CN1622811A - Use of alkylphosphocholines for the preventative treatment of protozoan diseases - Google Patents

Abstract

The present invention relates to prophylactic treatment of protozoa containing alkylphosphocholines, especially hexadecylphosphocholines or 1,1-dimethyl-piperidin-4-yl-octadecyl phosphate. Pharmaceutical composition for diseases, especially leishmaniasis. The invention also relates to the dosing regimen of said composition for the prophylactic treatment of said disease.

Description

Application of Alkyl Phosphocholine in Preventive Treatment of Protozoan Diseases

Introduction

The present invention relates to compounds comprising alkylphosphocholines, especially cetylphosphocholine (miltefosine) or 1,1-dimethyl-piperidinio-4-yl-octadecylphosphate Esters (perifosine (perifosine), D-21266) are used for preventive treatment of protozoan diseases, especially pharmaceutical compositions for oral administration of leishmaniasis; further, the present invention relates to prophylactic treatment of protozoan The dosage regimen for oral administration of the pharmaceutical composition during the course of animal diseases, especially leishmaniasis, involves a drug combination comprising the pharmaceutical composition, an antiemetic and/or an antidiarrheal.

current technology

Leishmaniasis is a variety of local diseases caused by flagellates of the genus Leishmania and transmitted by various blood-sucking insects. Manifestations of leishmaniasis can be visceral (kala-azar), mucocutaneous (nasopharyngeal mucocutaneous leishmaniasis), or cutaneous (cutaneous leishmaniasis (Aleppo sore) or diffuse cutaneous leishmaniasis). The incubation period is weeks to months. Particularly high mortality rates have been observed in untreated cases of kala-azar and nasopharyngeal leishmaniasis.

Known active agents used in standard therapy for the treatment of cases of leishmaniasis, namely pentavalent antimony compounds (such as sodium antimonyl gluconate) and aromatic diamidines must be administered by parenteral injection, which It not only causes serious side effects because of its high toxicity, but also brings the danger of infection.

Patent application DE-A 4132344 filed by Eibl et al. in 1991 and in EP-A 534445 described for the first time that alkylphosphocholines, especially cetylphosphocholine (miltefosine), are suitable for oral and topical treatment Leishmaniasis fact.

Many other authors describe the use of alkylphosphocholines as a new class of drugs with significant antiprotozoal activity in the treatment of leishmaniasis. Therefore, T.Jha et al. in "The Orally Active Agent Miltefosine for the Treatment of Visceral Leishmaniasis in India" - "New England Journal of Medicine" (N.Engl.J.Med.) (1999), 341(24 ), 1795-1800 reported a study of 120 patients who received 50-150 mg of miltefosine daily for several weeks. S. Sundar et al. "Oral treatment of visceral leishmaniasis with miltefosine" - Ann.Trop.Med.Parasitol (1999), 93(6), 589-597 The use of oral miltefosine 100-200 mg/day in visceral leishmaniasis was observed in small trials.

Although miltefosine can be obtained in dry form as a crystalline precipitate with a defined melting point above 200°C, it is not controlled due to its extremely high hygroscopicity. Absorption of water molecules can result in a weight gain of up to 30% by weight, lowering the melting point and causing crystal clumping and aggregation. The processability of aqueous miltefosine is insufficient for further processing into solid pharmaceutical compositions such as tablets, capsules or sachets. In particular, aqueous miltefosine is insufficiently mobile. Satisfactory flowability is an indispensable prerequisite for the production of pharmaceutical compositions on an industrial scale.

In addition, anhydrous miltefosine showed a marked tendency to become electrostatically charged, especially when it was stirred in the dry state. Electrostatically charged miltefosine is still not fluid enough for further processing into solid pharmaceutical compositions. In addition, electrostatic charges are always of major safety concern due to the hazards associated with them, including explosion and damage to sensitive charged components.

In order to avoid the above-mentioned problems in the production of solid pharmaceutical compositions containing miltefosine, Eibl et al. proposed that 1 part by weight of silicon dioxide suspension be evaporated to dryness in a solution containing 1 part by weight of miltefosine. A technical solution for the application of miltefosine on the surface of silica particles. The fluidity of solid dispersions obtained by solutions such as those proposed by Eibl et al. is practically sufficient for packaging into capsules, at least on a laboratory scale. However, the method described by Eibl et al. is based on the use of highly volatile and at the same time (due to electrostatic charge) non-flammable solvents. The only solvents that satisfy all practical applications in the prior art are dichloromethane and chloroform. However, halogenated hydrocarbons, especially chloroform, are classified as toxic and carcinogenic compounds. Furthermore, halogenated hydrocarbons accumulate in adipose tissue and are only slowly broken down.

Patent WO99/37289 has already described the composition by physically mixing alkylphosphocholine, especially hexadecylphosphocholine, at least one selected from fine-grained silica, talc, magnesium stearate and mixtures thereof A flow control agent and/or a lubricant of the group and at least one filler selected from the group consisting of lactose, microcrystalline cellulose and mixtures thereof to solve the above problems.

According to WO 99/37289, it is possible by purely physical mixing of an alkylphosphocholine, especially miltefosine, a flow control agent and/or a lubricant and at least one filler to obtain Flowable solid drug mixture in doses or sachets.

According to this WO publication, the solid pharmaceutical composition can be used for filling capsules, preferably hard capsules, or compressed into tablets or effervescent tablets or packed into sachets as a drinkable mixture or an effervescent mixture.

The content of miltefosine per dosage unit is in the range of 10-800 mg, preferably in the range of 10-500 mg, and particularly preferably in the range of 50-250 mg. The most preferred content is in the range of 50-150 mg.

German patent application DE-A 4132344 specifically describes the preparation method of cetylphosphorylcholine miltefosine in the examples. Furthermore, processes for the production and purification of 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.

Description of the invention

Surprisingly and surprisingly, it has been found that according to one aspect of the present application, alkylphosphocholines, especially cetylphosphocholine (miltefosine) or 1,1-dimethyl-piperidinio (piperidinio) -4-yl-octadecyl phosphate (perifosine, D-21266) is suitable for the prophylactic treatment of protozoan diseases, especially leishmaniasis. Neither alkylphosphocholines, especially cetylphosphocholines, nor 1,1-dimethyl-piperidinio-4-yl-octadecylphosphate have been described in the prior art for the prevention of Application in protozoan diseases, especially leishmaniasis, also has no apparent information on this.

In one aspect the present invention provides a dosage regimen for the prophylactic treatment of leishmaniasis by oral administration of said pharmaceutical composition.

In a preferred embodiment, the following dosage regimen is suitable for the prophylactic treatment of human leishmaniasis by oral administration:

Total daily dose: 10-250 mg active ingredient miltefosine, preferably 20-150 mg, especially 30-100 mg;

Single or multiple doses per day: preferably as a single daily dose of 10-50 mg total daily dose of the active ingredient;

The active ingredient is administered orally in doses of 50-250 mg per day as multiple doses per day, preferably as two doses per day (for a total daily dose of 100 mg of active ingredient) or as three doses per day (for a total daily dose of 150 mg), preferably 50-150 mg of active ingredient. For patient compliance, a daily dose divided into 4-5 doses will generally be taken as an upper limit. However, for prophylactic purposes, the active agent can also be administered in divided doses other than 1 to 5 doses per day.

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

Prophylaxis can also be initiated with an initial dose, followed by a maintenance dose, for example 100 mg of active ingredient or more as an initial dose, followed by a maintenance dose of, for example, 30 mg of active ingredient.

Period for prophylaxis: 2 weeks to 6 months, preferably as long as the risk of infection persists.

Another aspect of the invention provides a dosage regimen for the prophylactic treatment of non-human mammalian leishmaniasis by oral administration of the pharmaceutical composition of the invention.

Can treat all mammals. The application of this dosage regimen enables the prophylactic treatment of all types of leishmaniasis, especially major leishmaniasis and infantile leishmaniasis. According to this dosage regimen, for oral administration, the total daily dose for prophylactic treatment is between 0.5-15 mg active ingredient miltefosine or perifoxine/kg animal body weight (mg active ingredient/kg) range. In a preferred embodiment, this prophylaxis is initiated with an initial total single dose (saturation dose) of 3-15 mg active ingredient/kg, preferably 5-10 mg active ingredient/kg and then continued administration of 1-10 mg active ingredient total daily dose (maintenance dose) in the range of 3-5 mg active ingredient/kg. The duration of prophylactic application ranges from 2 weeks to 6 months, preferably for the duration of the risk of infection.

Another aspect of the present invention provides a drug combination consisting of the pharmaceutical composition and an antiemetic drug and/or an antidiarrheal drug for oral prophylactic 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 antidiarrheal. Administration can be performed simultaneously or sequentially. Antiemetics and antidiarrheals can be administered independently of each other. Antiemetics and/or antidiarrheals can be present in the pharmaceutical composition or in the pharmaceutical preparation alone.

Examples of suitable antiemetics are 5-HT3 receptor antagonists, substituted benzamides, corticosteroids, antihistamines, phenothiazine [sic] neuroleptics, propyl phenyl ketone psychotropics Tranquilizers, benzodiazepines, and cannabinoids. Preferred antiemetics are especially metoclopramide, domperidone and aripride.

Suitable antidiarrheals are especially opioids such as loperamide.

The oral solid pharmaceutical composition is preferably suitable for the prophylactic treatment of leishmaniasis. Examples of other diseases caused by protozoa are malaria, trypanosomiasis, toxoplasmosis, babesiosis, amoebic dysentery and Giardia lamblia.

typical implementation

The following examples are used to explain the present invention more specifically.

Examples of oral solid pharmaceutical compositions that can be used

Embodiment 1: hard capsule (content: 10mg miltefosine)

100 g cetylphosphocholine, 808.50 g lactose, 448.50 g microcrystalline cellulose, 26 g talc and 13 g fine-grained silicon dioxide were sieved through a 0.8 mm mesh mesh and then homogenized in a suitable mixer for 30 minutes. Then 4 g of magnesium stearate (0.8 mm sieve) was added and the ingredients were blended for a further 5 minutes. The mixture obtained in this way is encapsulated in 140 mg portions into hard capsules weighing 50 mg in known manner using a suitable encapsulating machine for the process.

Each capsule (total weight: 190 mg) obtained in this way contained 10 mg of cetylphosphorylcholine.

The ratio of cetylphosphorylcholine:flow control agent/surfactant:filler in the filling mixture is 1:0.4:12.4 (parts by weight).

Embodiment 2: hard capsule (content: 100mg miltefosine)

1000 mg cetylphosphocholine, 584 g lactose, 345 g microcrystalline cellulose, 50 g talc, 15 g fine-grained silicon dioxide and 6 g magnesium stearate were mixed by the method described in Example 1.

The filling mixture obtained in this way is encapsulated in 200 mg portions into hard capsules weighing 76 mg in known manner using a suitable encapsulating machine for the process.

Each capsule (total weight: 276 mg) obtained in this way contained 100 mg cetylphosphorylcholine. The ratio of cetylphosphorylcholine:flow control agent:filler in the filling mixture is 1:0.07:0.9 (parts by weight).

Embodiment 3: hard capsule (content: 250mg miltefosine)

250 mg cetylphosphorylcholine, 80 g lactose, 50 g microcrystalline cellulose, 5 g talc, 5 g fine-grained silicon dioxide and 15 g magnesium stearate were mixed as described in Example 1. The filling mixture obtained in this way is encapsulated in 405 mg portions into hard capsules weighing 97 mg in known manner using a suitable encapsulating machine for the process.

Each capsule obtained in this way has a total weight of 502 mg and contains 250 mg cetylphosphorylcholine. The ratio of cetylphosphorylcholine:flow control agent:filler in the filling mixture is 1:0.1:0.52 (parts by weight).

Embodiment 4: tablet (content: 250mg cetyl phosphorylcholine)

50 g of cetylphosphorylcholine, 24.25 g of microcrystalline cellulose and 22.00 g of anhydrous dicalcium phosphate were sieved and mixed. 3.75 g of magnesium stearate were sieved and added to the mixture. The mixture is then mixed again. The mixture obtained in this way is subsequently compressed into tablets each weighing 500 mg. Each tablet contains 250mg cetyl phosphorylcholine.

The ratio of cetylphosphorylcholine:flow control agent/surfactant:filling agent in the tablet is 1:0.07:0.925 (parts by weight).

Embodiment 5: tablet (content: 30mg cetylphosphocholine)

23g cetylphosphocholine, 23g microcrystalline cellulose and 52g spray-dried lactose were sieved and mixed. Add 1 g of colloidal silicon dioxide and 1 g of magnesium stearate. The mixture is then mixed again. The mixture obtained in this way is subsequently compressed into tablets each weighing 130.5 mg. Each tablet contains 30mg cetyl phosphorylcholine.

The ratio of cetylphosphorylcholine:flow control agent/surfactant:filling agent in the tablet is 1:0.087:0.31 (parts by weight).

Embodiment 6: effervescent tablet and effervescent mixture (cetylphosphocholine content: 250mg)

1700 g of sodium bicarbonate granules were heated in an oven at 100° C. for 60 minutes. After cooling to room temperature, the converted bicarbonate was mixed with 160 g of monobasic calcium phosphate granules, 1030 g of anhydrous citric acid granules, 100 g of talc and 50 g of magnesium stearate. To the mixture obtained in this way was added 300 g of cetylphosphorylcholine, followed by mixing for 10 minutes. The effervescent mixture obtained in this way is compressed into tablets each weighing 278 mg. Each effervescent tablet contains 250mg cetyl phosphorylcholine.

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

Another possibility is to pack a 278 mg portion of the effervescent mixture into sachets to obtain an effervescent mixture.

Embodiment 7: effervescent tablet and effervescent mixture (content: 50mg cetyl phosphorylcholine)

1600 g of sodium bicarbonate granules were heated in an oven at 100° C. for 60 minutes. After cooling to room temperature, the converted bicarbonate was mixed with 150 g monobasic calcium phosphate granules, 900 g anhydrous citric acid granules, 80 g talc and 30 g magnesium stearate. To the mixture obtained in this way was added 200 g of cetylphosphorylcholine, followed by mixing for 10 minutes.

The mixture obtained in this way is compressed into tablets each weighing 740 mg. Each effervescent tablet contains 50mg cetyl phosphorylcholine.

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

Another possibility is to pack a 740 mg portion of the effervescent mixture into sachets to obtain an effervescent mixture.

Example 8: Drinkable mixture (sachet) (content: 50 mg cetylphosphocholine)

Mix 5g cetylphosphocholine, 308g lactose, 280g microcrystalline cellulose, 5g saccharin and 2g colloidal silicon dioxide. Pack this mixture into sachets. These sachets each weigh 6 g and contain 50 mg cetylphosphocholine.

The ratio of cetylphosphorylcholine:flow control agent/surfactant:filler in the mixture is 1:0.4:117.5 (parts by weight).

Example 9: Drinkable mixture (sachet) (content: 200mg cetylphosphocholine)

Mix 20g cetylphosphocholine, 306g lactose, 403g microcrystalline cellulose, 5g saccharin and 6g colloidal silicon dioxide. Pack this mixture into sachets. These sachets each weigh 7.4 g and contain 200 mg cetylphosphocholine.

The ratio of cetylphosphorylcholine:flow control agent/surfactant:filler in the mixture is 1:0.3:35.5 (parts by weight).

These embodiments may also contain perifosine in place of the active ingredient miltefosine.

Claims (16)

1. alkyl phosphate choline is used for the application of the medicine of prophylactic treatment people protozoan disease in production.

2. the application of claim 1, wherein the active component alkyl phosphate choline of orally give 10-250mg total every day of dosage range in the time limit of 2 week-6 month preferably gives it time bar that risk of infection continues.

3. claim 1 and 2 application, it is characterized in that cetyl phosphocholine (miltefosine) or 1,1-dimethyl-piperidines-4-base-phosphoric acid stearyl (perifosine) is used to produce special medicine by oral administration prophylactic treatment people leishmaniasis, and the active component miltefosine or the perifosine of orally give 10-250mg total every day of dosage range preferably give it time bar that risk of infection continues in the time limit of 2 week-6 month.

4. the application of claim 1-3 is characterized in that total every day of the dosage of active component miltefosine or perifosine is about the about 150mg of 20-.

5. the application of claim 1-3 is characterized in that total every day of the dosage of active component miltefosine or perifosine is about 30-100mg.

6. any one application among the claim 1-5, it is characterized in that with total every day dosage be 50,100 or the oral administration of the active component miltefosine of 150mg or perifosine carries out once every day, twice or three times.

7. any one application among the claim 1-6 is characterized in that the part administration (for example 100mg active component/sky=2 * 50mg active component/sky or 150mg active component/sky=3 * 50mg active component/sky) that dosage equates several times with every day.

8. any one application among the claim 1-7, it is characterized in that beginning to give initial dose, give maintenance dose subsequently, wherein advantageously described initial dose comprises 100mg active component or the above active component of 100mg, and described maintenance dose comprises the 30mg active component.

9. any one application among the claim 1-8 is characterized in that described leishmaniasis is kala azar, mucocutaneous leishmaniasis and/or cutaneous leishmaniasis.

10. alkyl phosphate choline, particularly cetyl phosphocholine (miltefosine) or 1,1-dimethyl-piperidines-4-base-phosphoric acid stearyl (perifosine) is used for being different from by the oral administration prophylactic treatment application in the medicine of the protozoan disease of people's mammal, especially leishmaniasis in production, wherein gives 0.5-15mg active component miltefosine/kg weight of mammal (total every day of dosage of the scope of mg active component/kg).

11. the application of claim 10 it is characterized in that the scope of initial total single dose (Sa) at 3-15mg active component/kg, and total dosage every day (maintenance dose) subsequently is in the scope of 1-10mg active component/kg.

12. the application of claim 10 or 11 is characterized in that the scope of described Sa at 5-10mg active component/kg.

13. the application of claim 10 or 11 is characterized in that the scope of described maintenance dose at 3-5mg active component/kg.

14. any one application among the claim 10-13, it is characterized in that with oral administration carry out 2 week-6 month time limit, advantageously oral administration is carried out the time limit that risk of infection continued.

15. any one application among the claim 10-14 is characterized in that described leishmaniasis is kala azar, mucocutaneous leishmaniasis and/or cutaneous leishmaniasis.

16. be used for the protozoan disease of prophylactic treatment mammal, especially the medicinal coupling of leishmaniasis, comprise a kind of pharmaceutical composition and Bendectin and/or diarrhea, described pharmaceutical composition comprises alkyl phosphate choline, cetyl phosphocholine (miltefosine) or 1 particularly, 1-dimethyl-piperidines-4-base-phosphoric acid stearyl (perifosine), wherein can be jointly or comprise alkyl phosphate choline independently of one another, cetyl phosphocholine (miltefosine) or 1 particularly, pharmaceutical composition and the Bendectin and/or the diarrhea of 1-lupetidine-4-base-phosphoric acid stearyl (perifosine).