FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION: "Stable formulation for calcium Benzamidosalicylate"
2. APPLICANT (S)
(a) NAME: Genesen Labs ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS: Genesen Labs ltd.,
R-75,TTC Industrial estate, Thane-Belapur road,
Navi Mumbai India 400701. Tel No. 91-22-66888720. Fax No. 91-22-66888730.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Stable formulation for Calcium Benzamidosalicylate
Field of Invention:
The present invention relates to formulation of Calcium Benzamidosalicylate, in particular, film-coated tablet and to processes for the production of said formulation. The present invention further relates to the stable formulation for the same.
Background of Invention:
Calcium Benzamidosalicylate chemically known as calcium 4-benzamido-2-hydroxybenzoate is an agent for anti-tuberculosis and the preparation disclosed in GB 711,163 by Hertz Pharmaceutical Ltd in Nov. 17, 1951.
It is important to note that the Calcium Benzamidosalicylate formulation is firstly disclosed in this instant application in form of film coated tablet which having a substantive advantages in terms of oral formulation.lt is moreover known that Calcium Benzamidosalicylate is chemically labile, thus the stability of the pharmaceutical forms must also be taken into consideration.

Surprisingly, it has been possible to prepare film-coated tablet comprising Calcium Benzamidosalicylate without the use of pre swollen starch. Suitable auxiliaries were selected on the basis of the compatibility investigations mentioned in Examples. It was surprising in this context that the stability of Calcium Benzamidosalicylate is enhancing in the presence of film coating material as well as the stable formulation. It was moreover surprising that the finished film-coated tablet exhibit an adequate stability although the active compound, due to the preparation, is stressed during the film-coated process by moisture and heat.
Film-coated of tableted drug products is a process widely practiced in the pharmaceutical field. Typically this process involves spraying a solution or suspension of a polymeric material conventionally utilized for Film-coated purposes onto a tablet which is being tumbled in a stream of warm air. As the solvent evaporates the polymeric film coating is uniformly deposited on the tablet surface. Film coating can be done in either aqueous or organic solvent systems, but organic systems are often preferred because they avoid the degradation of active substance due to moisture problems associated with many aqueous system. Film coating of Calcium Benzamidosalicylate tablet is utilized to mask the drug's bitter taste and degradation, to provide protection from destructive environmental elements, and for esthetic purposes.

It is known that Calcium Benzamidosalicylate is subject to degradation upon aging and that such degradation is accelerated by heat, moisture and light.
Further, the drug is not only extremely insoluble in water but is also very soluble in many commonly used organic solvents. Such high solubility and propensity to degrade in the presence of heat, moisture and light have therefore made it difficult to maintain the pharmaceutical integrity of Calcium
Benzamidosalicylate tablet.
In the art of tablet film coating, conventional plasticizing agents are frequently added to the polymeric solution or suspension to improve the flexibility of the film coating and thus minimize the filling in or covering over of engraved (cut in to the surface of the tablet) or embossed (raised above the surface) indicia and designs in the tablet face. In order to significantly retard the degradation of Calcium Benzamidosalicylate induced by the natural heat, moisture or light factors of the environment and to successfully mask its taste, the film coating must exceed a certain minimum thickness. Without plasticizers such as polyethylene glycol, triethylene glycol, thickness can not be achieved for a tablet containing Calcium Benzamidosalicylate without considerable loss of the definition of the indicia and designs in or on the tablet. Preservation of such engraved or embossed indicia and designs is important not only for general

appearance and trade dress purposes, but more important, to meet regulatory requirements regarding identification of drug product,
Summary of Invention:
The invention relates to a thin film coating on solid oral formulation such as tablet of Calcium Benzamidosalicylate, and process for production of Calcium Benzamidosalicylate formulation in particular, The method of the invention comprises applying a water-soluble or organic solvent soluble, pharmaceutically-acceptable polymeric hydrophlic coating such as combination of HPMC, Polyethylene glycol, talcum and titanium dioxide as coating materials onto the exterior surfaces of the tablet. Further, the stable novel formulation of Calcium Benzamidosalicylate in form of film coated tablet by using the pharmaceutically acceptable excipientes.

Detail Description of Invention:
The method of this invention comprises the stable formulation for Calcium Benzamidosalicylate by accompanying the pharmaceutically acceptable excipientes used in pharmaceutical formulation e.g. for oral administration.
In preferred embodiment according to the formulation may be in the form of film coated tablet where in the formulation comprising The tablet formulation according to the present invention tablet core comprising therapeutically equivalent Calcium Benzamidosalicylate in the finely powder particles with particles size 1 to 100 urn but preferably 1 to 10 urn and maximum residue on a 40 urn sieve of up to 5% and further excipientes that are suitable for production of granules and lubrication which further to compression to form tablet core.
In further embodiment the invention provides in an another aspect novel process for production of film coated tablet containing Calcium Benzamidosalicylate comprising finely grinding Calcium Benzamidosalicylate of particles size 1 to 100 urn but preferably 1 to 10 urn with maximum residue on a 40 mesh sieve of up to 5%.

The suitable method for preparation of film coated tablet of Calcium Benzamidosalicylate within in the scope of description of invention comprising the steps of dry mixing with active ingredient, granulation, lubrication and compression to form tablet core which concomitantly to further film coating wherein, the suitable excipientes for the production of granules for example: Avicel® type (FMC Corp.), for example of the types AVICEL PH101, 102, 105, RC581 or RC 591, Emcocel® type (Mendell Corp.) or Elcema® type (Degussa); carbohydrates, such as sugars, sugar alcohols, starches or starch derivatives, for example lactose, dextrose, saccharose, glucose, sorbitol, mannitol, xylitol, potato starch, maize starch, rice starch, wheat starch or, crosscarmalose sodium, wherein for dry mixing with Calcium Benzamidosalicylate may be preferably maize starch and crosscarmalose sodium in 0.1 to 10% weight of tablet core.
Granulation may be by using binders such as gelatin, tragacanth, agar, alginic acid, cellulose ethers, for example methylcellulose, carboxymethylcellulose or hydroxypropylmethylcellulose,

polyethylene glycols or ethylene oxide homopolymers, especially having a degree of polymerisation of approximately from 2.0x10 3 to 1.0x10 5 and an approximate molecular weight of about from 1.0x10 5to 5.0x10 6' for example excipients known by the name Polyox® (Union Carbide), polyvinylpyrrolidone (PVP k-30) or povidones, especially having a mean molecular weight of approximately 1000 and a degree of polymerization of approximately from 500 to 2500, and also agar or gelatin; but preferably the polyvinylpyrrolidone (PVP k-30) alone or mixture thereof in 0.1 to 10% weight of tablet core.
The lubrication and compacting the granules may be those which are suitable for the conventional direct compression method for examples dry lubricants such as potato, wheat and maize starch, microcrystalline cellulose, HPMC for example commercial products available under the trademarks Avicel®, Filtrak®, Heweten® or Pharmacel®, highly dispersed silicon dioxide, for example Aerosil®, mannitol, lactose, and also polyethylene glycol, especially having a molecular weight of from 4000 to 6000, crosslinked polyvinylpyrrolidone (Polyplasdone® XL or Kollidon® CL), crosslinked carboxymethylcellulose (Acdisol® CMC-XL), carboxymethylcellulose [Nymcel®, for example ZSB-10, (Nyma)], hydroxypropylmethylcellulose, for example the quality HPMC 603, carboxymethyl starch [Explotab® (Mendell) or Primojel®

(Scholtens)], microcrystalline cellulose, for example Avicel® PH 102, dicalcium phosphate, for example Emcompresse or talcum powder. The addition of small amounts of, for example, lubricants, such as magnesium stearate, is also advantageous.
But preferably the combination pack consists of talcum powder, HPMC and magnesium stearate in 0.1 to 10 % weight of tablet core for easy compression and less de-dusting.
Furthermore the above preferred pharmaceutically accepting excipientes are suitable for the production of Calcium Benzamidosalicylate tablet with taking in to account of the stability and compatibility with active ingredients. Granules may be produced in a manner known per se, for example using wet granulation methods known for the production of "built-up" granules or "broken-down" granules.
Methods for the formation of built-up granules may operate continuously and comprise, for example simultaneously spraying the granulation mass with granulation solution and drying, for example in a drum granulator, in pan granulators, on disc granulators, in a fluidized bed, by spray-drying or spray-

solidifying, or operate discontinuously, for example in a fluidized bed, in a batch mixer or in a spray-drying drum.
Preferred are methods for the production of broken-down granules, which may be carried out discontinuously and in which the granulation mass first forms a wet aggregate with the granulation solution, which aggregate is then comminuted or formed into granules of the desired particle size and the granules then being dried. Suitable equipment for the granulation step is planetary mixers, low and high shear mixers, wet granulation equipment including extruders and spheronisers include.
Compression to form tablet cores may be carried out in conventional tableting machines or rotary tableting machine. The tablet cores may be of various shapes, for example round, oval, oblong, cylindrical etc., and various sizes, depending on the amount of Calcium Benzamidosalicylate.
The film coatings on tablet core by Water- permeable or organic solvent-permeable film-forming materials are, for example, hydrophilic mixtures of polyvinylpyrrolidone or of a copolymer of polyvinylpyrrolidone and polyvinyl acetate with hydroxypropylmethylcellulose, polyethylene glycol or mixtures of shellac with hydroxypropylmethylcellulose, polyvinyl acetate or copolymers thereof with polyvinylpyrrolidone, or mixtures of water-soluble cellulose derivatives, such as hydroxypropylmethylcellulose, and water-insoluble ethylcellulose.

Elastic, film-like materials are especially hydrophilic, partially etherified cellulose derivatives. Hydrophilic, partially etherified cellulose derivatives are, for example, lower alkyl ethers of cellulose having an average degree of molar substitution (MS) that is higher than one and lower than three and an average degree of polymerization of approximately from 100 to 5000 and pigments for coating such as iron oxide and titanium dioxide or a mixture thereof .
The exact dose of Calcium Benzamidosalicylate and the particular formulation to be administered depend upon a number of factors, e.g. the condition to be treated, the desired duration of treatment and the rate of release of the Calcium Benzamidosalicylate. For example, the amount of Calcium Benzamidosalicylate required and the release rate thereof may be determined by in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.
Preferred regimes include the therapy for Calcium Benzamidosalicylate (BEPASK) inside on the same grounds as PASK, especially in poor Portability PASK (with diarrhoeal events), and the need to limit the introduction of the body of sodium ions. Daily intake for an adult 9-12 g (3 g 3 - 4 times a day) for

the depleted patients (weight less than 50 kg), 3-6 milk or alkaline water. Children appoint 0.2 g per 1 kg of body weight per day (3 receiving) in total daily intake of not more than 1.9 gm. (ref by. http://lekarstwo.ru/en/preDarati/bepascum.html.)
The following examples illustrate the invention.
Example 1

Tablet Core mg mg mg
Calcium Benzamidosalicylate 250 500 1000
Maize starch 27 56 112.4
Crosscarmalose sodium
PVPk-30
Talcum powder 6
3.1
12.8 10
6
26 19.8 12.3 52.6
HPMC
Magnesium stearate 6.8 2.12 12 4 24.4 8.4
Total (Tablet core) 307.82 614 1229.9
Coating Mixture Methylene dichloride Isopropyl alcohol 8
40
50 16 80
95 32.6 164
194
Total 315.82 640.00 1262.50

Mix properly Calcium Benzamidosalicylate (0.250 kg) and Crosscarmalose sodium (0.005 kg) and shifted through the SS sieve (40 mesh), weigh out the maize starch (0.028 kg) and passed through the SS sieve (100 mesh) and transfer to SS container to rotate for 10 minutes for proper mixing in high speed mixer. In granulation process a hot yellow solution of purified water and PVPk-30 (as binder) added till to form cohesive mass. Granulate the wet granules using suitable device and dry in tray dryer and shift the wet granules through the SS sieve (8 mesh). Dry the granules and shifted through SS sieve (20 Urn) and transfer to milt mill and again shifted though SS sieve (20 mesh) until adequate consistency achieved. Finally mixture of Talcum powder (0.013 kg), HPMC (0.006 kg) and magnesium sterate (0.002 kg) as lubricant shifted through SS sieve (60 mesh) added to granules with proper mixing. Compress the final mixture to form Calcium Benzamidosalicylate core tablet. Film coat the tablet with an organic preparation consisting of coating materials mixture HPMC, polyethylene glycol, titanium dioxide, quinoline yellow (0.008 kg) in mixture organic solvent, Methylene dichloride and isopropyl alcohol by using the auto coater to form a film coated tablet.

Claims:
1) A film coated tablet of therapeutically effective dose of Calcium Benzamidosalicylate comprising the step of:
a) a tablet core consisting the therapeutically effective dose of Calcium Benzamidosalicylate, preferably in finely powdered having medium particle size of approximately 1 to 100 yM and suitable excipients for the production of granules which concomitantly to the tablet core and coating;
b) coating of suitable hydrophilic film coating exceipientes or materials
for outer coating of tablet core and the percentage of coating is 0.1 to
10% with respective to the tablet core;
c) a tablet core comprising the therapeutically effective dose of Calcium
Benzamidosalicylate with suitable pulverulent filler optionally having
flow condition i.e. disintegrent, binder and lubricant for wet or dry
granulation with optional comminution of granules and with
subsequent compression and coating;

2) A film coated tablet of Calcium Benzamidosalicylate according to claim 1 wherein, Calcium Benzamidosalicylate having particles size 1 to 100 pm but preferably 1 to 10 pm.
3) A film coated tablet of Calcium Benzamidosalicylate according to claim 1 wherein, the film coating materials mixture consisting of HPMC, polyethylene glycol, titanium dioxide and percentage of coating mixture is preferably 2-3% weight of tablet core.
4) A film coated tablet of Calcium Benzamidosalicylate according to claim
1 wherein, tablet core consisting of suitable disintegrants such as polyvinyl pyrrolidone, modified starch, sodium starch glycolate and crosscarmellose sodium in 0.1 to 10 % weight of tablet core or in mixture thereof.
5) A film coated tablet of Calcium Benzamidosalicylate according to claim
1 wherein, tablet core consisting of suitable binder such as sucrose , lactose, starch, cellulose, microcrystalline cellulose, hydroxypropyl cellulose, polyethylene glycol and polyvinylpyrrolidione (PVP k 30) in 0.1 to 10% weight of tablet core or in mixture thereof.

6) A film coated tablet of Calcium Benzamidosalicylate according to claim
1 wherein, tablet core consisting of lubricants such as talc,
silica, vegetable sterin, HPMC and magnesium stearate in 0.1-10 % weight of tablet core or in mixture thereof.
7) A film coated tablet of Calcium Benzamidosalicylate according to claim 1 wherein, tablet core preferably consisting crosscarmeUose sodium as a disintegrant in 0.1 to 0.2 % weight of tablet core.
8) A film coated tablet of Calcium Benzamidosalicylate according to claim 1 wherein, tablet core preferably consisting of polyvinylpyrrolidione (PVPk30) as a binder in 0.5 to1.5% weight of tablet core.
9) A film coated tablet of Calcium Benzamidosalicylate according to claim
1 wherein, tablet core preferably consisting mixture of talc, HPMC and
magnesium stearate as lubricants in 6 to 7% weight of tablet core.

10) A film coated tablet of Calcium Benzamidosalicylate according to claim 1 wherein, a process for producing the tablet comprises finely powdered Calcium Benzamidosalicylate with a particle size approximately 1 to 100 uM but preferably size 1to 10 urn ,with admixture of excipients that are suitable for granulation process , forming active ingredient in to granules, compressing granules to form tablet cores using tableting process and provide the cores with hydrophilic outer coating as a film coating.