FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"STABLE CHLORAMBUCIL ORAL COMPOSITION"

2. APPLICANT
(a) NAME: MAC CHEM PRODUCTS INDIA PVT. LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 304, Town Centre, Andheri-kurla Road, Andheri (E),
Mumbai-400059, Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF INVENTION:
The present invention relates to stable pharmaceutical composition, in particular to compositions, which comprises Chlorambucil as active ingredient alongwith pharmaceutically acceptable excipients preferably in oral dosage form, which is useful in the treatment of malignancies, autoimmune disease and like that.
BACKGROUND OF THE INVENTION:
Chlorambucil is a chemotherapy drug that is given as a treatment for some types of cancer. The IUPAC name of Chlorambucil is 4-[bis(2-chlorethyl)amino]benzenebutanoic acid having structural formula as follows.

It is most commonly used to treat chronic lymphocytic leukemia, low-grade non-Hodgkin lymphoma, Hodgkin lymphoma, and Waldenstrom's macroglobulinaemia.
Chlorambucil is a bi functional nitrogen mustard alkylating agent, that has been found active against selected human neoplastic disease and it is available in tablet form for oral administration. It is rapidly and completely absorbed from the gastrointestinal tract. After single doses of 0.6-1.2 mg/kg, peak plasma Chlorambucil level are reached within one hour and the terminal half life of the parent drug is estimated at 1.5 hours. 0.1-0.2 mg/kg/day or 3 or 6 mg/m2/day is used for Antineoplastic treatment.
Chlorambucil is indicated in the treatment of chronic lymphatic leukemia, malignant lymphomas including lymphosarcoma, gaint follicular lymphomas and Hodkin's disease. It is not curative in any of these disorders but may produce clinically useful palliation.
US Patent No. 5527787, discloses a novel composition having antibacterial and antiviral activity and method of treating diseases caused by bacteria and viral pathogen, the composition comprises of basic ingredients such as Chlorambucil, melphalan,

procarbazine HC1, and Cyclophosphamide and the preferred example shows the composition included 0.4 mg Chlorambucil, 0.4 mg Melphalan, 10.0 mg Procarbazine HCI and 10.0mg Cyclophosphamide.
US Patent Publication No.US2003/0082229 Al discloses a composition for parenteral use comprising of a solvent, made up of an alcohol and a lipid and a water soluble agent such as Chlorambucil dissolved in the said solvent, the composition is further diluted with an infusion fluid, such as normal saline, before infusion into a patient.
The general prior art methods for production of chlorambucil tablets involved wet granulation, blending and compression. Most of such tablets contained excipients of relatively high moisture content for example, com starch which generally contains 10-14% moisture is not compatible as chlorombucil is moisture sensitive drug.
Further, US Patent Publication No. US 2004/0034099A1 discloses the formulation of Melphalan and Chlorambucil tablet in which they have used Opadry brown as coating material.
US Patent Publication No. 20040213847 describes the composition of opadry brown as a suspension of Hydroxy cellulose (HPC), Hydroxypropyl methyl cellulose (HPML), Polyethylene glycol, Hydroxypropyl cellulose, Titanium dioxide (TiO2), yellow iron oxide and red iron oxide.
As the Chlorambucil is very sensitive to oxidation and moisture it hydrolyzes in water or in alkaline solution. The rate of hydrolysis is more rapid and it is independent of pH between 4.5 and 10. In aqueous solution maximum stability is achieved at pH less than 2, hydrolysis may be retarded by addition of alcohol or propylene glycol to aqueous solution and to protect the chemical from the exposure to light, it should be kept in tightly, closed container and under an inert atmosphere and refrigerator temperature.
The US Food & Drug Administration (FDA) has announced that Glaxo-Welcome, recalled its Leukeran (Chlorambucil) tablet because of impurity specification due to

which it resulted in poor stability. The available product of Glaxo-Welcome in the market is Leukeran 5 mg compressed coating tablet.
To enhance stability of Chlorambucil by preparing compressed coating tablet, is described in 'Althotech Pharma Inc, Modified-Release Drug Delivery Technology'-Google Books Result (By Micheal J. Rathbone, Jonathan Hadgraft....-2002-Medical-996 pages). It is prepared using special compression machine capable of producing a small tablet first and then passing it on to the next stage where the core is covered with other granules and is compressed. This type of coating is accomplished basically by two rotary pressed coupled by a single drive shaft and joined by a transfer system, so that tablet made on one turret, where a coating is impressed upon them, the coating process is thus one continuous cycle.
The core tablet which is compressed on the first turret picked up by means of a transfer cup, deposited in a die on the coating turret, in which one layer of the coating granulation has already been deposited. An addition layer of coating material is then placed in the die above the core and the whole contents of the die are then compressed. The finished tablet thus consists of a core with a coating around it.
European Patent'No. 181650 describes the tablet comprising a quickly dispersible core, characterized in that the core, which contains the active substances which are prone to sublimation and/or recrystallisation, is covered by a compression coating, is quickly dispersible which contains one or more disintegrating agents. Core tablet - when stored at room temperature and examined periodically, after 3 months it appeared fluty white deposits and recrystallization occurs, and after compression coating no changes had been observed upto 12 months.
E.g.- Cyclandelate tablet-Compressed Coated.
According to the Reference JPS Vol. 80 No. 2 February 1991, beta-Cyclodextrin complex was prepared by adding 1294.5 mg of Chlorambucil and 302.6 mg of, beta-Cyclodextrin to 10ml water in a 15 ml screw capped vial. The vial was sealed and vibrated in a

controlled temperature 30°C batch for 24 hours. The precipitate was removed by filtration and dried over P2O5. The ground mixture was prepared by hand mixing in an agate mortar and pastle for 10 min. samples were quickly transferred to screw capped vials to protect content from moisture.
Cyclodextrin is proven useful in stabilizing chlorambucil against chemical decomposition in aqueous solution. Now those complexes of cyclodextrins and Chlorambucil have been isolated and characterized, it is anticipated that these complexes would be useful in the preparation of solid dosage form having extended shelf life.
The batches were taken with compressed coating tablet containing p-Cyclodextrin-CHL complex, and can be prepared at 2-8°C (Assay -100%) 1 M condition, but the batch failed at 40°C/75%, 30°/65% and 8-25°C. However, the compressed coated tablet without f$-Cyclodextrin failed at 1 M at all the mentioned conditions.
Thus, there is a need of stable Chlorambucil composition in the solid dosage form comprising a stable coating composition which can exhibit extended shelf life and can be prepared by a simple, efficient and cost effective method without using any high-tech machinery.
OBJECT OF THE INVENTION:
The main object of the invention is to provide a stable pharmaceutical composition comprising Chlorambucil in the solid dosage form, prepared by simple method and inexpensive excipients.
Another object of the present invention is to provide a process for preparation of the said composition without using any hi-tech machine and technology.
SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a stable film coated pharmaceutical composition of Chlorambucil which can be prepared by a simple and direct compression method without using any hi-tech machine and technology and process for preparation thereof.

The coating excipients are selected so as to protect Chlorambucil from oxidation and moisture. The said coating composition is developed with high polymer concentration, using suitable plasticizers mixed with suitable solvent system to form a desired film and to protect core tablet.
The present invention also optimized the coating concentration to get a maximum thickness over a core tablet and to stabilize the formulation for sufficient period of time.
Another aspect of the present invention is to provide the method of preparation of said Chlorambucil composition which involves following steps:
a) sifting and dry mixing active ingredient and excipients through appropriate mesh size and blending the said mixture in drum mixer or core blender;
b) Adding lubricant to the mixture of step (a) and blending it for 20 mins to form granules; adding lubricant to the mixture of step (a) and blending the same for 20 mins to form granules.
c) Compressing the blended granules into a tablet and film coating the tablet.
d) Film Coating the said tablet with appropriate coating composition
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated
According to the stable pharmaceutical composition of the present invention, the Chlorambucil is present in an amount of 2 to 5 mg by weight. The said stable pharmaceutical composition is coated by a moisture sensitive coating material composition comprising polymer and plasticizer to form a desired film and suitable solvent system to protect core tablet.
Thus, according to preferred aspect, stable pharmaceutical composition of the present invention comprising a core containing 2-5 wt % of Chlorambucil as an active ingredient and a moisture resistance coat surrounding said core which comprises one or more polymers in the range of 10 to 60% and plasticizer in the range of 5 to 15% along with

other pharmaceutical excipients, useful for treating chronic lymphocytic leukemia, low
grade non-Hodgkin lymphoma, hodgkin lymphoma, or Waldenstrom's
macroglobulinaemia.
Suitable polymer is selected from but not limited to Hydroxy propyl methyl cellulose, Ethyl cellulose and the like in the range of 10-60 wt%.
Suitable plasticizer is selected from but not limited to Diethylphthalate in the range of 5-15wt. % preferably 12%.
The said stable pharmaceutical composition further comprises of diluents, disintegrants, buffering agent and lubricant.
Suitable diluent combinations used for the purpose of the present invention selected from the group of microcrystalline cellulose, dibasic calcium phosphate, lactose in range of 50-80%, preferably 70% by weight.
Suitable disintegrants like crosscarmellose sodium or cross povidone, or sodium starch glycolate, or in combination is used in the range of 5-20% preferably 15%.
Suitable buffering agent is present in the range of 2-5%, and lubricants like, talc or magnesium stearate or calcium stearate or Aerosil alone or in combinations thereof are present in range of 2-5%.
In another embodiment of the present invention the said composition of Chlorambucil is prepared by a simple and direct compression method without using hi-tech machine and technology. According to this embodiment, the method of preparation of said Chlorambucil composition involves the following steps;
a. Sifting and dry mixing active ingredient and excipients through appropriate mesh size and blending the said mixture in drum mixer or core blender sifting and dry mixing active ingredient and excipients through

appropriate mesh size and blending the said mixture in drum mixer or core blender
b. adding lubricant to the mixture of step (a) and blending
c. compressing the blended granules into a tablet and film coating the tablet
d. Film Coating the said tablet with appropriate coating composition
The said process does not contain costly excipients, equipment and consume very less time as compared to various process described in the prior art.
The following embodiments and aspects thereof are described in conjunction with procedures, tools and processes which are meant to be exemplary and illustrative, not limiting in scope. In various embodiments, one or more of the above described problems have been reduced or eliminated, while other embodiments are directed to other improvements.
EXAMPLES:
I) Core Tablet-
i. Geometrically accurately weighed Chlorambucil and excipients were sifted through appropriate mesh size and were blended in drum mixer or core blender.
ii. Lubricant was added to the mixture of step 1 and was blended for 20 mins.
iii. The blender was unloaded into double lined HDPE and the weight was recorded.
iv. Compression machine was set and the fill weight, thickness and hardness of tablet were adjusted. The blended granules are compressed into tablet.
II) Coating -
6 Coating solutions with various concentration of coating excipients were prepared to obtain moisture resistance film and satisfactory Stability of drug.

Excipients Coating Composition (in %)
1 2 3 4 5 6
1) HPMC - - 10 12 15 25
2) Ethyl cellulose - - 40 50 50 55
3) Eudragit 30 40 - - - -
4) Diethyl phthalate 5 10 10 12 15 20
5) Opacifier (titanium di oxide) 10 15 22 25 25 25
6) Glidant(Talc) 5 5 5 5 5 5
7) Colourant 3 3 3 3 3 3
Coating Solvent, a:b::60:40
a) Dimethylene Chloride Quantity sufficient to dissolve 7% of total excipients
b) Methanol
Coating Solution Preparation:
6 to 7% of total weight of excipients were added in solvent mixture of methylene chloride/methanol in 60:40 combination. Vigorous and continuous stirring for 1 hr, homogenized the solution for further 15-20 minutes. The filtered solution was used to coat the core tablet.
The coating concentration optimized, weight gain of tablet (NMT 4%) sufficiently to obtain desired Disintegration Time and dissolution parameter.
Tablet composition of 3, 4, 5 found to be best among them with respect to satisfactory description, surfactant, colour and texture.
Best Obtained Results: - Tablets coated with various coating composition.

Tablets Assay (2-8uC) D T Similar Column
(2-8°C) Dissolution
(2-8°C)
Comp. no. Initia 1 3M 6M 12M Initial 3M 6M 12M Initial 3M 6M 12M
3. 100.2 99.3 98.9 98.3 2min 2m in 2min 2min 99.2% 98.8% 98.
5% 98%
4. 100.8 99.9 98.7 98.7 2min 2m in 2min 2min 100% 98% 97. 8% 97%
5. 99.8 97.7 97.6 96 6min 9min 10 min 13 min 95% 92% 90 % 89%
Stability of Chlorambucil: - All batches with various coating formulae, when studied for 3 months, 6 months, 12 months at 2-8°C condition, the data found satisfactory.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

We Claim,
1. A stable pharmaceutical composition comprising a core containing Chlorambucil as an active ingredient and a moisture resistance coat surrounding said core which includes one or more polymers in the range of 10 to 60% and plasticizer in the range of 5 to 15% along with other pharmaceutical excipients, useful for treating chronic lymphocytic leukemia, low grade non-Hodgkin lymphoma, hodgkin lymphoma, or Waldenstrom's macroglobulinaemia.
2. The composition as claimed in claim 1 wherein the said polymers are selected from Hydroxypropyl methyl cellulose, Ethyl cellulose or combinations thereof.
3. The composition as claimed in claim 1 and 2 wherein Hydroxy propyl methyl cellulose used in the range of 10-15 wt. % preferably 12 wt. %.
4. The composition as claimed in claim 1 and 2 wherein Ethyl cellulose is used in the range of 40-60 wt.%, preferably 50wt.%
5. The composition as claimed in claim 1 wherein said plasticizer is Diethylphthalate used in range of 5-15 wt. % preferably 12 wt. %.
6. The composition as claimed in claim 1, wherein the other pharmaceutical excipients for core tablet are selected from diluents, disintegrants, buffering agent, lubricants.
7. The composition as claimed in claim 1 wherein diluents are selected from the group of Microcrystalline cellulose, Dibasic calcium phosphate, lactose or combinations thereof and is in the range of 50-80 wt.%, preferably 70wt.% by weight.
8. The composition as claimed in claim 1 and 3 wherein, disintegrants are selected from the group of cross carmellose sodium, cross povidon, or sodium starch glycolate, or in combination thereof, in range of 5-20 wt.% preferably 15wt %

9. The composition as claimed in claim 1 and 3 wherein, buffering agent is in range of 2-5 wt.%
10. The composition as claimed in claim 1 and 3 wherein lubricants are selected from talc, magnesium stearate, calcium stearate, Aerosil or in combinations thereof in the range of 2-5 wt.% are used.
11. The composition as claimed in claim 1 wherein weight of coating composition to gain weight of coated tablet by 2 to 4 % w/w weight preferably 3% weight gain.
12. Process for preparation of the stable pharmaceutical composition of claim 1, comprising the steps of:

(a) sifting and dry mixing active ingredient and excipients through appropriate mesh size and blending the said mixture in drum mixer or core blender
(b) adding lubricant to the mixture of step (a) and blending the same for 20 mins to form granules.
(c) compressing the blended granules into a tablet and film coating the tablet.
(d) Film Coating the said tablet with appropriate coating composition
Dated this the 3rd day of November, 2008
Dr. P. Aruna Sree
Agent of the Applicant