Title of Invention

"QUICK RELEASE FLUDARA TABLET COMPOSITION"

Abstract The invention relates to a fast releasing tablet formulation containing 99.19 % of pure Fludara (ultrapure Fludara) as an active substance in a defined composition of remaining impurities.
Full Text The present invention relates to quick release fludara tablet composition.
This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 60/404,399 filed August 20, 2002.
This invention relates to a quick-release tablet forraulation with > 99.19% pure fludara (high-purity fludara)
(Formula Removed)
as active ingredient with a defined composition of residual contaminants.
Tablet formulations with fludara at a punty of In US 3,903,297, a tablet formulation that consists of active ingredient with lactose, microcrystalline cellulose, colloidal silicon dio.xide and magnesium stearate is described by way of example (Example 2). The fact that a formulation can also contain CTOSScaramellose-Na is also described by way of example (Example 5). In WO 00/71134, in general tablet formulations that consist of lactose, microcrystaUme cellulose, colloidal silicon dioxide, crosscaramellose-Na and magnesium stearate are described. Such a composition can also contain a chemotherapeutic substance.
From WO 97/40846, tablet coatings are known that contain hydroxypropyl methyl cellulose, titamum dio.xide and pigments, such as, e.g., iron oxide pigments.
From WO 00/50423, tablet formulations are known that consist of lactose, microcrystalline cellulose, crosscaramellose-N'a, etc, and tliat dissolve quicklv.
6,197,785, EP 1065206, EP 819430, EP 1065204 and EP 985666 descnbe tablet formulations that can be used for oral administration and that consist of lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, crosscaramellose-Na, talc, etc. As an active ingredient, i.a., fludara can be included.
Fludara formulations that have the active ingredient at a purity of >99.5% and disclose a defined composition of the contaminants of the active ingredient in the formulation are not known to date.
From WO 99/29710, the active ingredient fludara with a purity of >99.19% is known. Also in this prior an, however. no defined composition of the pure fludara that is contained in a formulation is provided.
It would therefore be desirable to have a stable tablet fonnulation that has fludara at high purity with a defined concentration of residual contaminants, that dissolves quickly and thus releases the active ingredient quickly.
It has now been found that a tablet formulation in which the active ingredient fludara is present at a purity of >99.19% in non-micronized but sieved form, with a defined concentration of residual contaminants, overcomes the drawbacks of the known tablets.
The tablet formulation comprises the active ingredient in an amount of 5 to 100 mg, preferably of 8 to 75 mg, especially preferably m an amount of 10 to 50 mg, selected in an amount of 10 to 20 mg.
The preferred formulation substances are lactose, colloidal silicon dioxide, microcrystalline cellulose (a\-ice[), crosscaramellose-sodiv.m (sodium carbox^methvl cellulose) and magnesium stearate.
Other formulation substances that are known in general to one skilled in the art are also conceivable, however.
The formulation substances in the tablet comprise a total amount of 100 to 250 mg, preferably a total amount of 120 to 200 mg, especially preferably a total amount of 130 to 180 mg.
A subject of this invention is thus a quick-release tablet formulation that comprises I to 100 mg of the active ingredient fludara at a purity of >99.19%, together with
Lactose monohydrate,
Colloidal silicon dioxide.
Microcrystalline cellulose (avicel),
Crosscaramellose-Na (sodium carboxymethyl cellulose),
and magnesium stearate,
characterized in that the contaminants in the fludara do not exceed a percentage as
follows:
0.02% 2-Fluoro-9-(ß-D-arabinofuranosYl)-9H-purine-6-amine, 0-12% 6-Amino-9(5-0-phosphono-ß-D- arabinofuranosyl)-9H-purin-2-ol, 0.02% 2-Fluoro-9H-purine-6-amine, 0.02% 6-Amino-9H-purin-2-ol,
0.05%) 2-Fluoro-9-(5-0-phosphono-ß-D-ribofuranosyl)-9H-purine-6-amine, 0.1 % 9-(3,5-0-diphosphono-ß-D-arabinofuranosy])-2-fluoro-9H-purine-6-amine,
0.1 % 9-(2,5-0-diphosphono- ß-D-arabinofuranosyi)-2-fluoro-9H-punne-6-amme,
0.02% 2-Fluoro-9-(5-0-phosphono- ß- -D- arabinofuranosyl)-9H-punne-6-amine, 0.06% 2-Ethoxy-9-(5-0-phosphono- ß -D- arabmofuranosyl)-9H-purine-6-ainiiie, 0.02% 2-(6-.\mino-9H-purin-2-yl)-9-(5-0-phosphono-ß-D-arabinofuranosyl)-
9H-purine-6-amine and 0,0'-bis[2-(6-amino-2-fiuoro-9H-purin-9-yl)-5-
deoxy-a-D-arabinofuranos-5-yl]-phosphate, 0.1% 9-(2-Chloro-2-deoxy-5-phosphono- ß -D- arabinofuranosyl)-2-fluoro-9H-
purine-6-amine and 0.1% 9-(2,5-Anhydro-(3-D-arabinofuranosyI)-2- fluoro-9H-purine-6-ainine.
Preferred is a quick-release tablet formulation that comprises
1 to 70.00 mg of the active ingredient fludara at a purity of >99.19%, together
with 50 to 100 mg of lactose monohydrate, 0.1 to 5 mg of colloidal silicon dioxide, 40 to 100 mg of microcry'stalhne cellulose (avicel), 1 to 10 mg of crosscaramellose-Na (sodium carboxymethyl cellulose) and 0.5 to 10 mg of magnesium stearate.
Especially preferred are those quick-release tablet formulations that comprise 1 to 50.00 mg of the active ingredient fludara at a purity of >99.19%, together
with 60 to 90 mg of lactose monohydrate, 0.5 to 1 mg of colloidal sihcon dioxide, 50 to 90 mg of microcrystalline cellulose (avicel),
1.5 to 5 mg of crosscaramellose-Na (sodium carboxymethyl cellulose) and I to 3 mg of magnesium stearate.
Selected is such a quick-release table formulation that compnses 10 ma of the active ing]-edient fludara at a purity of >99.19%, together with
74,75 mg of lactose monohydrate,
0.75 mg of colloidal silicon dioxide,
60.00 mg of microcrv'stalline cellulose (avicel),
3.00 mg of crosscaramellose-Na (sodium carbox>Tnethy} cellulose) and
1.5-2.00 mg of magnesium stearate.
Preferred are also those formulations that comprise the active ingredient fludara at apurityof>99.37%.
Still more preferred are those formulations that comprise the active ingredient fludara at a purity of >99.57%.
Especially preferred are those formulations that comprise the active ingredient fludara at a punty of >99.S0%-
Especially preferred are those formulations that comprise the active ingredient fludara at a purity of >99.85%.
The formulations according to the invention are processed into molding compounds according to generally known methods, and said molding compounds are then pressed into tablet cores. These tablet cores can be provided with coatings with generally known methods. In principle, all coatings that are known to one skilled in the art can be used. A preferred coating comprises, e.g., the following components:
1 to 5 mg, preferably 1 to 3 mg, especially preferably 2.250 mg of hydroxypropyl methyl cellulose,
0.1 to 1 mg, preferably OT to 0.8 mg, especially preferably 0.450 mg of talc,
0.1 to 5 mg, preferably 0.1 to 2 mg, especially preferably 1.187 mg of titanium dioxide.
0.01 to 0.1 mg, preferably 0.01 to 0.05 mg, especially preferably 0.036 mg of yellow iron oxide pigment, and
0.01 to 0.1 mg, preferably 0.01 to 0.05 mg, especially preferably 0.036 mg of red iron oxide pigment, and
These coatings are also subjects of this invention.
The tablet formulations according to the invention can be used for the production of a medication for treating cancer.
This invention thus also comprises the use of the formulations according to the invention for the production of a medication for treating cancer.
The present invention relates to a quick-release tablet formulation that
comprises 1.08% to 30.77% of the active ingredient fludara at a purity of
>99.19%, together with 30.77% to 54% of lactose monohydrate, 0.11 to
1.53% of colloidal silicon dioxide, 30.77 to 43.19% of microcrystalline
cellulose (avicel), 1.08 to 3.08% of crosscaramellose-Na (sodium
carboxymethyl cellulose), and 0.54 to 3.08% of magnesium stearate,
characterized in that the contaminants in the fludara do not exceed a
percentage as follows:
0.02% 2-Fluoro-9-(ß-D-arabinofuranosyl)-9H-purine-6-amide
0.12% 6-Amino-9(5-0-phosphono-ß-D-arabiofuranosyl)-9H- purine-2-ol
0.02% 2-Fluoro-9H-purine-6-amine
0.02% 6-Amino-9H-purin-2-ol
0.05% 2-Fluro-9-(5-0-phosphono-ß-D-ribofurano^yl)-9H-purine-6-amine
0.1% 9-(3, 5-0-diphosphono-3-D-arabinofuranosyl)-2-fluoro-9H-purine-6-
amine
0.1% 9-(2, 5-0-diphosphono-ß-D-arabinofuranosyl)-2-fluoro-9H-purine-6-
amine
0.02% 2-Fluoro-9-(5-0-phosphono-ß-D-arabinofuranosyl)-9H-purine-6-
amine
0.06% 2-Ethoxy-9-(5-0-phosphono-ß-D-arabinofuranosyl)-9H-purine-6-
amine
0.02%2-(6-Amino-9H-purin-2-yl)-9-(5-O-phosphono-ß-D-
arabinofuranosyl)9H-purine-6-amine and 0,0'-bis[2-(6-amino-2 -fluoro-
9H-purin-9-yl)-5-deoxy-a-D-arabinofuranos-5-yl]-phosphate
0.1% 9-(2-Chloro-2-deoxy-5-phosphono-ß-D-arabinofuranosyl)-2 fluoro-
9H-purine-6-amine
0.1% 9(2,5-Anhydro-ß-D-arabinofuranosyl)-2-fluoro-9H-purine- 6-amine.
The embodiment of the Quick-release tablet formulation comprises 0.88% to 20.91% of the active ingredient fludara at a purity of >99.19%, together with 37.66% to 52.63%) of lactose monohydrate, 0.42%> to 0.44%) of colloidal silicon dioxide, 37.66%> to 43.85%) of microcrystalline cellulose (avicel), 1.32%) to 2.09%) of crosscarmellose-Na (sodium carboxymethyl cellulose) and 0.88 %) to 1.26% of magnesium stearate.
Another embodiment of Quick-release tablet formulation comprises 6.65%o to 6.67%o of the active ingredient fludara at a purity of >99.19% together with 49.67%) to 49.8%o of lactose monohydrate, 0.49%o to 0.50%) of colloidal silicon dioxide, 39.8%) to 40%) of microcrystalline cellulose (aviecl), 1.99% to 2%o of crosscarmellose-Na (sodium carboxymethyl cellulose) and 1% to 1.33%o of magnesium stearate.
In the Quick-release tablet formulation comprises the active ingredient fludara is at a purity of >99.37%), >99.57%), >99.80%), >99.85%).
The tablet core is encased by a coating that optionally comprises 1 to 5 mg of hydroxypropyl methyl cellulose, 0.1 to 1 mg of talc, 0.1 to 5 mg of titanium dioxide, 0.01 to 0.1 mg of yellow iron oxide pigment and 0.01 to 0.1 mg of red iron oxide pigment.
In another embodiment it comprises 1 to 3 mg of hydroxypropyl methyl cellulose, 0.1 to 0.8 mg of talc, 0.1 to 2 mg of titanium dioxide, 0.01 to 0.05 mg of yellow iron oxide pigment and 0.01 to 0.05 mg of red iron oxide pigment.
In still another embodiment tablet core is encased by a coating comprises 2.250 mg of hydroxypropyl methyl Cellulose, 0.450 mg of talc, 1.187 mg of titanium dioxide, 0.036 mg of yellow iron oxide pigment and 0.036 mg of red iron oxide pigment.
Without further elaboration, it is believed that one skilled in the art can, using preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be constructed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
The components of the composition interact synergistically to produce unexpected properties.
The following examples describe the production of the fludara of hish-punty tablet formulations according to the invention as well as a companson of the conventional composition of 99.19% pure tludara.
Example 1
Production of a Tablet Formulation
For the production of a tablet formulation according to the invention, the active ingredient fludara (fludarabine phosphate) is first sieved and then processed with lactose monohydrate, microcrystallme cellulose (avicel) and colloidal silicon dioxide to an approximately 30% dry mixture. The mixture is then also sieved. The quality or particle size is examined by means of sieve analysis. Crosscaramellose sodium (sodium carboxymethyl cellulose) and magnesium stearate in additional mixed sequences are then added successively to the dry mixture.
The molding compound is pressed into tablet cores.
A thus produced tablet formulation comprises, for example, the following
individual components:
Fludara >99.19% high-purity 10.00 mg
Lactose monohydrate 74.75 mg
Colloidal silicon dioxide 0.75 mg
Microcrystalline cellulose (avicel) 60.00 mg
Crosscaramellose-Na 3.00 mg
(Sodium carboxymethyl cellulose)
JVIagnesium stearate 1.5-2.00 mg
The tablet cores are then painted with an aqueous film suspension. Such a film coating comprises, for example, the following components;
Hydroxypropyl methyl cellulose 2.250 mg
Talc 0.450 rag
Titanium dioxide 1.187 mg
Iron oxide pigment, yellow 0.036 mg
Iron oxide pigment, red 0.036 mg
The total weight of the tablet is 154 mg.
The thus produced film tablets can then be further processed. The film tablets can be packaged in, e.g., Alu-blisters, by which the stability of the formulation is ensured.
Example 2
Comparison of a conventional composition of 99.19%, or >99.57% pure fludara and 99.19% fludara that is purified with an ion exchanger.
The results are presented in the table below.

(Table Removed)
* High-purity Fludara
The results show that a formulation that consists of commercially available fludara (maximum 97.67% fludara) or a formulation with fludara that is purified via an ion exchanger (maximum 99.19% fludara) has considerably more contaminating byproducts than the high-purity fludara that is contained in the formulations according to the invention (>99.37% to >99.57% fludara).
With conventional punfication processes, such as the very potent ion exchange chromatography, only a quite moderate degree of purity can be achieved.
The fiucara formulations according to the invention contain the hiah-ountv fludara that is released via the sodium salt that is ah'eady described in VvO 99/29710. A still higher degree of purity of the fiudara can be produced with the potassium salt (99.8°/o) or with the hthium. salt (99.85%).
The entire disclosures of all applications, patents and publications, cited herein and of corresponding German Application No. 101 64-510.4, filed December 20, 2001, and U.S. Provisional Application Serial No. 60/404,399, filed August 20, 2002 are incorporated by reference herein.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing descripfion, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.






We Claim:
1. Quick-release fludara tablet composition that comprises 1.08% to 30.77% of the active ingredient fludara at a purity of >99.19%, together with
30.77% to 54% of lactose monohydrate,
0.11 to 1.53% of colloidal silicon dioxide,
30,77 to 43.19% of microcrystalline cellulose (avicel),
1.08 to 3.08% of crosscaramellose-Na (sodium carboxymethyl cellulose),
0.54 to 3.08% of magnesium stearate,
and optionally comprising conventional coating composition such as herein described.
characterized in that the contaminants in the fludara do not exceed a percentage as follows:
0.02% 2-Fluoro-9-(ß-D-arabinofuranosyl)-9H-purine-6-amide
0.12% 6-Amino-9(5-O-phosphono-ß-D-arabiofuranosyl)-9H-purine-2-ol
0.02% 2-Fluoro-9H-purine-6-amine
0.02% 6-Amino-9H-purin-2-ol

0.05% 2-Fluro-9-(5-O-phosphono-ß-D-ribofuranosyl)-9H-purine-6-ainine
0.1% 9-(3, 5-O-diphosphono-3-D-arabinofuranosyl)-2-fluoro-9H-purine-6-amine
0.1% 9-(2, 5-O-diphosphono-ß-D-arabinofuranosyl)-2-fluoro-9H-purine-6-amine
0.02% 2-Fluoro-9-(5-O-phosphono-ß-D-arabinofuranosyl)-9H-purine-6-amine
0.06% 2-Ethoxy-9-(5-O-phosphono-ß-D-arabinofuranosyl)-9H-purine-6-amine
0.02% 2-(6-Amino-9H-purin-2-yl)-9-(5-O-phosphono-ß-D-arabinofuranosyl)9H-purine-6-amine and 0,0'-bis[2-(6-amino-2 -fluoro-9H-purin-9-yl)-5-deoxy-a-D-arabinofuranos-5-yl]-phosphate
0.1% 9-(2-Chloro-2-deoxy-5-phosphono-ß-D-arabinofuranosyl)-2 fluoro-9H-purine-6-amine
0.1% 9(2,5-Anhydro-ß-D-arabinofuranosyl)-2-fluoro-9H-purine-6-amine.
2. Quick-release fludara tablet composition as claimed in claim 1, wherein it comprises 0.88% to 20.91% of the active ingredient fludara at a purity of >99.19%, together with
37.66% to 52.63% of lactose monohydrate,
0.42% to 0.44% of colloidal silicon dioxide.
37.66% to 43.85% of microcrystalline cellulose (avicel),
1.32% to 2.09% of crosscarmellose-Na (sodium carboxymethyl cellulose) and
0.88 % to 1.26% of magnesium stearate.
3. Quick-release fludara tablet composition as claimed in claim 1 to
2, wherein it comprises 6.65% to 6.67% of the active ingredient
fludara at a purity of >99.19% together with
49.67% to 49.8% of lactose monohydrate,
0.49% to 0.50% of coUoidal silicon dioxide,
39.8% to 40% of microcrystalline cellulose (aviecl),
1.99% to 2% of crosscarmellose-Na (sodium carboxymethyl cellulose) and
1% to 1.33% of magnesium stearate.
4. Quick-release fludara tablet composition as claimed in claims 1 to
3, wherein it comprises the active ingredient fludara at a purity of
>99.37%.
5. Quick-release fludara tablet composition as claimed in claims 1 to
4, wherein it comprises the active ingredient fludara at a purity of
>99.57%.
6. Quick-release fludara tablet composition as claimed in claims 1 to
5, wherein it comprises the active ingredient fludara at a purity of
>99.80%.
7. Quick-release fludara tablet composition as claimed in claims 1 to
6, wherein it comprises the active ingredient fludara at a purity of
>99.85%.
8. Quick release fludara tablet composition as claimed in claims 1 to
7, wherein the tablet core is optionally encased by a coating that comprises the following components:
8, 9 to 44. 65% of hydryxypropyl methyl cellulose, 0.9 to 8. 9% of talc,
0.9 to 44. 65% titanium dioxide,
0.09 to 0. 9% of yellow iron oxide pigment and
0.09 to 0. 9% of red iron oxide pigment.
9. Quick-release fludara tablet composition as claimed in claims 1 to
8, wherein the tablet core is encased by a coating that comprises
the following components:
16. 95 to 50. 85% of hydryxypropyl methyl cellulose,
1. 69 to 13. 56% of talc,
1. 69 to 33. 89% titanium dioxide.
0. 17 to 0. 85% of yellow iron oxide pigment and 0. 12 to 0. 85% of red iron oxide pigment.
10. Quick-release fludara tablet composition as claimed in claims 1 to 9, wherein the tablet core is encased by a coating that comprises the following components:

56. 83% of hydryxypropyl methyl Cellulose,
11. 37% of talc,
29. 98% titanium dioxide,
0. 91% of yellow iron oxide pigment and
0, 91% of red iron oxide pigment.

Documents:

1778-delnp-2004-abstract.pdf

1778-DELNP-2004-Assignment-(16-12-2009).pdf

1778-delnp-2004-claims.pdf

1778-delnp-2004-complete specification (as file).pdf

1778-delnp-2004-complete specification (granted).pdf

1778-DELNP-2004-Correspondence Others-(01-09-2011).pdf

1778-DELNP-2004-Correspondence-Others-(16-12-2009).pdf

1778-delnp-2004-correspondence-others.pdf

1778-delnp-2004-correspondence-po.pdf

1778-delnp-2004-description (complete).pdf

1778-DELNP-2004-Form-1-(16-12-2009).pdf

1778-delnp-2004-form-1.pdf

1778-delnp-2004-form-19.pdf

1778-DELNP-2004-Form-2-(16-12-2009).pdf

1778-delnp-2004-form-2.pdf

1778-delnp-2004-form-3.pdf

1778-delnp-2004-form-5.pdf

1778-DELNP-2004-GPA-(16-12-2009).pdf

1778-delnp-2004-gpa.pdf

1778-delnp-2004-pct-210.pdf

1778-delnp-2004-pct-301.pdf

1778-delnp-2004-pct-304.pdf

1778-delnp-2004-pct-306.pdf

1778-delnp-2004-pct-332.pdf

1778-delnp-2004-pct-409.pdf

1778-delnp-2004-petition-137.pdf


Patent Number 243759
Indian Patent Application Number 1778/DELNP/2004
PG Journal Number 45/2010
Publication Date 05-Nov-2010
Grant Date 03-Nov-2010
Date of Filing 22-Jun-2004
Name of Patentee ALCAFLEU MANAGEMENT GMBH & CO. KG,
Applicant Address LILIENTHALSTRASSE 4, 15732 SCHONEFELD OT WALTERSDORF, GERMANY,
Inventors:
# Inventor's Name Inventor's Address
1 WOLFGANGHEIL AM WASSERTURM 24, D-21435 STELLE, GERMANY.
2 ULF TILSTAM DE GRUNNE LANN 40, B-1970 WEZEMBEEK, OPPEM, BELGIUM.
3 RALPH LIPP HOLZUNGSWEG 63, D-14169 BERLIN, GERMANY.
4 JOHANNES-WILHELM TACK THASANDERWEG 28, 13595 BERLIN, GERMANY.
PCT International Classification Number A61K 9/20
PCT International Application Number PCT/EP02/13252
PCT International Filing date 2002-11-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10164510.4 2001-12-20 Germany