Title of Invention	A FILM COATED TABLET WITH CYCLOPHOSPHAMIDE AS ACTIVE COMPOUND
Abstract	A film-coated tablet with cyclophosphamide as active compound, comprising in the core cyclophosphamide, one or more fillers selected from the group consisting of lactose monohydrate, D-mannitol and CaHPO4, one or more dry binders selected from the group consisting of nonpreswollen corn starch and microfine cellulose, highly disperse silica as flow regulator, and a lubricant selected from the group consisting of magnesium stearate, stearic acid, glycerol palm ito stearate, polyethylene glycol, talcum and glycerol monobehenate, wherein the core can comprise the auxiliaries either individually or alternatively in any desired mixture.

Title of Invention

A FILM COATED TABLET WITH CYCLOPHOSPHAMIDE AS ACTIVE COMPOUND

Abstract

A film-coated tablet with cyclophosphamide as active compound, comprising in the core cyclophosphamide, one or more fillers selected from the group consisting of lactose monohydrate, D-mannitol and CaHPO4, one or more dry binders selected from the group consisting of nonpreswollen corn starch and microfine cellulose, highly disperse silica as flow regulator, and a lubricant selected from the group consisting of magnesium stearate, stearic acid, glycerol palm ito stearate, polyethylene glycol, talcum and glycerol monobehenate, wherein the core can comprise the auxiliaries either individually or alternatively in any desired mixture.

Full Text	WO 99/65499 PCT/EP99/03920 Cyclophosphamide film-coated tablets The invention relates to cyclophosphamide film-coated tablets and to a process for their preparation. The invention can be used in the pharmaceutical industry. Cyclophosphamide is an agent haying a broad antitumor spectrum which has been introduced in chemotherapy for decades for . the treatment of solid tumors" such as breast carcinoma, bronchial carcinoma and hemoblastoses. Until now, known pharmaceutical forms have been tablets, coated tablets and mainly lyophilizates with various auxiliaries such as mannitol or urea. EP 0519099 describes tablets comprising cyclophosphamide and preswollen starch, prepared by a direct tableting process. Since cyclophosphamide is harmful to health and for this reason direct contact with this substance represents a potential risk, the tablets prepared according to EP 0519099 are used as cores for press-coated tablets and. thus coated by means of a second tablet ing. This process is technically complicated. Special tableting machines are furthermore needed for the preparation of press-coated tablets. The need thus exists for a simple and economical preparation of solid pharmaceutical form [sic] comprising cyclophosphamide for oral administration. It is necessary to take into consideration here that the pharmaceutical forms have to be coated in order that direct contact with the cytotoxic active compound is avoided. It is moreover known that eyclophosphamide is chemically labile, thus the stability of the WO 99/65499 PCT/EP99/03920 - 2 - pharmaceutical forms must also be taken into consideration. Surprisingly, it has been possible to prepare film-coated tablets comprising cyclophosphamide without the use of preswollen starch. Suitable auxiliaries were selected on the basis of the compatibility investigations mentioned in Example I [sic] . It was surprising in this context that the stability of cyclophosphamide is somewhat indifferent in the presence of preswollen starch. It was moreover surprising that the finished film-coated tablets exhibit an adeoua.te stability although the active compound, due to the preparation is stressed during the film-coating process by moisture and heat Example 1 Investigations on the compatibility of cyclophosphamide with various tableting auxiliaries 53.5 mg of cyclophosphamide and 86.5 mg of (auxiliary 1-10) [sic] or 3.0 mg of (auxiliary 11-18) [sic] were in each case mixed, and compressed. The. pressed tablets were stored at 31°C for 6 months. The decomposition of the active compound took place [sic] by means of chloride determination. The results are summarized in the following table. WO 99/65499 PCT/EP99/03920 - 3 - Function of the auxiliary Auxiliary Decomposition of cyclo-phosphamide Dis-coloration FILLER 1 Lactose, anhydrous 2.52 ++ 2 Calcium phosphate 3.85 - 3 Calcium phosphate anhydrous 2.02 - 4 Emcompress (CaHPO4) 1.50 5 D-mannitol 1.15 - 6 Lactose monohydrate 0.70 - FILLER/DRY BINDER/ 7 Microcrystalline cellulose 1.50-1.73* - DISINTEGRATION 8 Cellulose (Elcema) 0.85-1.32* - + PROMOTER 9 Preswollen starch . 1.02 - + 10 Corn starch 0.75 - DISINTEGRATION PROMOTER 11 Crosslinked poly-vinylpyrrolidone 1.5 + + FLOW REGULATOR 12 Highly disperse silica 0.46-1.72* - + FLOW REGULATOR/ 13 Magnesium sterate [sic] 1.51 - + LUBRICANT 14 Stearic acid 0.94 - + 15 Glycerol palmitostearate 0.82 - 16 Polyethylene glycol 0.68 - 17 Talc 0.55 - 18 Glycerol monobeherate [sic] 0.30 - Dependent on type WO 99/65499 PCT/EP99/03920 - 4 - Example 2 Preparation of tablet cores (50 mg of cyclophosphamide) Direct tableting 0.535 mg of cyclophosphamide, 0.390 mg of lactose monohydrate, 0.400 mg of microfine cellulose, 0.200 mg of corn starch, 0.040 mg of talc and 0.020 mg of highly disperse silica are sieved and homogenized. 0.015 mg of magnesium stearate is then added and mixed. The mass prepared in'this way is processed to give tablets: Weight: 160 mg Hardness: > 30 N Disintegration: Example 3 Preparation of film-coated tablets (50 mg of eye1opho sphami de) 11.83 g of polyethylene glycol and 2.37 g of polysorbate 80 are dissolved in 75.21 g of water. 1.9 g of carboxymethylcellulose sodium are dissolved in 80.0 g of water. The solutions are brought together. 23.67 g of talc, 23.67 g of titanium dioxide and 0.24 g of simeticone [sic] are then added and the mixture is homogenized. 17.73 g of a 30% strength ethyl acrylate/methyl metharcrylate [sic] copolymer dispersion in water are then added. The tablet cores are then sprayed with the prepared suspension in a suitable apparatus: Theoretical weight of a film-coated tablet: 166 mg WO 99/65499 PCT/EP99/03920 _ 5 _ Example 4 Investigation of the stability of cyclophosphamide film-coated tablets Decomposition of cyclophosphamide after 3 months 26°C/60% RH 3 l°C/40% Batch 1 0.30 .4 .12 Batch 2 0.17 2 .36 Stability of the film-coated tablets of ,up-_to_3_ years is expected on storage at -6- 1. A film-coated tablet with cyclophosphamide as active compound, comprising in the core cyclophosphamide, one or more fillers selected from the group consisting of lactose monohydrate, D-mannitol and CaHPO4, one or more dry binders selected from the group consisting of nonpreswollen corn starch and micro fine cellulose, highly disperse silica as flow regulator, and a lubricant selected from the group consisting of magnesium s tear ate, stearic acid, glycerol palmitostearate, polyethylene glycol, talcum and glycerol monobehenate, wherein the core can comprise the auxiliaries either individually or alternatively in any desired mixture. 2. The film-coated tablet as claimed in claim 1> comprising, per 1 part of cyclophosphamide in the core, lactose monohydrate, micro fine cellulose, nonpreswollen corn starch, talcum, highly disperse silica and magnesium stearate in the following ratio. lactose monohydrate 0.2-1.5, preferably 0.5-1, particularly 0.73; microfme cellulose 0.2-1.5, preferably 0.5-1, particularly 0.74; nonpreswollen corn starch 0.1-1.5, preferably 0.2-0.7, particularly 0.37; talcum 0.01-1.5, preferably 0.05-0.08, particularly 0.07; highly disperse silica 0.01-0.1, preferably 0.01-0.5, particularly 0.04; magnesium stearate 0.01-0.,l preferably 0.01-0.05, particularly 0.03. 3. The film-coated tablet as claimed in claim 1 or 2, wherein the core -7- comprises 50.0 mg cyclophosphamide (53.5 mg cyclophosphamide monohydrate), 39.0 mg lactose monohydrate, 20.0 mg nonpreswollen corn starch, 40.0 mg microfine cellulose, 2.0 mg highly disperse silica, 4.0 mg talcum, and 1.5 mg magnesium stearate. 4. A method for manufacturing of tablet cores suitable to be provided with a film coat, wherein the steps that cyclophosphamide, lactose monohydrate, microfine cellulose, nonpreswollen corn starch, talcum and highly disperse silica are sieved and homogenized, then magnesium stearate is added and mixed, and the so obtained mass is pressed into tablet cores. 5. The method as claimed in claim 4, wherein in the core the amount of lactose monohydrate, microfine cellulose, nonpreswollen corn starch, talcum, highly disperse silica aad magnesias stearate, per 1 part of cyclophosphamide, is as follows: lactose monohydrate 0.2-1.5, preferably 0.5-1, particularly 0.73; microfme cellulose 0,2-1.5, preferably 0.5-1, particularly 0.74; nonpreswollen corn starch 0.1-1.5, preferably 0.2-0.7, particularly 0.37; talcum 0.01-1,5, preferably 0.05-0,08, particularly 0.07; highly disperse silica 0.01-0.1, preferably 0.01-0.5, particularly 0.04; magnesium stearate 0.01-0.1, preferably 0.01-0.05, particular^ 0.03. -8- 6. The method as claimed in claim 4 or 5, wherein the core contains 50.0 mg cyclophosphamide (53.5 rag cyclophosphamide monohydrate), 39.0 mg lactose monohydrate, 20.0 mg nonpreswollen corn starch, 40.0 mg microfine cellulose, 2.0 mg highly dispersed silica, 4.0 mg talcum, and 1.5 mg magnesium stearate. 7. A process for manufacturing a film-coated tablet, wherein the tablet cores obtained as claimed in anyone of claims 4 to 6 are sprayed with a suspension obtained by dissolving of 11.83 g polyethylene glycol and 2.37 g poly sorb ale 80 in water, further dissolving of 1.9 g carboxymethylceliulose sodium in 80.0 g water, then bringing the two solutions together, adding of 23.67 g talcum, 23.67 g titanium dioxide and 0.24 g simeticone thereto, then homogenizing, then adding of 17.73 g of a 30% ethyl acrylate-m ethyl meth aery late copolymer dispersion thereto. 8. A tablet core obtained by the process as claimed in anyone of claims 4 to 6. 9. A film coated tablet obtained by the process as claimed in claim 7. A film-coated tablet with cyclophosphamide as active compound, comprising in the core cyclophosphamide, one or more fillers selected from the group consisting of lactose monohydrate, D-mannitol and CaHPO4, one or more dry binders selected from the group consisting of nonpreswollen corn starch and microfine cellulose, highly disperse silica as flow regulator, and a lubricant selected from the group consisting of magnesium stearate, stearic acid, glycerol palm ito stearate, polyethylene glycol, talcum and glycerol monobehenate, wherein the core can comprise the auxiliaries either individually or alternatively in any desired mixture.

Full Text

WO 99/65499 PCT/EP99/03920
Cyclophosphamide film-coated tablets
The invention relates to cyclophosphamide film-coated tablets and to a process for their preparation. The invention can be used in the pharmaceutical industry.
Cyclophosphamide is an agent haying a broad antitumor spectrum which has been introduced in chemotherapy for decades for . the treatment of solid tumors" such as breast carcinoma, bronchial carcinoma and hemoblastoses.
Until now, known pharmaceutical forms have been tablets, coated tablets and mainly lyophilizates with various auxiliaries such as mannitol or urea.
EP 0519099 describes tablets comprising cyclophosphamide and preswollen starch, prepared by a direct tableting process.
Since cyclophosphamide is harmful to health and for this reason direct contact with this substance represents a potential risk, the tablets prepared according to EP 0519099 are used as cores for press-coated tablets and. thus coated by means of a second tablet ing. This process is technically complicated. Special tableting machines are furthermore needed for the preparation of press-coated tablets.
The need thus exists for a simple and economical preparation of solid pharmaceutical form [sic] comprising cyclophosphamide for oral administration. It is necessary to take into consideration here that the pharmaceutical forms have to be coated in order that direct contact with the cytotoxic active compound is avoided.
It is moreover known that eyclophosphamide is chemically labile, thus the stability of the

WO 99/65499 PCT/EP99/03920
- 2 -
pharmaceutical forms must also be taken into
consideration.
Surprisingly, it has been possible to prepare film-coated tablets comprising cyclophosphamide without the use of preswollen starch.
Suitable auxiliaries were selected on the basis of the compatibility investigations mentioned in Example I [sic] . It was surprising in this context that the stability of cyclophosphamide is somewhat indifferent in the presence of preswollen starch.
It was moreover surprising that the finished film-coated tablets exhibit an adeoua.te stability although the active compound, due to the preparation is
stressed during the film-coating process by moisture
and heat
Example 1
Investigations on the compatibility of cyclophosphamide
with various tableting auxiliaries
53.5 mg of cyclophosphamide and 86.5 mg of (auxiliary 1-10) [sic] or 3.0 mg of (auxiliary 11-18) [sic] were in each case mixed, and compressed. The. pressed tablets were stored at 31°C for 6 months. The decomposition of the active compound took place [sic] by means of chloride determination. The results are summarized in the following table.

WO 99/65499 PCT/EP99/03920
- 3 -

Function of the auxiliary

Auxiliary
Decomposition of cyclo-phosphamide
Dis-coloration
FILLER
1
Lactose, anhydrous
2.52
++

2
Calcium phosphate
3.85
-

3
Calcium phosphate anhydrous
2.02
-

4
Emcompress (CaHPO4)
1.50

5
D-mannitol
1.15
-

6
Lactose monohydrate
0.70
-
FILLER/DRY BINDER/
7
Microcrystalline cellulose
1.50-1.73*
-
DISINTEGRATION
8
Cellulose (Elcema)
0.85-1.32*
- +
PROMOTER
9
Preswollen starch .
1.02
- +

10
Corn starch
0.75
-
DISINTEGRATION PROMOTER
11
Crosslinked poly-vinylpyrrolidone
1.5
+ +
FLOW REGULATOR
12
Highly disperse silica
0.46-1.72*
- +
FLOW REGULATOR/
13
Magnesium sterate [sic]
1.51
- +
LUBRICANT
14
Stearic acid
0.94
- +

15
Glycerol palmitostearate
0.82
-

16
Polyethylene glycol
0.68
-

17
Talc
0.55
-

18
Glycerol monobeherate [sic]
0.30
-
Dependent on type

WO 99/65499 PCT/EP99/03920
- 4 -
Example 2
Preparation of tablet cores (50 mg of cyclophosphamide) Direct tableting
0.535 mg of cyclophosphamide, 0.390 mg of lactose
monohydrate, 0.400 mg of microfine cellulose, 0.200 mg of corn starch, 0.040 mg of talc and 0.020 mg of highly disperse silica are sieved and homogenized. 0.015 mg of magnesium stearate is then added and mixed. The mass prepared in'this way is processed to give tablets:
Weight: 160 mg
Hardness: > 30 N Disintegration: Example 3
Preparation of film-coated tablets (50 mg of eye1opho sphami de)
11.83 g of polyethylene glycol and 2.37 g of polysorbate 80 are dissolved in 75.21 g of water. 1.9 g of carboxymethylcellulose sodium are dissolved in 80.0 g of water. The solutions are brought together. 23.67 g of talc, 23.67 g of titanium dioxide and 0.24 g of simeticone [sic] are then added and the mixture is homogenized. 17.73 g of a 30% strength ethyl acrylate/methyl metharcrylate [sic] copolymer dispersion in water are then added. The tablet cores are then sprayed with the prepared suspension in a suitable apparatus:
Theoretical weight of a film-coated tablet: 166 mg

WO 99/65499 PCT/EP99/03920
_ 5 _
Example 4
Investigation of the stability of cyclophosphamide film-coated tablets

Decomposition of
cyclophosphamide
after
3 months

26°C/60% RH

3
l°C/40%
Batch 1

0.30

.4
.12
Batch 2

0.17

2
.36
Stability of the film-coated tablets of ,up-_to_3_ years is expected on storage at
-6-
1. A film-coated tablet with cyclophosphamide as active compound,
comprising in the core cyclophosphamide, one or more fillers selected
from the group consisting of lactose monohydrate, D-mannitol and
CaHPO4, one or more dry binders selected from the group consisting of
nonpreswollen corn starch and micro fine cellulose, highly disperse
silica as flow regulator, and a lubricant selected from the group
consisting of magnesium s tear ate, stearic acid, glycerol palmitostearate,
polyethylene glycol, talcum and glycerol monobehenate, wherein the
core can comprise the auxiliaries either individually or alternatively in
any desired mixture.
2. The film-coated tablet as claimed in claim 1> comprising, per 1 part of
cyclophosphamide in the core, lactose monohydrate, micro fine
cellulose, nonpreswollen corn starch, talcum, highly disperse silica and
magnesium stearate in the following ratio.
lactose monohydrate 0.2-1.5, preferably 0.5-1, particularly 0.73; microfme cellulose 0.2-1.5, preferably 0.5-1, particularly 0.74; nonpreswollen corn starch 0.1-1.5, preferably 0.2-0.7, particularly 0.37; talcum 0.01-1.5, preferably 0.05-0.08, particularly 0.07; highly disperse silica 0.01-0.1, preferably 0.01-0.5, particularly 0.04; magnesium stearate 0.01-0.,l preferably 0.01-0.05, particularly 0.03.
3. The film-coated tablet as claimed in claim 1 or 2, wherein the core

-7-
comprises 50.0 mg cyclophosphamide (53.5 mg cyclophosphamide monohydrate), 39.0 mg lactose monohydrate, 20.0 mg nonpreswollen corn starch, 40.0 mg microfine cellulose, 2.0 mg highly disperse silica, 4.0 mg talcum, and 1.5 mg magnesium stearate.
4. A method for manufacturing of tablet cores suitable to be provided with
a film coat, wherein the steps that cyclophosphamide, lactose
monohydrate, microfine cellulose, nonpreswollen corn starch, talcum
and highly disperse silica are sieved and homogenized, then magnesium
stearate is added and mixed, and the so obtained mass is pressed into
tablet cores.
5. The method as claimed in claim 4, wherein in the core the amount of
lactose monohydrate, microfine cellulose, nonpreswollen corn starch,
talcum, highly disperse silica aad magnesias stearate, per 1 part of
cyclophosphamide, is as follows:
lactose monohydrate 0.2-1.5, preferably 0.5-1, particularly 0.73; microfme cellulose 0,2-1.5, preferably 0.5-1, particularly 0.74; nonpreswollen corn starch 0.1-1.5, preferably 0.2-0.7, particularly 0.37; talcum 0.01-1,5, preferably 0.05-0,08, particularly 0.07; highly disperse silica 0.01-0.1, preferably 0.01-0.5, particularly 0.04; magnesium stearate 0.01-0.1, preferably 0.01-0.05, particular^ 0.03.

-8-
6. The method as claimed in claim 4 or 5, wherein the core contains 50.0
mg cyclophosphamide (53.5 rag cyclophosphamide monohydrate), 39.0
mg lactose monohydrate, 20.0 mg nonpreswollen corn starch, 40.0 mg
microfine cellulose, 2.0 mg highly dispersed silica, 4.0 mg talcum, and
1.5 mg magnesium stearate.
7. A process for manufacturing a film-coated tablet, wherein the tablet
cores obtained as claimed in anyone of claims 4 to 6 are sprayed with a
suspension obtained by dissolving of 11.83 g polyethylene glycol and
2.37 g poly sorb ale 80 in water, further dissolving of 1.9 g
carboxymethylceliulose sodium in 80.0 g water, then bringing the two
solutions together, adding of 23.67 g talcum, 23.67 g titanium dioxide
and 0.24 g simeticone thereto, then homogenizing, then adding of 17.73
g of a 30% ethyl acrylate-m ethyl meth aery late copolymer dispersion
thereto.
8. A tablet core obtained by the process as claimed in anyone of claims 4
to 6.
9. A film coated tablet obtained by the process as claimed in claim 7.
A film-coated tablet with cyclophosphamide as active compound, comprising in the core cyclophosphamide, one or more fillers selected from the group consisting of lactose monohydrate, D-mannitol and CaHPO4, one or more dry binders selected from the group consisting of nonpreswollen corn starch and microfine cellulose, highly disperse silica as flow regulator, and a lubricant selected from the group consisting of magnesium stearate, stearic acid, glycerol palm ito stearate, polyethylene glycol, talcum and glycerol monobehenate, wherein the core can comprise the auxiliaries either individually or alternatively in any desired mixture.

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Patent Number

201460

Indian Patent Application Number

IN/PCT/2000/00552/KOL

PG Journal Number

08/2007

Publication Date

23-Feb-2007

Grant Date

23-Feb-2007

Date of Filing

23-Nov-2000

Name of Patentee

ASTA MEDICA AKTIENESLLSCHAFT

Applicant Address

AN DER PIKARDIE 10, D-01277 DRESDEN, GERMANY

Inventors:

#	Inventor's Name	Inventor's Address
1	RAWERT JURGEN	BEZIRKSSTRASSE 27, D-63755 ALZENAU, GERMANY
2	SAUERBIER DIETER	RAUHE HORST 18, D-33824 WERTHER, GERMANY
3	WICHERT BURKHARD	ROONSTRASSE 48, D-33615 BIELEFELD, GERMANY
4	ENGEL JURGEN	ERLENWEG 3, D-63755 ALZENAU, GERMANY

PCT International Classification Number

A 61K 9/28;

PCT International Application Number

PCT/EP99/03920

PCT International Filing date

1999-06-08

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	198 26 517.4	1998-06-15	Germany