniasis was first reported by Eibl et al. ^' l ^{ή of} the 1991 submitted ^{^} Patent Application DE-A-4132344 and EP-A-534445.

Numerous other authors describe the treatment of leishmaniasis with alkylphosphocholines as a new class of drugs with remarkable antiprotozoal efficacy.

Thus, T. Jha et al., Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis, N. Engl. J. Med. (1999), 341 (24), 1795-1800 report a study of 120 patients, where 50 to 150 mg of miltefosine per day was used for several weeks.

S. Sundar et al., Oral Treatment of Visceral Leishmanisis with Miltefosine, Ann. Trop. Med. Parasitol. (1999), 93 (6), 589-597 observe in a pilot study the oral application of 100 to 200 mg of miltefosine per day in visceral leishmaniasis.

Miltefosine is difficult to handle, although it is available in dry form as crystalline platelets with a defined melting point in excess of 200 ° C since it is very hygroscopic. The uptake of water molecules can lead to an increase in weight of up to 30% by weight, a lowering of the melting point and a caking and clumping of the crystals. The processability of the hydrous miltefosine is insufficient for further processing into solid pharmaceutical compositions such as tablets, capsules or sachets. In particular, the fluidity of hydrous miltefosine is insufficient. Satisfactory flowability, however, is one of the indispensable prerequisites for the production of pharmaceutical compositions on an industrial scale.

In addition, anhydrous miltefosine exhibits a considerable tendency to electrostatic charge, especially when stirred in a dry state. Also, the fluidity of electrostatically charged miltefosine is insufficient for further processing into solid pharmaceutical compositions. In addition, electrostatic charges are always associated with significant safety concerns because of the associated risks of both explosions and damage to sensitive electronic parts. To circumvent the above problem in the preparation of solid, miltefosine-containing pharmaceutical compositions, Eibl et al. To apply miltefosine to the surface of silica particles by evaporating a suspension of 1 part by weight of silica in a solution containing 1 part by weight of miltefosine to dryness. The fluidity of the according to the proposal of Eibl et al. The solid dispersion obtained is indeed sufficient for filling into capsules, at least on a laboratory scale. The Eibl et al. However, the method described is based on the use of a highly volatile and at the same time (because of the electrostatic charge) non-flammable solvent. For all practical applications, there are in the prior art only the solvents methylene chloride and chloroform, which meet these requirements. Halogenated hydrocarbons, especially chloroform, are, however, classified as toxic and carcinogenic compounds. Furthermore, halohydrocarbons are enriched in the fatty tissue and degraded only slowly.

It has already been described in patent WO 99/37289 that the abovementioned problems can be solved by reacting an alkylphosphocholine, in particular hexadecylphosphocholine, at least one flow agent and / or lubricant selected from the group consisting of finely divided silica, talc, magnesium stearate and mixtures thereof and physically mixing at least one filler of the group consisting of lactose, microcrystalline cellulose and mixtures thereof.

According to WO 99/37289 it is possible, by simple physical mixing of alkylphosphocholines, in particular miltefosinv, to obtain a flow agent and / or lubricant and at least one filler, a solid pharmaceutical mixture having a fluidity which is sufficient for further processing, for example into capsules, Tablets or sachets.

According to this WO document, the solid pharmaceutical composition can be filled into capsules, preferably hard gelatine capsules, or pressed into tablets or effervescent tablets or, as a drinking mixture or effervescent mixture, filled into sachets. 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 and more preferably in the range of 50 to 250 mg. The most preferred content is in the range of 50 to 150 mg.

The representation of miltefosine is described in detail in the examples of hexadecylphosphocholine in the German patent application DE-A-4132344. Further methods for producing and purifying miltefosine are described, for example, in German patent applications DE-A 2752125, DE-A 3641379, DE-A 3641491, DE-A 4013632 and DE-A 3641377.

Presentation of the invention

Surprisingly and unexpectedly, it has been found in one aspect of the application that alkylphosphocholines, in particular

Hexadecylphosphocholine (Miltefosine) or octadecyl (1,1-dimethylpiperidinio-4-yl) -phosphate (Perifosin, D-21266) are suitable for a preventive treatment of protozoal diseases, in particular leishmaniasis. A pharmaceutical application of

Alkylphosphocholines, in particular hexadecylphosphocholine or octadecyl (1,1-dimethylpiperidinio-4-yl) phosphate for the prevention of protozoal diseases, in particular leishmaniasis, are neither described nor suggested in the prior art reports.

According to one aspect of the present invention, there is provided a dosage regimen for the preventive treatment of leishmaniasis in humans by oral administration of the pharmaceutical composition.

In a preferred embodiment, the following dosage regimen is useful for the preventive treatment of leishmaniasis in humans by oral administration:

Total daily dose: 10-250 mg of miltefosine active, preferably 20-150 mg, especially 30-100 mg; daily single or multiple dose: a total daily dose of 10-50 mg of active ingredient is preferably administered as a single daily dose; a dose of 50-250 mg active ingredient, preferably 50-150 mg active ingredient, is administered orally daily as a multiple daily dose, preferably as two doses per day (total daily dose 100 mg active ingredient) or as three doses per day (total daily dose 150 mg active ingredient). In terms of patient compliance, a daily dose divided into 4-5 doses is generally considered to be the upper limit. For preventive purposes, however, it is also possible to administer the remedy differently than divided into 1-5 doses per day.

In a preferred embodiment, daily multiple doses of the same size are administered (eg, 100 mg drug / day = 2 x 50 mg drug / day or 150 mg drug / day = 3 x 50 mg drug / day).

Prophylaxis is also possible with an initial dose followed by maintenance doses using as initial dose e.g. 100 mg or more of active ingredient, followed by maintenance doses of e.g. B. 30 mg of active ingredient.

Prophylactic duration of use: 2 weeks to 6 months, preferably over the duration of the risk of infection.

According to another aspect of the invention, a dosage regimen for the preventive treatment of leishmaniasis in non-human mammals by oral administration of the pharmaceutical composition of the invention is provided.

All mammals can be treated. The dosing regimen enables the preventive treatment of all types of leishmaniasis, in particular leishmaniasis major and leishmaniase infantum. According to the dosing schedule, the total daily dose in the case of prophylactic treatment in the case of oral administration is in the range of 0.5-15 mg of miltefosine or perifosin active ingredient per kg body weight of the animal (mg active substance / kg). In a preferred embodiment, prophylaxis is initiated with a total initial dose (loading dose) in the range of 3-15, preferably 5-10 mg / kg and then with a total daily dose (maintenance doses) in the range of 1-10, preferably 3-5 mg of drug / kg continued. The preventive application period is in the range from 2 weeks to 6 months, preferably over the duration of the risk of infection.

According to a further aspect, there is provided a combination of the pharmaceutical composition with an antiemetic and / or an antidiarrhoeal for oral administration in the preventive 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 antidiarrhoeal agent. Administration may be simultaneous or sequential. Antiemetic and antidiarrhoeal can be administered independently. The antiemetic and / or antidiarrhoeal agent may be contained either in the described pharmaceutical composition or in a pharmaceutical formulation independent thereof.

Suitable antiemetics include, for example, 5-HT3 receptor antagonists, substituted benzamides, corticosteroids, antihistamines, phenothiazine-type neuroleptics, butyrophenone-type neuroleptics, benzodiazepines, and cannabinoids. Preferred antiemetics include metoclopramide, domperidone and alizapride.

Suitable antidiarrhoeal agents include, but are not limited to, the opioids, e.g. Loperamide.

The solid oral pharmaceutical compositions are preferably useful for the preventative treatment of leishmaniasis. Other diseases caused by protozoa include malaria, trypanosomiasis, toxoplasmosis, babesiosis, amoebic dysentery and lambliasis.

embodiments

The invention will be explained in more detail by the following examples.

Examples of solid oral pharmaceutical formulations that can be used 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 finely divided silica are passed through a sieve with a mesh size of 0.8 mm and then homogenized for 30 minutes in a suitable mixer. Then add 4 g of magnesium stearate (0.8 mm sieve) and mix the components for another 5 minutes. The resulting mixture is filled in known manner in 140 mg portions into hard gelatin capsules weighing 50 mg, using a suitable encapsulating machine. Each of the capsules thus obtained (total weight: 190 mg) contains 10 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: flow agent / surfactant: fillers in the filling mixture is 1: 0.4: 12.4 (parts by weight).

Example 2: 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 finely divided silica and 6 g of magnesium stearate were mixed according to the method described in Example 1.

The resulting filling mixture is filled in known manner into 200 mg portions in hard gelatin capsules weighing 76 mg, using a suitable encapsulating machine. Each of the capsules thus obtained (total weight: 276 mg) contains 100 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: flow agent: fillers in the filling mixture is 1: 0.07: 0.9 (parts by weight).

Example 3: 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 finely divided silicon dioxide and 15 g of magnesium stearate were mixed according to Example 1. The thus obtained Filling mixture is filled in known manner in 405 mg portions in hard gelatin capsules with a weight of 97 mg, using a suitable Einkapselmaschine.

Each of the capsules thus obtained has a total weight of 502 mg and contains 250 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: flow agent: fillers in the filling mixture is 1: 0.1: 0.52 (parts by weight).

Example 4: Tablets (content: 250 mg hexadecylphosphocholine)

50 g of hexadecylphosphocholine, 24.25 g of microcrystalline cellulose and 22.00 g of anhydrous dicalcium phosphate are sieved and blended. 3.75 g of magnesium stearate are sieved and added to the mixture. The mixture is then mixed again. The resulting mixture is then compressed into tablets weighing 500 mg each. The tablets each contain 250 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: flow agent / surfactant: fillers in the tablet is 1: 0.07: 0.925 (parts by weight).

Example 5: Tablets (content: 30 mg hexadecylphosphocholine)

23 g of hexadecylphosphocholine, 23 g of microcrystalline cellulose and 52 g of spray-dried lactose are sieved and blended. 1 g colloidal

Silica and 1 g of magnesium stearate are added. The

Mixture is then mixed again.

The resulting mixture is then compressed into tablets weighing 130.5 mg each. The tablets each contain 30 mg of hexadecylphosphocholine.

The ratio of hexadecylphosphocholine: flow agent / surfactant:

Fillers in the tablet is 1: 0.087: 0.31 (parts by weight).

Example 6 Effervescent Tablets and Effervescent Mixture (content of hexadecylphosphocholine: 250 mg) 1700 g of granular sodium bicarbonate are heated in an oven at 100 ° C for 60 min. After cooling to room temperature, the converted bicarbonate is mixed with 160 g of granular monobasic calcium phosphate, 1030 g of granular anhydrous citric acid, 100 g of talc and 50 g of magnesium stearate. The ^'mixture thus obtained is mixed with 300 g of hexadecylphosphocholine und blended for 10 minutes.

The effervescent mixture thus obtained is compressed into tablets each weighing 278 mg. The effervescent tablets each contain 250 mg of hexadecylphosphocholine.

The ratio of hexadecylphosphocholine: flow agent / surfactant: fillers in the tablet is 1: 0.50: 0.53 (parts by weight).

Alternatively, you can fill 278 mg each of the effervescent mixture in a sachet, whereby one receives a effervescent mixture.

Example 7 Effervescent Tablets and Effervescent Mix (Content: 50 mg hexadecylphosphocholine)

1600 g of granular sodium bicarbonate are heated in an oven at 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. The mixture thus obtained is admixed with 200 g of hexadecylphosphocholine and mixed for 10 minutes.

The resulting mixture is compressed into tablets weighing 740 mg each. The effervescent tablets each contain 50 mg of hexadecylphosphocholine.

The ratio of hexadecylphosphocholine: flow agent / surfactant: fillers in the tablet is 1: 0.55: 0.75 (parts by weight).

Alternatively, 740 mg each of the effervescent mixture can be added to a sachet to give a shower mix. Example 8: Drinking mixture (sachets) (content: 50 mg hexadecylphosphocholine)

5 g of hexadecylphosphocholine, 308 g of lactose, 280 g of microcrystalline cellulose, 5 g of saccharin and 2 g of colloidal silica are mixed. The mixture is filled into sachets. The sachets each weigh 6 g and contain 50 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: flow agent surfactant: fillers in the mixture is 1: 0.4: 117.5 (parts by weight).

Example 9: Drinking mixture (sachets) (content: 200 mg hexadecylphosphocholine)

20 g of hexadecylphosphocholine, 306 g of lactose, 403 g of microcrystalline cellulose, 5 g of saccharin and 6 g of colloidal silica are mixed. The mixture is filled into sachets. The sachets each weigh 7.4 g and contain 200 mg of hexadecylphosphocholine. The ratio of hexadecylphosphocholine: flow agent / surfactant: fillers in the mixture is 1: 0.3: 35.5 (parts by weight).

The examples may also contain perifosine instead of the active ingredient miltefosine.

Claims

claims Use of alkylphosphocholines for the manufacture of a medicament for the preventive treatment of Protozoan diseases in humans. 2. Use according to claim 1, wherein over a period of 2 weeks to 6 months, preferably over the duration of the risk of infection total daily doses in the range of 10 to 250 mg Alkylphosphocholine active ingredient administered orally. 3. Use according to claim 1 and 2, characterized in that hexadecylphosphocholine (Miltefosin) or octadecyl (1,1, -dimethyl-piperidinio-4-yl) -phosphate (perifosine) for the preparation of a Medicinal product is used for the preventive treatment of, in particular, leishmaniasis in humans by oral administration and over a period of 2 weeks to 6 months, preferably over the duration of the risk of infection, total daily doses in the range of 10 to 250 mg miltefosine or Perifosin drug be administered orally. 4. Use according to claim 1 to 3, characterized in that the total daily dose is about 20 to about 150 mg of miltefosine or perifosine active ingredient. 5. Use according to claim 1 to 3, characterized in that the total daily dose is about 30-100 mg miltefosine or perifosine active ingredient. Use according to one of Claims 1 to 5, characterized in that the oral administration is carried out once, twice or three times a day with total daily doses of 50, 100 or 150 mg of miltefosine or perifosine active ingredient. Use according to one of claims 1 to 6, characterized in that multiple daily doses in equal portions (eg 100 mg active ingredient / day = 2 x 50 mg active ingredient per day, 150 mg active substance per day = 3 x 50 mg active substance day) be administered. 8. Use according to one of claims 1 to 7, characterized by an initial dose, followed by maintenance doses, wherein advantageously the initial dose 100 mg or more active ingredient and the maintenance doses have 30 mg of active ingredient. 9. Use according to one of claims 1 to 8, characterized in that the leishmaniasis is visceral, mucocutaneous and / or cutaneous leishmaniasis. 10. Use of alkylphosphocholine, especially hexadecylphosphocholine (Miltefosine) or octadecyl (1,1-dimethyl-piperidinio-4-yl) -phosphate (perifosine) for the manufacture of a medicament for the preventive treatment of protozoal diseases, in particular leishmaniasis in from Oral administration to humans of various mammals, in which total daily doses ranging from 0.5 to 15 mg of miltefosine active ingredient per kg of body weight of the mammal (mg active substance / kg) are administered. 11. Use according to claim 10 ,. characterized in that the initial total dose (loading dose) is in the range of 3-15 mg / kg and the subsequent total daily doses (maintenance doses) are in the range of 1-10 mg / kg. 12. Use according to claim 10 or 11, characterized in that the Aufsättigungsdosis is in the range of 5-10 mg active ingredient / kg. 13. Use according to claim 10 or 11, characterized in that the maintenance dose is in the range of 3-5 mg / kg active ingredient. 14. Use according to any one of claims 10 to 13, characterized in that the oral administration takes place over a period of 2 weeks to 6 months, advantageously over the duration of the risk of infection. 15. Use according to any one of claims 10 to 14, characterized in that the leishmaniasis is visceral, mucocutaneous and / or cutaneous leishmaniasis. 6. Pharmaceutical combination for the preventive treatment of protozoal diseases, in particular leishmaniasis in mammals, containing a Alkylphosphocholin, in particular hexadecylphosphocholine (Miltefosin) or octadecyl (1,1, -dimethyl-piperidinio-4-yl) -phosphate (perifosine) containing pharmaceutical Composition, an antiemetic and / or an antidiarrheal, wherein the alkylphosphocholine, in particular Hexadecylphosphocholine (Miltefosin) or octadecyl (1,1-dimethyl-piperidinio-4-yl) -phosphate (perifosine) containing pharmaceutical Composition, the antiemetic and / or the antidiarrhoeal agent can be administered either together or independently.