Title of Invention

PROCESS FOR PRODUCING MICRO-TABLETS OR MICRO-PELLETS FROM PHARMACEUTICAL COMPOSITION OF FUMARIC ACID, AND MICRO-TABLETS OR MICRO-PELLETS, SO PRODUCED

Abstract A process for producing micro-tablets or micro-pellets from pharmaceutical composition constituted of one or more salts of fumaric acid monoalky esters of the general formula and dialkyl fumarate of the formula wherein A is a bivalent cation from the series consisting of Ca, Mg, Zn or Fe or a monovalent cation from the series Li, Na or K, respectively, and n denotes the numeral 1 or 2 depending on the type of cation, said process comprising : mixing said one or more salts of fumaric acid monoalkyl esters and said dialkyl fumarate, optionally, in combination with commonly used pharmaceutical excipients and vehicles, and preparing micro-tablets or micro-pellets from the resultant mixture/product in the manner such as herein described/exemplified, said micro-tablets/micro-pellets being, on administration, capable for treatment of psoriatic arthritis, neurodermatitis, psoriasis and enteritis regionalis Crohn, without any severe side effects, as experienced from the same composition in hithertoknown tablet forms, but maintaining same, if not better, efficacy.
Full Text The present invention relates to process for producing micro-tablets or micro-
pellets from pharmaceutical composition of fumaric acid, and micro-tablets
or micro-pellets, so produced. The invention particularly pertains to the
use of certain fumaric acid monoalkyl ester salts either alone or in
combination with a dialkyl fumarate for preparing mi-
cro-tablets for the treatment of psoriatic arthritis,
neurodermatitis, psoriasis and enteritis regionalis
Crohn.
EP-A-0 188 749 already describes fumaric acid deriva-
tives and pharmaceutical compositions containing the
same for the treatment of psoriasis. Likewise, pharma-
ceutical compositions for treating psoriasis which con-
tain a mixture of fumaric acid and other fumaric acid
derivatives are known from DE-A-25 30 372. A content of
free fumaric acid is obligatory.
DE-A-26 21 214 describes drugs for treating psoriasis
which contain fumaric acid monoethyl ester and mineral
salts thereof as the active ingredient. The use of fu-
maric acid monoethyl ester salts of calcium, zinc and
magnesium and of fumaric acid dimethyl ester for the
treatment of psoriasis is also known from the publica-
tion "Hautarzt" (Dermatologist) 1987, pages 279 to 285.
Finally, EP-A-0 312 697 discloses pharmaceutical compo-
sitions containing one or more compounds selected from
the calcium, magnesium, zinc and iron salts of fumaric
acid monomethyl ester, alone or preferably in admixture
with C1-5 alkyl fumarates. A preparation according to
example 4 of this document contains 87.5 mg of mono-
ethyl fumarate Ca salts, 120.0 mg of dimethyl fumarate,
5.0 mg of monoethyl fumarate Mg salt and 3.0 mg of
monoethyl fumarate Zn salt, which corresponds to 164 mg
of fumaric acid. The preparation is presented in the
form of enteric-coated tablets and is approved for dis-
tribution in the German market under the trademark Fu-
maderm®.
As early as phase 3 of the clinical tests and in post-
marketing studies of this product, it was found that
about 60 % of the patients developed gastro-intestinal
symptoms in the form of diarrhoea, stomach pains and
bloating during the initial phase of the Fumaderm®
therapy. Other side effects are so-called flushes, i.e.
redness of the face, and sensations of heat.
Even though the tablets are generally tolerated rela-
tively well, the above-mentioned symptoms keep occur-
ring, especially at the onset of therapy. In the course
of the treatment, these undesirable side effects often
decrease. However, the intake of Fumaderm® causes se-
vere gastro-intestinal complaints in some patients.
These symptoms in the stomach and intestine affect pa-
tient compliance and can be so unpleasant for the pa-
tient that therapy is sometimes discontinued.
Therefore, it was the object of the present invention
to provide a pharmaceutical preparation which avoids
the above-mentioned side effects, especially gastro-
intestinal complaints, while the same pharmaceutical
ingredients are administered.
Tests carried out by the Applicant have shown that
methyl hydrogen fumarate, a metabolite of dimethyl fu-
marate which forms the main component of the prepara-
tion Fumaderm® initially increases the endotoxin-
stimulating TNF-a secretion in human mononuclear cells
of the peripheral blood (peripheral blood mononuclear
cells = PBMC) and in isolated monocytes. With multiple
re-exposure, the endotoxin-induced increase in TNF-a
secretion is reduced, i.e. adaptation takes place.
Possibly, this initial induction of TNF-a is responsi-
ble for the known side effect of the Fumaderm® prepara-
tion such as gastro-intestinal complaints or the flush
symptoms. The tendency towards decrease of endotoxin-
induced TNF-a secretion after repeated methyl hydrogen
fumarate exposure may be an explanation for the adapta-
tion effect, i.e. the decrease of side effects after
sustained Fumaderm® therapy. Accordingly, it was the
first objective of additional tests to inhibit TNF-a
secretion with other drugs and thus to control the side
effects of Fumaderm® administration.
Surprisingly and unexpectedly, it was found in the
course of these tests that formulation of the active
ingredient in the form of micro-tablets resulted in a
substantial reduction of gastro-intestinal symptoms.
Therefore, the present invention provides a process for producing micro-tablets or micro-pellets from
pharmaceutical composition constituted of one or more salts of fumaric acid monoalky esters of the
general formula

and dialkyl fumarate of the formula

wherein A is a bivalent cation from the series consisting of Ca, Mg, Zn or Fe or a
monovalent cation from the series Li, Na or K, respectively, and n denotes the numeral 1 or 2
depending on the type of cation, said process comprising :
mixing said one or more salts of fumaric acid monoalkyl esters and said dialkyl
fumarate, optionally, in combination with commonly used pharmaceutical excipients and
vehicles, and preparing micro-tablets or micro-pellets from the resultant mixture/product in the
manner such as herein described/exemplified, said micro-tablets/micro-pellets being, on
administration, capable for treatment of psoriatic arthritis, neurodermatitis, psoriasis and
enteritis regionalis Crohn, without any severe side effects, as experienced from the same
composition in hithertoknown tablet forms, but maintaining same, if not better, efficacy.
Preferably, the size or the mean diameter, respective-
ly, of the micro-pellets or micro-tablets is in the
range of 300 to 2.000 µm, especially in the range of
500 to 1.500 µm and most preferably 1.000 µm.
The micro-tablets or micro-pellets may be filled in
capsules or sachets and administered in this form. In
addition, the micro-tablets themselves or the capsules
may be provided with an enteric coating which is ap-
plied by conventional processes. Capsules may be hard
or soft gelatine capsules.
Preferred compositions according to the invention con-
tain the calcium salt of the fumaric acid monomethyl
ester and/or the calcium salt of the fumaric acid mono-
ethyl ester, optionally in admixture with dimethyl fu-
marate. The total weight of the active ingredients is
10 to 300 mg. Preferably, the composition in the form
of micro-tablets contains 10 to 290 parts by weight of
the fumaric acid monoalkyl ester (calcium salt) and 290
to 10 parts by weight of dimethyl fumarate. According
to another embodiment, this composition may also con-
tain 1 to 50 parts by weight of fumaric acid monoalkyl
ester zinc salt.
Another preferred embodiment in the form of micro-
tablets contains 1 to 250 parts by weight of fumaric
acid monoalkyl ester (calcium salt), 250 to 10 parts by
weight of dimethyl fumarate, 1 to 50 parts by weight of
fumaric acid monoalkyl ester (magnesium salt) and 1 to
50 parts by weight of fumaric acid monoalkyl ester
(zinc salt), the total weight of the active ingredients
being 30 to 300 mg.
For systemic initiation as well as for termination of
the treatment in stages (decreasing dosage), a low dose
is advantageous. Such a dose may, for example, consist
of 30 mg of dimethyl fumarate, 20 mg of monoethyl fu-
marate (calcium salt) and 3 mg of monoethyl fumarate or
monomethyl fumarate (zinc salts). Therapeutic doses af-
ter an initial phase may, for example, be comprised of
20 mg of dimethyl fumarate, 87 mg of monoethyl fumarate
(calcium salt) and 3.0 mg of monoethyl fumarate or
monomethyl fumarate (zinc salt) .
For example, the fumaric acid derivatives used in the
invention are obtained according to the processes de-
scribed in EP 0 312 697. ______
Without wishing to be bound by theoretic contempla-
tions, it is assumed that the gastro-intestinal symp-
toms may be caused by local stimulation of the epithe-
lial cells of the intestine which induces TNF-a secre-
tion. Upon administration of conventional tablets, the
ingredients of these tablets are released in the intes-
tine in a concentration which is too high, causing lo-
cal irritation of the intestinal mucous membrane. As a
result of this local irritation very high concentra-
tions of TNF-a are presumably released for a short pe-
riod of time which may be responsible for the gastro-
intestinal side effects. On the other hand, when en-
teric-coated micro-tablets in capsules are applied, lo-
cally low concentrations of the active ingredients on
the epithelial cells of the intestine are achieved. By
peristaltic movements of the stomach, the micro-tablets
are gradually moved into the small intestine with en-
hanced distribution of the active ingredients.
In other words, enteric-coated micro-tablets in the
same dose disperse in the stomach already and are fed
to the intestine in portions (boluswise) , where the ac-
tive ingredients are released in smaller doses. As a
Jesuit, local irritation of the epithelial cells of the
intestine and the release of TNF-a are avoided. This is
a possible explanation for the enhanced toleration of
micro-tablets in the gastro-intestinal tract vis-a-vis
conventional tablets. However, it was not to be ex-
pected that a mere change in galenics would lead to
such a drastic reduction of side effects.
The following examples will show the production and ac-
tion of the micro-tablets according to the invention.
Example 1
Preparation of enteric-coated micro-tablets in capsules
containing 87.0 mg of monoethyl fumarate-Ca salt, 120.0
mg of dimethyl fumarate and 5.0 mg of monoethyl fuma-
rate-Mg salt, which corresponds to a total of 164 mg of
fumaric acid
Taking the necessary precautions (breathing mask,
gloves, protective clothing, etc.), 8.700 kg of mono-
ethyl fumarate-Ca salt, 12.000 kg of dimethyl fumarate,
0.500 kg of monoethyl fumarate-Mg salt and 0.30 kg of
monoethyl fumarate-Zn salt are crushed, intensely mixed
and homogenised by means of a sieve 800. Then an ex-
cipient mixture of the following composition is pre-
pared: 18.00 kg of starch derivative (STA-RX® 1500),
0.30 kg of micro-crystalline cellulose (Avicel® PH
101), 0.75 kg of PVP (Kollidon® 120), 4.00 kg of Pri-
mogel®, 0.25 kg of colloidal silicic acid (Aerosil®) .
The entire powder mixture is added to an active ingre-
dient mixture, homogenised by means of a sieve 200,
processed in the usual manner with a 2 % aqueous solu-
tion of polyvinyl pyrrolidone (Kollidon® K25) to obtain
a binder granulate and mixed in a dry state with the
outer phase consisting of 0.50 kg of Mg stearate and
1.50 kg of talcum. Then the powder mixture is pressed
by the conventional method into convex micro-tablets
with a gross mass of 10.0 mg and a diameter of 2.0 mm.
Instead of this classic tabletting method other methods
for making tablets such as direct tabletting or a
method for making solid dispersions by the melt method
and the spray drying method may also be used.
The gastric acid-resistant coating may be poured or
sprayed on in a classic coating pan or applied in a
fluidised bed apparatus. In order to achieve resistance
to gastric acid, portions of a solution of 2.250 kg of
hydroxy propyl methyl cellulose phthalate (HPMCP, Phar-
macoat® HP 50) are dissolved in a mixture of the fol-
lowing solvents: acetone 13.00 1, ethanol (94 % by
weight denatured with 2 % ketone) 13.50 1 and deminer-
alised water 1.50 1. 0.240 kg of castor oil are added
as softening agent to the finished solution and applied
in portions to the tablet cores in the usual manner.
After drying is completed, a suspension of the follow-
ing composition is applied as a film-coat in the same
apparatus: talcum 0.340 kg, titanium(VI) oxide Cronus
RN 56 0.400 kg, coloured lacquer L red lacquer 86837
0.324 kg, Eudragit E 12.5 % 4.800 kg and polyethylene
glycol 6000 pH 11 XI 0.120 kg in a solvent mixture of
the following composition: 2-propanol 8.170 kg, aqua
demineralisata 0.200 kg and glycerine triacetate (Tri-
acetin) 0.600 kg.
The enteric-coated micro-tablets are then filled into
hard gelatine capsules at a net weight of 500.0 mg and
sealed.
Example 2
Preparation of enteric-coated micro-tablets in capsules
containing 87.0 mg of monoethyl fumarate-Ca salt, 120.0
mg of dimethyl fumarate and 5.0 mg of monoethyl fuma-
rate-Mg salt, which corresponds to a total of 164 mg of
fumaric acid
Taking the necessary precautions (breathing mask,
gloves, protective clothing, etc.), 8.700 kg of mono-
ethyl fumarate-Ca salt, 12.000 kg of dimethyl fumarate,
0.500 kg of monoethyl fumarate-Mg salt and 0.30 kg of
monoethyl fumarate-Zn salt are crushed, intensely mixed
and homogenised by means of a sieve 800. Then an ex-
cipient mixture of the following composition is pre-
pared: 24.70 kg of micro-crystalline cellulose (Avicel®
PH 200), 3.00 kg of croscarmellose sodium (AC-Di-SOL-
SD-711), 2.50 kg of talcum, 0.10 kg of anhydrous silica
(Aerosil® 200) and 1.00 kg of magnesium stearate. The
entire excipient mixture is added to the active ingre-
dient mixture and homogenised. Then the powder mixture
is pressed by direct tabletting into convex micro-
tablets with a gross mass of 10.0 mg and a diameter of
2.0 mm. Instead of this classic tabletting method other
methods for making tablets such as solid dispersions by
the melt method, the spray drying method or tabletting
of binder granulates may also be used.
The gastric acid-resistant coating may be poured or
sprayed on in a classic coating pan or applied in a
fluidised-bed apparatus. For example, a solution of
0,94 kg of Eudragit® L in isopropanol is prepared which
also contains 0.07 kg of dibutyl phthalate. This solu-
tion is sprayed onto the tablet cores.
After that, a dispersion of 17.32 kg of Eudragit® L
D-55 and a mixture of 2.80 kg of micro-talcum, 2.00 kg
of Macrogol 6000 and 0.07 kg of Dimetican in water is
prepared and sprayed onto the cores.
The enteric-coated micro-tablets are then filled into
hard gelatine capsules at a net weight of 760.0 mg and
sealed.
Therapy examples
Micro-tablets containing the same four active ingredi-
ents in the same quantitative composition as the com-
mercial product Fumaderm® were prepared according to
the above production examples. A Fumaderm® tablet with
enteric coating corresponds to about 102 enteric-coated
micro-tablets having the same composition. As described
in the production examples, these micro-tablets are
filled into capsules for more convenient administra-
tion. Two capsules correspond to one tablet of Fuma-
derm®.
For easier comparison, two patients who developed se-
vere gastro-intestinal symptoms during therapy with Fu-
maderm® tablets were treated with the enteric-coated
micro-tablets according to the invention. After admini-
stration of these micro-tablets, these patients sur-
prisingly no longer complained about gastro-intestinal
troubles which had been observed during administration
of conventional tablets. The same improvement of pso-
riasis was observed as with Fumaderm® tablets of the
prior art. Under certain circumstances, a smaller dose
may suffice to achieve clinical success when micro-
tablets are administered.
The results of the treatment are presented in the fol-
lowing table:
The table shows that even an increased dose of micro-
tablets (9 capsules per day) had no or only slight side
effects, while the lower dose of the commercial product
Fumaderm® already caused severe gastro-intestinal symp-
toms .
The results of the treatment also show that the effec-
tiveness of micro-tablets for treating psoriasis is at
least equivalent, if not better than that of the com-
mercial product. On the whole, the formulation of fu-
maric acid derivates in the form of micro-tablets
therefore show a significant improvement vis-a-vis
therapy with conventional tablets.
The above fact is corroborated by further clinical study with "Fumaderm"
in the form of micro-tablets/micro-pellets, which are resistant to gastric juices,
and details thereof are provided hereinafter:
Design of study: Open, non-comparative, mono-centric clinical study.
Object of study: Clarification with respect to long-term tolerability of micro-
pellets given to patients with serious gastro-intestinal trouble
under therapy with tablets.
Indication: Psoriasis vulgaris
Number of patients: 15

Evaluation: provisional evaluation after 3 months
Results: Provisional evaluation after 3 months
A clearly enhanced gastrointestinal tolerability of fumaric acid
derivatives by micro pelletising can be detected.
An improvement of the clinical results by taking of micro pellets
appears as well; this may be caused by the higher dosage which
is now possible.
4 patients have been leaving the study in the first three months
(after 2, 9, 55 and 89 days) because of gastro-intestinal side
effects.
From the results, shown in the graphical representation of Fig. 1 of the
accompanying drawings, it can be ascertained that there has improvement in
tolerance through treatment using Fumaderm® as gastroduric micro-tablets,
after discontinuing therapy using Fumaderm® as gastroduric tablets (all
patients; n=15).
It can be also seen from the graphical representation shown in Fig. 2 of
the accompanying drawings that there has been significant impact of the
tehrapy with Fumaderm® in the form of micro-pellets being resistant to gastric
juices on the clinical results of Psoriasis, compared with the results of
Fumaderm® in the form of tablets being resistant to gastric juices at the time
of therapy break off (without patients leaving untimely; n=11).
Figs. 3 and 4 of the accompanying drawings represent diagrams showing the
dissolution rate of dimethylfumarate and monoethylfumarate, respectively. As it can
be ascertained, enteric-coated tablets are tested versus enteric-coated micro-
tablets. As is evident, the micro-tablets release the agent quicker than the tablets.
Monoethylfumarate is released almost completely after less than 20 minutes and
methylfumarate reached its maximum also soon after 20 minutes; a time where the
tablets have only released 20%, as shown particularly in Fig. 4.
WE CLAIM:
1. A process for producing micro-tablets or micro-pellets from pharmaceutical composition
constituted of one or more salts of fumaric acid monoalky esters of the general formula

wherein A is a bivalent cation from the series consisting of Ca, Mg, Zn or Fe or a
monovalent cation from the series Li, Na or K, respectively, and n denotes the numeral 1 or 2
depending on the type of cation, said process comprising :
mixing said one or more salts of fumaric acid monoalkyl esters and said dialkyl
fumarate, optionally, in combination with commonly used pharmaceutical excipients and
vehicles, and preparing micro-tablets or micro-pellets from the resultant mixture/product in the
manner such as herein described/exemplified, said micro-tablets/micro-pellets being, on
administration, capable for treatment of psoriatic arthritis, neurodermatitis, psoriasis and
enteritis regionalis Crohn, without any severe side effects, as experienced from the same
composition in hithertoknown tablet forms, but maintaining same, if not better, efficacy.
2. The process as claimed in claim 1, wherein calcium salt of fumaric acid monoethyl
ester or monomethyl ester is employed.
3. The process as claimed in claim 1 or 2, wherein calcium salt of the fumaric acid
monoalkyl ester is employed in admixture with dimethyl fumarate.
4. The process as claimed in claim 1, wherein calcium and zinc salt of the fumaric acid
monoalkyl ester in admixture with dimethyl fumarate is employed.
5. The process as claimed in claim 1, wherein calcium, magnesium and zinc salt of the
fumaric monoethyl ester in admixture with dimethyl fumarate is employed.
6. The process as claimed in any of the claims 1 to 5, wherein calcium salt of the fumaric
acid monoalkyl ester is employed in an amount of 10 to 300 mg, the total weight of the active
ingredients being 10 to 300 mg.
7. The process as claimed in claim 3, wherein 10 to 290 parts by weight of calcium salt of
the fumaric acid monoalkyl ester and 290 to 10 parts by weight of dimethyl fumarate are
employed, the total weight of the active ingredients being 20 to 300 mg.
8. The process as claimed in claim 4, wherein 10 to 250 parts by weight of calcium salt of
the fumaric acid monoalkyl ester, 1 to 50 parts by weight of dimethyl fumarate and 1 to 50
parts by weight of zinc salt of the fumaric acid monoalkyl ester are employed, the total weight
of the active ingredients being 20 to 300 mg.
9. The process as claimed in any of the claims 1 to 5, wherein 10 to 250 parts by weight
of calcium salt of the fumaric acid monoalkyl ester, 250 to 10 parts by weight of dimethyl
fumarate, 1 to 50 parts by weight of magnesium salt of the fumaric acid monoalkyl ester and 1
to 50 parts by weight of zinc salt of the fumaric acid monoalkyl ester are employed, the total
weight of the active ingredients being 30 to 300 mg.
10. Micro-tablets or micro-pellets as produced by the process claimed in any of the
preceding claims, wherein the micro-tablets or micro-pellets have an enteric coating (coating
resistant to gastric acid), and, preferably, the micro-tablets or micro-pellets are filled into
capsules or sachets.


A process for producing micro-tablets or micro-pellets from pharmaceutical composition constituted of one or more salts of fumaric acid monoalky esters of the general formula

and dialkyl fumarate of the formula

wherein A is a bivalent cation from the series consisting of Ca, Mg, Zn or Fe or a monovalent cation from the series Li, Na or K, respectively, and n denotes the numeral 1 or 2 depending on the type of cation, said process comprising :
mixing said one or more salts of fumaric acid monoalkyl esters and said dialkyl fumarate, optionally, in combination with commonly used pharmaceutical excipients and vehicles, and preparing micro-tablets or micro-pellets from the resultant mixture/product in the manner such as herein described/exemplified, said micro-tablets/micro-pellets being, on administration, capable for treatment of psoriatic arthritis, neurodermatitis, psoriasis and enteritis regionalis Crohn, without any severe side effects, as experienced from the same composition in hithertoknown tablet forms, but maintaining same, if not better, efficacy.

Documents:

in-pct-2000-496-kol-abstract.pdf

IN-PCT-2000-496-KOL-AMANDED-FORM 1.pdf .pdf

IN-PCT-2000-496-KOL-AMANDED-SPECIFICATION.pdf .pdf

IN-PCT-2000-496-KOL-AMANDEDREPLY TO EXAMINATION REPORT.pdf

in-pct-2000-496-kol-assignment.pdf

IN-PCT-2000-496-KOL-ASSIGNMENT1.1.pdf

in-pct-2000-496-kol-claims.pdf

in-pct-2000-496-kol-correspondence.pdf

IN-PCT-2000-496-KOL-CORRESPONDENCE1.1.pdf

in-pct-2000-496-kol-description (complete).pdf

in-pct-2000-496-kol-drawings.pdf

in-pct-2000-496-kol-examination report.pdf

IN-PCT-2000-496-KOL-EXAMINATION REPORT1.1.pdf

in-pct-2000-496-kol-form 1.pdf

IN-PCT-2000-496-KOL-FORM 13.1.pdf

in-pct-2000-496-kol-form 13.pdf

IN-PCT-2000-496-KOL-FORM 18.1.pdf

in-pct-2000-496-kol-form 18.pdf

IN-PCT-2000-496-KOL-FORM 3.1.pdf

in-pct-2000-496-kol-form 3.pdf

IN-PCT-2000-496-KOL-FORM 5.1.pdf

in-pct-2000-496-kol-form 5.pdf

in-pct-2000-496-kol-gpa.pdf

IN-PCT-2000-496-KOL-GPA1.1.pdf

IN-PCT-2000-496-KOL-GRANTED-ABSTRACT.pdf

IN-PCT-2000-496-KOL-GRANTED-CLAIMS.pdf

IN-PCT-2000-496-KOL-GRANTED-DESCRIPTION (COMPLETE).pdf

IN-PCT-2000-496-KOL-GRANTED-DRAWINGS.pdf

IN-PCT-2000-496-KOL-GRANTED-FORM 1.pdf

IN-PCT-2000-496-KOL-GRANTED-FORM 2.pdf

IN-PCT-2000-496-KOL-GRANTED-SPECIFICATION.pdf

IN-PCT-2000-496-KOL-OTHERS.pdf

in-pct-2000-496-kol-pa.pdf

in-pct-2000-496-kol-priority document.pdf

in-pct-2000-496-kol-reply to examination report.pdf

in-pct-2000-496-kol-specification.pdf

in-pct-2000-496-kol-translated copy of priority document.pdf


Patent Number 250657
Indian Patent Application Number IN/PCT/2000/496/KOL
PG Journal Number 03/2012
Publication Date 20-Jan-2012
Grant Date 17-Jan-2012
Date of Filing 09-Nov-2000
Name of Patentee FUMAPHARM AG
Applicant Address HALDENSTRASSE 24A, 6006 LUZERN
Inventors:
# Inventor's Name Inventor's Address
1 JOSHI RAJENDRA KUMAR ALTSTETTERSTRASSE 224, CH-8048 ZURICH
2 STREBEL HANS-PETER MATTENWEG 7, CH-5630 MURI
PCT International Classification Number A61K 31/225
PCT International Application Number PCT/EP1999/07568
PCT International Filing date 1999-10-08
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 198 48 260.4 1998-10-20 Germany