FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
TASTE MASKED COMPOSITION 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 describes the nature of the invention

TASTE MASKED COMPOSITION OF RACECADOTRIL
Field of the invention
The present invention relates to a novel taste masked oral pharmaceutical compositions comprising racecadotril, more particularly dry powder for suspension comprising racecadotril, and the process for preparing the same.
Background of the invention
Racecadotril (acetorphan) is an antidiarrhoeal drug having the following structure.



Racecadotril acts by preventing the breakdown of endogenous enkephalins thereby reducing the hypersecretion of water and electrolytes into the intestinal lumen. It reduces the incidence and duration of acute diarrhea. It is also devoid of post treatment constipation which is generally associated with antimotility agents like Loperamide. This drug is particularly useful for the treatment of diarrhea in case of children. It should be noted that the mortality rate for children under the age of 5 caused by acute diarrhea is estimated by WHO at 1.8 million deaths annually.
Racecadotril is also having an inherent bitter taste. Since, the taste is an important parameter governing the compliance and this becomes more important when such dosage form is required to be administered to children. This makes it unsuitable for the pediatric use. The bitter taste of drugs causes difficulties in swallowing or causes


patients to avoid their medication, thereby resulting in low patient compliance. Further, Racecadotril has very low solubility.
The bitter taste of the racecadotril thus generates a challenge to formulate it as an acceptable dosage form. Further, the hydrophobic nature of the racecadotril makes it difficult to form into an acceptable dosage form.
Conventional taste masking techniques such as use of sweeteners, amino acids, flavoring agents are often unsuccessful in masking the taste of the highly bitter drugs like racecadotril. Various methods for taste masking have been tried earlier like, complexation with pharmaceutically acceptable excipients such as cyclodextrin and coating of drugs by lipids and various polymeric materials. Of these, coating is the most widely used technique for taste masking. Coating of active ingredient can be done by any technique known in the art like microencapsulation, hot melt granulation, wurster coating, and spray drying. The bitter taste of drugs can be reduced or fully eliminated, if the bitter drug forms an inclusion complex with an appropriate cyclodextrin. This method is also applied for the taste masking of various drugs.
The drug racecadotril is on the market in a number of countries for Paediatric use in the form of a sachet filled with dry powder formulation (and sold as TIORFAN®-a trademark of Society Civil de Recherche Bioprojet). The sachet comprises of inactive ingredients such as Sucrose, Colloidal silicon dioxide, Polyacrylate dispersion 30%, apricot flavour. The racecadotril is coated with Eudragit NE30D (Polyacrylate dispersion 30%) to mask the bitter taste of drug. These polymers are known to be permeable to aqueous solvents. Upon exposure to an aqueous environment, drug leaching is a frequent occurrence with these coatings since they are greatly porous and therefore permeable to water.


Racecadotril is also available for adult use in form of a capsule filled with dry powder formulation (and sold as TIORFAN®-a trademark of Society Civil de Recherche Bioprojet). Racecadotril is also marketed as HIDRASEC® by SmithKline Beecham. The marketed form is a dry powder filled into a hard gelatin capsule. The capsule based compositions are not suitable for pediatric use and also they have the bitter taste of Racecadotril. Racecadotril is yet not available in the market in the form of dry powder for suspension, which is well accepted dosage form for pediatric use.
The hydrophobic nature of drugs like racecadotril may create many formulation development related problems. These problems can be low dissolution, low bioavailability.
The above mentioned conventional methods of taste masking suffer from different disadvantages, such as requirement of large amount of coating material to mask the taste, which will ultimately retard the drug release or increase the size of dosage form, leakage of drug from coating etc. Surprisingly, it is found by the inventors of instant invention that the taste masking of bitter drugs like racecadotril, which is hydrophobic in nature, can be effectively done by using ion exchange resins wherein the dosage form is easy to manufacture and suitable for pediatric administration.
Summary of the invention
The present invention relates to the novel taste masked oral pharmaceutical compositions comprising racecadotril and the process involved therein.
The first embodiment of the present invention is to provide taste masked oral dosage form of racecadotril.


Another embodiment of the present invention is to provide taste masked oral pharmaceutical composition comprising racecadotril, ion exchange resin and atleast one pharmaceutically acceptable excipient.
Another embodiment of the present invention is to provide taste masked oral pharmaceutical composition comprising racecadotril, ion exchange resin, atleast one wetting agent and atleast one pharmaceutically acceptable excipient.
Another embodiment of the present invention is to provide taste masked oral dry powder for suspension of racecadotril.
Another embodiment of the present invention is to provide taste masked oral dry powder for suspension comprising racecadotril, ion exchange resin, atleast one wetting agent and atleast one pharmaceutically acceptable excipient.
Yet another embodiment of the present invention is to mask the bitter taste of racecadotril by combining it with an ion exchange resin.
In yet another embodiment, the present invention includes the formulation of the resinate complex into acceptable oral dosage forms like rapid-disintegrating tablets, rapid-disintegrating films, effervescent tablets, chewable tablets, chewing gum, suspensions, sprinkle granules, sachets, powder for reconstitution in suspension (dry syrups).
In yet another embodiment, the present invention provides following process for preparing taste mask pharmaceutical composition comprising racecadotril.
1. Mix Racecadotril, Ion exchange resin and optionally wetting agent in appropriate container for sufficient time.


2. Allow the dispersion from step -1 to settle for sufficient time and then filter the wet powder mass.
3. Dry the wet mass from step-2 and then sift through appropriate screen.
4. Blend this resinate complex from step 3 with atleast one pharmaceutical^ acceptable excipient.
5. The blend from step - 4 can be converted into suitable dosage form e.g. compressed into tablets or filled into capsules, sachet or can be used in preparation of oral dry powder for suspension.
Detailed description of the invention
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
The term "resinate complex" as used herein or elsewhere includes the complex formed by mixing the drug with a suitable ion-exchange resin in taste masking effective concentration. The complexation may be carried out in an aqueous solvent or non-aqueous solvent. The desired solvent may include water or compatible non aqueous solvent like alcohol or polyhydric alcohols.
The term "dosage form" or "composition" or "formulation" as used herein refers to any suitable physical form of the drug containing fixed dose of the active ingredient. Composition of the present invention includes without limitation a wider variety of dosage form like e.g. tablets, capsules, sachets, powders or liquid dosage form like emulsions, suspensions, solution etc. The tablet dosage form may be in chewable dosage form or the suspension is in the form of reconstituable dry powders.


The term "Racecadotril" or "drug" as described herein is intended to include racecadotril free base or pharmaceutically acceptable salts thereof, racemic mixture, individual enantiomer or mixtures or polymorph thereof.
The formulations of the present invention comprise from 1 to 200 mg of racecadotril, more suitably 5 to 30mg of racecadotril.
The term "ion-exchange resin" as used herein or elsewhere includes both cation and anion exchange resin. These can be illustrated by the following examples but it should not be considered as limiting in nature. The different types of cation exchange resin which can be used are: AMBERLITE® IRP-64 (Polacrilex Resin), AMBERLITE® IRP-69 (Sodium polystyrene sulfonate USP), Doshion P544 (C), and AMBERLITE® IRP-88 (Polacrilin Potassium), Purolite® C115KMR and Purolite® C115HMR etc. AMBERLITE® IRP-88 (Polacrilin Potassium) is the preferred resin. The DUOLITE® and AMBERLITE® resins are available from the Rohm and Haas Company, Philadelphia. The DOWEX® resins, available from the Dow Chemical Company, Midland, Mich, are also useful in the practice of the present invention. Said DOWEX® resins are strong cationic exchangers based upon polystyrenesulphonic acid with variable crosslinking (1-12% divinylbenzene) in a variety of particle sizes and anionic resins such as: DUOLITE® API43 / 1083 (cholestyramine resin USP). The choice of use of cationic exchange resin or anionic exchange resin in pharmaceutical composition is based upon the nature of drug. The resinate complex comprising drug and resin is held together by weak chemical bond.
The term "pharmaceutically acceptable excipient" as used herein can be defined as any pharmaceutically inactive ingredient which can be combined to the active ingredient without affecting the therapeutic or biopharmaceutical profile of the active ingredient. The acceptable inactive ingredients can be suspending agents, fillers, binders, lubricants, glidants, disintegrants, stabilizers, wetting agents, sweetening


agents, flavoring agents, pharmaceutical grade dyes or pigments, effervescent agent, viscosity modifiers agents, pH modifiers, preservatives, opacifiers and the like.
The acceptable suspending agent which can be incorporated in the formulation should possess following properties like, they should impart proper viscosity, good mouth feel, and better rheological properties. Better rheological properties leads to required homogeneity and dose reproducibility of the suspension dosage form. The preferred polymers are xanthan gum and microcrystalline cellulose / sodium carboxymethyl cellulose. Additionally a protective colloid can be included in the formulation, for example xanthan gum, carboxymethyl cellulose, hypromellose.
The glidant or lubricant that can be incorporated in the formulation are one or more of talc, silicon hydrogel, colloidal silicondioxide, calcium silicate, magnesium silicate, magnesium stearate, glyceryl monostearate, sodium stearyl fumarate, stearic acid, Leucine, beeswax, cornstarch and the like.
The filler or diluent that can be incorporated in the formulation are selected from Mannitol, Sorbitol, Xylitol, Lactose, Sucrose, Cellulose derivatives, Starch and its derivatives.
The suitable binder that can be incorporated in the formulation is one or more of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, ethylcellulose, tragacanth, gum arabic, and the like.
The sweetener that can be incorporated is selected from aspartame, saccharose, acesulfame, sodium glycyrrhizinate, cyclamate, sucrose or sucralose; sugar alcohols such as sorbitol, mannitol, xylitol and the like or mixtures thereof. The opacifiers may be one or both of titanium oxide and opadry.


The wetting agent that can be incorporated is selected from anionic surfactants such as sodium alkyl sulfates and the like, and also nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters and polyoxyethylene fatty acid esters and the like.
The preservative that can be incorporated in the formulation is selected from Sodium methyl paraben, Sodium propyl paraben, Sodium benzoate, Sorbic acid and the like.
Examples of flavoring agent includes any natural or synthetic, solid or liquid flavoring such as strawberry flavour, vanilla flavour, pineapple flavour, yoghurt flavour and other flavours known in the art.
The different types of effervescent agents that can be used in the present invention are as given below but it is not limiting in any way. The term effervescent agents that can be used here are intended to evolve gas during the compounding process of the dry powder for suspension. The gas that evolves is carbon dioxide; it is obtained by reaction of a soluble acid source and a carbonate source. The soluble acid sources that can be incorporated by example and without limiting are citric, tartaric, malic, fumaric, adipic, succinic and the like and acid salts and anhydrides thereof. Acid salts may also include sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate, acid citrate salts, sodium acid sulfite and the like. Carbonate sources include dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate, amorphous calcium carbonate and the like or mixtures thereof.
The resinate complex can be formed by simple process like, by adding a specified amount of drug and a specified amount of an ion-exchange resin, provides simplified manufacturing process, wherein a number of manufacturing steps involved in the art


are avoided. For example, the process steps of solubilizing an active substance, converting or otherwise changing a salt form of an active substance to a free acid or free base form, forming a hydrate of an active substance or changing an active substance to a polymorphic form thereof and the like to make the active more palatable can be avoided. The other advantage of the resinate complex is that it can be formed into different dosage forms like rapid-disintegrating tablets, rapid-disintegrating films, effervescent tablets, chewable tablets, chewing gum, suspensions, sprinkle granules, sachets, capsules which can be hard gelatin capsule or soft gelatin capsule and dry powder for reconstitution in suspension.
The ion-exchange resins provide certain advantages as compared to the conventional taste masking process. Resins being polyelectrolyte have extensive binding sites leading to very high drug loading ability. Resins can be effectively utilized for the preparation of taste masked formulation, modified release formulation and also some resins possess therapeutic efficacy. They can be effectively formulated into semisolid dosage form, solid dosage form or into palatable liquid dosage form. Resins also add significantly to the stability of the formulation at ordinary conditions of temperature, oxygen, light and humidity as these are more stable compared to other hydrophilic or hydrophobic polymers. The resinate complexes also add in the stability of the drug-resin complex due to its electrostatic nature.
The general manufacturing process for the novel taste masked pharmaceutical composition of Racecadotril comprises of following steps:
1. Mix Racecadotril, Ion exchange resin and optionally wetting agent in appropriate container for sufficient time.
2. Allow the dispersion from step -1 to settle for about 10-14 hours and then filter the wet powder mass.
3. Dry the wet mass from step-2 and then sift through appropriate screen.


4. Blend this resinate complex from step 3 with atleast one pharmaceutically acceptable excipient.
5. The blend from step - 4 can be converted into suitable dosage form e.g. compressed into tablets or filled into capsules, sachet or can be used in preparation of oral dry powder for suspension.
Examples:
The invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be constructed as limit to the scope of the reaction in any manner.


Example 1
Table 1: Manufacturing Formula for Racecadotril Dry Syrup

S.No. Excipients Mg / 3 gm
1. Racecadotril 30.00
2. Polacrillin Potassium 90.00
3. Sodium Lauryl sulphate 0.50
4. Purified Water* q.s
5. Sucrose (Pharma grade) 2413.30
6. Sodium Methyl Paraben 12.00
7. Sodium Propyl Paraben 1.20
8. Microcrystalline Cellulose and Carboxymethylcellulose Sodium 150.00
9. Aspartame 120.00
10. Colloidal Silicon Dioxide 120.00
11. Color Sunset yellow FCF 3.00
12. Pineapple Flavor 60.00
Total 3000.00
* removed during drying
Manufacturing Process:
1. Racecadotril, Polacrilin potassium, Sodium lauryl sulphate and purified water were mixed in SS vessel for 45 minutes.
2. The dispersion from step -1 was allowed to settle for 12 hours and then filtered to get wet powder mass.
3. The wet mass from step-2 was dried at 60°C for suitable time and then sifted through # 22 mesh ss screen.
4. The drug blend from step - 3 was mixed with sucrose.


5. The blend from step - 4 was mixed with Sodium methyl paraben, Sodium propyl paraben, Aspartame, Colloidal silicon dioxide, Microcrystalline Cellulose and Carboxymethylcellulose Sodium.
6. The flavour and colour are finally mixed in the blend from step -5.
7. The blend from step -6 was filled in bottles.
Example 2
Table 2: Manufacturing Formula for Racecadotril Dry Syrup

S.No. Excipients Mg / 3 gm
1. Racecadotril 30.00
2. Doshion P544 (C) (Ion exchange Resin) 90.00
3. Sodium Lauryl sulphate 0.50
4. Purified Water* q.s
5. Sucrose (Pharma grade) 2299.50
6. Sodium Benzoate 200.00
7. Xanthan Gum 200.00
8. Aspartame 100.00
9. Color Sunset yellow 4.00
10. Pineapple Flavor 76.00
Total 3000.00
*removed during drying
Manufacturing Process:
1. Mix Racecadotril, Doshion P544 (C), Sodium lauryl sulphate and purified water for 45 minutes.
2. Allow the dispersion from step -1 to settle for 12 hours and then filter to get wet powder mass.


3. Dry the wet mass from step-2 at 60°C for suitable time and then sift through # 22 mesh ss screen.
4. Mix the drug blend from step - 3 with sucrose.
5. Mix the blend from step - 4 with Sodium methyl paraben, Sodium propyl paraben, Aspartame, Colloidal silicon dioxide, Microcrystalline Cellulose and Carboxymethylcellulose Sodium.
6. Mix flavour and colour to the blend from step -5.
7. Fill the blend from step -6 in bottles.



ABSTRACT
The invention relates to a novel taste masked oral pharmaceutical compositions comprising racecadotril, more particularly dry powder for suspension comprising racecadotril using ion exchange resin and the process for preparing the same.