FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
TASTE-MASKED RAPIDLY DISINTEGRATING PHARMACEUTICAL COMPOSITIONS OF RACECADOTRIL
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:
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TECHNICAL FIELD OF THE INVENTION
The present invention relates to a taste-masked rapidly disintegrating pharmaceutical composition of racecadotril; process for preparing such composition and a method of using such composition.
BACKGROUND OF THE INVENTION
Racecadotril, also known as acetorphan, is a compound of structure (I) in the form of a racemate.

The compound is disclosed in EP 038 758 B1 wherein it is indicated to have, inter alia, enkephalinase inhibiting, antalgic and anti-diarrhoeal activity. It also discloses that the compound may be administered to humans by oral, parenteral or rectal routes. However, it does not disclose any specific composition.
The WO 01/97801 patent application assigned to Societe Civile Bioprojet discloses dry powder granulated formulations of racecadotril, particularly for the pediatric patients. It describes that liquid or suspension formulations are more desirable for pediatric patients having difficulties in swallowing a tablet or capsule formulation. The dry powder composition comprises granules of racecadotril together with a sweetening agent for taste-masking of the composition. The granules are coated with a coating to further assist the taste masking of the composition.
The WO 01/97803 patent application assigned to Laboratoire GlaxoSmithKline discloses granulate formulations for filling into capsules or reconstitution into
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suspensions. The granules are prepared by compaction or slugging and comprise a starch based intragranular disintegrant. The compositions also comprise a sweetening agent to improve palatability.
Racecadotril is sold in the market in a number of countries under the tradename HIDRASEC® (trademark of Smithkline Beecham pic) and TIORFAN® (trademark of Societe Civile de Recherche Bioprojet). The marketed form is in the form of a dry powder filled into a hard gelatin capsule. It may be desirable to have tablet formulation of racecadotril as tablet formulations may be advantageous compared to other dosage forms such as dry powders and suspensions in terms of convenience of preparation, packaging, transportation and administration.
The art recognizes that racecadotril is difficult to formulate into compositions because of its hydrophobic nature and bitter taste and there is a need for alternative compositions of racecadotril. We have surprisingly found that taste-masked compositions having superior organoleptic characteristics and palatability may be prepared by dispersing racecadotril in a low-melting excipient. We have also found that said taste-masked compositions may be prepared to provide compositions which may be orally administered without the need of swallowing.
SUMMARY OF THE INVENTION
In one aspect, the present invention discloses a taste-masked rapidly disintegrating pharmaceutical composition comprising a taste-masked particle comprising
(i) racecadotril,
(ii) a low-melting excipient, and
(iii) optionally one or more pharmaceutically acceptable excipients, wherein racecadotril is homogenously dispersed in the low-melting excipient.
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In another aspect, the invention discloses a taste-masked rapidly disintegrating tablet comprising
(i) 1 % to 90 % racecadotril;
(ii) 0,5 % to 30 % of a low-melting excipient comprising stQaric acid or
polyethylene glycol; (iii) 1 % to 80 % of a diluent comprising lactose or microcrystalline
cellulose; (iv) 1 % to 30 % of a disintegrant comprising crospovidone or
croscarmellose sodium;
(v) 0 to 10 % of polyvinylpyrrolidone;
(vi) 0 to 5 % of a sweetener comprising aspartame or saccharine sodium;
and (vii) 0.5 to 5 % of a lubricant or a glidant comprising talc, magnesium
stearate or colloidal silicon dioxide, wherein racecadotril is homogenously dispersed in the low-melting excipient.
In yet another aspect, the invention discloses a process for preparation of a taste-masked rapidly disintegrating pharmaceutical composition, wherein the process comprises:
(i) heating a low-melting excipient;
(ii) dispersing racecadotril homogeneously in the product of step (i)
(iii) solidifying the product of step (ii);
(iv) milling the product of step (iii) to obtain racecadotril particles;
(v) mixing racecadotril particles with one or more pharmaceutically acceptable excipients;
(vi) optionally granulating the mixture of step (v) to obtain granules; and
(vii) compressing the mixture of step (v) or granules of step (vi) into a tablet.
DETAILED DESCRIPTION OF THE INVENTION
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The term "racecadotril" as described herein includes racecadotril free base or
pharmaceutic* acceptable salt, solvate, polymorph or enantiomer thereof: or
their mixtures. Racecadotril may be present in an amount ranging from 1 % to 90
% by weight of the composition.
The term "rapidly disintegrating pharmaceutical composition" as described herein refers to a composition which disintegrates in a vehicle of administration in less
than 3 minutes, preferably In less than 1 minute. The preferred vehicle of administration is water.
The term "low-melting excipient" as described herein refers to an excipient having a melting point less than 80 °C. The low-melting excipient comprising waxes such as beeswax, candelila wax, carnauba wax, hard lanolin, microcrystalline wax, paraffin wax, and the like; fatty acids such as stearic acid,
palmitic acid, and the like: high molecular weight (CiM0) straight chain aliphatic
alcohol such as stearyl alcohol, cetyl alcohol cetostearyl alcohol, and the like; polyhydric alcohols such as polyethylene glycols; partially hydrogenated vegetable oils such as cottonseed oil, soyabean oil, and the like; triglycerides, preferably glyceryl esters of high molecular weight (C10-30) aliphatic acid such as glyceryl stearate, glyceryl palmitostearate, glyceryl behenate, glyceryl trilaurate, glyceryl trimyristate and the like; or mixtures thereof. The polyethylene glycol (PEG) may be selected from high molecular weight PEG'S having a molecular weight of more than 1000 daltons such as PEG-4000, PEG-6000, and the like. The low-melting excipient is preferably stearic acid or polyethylene glycol or mixtures thereof. The low-melting excipient may be present in an amount ranging from 0.5 % to 30 % by weight of the composition.
The pharmaceutical composition as described herein may further comprise one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder, sweetener, glidant or lubricant.
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DilUent m9y be selected from cellulose derivatives such as powdered cellulose, microcrystalline cellulose, and the like; starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, sugars such as lactose, sucrose, and the like; sugar alcohols such as mannitol, lactitol, sorbitol, erythritol, xylitol, maltitol, and the like; or mixtures thereof. The diluent may be present in an amount ranging from 1 % to 80 % by Weight Of tlffi GOUiPOStOOn.
Disintegrant may be selected from croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, calcium silicate and the like; or mixtures thereof. The disintegrant may be present in an amount ranging from 1 % to 30 % by weight of the composition.
Binder may be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, polyvinyl pyrrolidone, sodium alginate, gums, and the like; or mixtures thereof. The binder may be present in an amount ranging from 0 % to 10 % by weight of the composition.
Sweetener may be selected from aspartame, saccharin sodium, acesulfame
P0ta8SiUITl, dried invert SUgar, dextrose, glucose, fructose, galactose, levulose, maltose, neotame, sucralose, and the like; or mixtures thereof. The sweetener may be present in an amount ranging from 0 % to 5 % by weight of the composition.
The glidant or lubricant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, sodium stearyl fumarate; or mixtures thereof. The glidant or lubricant may be used interchangeably. The glidant or lubricant may be present in an amount ranging from 0.5 % to 5 % by weight of the composition.
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The compositions as described herein may additionally cdlYipHSe ex"cipiftrlt§ SUfth
A8A
as one or more flavors, colorants such as known F.D. & C. and D. & C. dyes, and
the like.
The compositions of the present inventions are prepared by melt granulation.
The process comprises heating a low-melting excipient and dispersing
racecadotril in the melt by continuous stirring to form a dispersion. The product is cooled at room temperature to obtain a solidified mass. The solidified mass is size-reduced by milling or such process to obtain racecadotril particles wherein racecadotril is homogenously dispersed in the low-melting excipient. The racecadotril particles may be formulated into compositions such as granules or
sachets or into tablets using conventional process such as direct compression,
dry granulation or wet granulation. Alternatively, the racecadotril particles or granules prepared thereof may be filled into capsules.
The compositions as described herein are meant for oral administration. For example, the tablet, granule or sachet composition may be placed in a vehicle of administration such as water or fruit juices, and the suspension is ingested orally. If desired or necessary, the compositions such as tablet or capsule may also be taken directly without forming into a suspension.
In one embodiment, taste-masked particles of racecadotril may be prepared by heating a low-melting excipient;
dispersing racecadotril homogenously in the low-melting excipient; optionally cooling the dispersion; and milling to obtain racecadotril particle.
In another embodiment, a taste-masked rapidly disintegrating tablet of racecadotril may be prepared by mixing the racecadotril particles with one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, sweetener, glidant, lubricant or binder; and compressing the mixture into a tablet.
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In another embodiment, a taste-masked rapidly disintegrating tablet of racecadotril may be prepared by mixing the racecadotril particles with one or more diluent, disintegrant, a binder; granulating the mixture with a solvent or a binder solution; drying the granules; mixing the granules with one or more diluent, disintegrant, sweetener, flavor, glidant or lubricant; and compressing the mixture into a tablet.
In another embodiment, a taste-masked rapidly disintegrating tablet of racecadotril may be prepared by mixing the racecadotril particles with one or more diluent, disintegrant and optionally a binder; compacting or slugging the mixture to obtain granules; mixing the granules with one or more diluent, disintegrant, sweetener, flavor, glidant or lubricant; and compressing the mixture into a tablet.
In yet another embodiment, a taste-masked sachet composition may be prepared by mixing the racecadotril particles or granules comprising racecadotril particles with one or more pharmaceutical^ acceptable excipients and filling the mixture into a sachet.
The pharmaceutical compositions as described herein may be illustrated by the following examples, but these are not to be construed as limiting the scope of the invention:
EXAMPLE 1

Ingredients Quantity (mg/tablet)
Racecadotril 30.0
Stearic acid 15.0
Lactose 150.0
Mannitol 30.0
Microcrystalline cellulose 30.0
Crospovidone 30.0
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Colloidal silicon dioxide 3.0
Aspartame 5.0
Sodium saccharin 2.0
Flavor 5.0
Magnesium stearate 3.0
Total 300
PROCEDURE: Racecadotril was sifted and passed through a 30 # sieve. Stearic acid was heated at a temperature of 60 °C to 70 °C and racecadotril was dispersed in the melt. The dispersion was continuously stirred and cooled at room temperature. The solidified mass was milled to obtain racecadotril particles. The racecadotril particles were mixed with lactose, mannitol, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, aspartame, sodium saccharin, flavor, magnesium stearate, and compressed into tablets using appropriate
tooling.
EXAMPLE 2

Ingredient Quantity (mg/tablet)
Racecadotril 30.00
Polyethylene glycol 4000 6.00
Stearic acid 6.00
Lactose 144.00
Microcrystalline cellulose 58.75
Polyvinylpyrrolidone 1.50
Croscarmellose sodium 15.00
Crospovidone 19.50
Aspartame 6.00
Flavor 6.00
Magnesium stearate 3.00
Total 300.00
PROCEDURE: Racecadotril was sifted and passed through a 30 # sieve. Stearic acid and polyethylene glycol were mixed, the mixture was heated at a temperature of 60 °C to 70 °C and racecadotril was dispersed in the melt. The dispersion was continuously stirred and cooled at room temperature. The solidified mass was milled to obtain racecadotril particles. The racecadotril particles were mixed with lactose, microcrystalline cellulose, crospovidone and
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polyvinylpyrrolidone, the mixture was granulated with water and the granules obtained were dried. The granules were mixed with croscarmellose sodium, aspartame, flavor and magnesium stearate, and compressed into tablets using appropriate tooling.
EXAMPLE 3

Ingredient Quantity (mg/tablet)
Racecadotril 30.00
Polyethylene glycol 4000 6.00
Stearic acid 6.00
Microcrystalline cellulose 213.00
Crospovidone 15.00
Croscarmellose sodium 15.00
Aspartame 6.00
Flavor 6.00
Magnesium stearate 3.00
Total 300.00
PROCEDURE: Racecadotril was sifted and passed through a 30 # sieve. Stearic acid and polyethylene glycol were mixed, the mixture was heated at a temperature of 60 °C to 70 °C and racecadotril was dispersed in the melt. The dispersion was continuously stirred and cooled at room temperature. The solidified mass was milled to obtain racecadotril particles. The racecadotril particles were mixed with microcrystalline cellulose, crospovidone, croscarmellose sodium, aspartame, flavor and magnesium stearate, and compressed into tablets using appropriate tooling.
The tablets of Example 1, 2 and 3 were placed in Disintegration test apparatus having specified quantity of water at 20°c, it was observed that tablets disintegrated less than 1 minute. The tablets passed the test for dispersible tablets defined in the British Pharmacopoeia, 1988, Volume II, page 895, i.e. tablets dispersed in water at 20°c, formed dispersion which was capable of passing through a sieve screen with a mesh aperture of 710 (am.
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The tablets of Example 1, 2 and 3 was subjected to a sensory evaluation test for evaluating taste-masking efficiency. A sample was prepared by placing tablets in a specified amount of water and allowing the tablets to disintegrate. A panel of volunteers was asked to drink the suspension as prepared above and asses the intensity of bitter taste on drinking based on a scale of 0-10. None of the volunteer reported bitter taste (score of 7 or more) thus demonstrating effective taste-masking properties of the compositions.
Although the present invention has been described with several examples and embodiments, it will be apparent to one of the ordinary skill in the art that many changes and modifications of the invention are possible and all such modifications are considered to be within the scope of the appended claims.
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We Claim:
1) A taste-masked rapidly disintegrating pharmaceutical composition comprising
a taste-masked particle comprising
(i) racecadotril,
(ii) a low-melting excipient, and
(iii) optionally one or more pharmaceutically acceptable excipients, wherein racecadotril is homogenously dispersed in the low-melting excipient.
2) The composition according to claim 1. wherein the low-melting excipient comprises waxes, fatty acids, C10-30 straight chain aliphatic alcohols, polyhydric alcohols, hydrogenated vegetable oils, glyceryl esters of C10-30 aliphatic acids, or mixtures thereof.
3) The composition according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group consisting of diluent, disintegrant, binder, sweetener, glidant and lubricant.
4) The composition according to claim 1, wherein the composition is in the form
of a tablet, granule or sachet.
5) A taste-masked rapidly disintegrating tablet comprising
(i) 1 % to 90 % racecadotril;
(ii) 0.5 % to 30 % of a low-melting excipient comprising stearic acid or
polyethylene glycol; (iii) 1 % to 80 % of a diluent comprising lactose or microcrystalline cellulose; (iv) 1 % to 30 % of a disintegrant comprising crospovidone or croscarmellose
sodium; (v) 0 to 10 % of polyvinylpyrrolidone;
(vi) 0 to 5 % of a sweetener comprising aspartame or saccharine sodium; and (vii) 0.5 to 5 % of a lubricant or a glidant comprising talc, magnesium stearate
or colloidal silicon dioxide,
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wherein racecadotril is homogenously dispersed in the low-melting excipient.
6) A process for preparation of a taste-masked rapidly disintegrating
pharmaceutical composition, wherein the process comprises:
(i) heating a low-melting excipient;
(ii) dispersing racecadotril homogeneously in the product of step (i)
(iii) solidifying the product of step (ii);
(iv) milling the product of step (iii) to obtain racecadotril particles;
(v) mixing racecadotril particles with one or more pharmaceutically
acceptable excipients; (vi) optionally granulating the mixture of step (v) to obtain granules; and (vii) compressing the mixture of step (v) or granules of step (vi) into a
tablet.
7) A taste-masked rapidly disintegrating pharmaceutical composition as
substantially described and exemplified herein.
Dated This 4th Day of October, 2006

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ABSTRACT
The present invention relates to a taste-masked rapidly disintegrating pharmaceutical composition of racecadotril; process for preparing such composition and a method of using such composition.