U.S. patent application number 10/890971 was filed with the patent office on 2004-12-02 for pharmaceutical formulation for preventing protozoal diseases.
Invention is credited to Engel, Jurgen.
Application Number | 20040242543 10/890971 |
Document ID | / |
Family ID | 29423336 |
Filed Date | 2004-12-02 |
United States Patent
Application |
20040242543 |
Kind Code |
A1 |
Engel, Jurgen |
December 2, 2004 |
Pharmaceutical formulation for preventing protozoal diseases
Abstract
A pharmaceutical formulation for the preventive treatment of a
protozoal disease. The pharmaceutical formulation comprises an
alkyl phosphocholine and an anti-emetic agent and/or an
antidiarrheal agent. The alkyl phosphocholine is administered
together with or separately from said anti-emetic and/or
antidiarrheal agent.
Inventors: |
Engel, Jurgen; (Alzenau,
DE) |
Correspondence
Address: |
GOODWIN PROCTER L.L.P
103 EISENHOWER PARKWAY
ROSELAND
NJ
07068
US
|
Family ID: |
29423336 |
Appl. No.: |
10/890971 |
Filed: |
July 14, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10890971 |
Jul 14, 2004 |
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10347178 |
Jan 8, 2003 |
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60351785 |
Jan 25, 2002 |
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Current U.S.
Class: |
514/78 ;
514/89 |
Current CPC
Class: |
Y02A 50/411 20180101;
Y02A 50/30 20180101; Y02A 50/409 20180101; A61K 31/685
20130101 |
Class at
Publication: |
514/078 ;
514/089 |
International
Class: |
A61K 031/685; A61K
031/675 |
Claims
I claim:
1. A pharmaceutical formulation comprising an alkyl phosphocholine
and an anti-emetic agent and/or an antidiarrheal agent, wherein
said alkyl phosphocholine is to be administered together with or
separately from said anti-emetic and/or antidiarrheal agent.
2. The pharmaceutical formulation of claim 1, which is for the
preventive treatment of a protozoal disease.
3. The pharmaceutical formulation of claim 1, wherein said alkyl
phosphocholine is administered orally at a daily dose of from about
10 to about 250 mg.
4. The pharmaceutical formulation of claim 1, wherein said alkyl
phosphocholine is hexadecyl phosphocholine (miltefosin), or
octadecyl 1,1-dimethyl-piperidino-4-yl phosphate (perifosin).
5. The pharmaceutical formulation of claim 2, wherein said
protozoal disease is leishmaniasis.
6. The pharmaceutical formulation of claim 4, wherein the total
daily dose is about 20 to about 150 mg per kg body weight of
miltefosin or perifosin.
7. The pharmaceutical formulation of claim 6, wherein the total
daily dose is about 30 to about 100 mg of miltefosin or
perifosin.
8. The pharmaceutical formulation of claim 1, wherein the alkyl
phosphocholine is miltefosin or perifosin which is administered
orally once, twice or three times daily in total daily dose of
about 50 mg, about 100 mg, or about 150 mg.
9. The pharmaceutical formulation of claim 1, which is for multiple
daily administrations in two or three equal portions.
10. The pharmaceutical formulation of claim 2, wherein the
protozoal disease is a visceral, mucocutaneous, or cutaneous
leishmaniasis.
11. The pharmaceutical formulation of claim 2, wherein said alkyl
phosphocholine is hexadecyl phosphocholine (miltefosin), or
octadecyl 1,1-dimethyl-piperidino-4-yl phosphate (perifosin), and
wherein said protozoal disease is leishmaniasis, and wherein said
formulation is administered at a daily dose of from about 0.5 to
about 15 mg of miltefosin or perifosin per kilogram of body
weight.
13. The pharmaceutical formulation of claim 1, which is to be
administered orally.
14. The pharmaceutical formulation of claim 13, wherein the oral
administration is continued over a period of from about 2 weeks to
about 6 months.
15. The pharmaceutical formulation of claim 1, wherein said
anti-emetic agent is selected from the group consisting of 5-HT3
receptor antagonists, substituted benzamides, corticosteriods,
antihistamines, neuroleptic agents of the phenothiazine type,
neuroleptic agents of the butyrophenone type, benzodiazepins and
cannabinoids.
16. The pharmaceutical formulation of claim 1, wherein said
anti-emetic agent is metoclopramide, domperidon or alizaprid.
17. The pharmaceutical formulation of claim 1, wherein said
antidiarrheal agent is an opiod.
18. The pharmaceutical formulation of claim 1, wherein said
antidiarrheal agent is loperamid.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional application of application Ser. No.
10/347,178 filed on Jan. 8, 2003, which claims the benefit of
Provisional Application No. 60/351,785, filed on Jan. 25, 2002,
which are both incorporated herein by reference.
FIELD OF INVENTION
[0002] The present invention relates to alkyl phosphocholines,
especially to pharmaceutical compositions containing hexadecyl
phosphocholine (miltefosin) or octadecyl
1,1-dimethyl-piperidino-4-yl phosphate (perifosin, D-21266) for
oral administration for the preventive treatment of protozoal
diseases, especially of leishmaniasis. The invention furthermore
relates to a dosage plan for the oral administration of this
pharmaceutical composition for the preventive treatment of
protozoal diseases, especially leishmaniasis, and a combination,
which comprises this pharmaceutical composition, an anti-emetic
and/or an antidiarrheal agent.
BACKGROUND OF THE INVENTION
[0003] Leishmaniasis is the collective name for various tropical
diseases, which are caused by flagellates of the leishmania species
and are transmitted by various blood-sucking insects. The
manifestations of leishmaniasis can be visceral (kala-azar),
mucocutaneous (American leishmaniasis) or cutaneous (Aleppo boil or
diffuse skin leishmaniasis). The incubation time ranges from weeks
to months. A very high mortality rate is observed in untreated
cases, especially in the case of kala azar and the American
leishmaniasis
[0004] Five-valent antimony compounds are the agent of choice in
the standard therapy for the treatment of leishmaniasis diseases,
such as sodium stilbogluconate, and aromatic diamidines which must
be administered by parenteral injection. This not only leads to
serious side effects because of the high toxicity of these
materials, but also harbors the risk of infection.
[0005] The suitability of alkyl phosphocholines, especially
hexadecyl phosphocholine (miltefosin) for the oral and topical
treatment of leishmaniasis, was described for the first time by
Eibl et al. in German patent application No. 4,132,344 and in
European application No. 534,445, both of which were filed in
1991.
[0006] Numerous other authors describe the treatment of
leishmaniasis with alkyl phosphocholines as a new class of drugs
with remarkable antiprotozoal effectiveness. For example, T. Jha et
al., Miltefosine, an oral agent, for the treatment of Indian
visceral leishmaniasis, N. Engl. J. Med. (1999), 341(24), 1795-1800
reported a study with 120 patients, to whom 50 to 150 mg of
miltefosin per day was administered over a period of several weeks.
In a pilot trial, S. Sundar et al., Oral treatment of visceral
leishmaniasis with miltefosine, Ann. Trop. Med. Parasitol. (1999),
93(6), 589-597 observed the oral use of 100 to 200 mg of miltefosin
per day in the case of visceral leishmaniasis.
[0007] Miltefosin is difficult to handle, because it is very
hygroscopic, although it can be obtained in dry form as crystalline
platelets with a defined melting point over 200.degree. C. The
absorption of water molecules can lead to an increase in weight of
up to 30%, to a lowering of the melting point and to an
agglomeration and lumping of crystals. Water-containing miltefosin
cannot be adequately further processed into pharmaceutical
preparations such as tablets, capsules or sachets. In particular,
the flowability of water containing miltefosin is inadequate.
However, a satisfactory flowability is one of the indispensable
prerequisites for the production of pharmaceutical compositions on
an industrial scale.
[0008] In addition, anhydrous miltefosin has an appreciable
tendency to develop electrostatic charges, especially when it is
stirred in the dry state. The flowability of electrostatically
charged miltefosin is also inadequate for further processing into
solid pharmaceutical compositions. Moreover, electrostatic charging
is always associated with appreciable safety concerns because of
the risk of explosions as well as damage to sensitive electronic
parts.
[0009] To get around the above-mentioned problem during the
production of pharmaceutical compositions containing solid
miltefosin, Eibl et al. proposed that miltefosin be applied to the
surface of silica particles in that a suspension of 1 part by
weight of silica in a solution with 1 by weight of miltefosin is
evaporated to dryness. The flowability of the solid dispersion,
obtained in accordance with the proposal of Eibl et al., is in fact
adequate for filling capsules at least on a laboratory scale.
However, the method described by Eibl et al. is based on the use of
a highly volatile solvent which, at the same time, because of the
risk of electrostatic charging, is not flammable. For all practical
applications, the only solvents, which are known in the art and
fulfill these requirements, are methylene chloride and chloroform.
However, halogenated hydrocarbons, especially chloroform, are
classified as toxic and carcinogenic compounds. Furthermore,
halogenated hydrocarbons accumulate in fatty tissue and are broken
down only slowly.
[0010] It was described in patent publication No. WO 99/37289 that
the above-mentioned problems can be solved by physically mixing an
alkyl phosphocholine, especially hexadecyl phosphocholine with at
least one flow promoter and/or lubricant, selected from the group
of finely divided silica, talc, magnesium stearate and mixtures
thereof, and at least one filler, from the group of lactose,
microcyrstalline cellulose and mixtures thereof.
[0011] In accordance with publication WO 99/37289, it is possible,
simply by mixing alkyl phosphocholines, especially miltefosin, a
flow promoter and/or a lubricant and at least one filler, to obtain
a solid pharmaceutical mixture with a flowabililty, which is
adequate for further processing, especially into tablets, capsules
or sachets.
[0012] In accordance with WO 99/37289 the pharmaceutical
composition can be filled into capsules, preferably hard gelatin
capsules, or pressed into tablets or effervescing tablets or, as a
beverage or effervescent mixture, filled into sachets.
[0013] The miltefosin content per dose unit ranges from 10 to 800
mg, especially from 10 to 500 mg and particularly from 50 to 250
mg. The most preferred content ranges from 50 to 150 mg.
[0014] The production of miltefosin is described in detail in the
examples for hexadecyl phosphocholine in German patent application
No. 4,132,344. Further methods for producing and purifying
miltefosin are described in German patent applications Nos.
2,752,125, 3,641,379, 3,641,491, 4,013,632, and 3,641,377.
DETAILED DESCRIPTION OF THE INVENTION
[0015] It was surprisingly and unexpectedly found according to one
aspect of the present invention that alkyl phosphocholines,
especially hexadecyl phosphocholine (miltefosin) and octadecyl
1,1-dimethyl-piperidinio-4-yl phosphate (perifosin, D-21266) are
suitable for the preventive treatment of protozoal diseases,
especially of leishmaniasis. Pharmaceutical administration of alkyl
phosphocholines, especially of hexadecyl phosphocholine or of
octadecyl 1,1-dimethyl-piperidinio-4-yl phosphate for the
prevention of protozoal diseases, especially of leishmaniasis, is
neither described nor made obvious in the publications of the state
of the art.
[0016] In accordance with one aspect of the present invention, a
dosage plan is provided for the preventive treatment of
leishmaniasis in man by the oral administration of the
pharmaceutical composition. In the case of a suitable embodiment of
the present invention, the following dosage plan is suitable for
the preventive treatment of leishmaniasis in man by oral
administration. Total dosage: 10 to 250 mg of miltefosin active
ingredient, suitably 20 to 150 mg and especially 30 to 100 mg.
Daily single or multiple dose: a total daily dose of 10 to 50 mg of
active ingredient is administered suitably as a single daily dose.
A dose of 50 to 250 mg of active ingredient and suitably of 50 to
150 mg of active ingredient is administered orally daily as a daily
multiple dose, suitably as two doses per day (total daily dose of
100 mg of active ingredient) or as three doses per day (total daily
dose of 150 mg). From the point of view of compliance by the
patients, a daily dose, divided into four to five doses, is
generally regarded as the upper limit. For preventive purposes,
however, it is also possible to administer the agent differently
than divided into one to five doses per day.
[0017] In the case of a suitable embodiment, daily multiple doses
of the same magnitude are administered (for example, 100 mg of
active ingredient per day=2.times.50 mg of active ingredient per
day or 150 mg of active ingredient per day=3.times.50 mg of active
ingredient per day).
[0018] Prophylaxis with an initial dose, followed by maintenance
doses is also possible, 100 mg of active ingredient or more, for
example, being administered as initial dose, followed by, for
example, 30 mg of active ingredient as maintenance doses.
[0019] Duration of the prophylactic use: 2 weeks to 6 months,
preferably for the duration of the risk of infection.
[0020] In accordance with a further aspect of the invention, a
dosage plan for the preventive treatment of leishmaniasis in
mammals other than man is made available by the oral administration
of the inventive pharmaceutical composition.
[0021] All mammals can be treated. A preventive treatment of all
types of leishmaniasis, especially of Leishmaniasis major and
Leishmaniasis infantum, is possible with the dosage plan. According
to the dosage plan, the total daily dose for the prophylactic
treatment in the case of an oral administration ranges from 0.5 to
15 mg of active ingredient (miltefosin or perifosin) per kg of body
weight of the animal (mg of active ingredient/kg). In the case of a
suitable embodiment, the prophylaxis is commenced with an initial
total individual dose (saturation dose) ranging from 3 to 15 and
preferably from 5 to 10 mg of active ingredient/kg and then
continued with a total daily dose (maintenance dose) training from
1 to 10 and suitably from 3 to 5 mg of active ingredient/kg. The
preventive administration ranges from 2 weeks to 6 months and,
suitably, for the duration of the risk of infection.
[0022] In accordance with a further aspect of the present
invention, a combination of the pharmaceutical composition with an
anti-emetic and/or an antidiarrheal agent is made available for
oral administration for the preventive treatment of
leishmaniasis.
[0023] In a suitable embodiment of the invention, the
pharmaceutical composition is administered in combination with an
anti-emetic and/or an antidiarrheal agent. The latter can be
administered simultaneously or consecutively. The anti-emetic and
the antidiarrheal agent can be administered independently of one
another. The anti-emetic and/or the antidiarrheal agent can be
contained either in the pharmaceutical compositon described or in a
pharmaceutical formulation, which is independent thereof.
[0024] Suitable anti-emetics are, for example, 5-HT3 receptor
antagonists, substituted benzamides, corticosteriods,
antihistamines, neuroleptic agents of the phenothiazine type,
neuroleptic agents of the butyrophenone type, benzodiazepins and
cannabinoids. Suitable anti-emetics include metoclopramide,
domperidon and alizaprid.
[0025] Suitable antidiarrheal include opiods, such as
loperamid.
[0026] The solid, oral pharmaceutical compositions are suitably
useful for the preventive treatment of leishmaniasis. Other
diseases, caused by protozoa, include for example, malaria,
trypanosomiasis, toxoplasmosis, babesiosis, amebic dysentery and
lambliasis.
EXAMPLES
[0027] The invention is explained in greater detail by means of the
following examples.
[0028] Examples of Solid, Oral Pharmaceutical Formulations, which
can be Used
Example 1
Hard Gelatin Capsule (Content: 10 mg of Miltefosin)
[0029] Hexadecyl phosphocholine (100 g), 808.5 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 width of 0.8
mm and then homogenized for 30 minutes in a suitable mixer.
Magnesium stearate (4 g, 0.8 mm sieve) is then added and the
components are mixed for a further 5 minutes. The mixture, so
obtained, is filled in 140 mg portions by known procedures into
hard gelatin capsules weighing 50 mg, a suitable encapsulating
machine being used. Each of the capsules so obtained (total weight:
190 mg) contains 10 mg of hexadecyl phosphate. The ratio of
hexadecyl phosphocholines to flow promoter/surfactant to fillers in
the mixture is 1:0.4:12.4 (parts by weight).
Example 2
Hard Gelatin Capsule (Content: 100 mg of Miltefosin)
[0030] Hexadecyl phosphocholine (1,000 g), 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 are mixed by the method
described in Example 1.
[0031] The mixture, so obtained, is filled in 200 mg portions by
known methods into hard gelatin capsules weighing 76 mg, a suitable
encapsulation machine being used for this purpose. Each of the
capsules, so obtained (total weight 276 mg), contains 100 mg of
hexadecyl phosphocholine. The ratio of hexadecyl phosphocholine to
flow promoter to filler in the mixture is 1:0.07:0.9 (parts by
weight).
Example 3
Hard Gelatin Capsule (Content: 250 mg of Miltefosin)
[0032] Hexadecyl phosphocholine (250 g), 80 g of lactose, 50 g of
microcrystalline cellulose, 5 g of talc, 5 g of finely divided
silica and 15 g of magnesium stearate are mixed by the method
described in Example 1. The mixture, so obtained, is filled in 405
mg portions by known methods into hard gelatin capsules weighing 97
mg, a suitable encapsulating machine being used for this
purpose.
[0033] Each of the capsules, so obtained has a total weight of 502
mg and contains 250 mg of hexadecyl phosphocholine. The ratio of
hexadecyl phosphocholine to flow promoter to filler in the mixture
is 1:0.1:0.52 (parts by weight).
Example 4
Hard Gelatin Capsule (Content: 250 mg of Miltefosin)
[0034] Hexadecyl phosphocholine (50 g), 24.25 g of microcrystalline
cellulose and 22.00 g of anhydrous dicalcium phosphate are screened
and mixed. Magnesium stearate (3.75 g) is screened and added to the
mixture. The mixture is then mixed once again. The mixture, so
obtained, is then pressed into tablets weighing 500 mg each. In
each case, the tablets contain 250 mg of hexadecyl phosphocholine.
The ratio of hexadecyl phosphocholine to flow promoter/surfactant
to fillers in the tablet is 1:0.007:0.925 (parts by weight).
Example 5
Tablets Containing 30 mg of Hexadecyl Phosphocholine
[0035] Hexadecyl phosphocholine (23 g), 23 g of microcrystalline
cellulose and 52 g spray-dried lactose are screened and mixed.
Colloidal silica (1 g) and 1 g of magnesium stearate are added. The
mixture is then mixed once again.
[0036] The mixture, so obtained, is then pressed into tablets
weighing 130.5 mg each. In each case, the tablets contain 30 mg of
hexadecyl phosphocholine. The ratio of hexadecyl phosphocholine to
flow promoter/surfactant to fillers is 1:0.087 0.31 (parts by
weight).
Example 6
Effervescent Tablets and Effervescing Mixture Containing 250 mg of
Hexadecyl Phosphocholine
[0037] Granular sodium hydrogen carbonate (1,700 g) is heated for
60 minutes in an oven at 100.degree. C. After being cooled to room
temperature, the converted hydrogen carbonate is mixed with 160 g
of granular monobasic calcium phosphate, 1,030 of anhydrous
granular citric acid, 100 g of talc and 50 g of magnesium stearate.
The mixture, so obtained, is mixed with 300 g of hexadecyl
phosphocholine for 10 minutes.
[0038] The effervescent mixture, so obtained, is pressed into
tablets weighing 278 mg each. In each case, the effervescent
tablets contain 250 mg of hexadecyl phosphocholine. The ratio of
hexadecyl phosphocholine to flow promoter/surfactant to fillers is
1:0.50:0.53 (parts by weight).
[0039] Alternatively, 278 mg of the effervescing mixture can be
filled into a sachet, an effervescing mixture being obtained.
Example 7
Effervescent Tablets and Effervescing Mixture Containing 50 mg of
Hexadecyl Phosphocholine
[0040] Granular sodium hydrogen carbonate (1,600 g) is heated for
60 minutes in an oven at 100.degree. C. After being cooled to room
temperature, the converted hydrogen carbonate 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, so obtained, is mixed with 200 g of hexadecyl
phosphocholine for 10 minutes.
[0041] The mixture, so obtained, is pressed into tablets weighing
740 mg each. In each case, the effervescent tablets contain 50 mg
of hexadecyl phosphocholine. The ratio of hexadecyl phosphocholine
to flow promoter/surfactant to fillers is 1:0.55:0.75 (parts by
weight).
[0042] Alternatively, 740 mg of the effervescing mixture can be
filled into a sachet, an effervescing mixture being obtained.
Example 8
Beverage Mixture (Sachets, Containing 50 mg of Hexadecyl
Phosphocholine
[0043] Hexadecyl phosphocholine (5 g), 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, which weigh 6
g each and contain 50 mg of hexadecyl phosphocholine. The ratio of
hexadecyl phosphocholine to flow promoter/surfactant to fillers is
1:0.4:117.5 (parts by weight).
Example 9
Beverage Mixture (Sachets, Containing 200 mg of Hexadecyl
Phosphocholine
[0044] Hexadecyl phosphocholine (20 g), 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, which weigh
7.4 g each and contain 250 mg of hexadecyl phosphocholine. The
ratio of hexadecyl phosphocholine to flow promoter/surfactant to
fillers is 1:0.3:35.5 (parts by weight).
[0045] Instead of miltefosin, the examples can contain
perifosin.
* * * * *