FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(Section 10 and Rule 13)
TITLE OF THE INVETION "TASTE-MASKED DRY POWDER FOR ORAL SUSPENSION OF CEFDITOREN"
Emcure Pharmaceuticals Limited., an Indian company, registered under the Indian Company's Act 1957 and having its
registered office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMEDFIELD OF THE INVENTION

TECHNICAL FIELD OF INVENTION:
This invention relates to a stable dry powder formulation of Cefditoren Pivoxil, which is suitable for use as a pharmaceutical composition in the form of an oral suspension product to treat bacterial infections. Further, the present invention also provides a process for preparing such pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Cefditoren, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(Z)-2-(4-methyl-thiazol-5-yl)vinyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, a gram balanced, broad spectrum oral cephem antimicrobial agent was first synthesized in 1989. It has been available in Japan since 1994 and was first approved in USA in 2001 for the treatment of acute bacterial exacerbation of chronic bronchitis, group A beta-hemolytic streptococcal pharyngotonsillitis, and uncomplicated skin/skin structure infections in adults and adolescent patients.
Cefditoren pivoxil is a novel prodrug of Cefditoren, in which a pivaloyloxymethyl group has been attached by an ester bond to a carboxylic acid at the 4-position of an antibiotic Cefditoren. The prodrug was developed for the purpose of imparting excellent oral absorption to Cefditoren and was first disclosed in European Patent No. 0175610 and is presently marketed as tablet and dry powder for oral suspension.
Cefditoren Pivoxil, however, exhibits a strong bitter taste whereas Cefditoren, which is the anti-bacterially active species, does not exhibit the bitter taste by itself upon oral administration. The other problem associated with Cefditoren pivoxil is of low aqueous solubility. It is traditionally known that the problem of aqueous solubility can be addressed by reducing the particle size. However, in the case of Cefditoren, amorphous nature of the drug imparts more bitterness to the drug. Therefore the problems of bitter taste and low aqueous solubility have vexed researchers working in the field of pharmaceutical composition.
U.S. Patent No.5,958,915 discloses addition of a water-soluble casein salt to Cefditoren pivoxil as a method for enhancing solubility of the drug and for minimizing the bitter taste. The marketed Cefditoren Pivoxil tablets, which are sold under the brand name Spectracer contains

casein. However, consumption of formulations using water-soluble casein may cause difficulties for individuals with lactose intolerance because of their inability to digest significant amounts of lactose, which is the predominant sugar.
U.S. Patent Application No 2004/0115272 discloses a method of conversion of crystalline Cefditoren pivoxil to amorphous form by grinding Cefditoren pivoxil in the presence of a pharmaceutical^ acceptable organic polymeric compound.
European Patent No. 0629404 discloses a pharmaceutical composition comprising Cefditoren pivoxil and a water soluble polymer-like hydroxypropylcellulose. This preparation was disclosed to have improved wettability, dispersibility and absorbability without increasing its bitterness.
European Patent No. 0339465 discloses a composition containing Cefditoren pivoxil and beta-cyclodextrin along with an ionic surfactant in a pharmaceutically acceptable carrier in an attempt to improve the dispersibility and absorbability. However, the highly enhanced bitter taste of this drug which is brought about by the addition of cyclodextrin can lead to a great discomfort to patients who receive the oral administration of formulation comprising the mixture of Cefditoren pivoxyl with cyclodextrin.
U.S. Patent Application No. 2006/0051411 discloses a pharmaceutical composition comprising amorphous Cefditoren pivoxil and a sugar ester fatty acid, which was obtained by mixing or wet-granulating particles containing amorphous Cefditoren pivoxil with the sugar ester fatty acid while amorphous Cefditoren pivoxil maintains its particle state.
However, all the above documents mainly focus on making a tablet formulation and there is very few published literature about manufacturing dry powder for oral suspension of Cefditoren pivoxil. Further, the liquid suspension dosage forms have stability problems associated with maintaining the drugs in suspension. Poorly formulated liquid pharmaceutical suspensions allow the drug to sediment and may not properly redisperse, thereby affecting the therapeutic concentration of drug in the suspension. This may result in underdosing or overdosing of the patient, which may seriously compromise the patient's recovery.

Therefore, there is still a need for a stable dry powder Cefditoren pivoxil formulation suitable for suspension in water for oral administration. The formulation should have minimum sedimentation of the pharmaceutically active agent, provide uniform distribution of the active agent and has a palatable taste. There is also a need for a simple efficient process for making such a stable dry powder Cefditoren pivoxil formulation having an extended shelf life at room temperatures.
SUMMARY OF THE INVENTION
The present invention relates to oral taste masked granules of Cefditoren pivoxil and a process for the manufacture thereof.
It is one of the embodimentsof the present invention to provide an oral pharmaceutical composition comprising taste masked granules of Cefditoren pivoxil. The traditional taste masking methods such as complexation, coating may affect the amorphous nature of drug and ultimately dissolution & bioavailability of the formulation. Moreover such a method, typically, does not involve any step that affects drug state and hence dissolution of drug remains unaffected.
In yet another embodiment, the present invention provides, oral taste masked granules of Cefditoren pivoxil, wherein the taste masked granules are prepared by non-aqueous granulation. Typically, the granules comprises of Cefditoren pivoxil, sweetening agent and flavouring agents.
In the preferred embodiments of the present invention, Cefditoren pivoxil having an average particle diameter less than 100 μm, particularly less than 50 μm and more particularly less than 20 μm is employed for manufacturing of pharmaceutical compositions.
According to another embodiment, oral taste masked granules comprise other pharmaceutically acceptable excipients selected from sweetening agentbinders, diluents/fillers, suspending agents, glidants, disintegrants, lubricants, structuring agents, wetting agents, solublizers, buffers, coloring agents, disintegrants, preservatives and pH stabilizers.

In another embodiment, the oral taste masked granules are used for preparing dry syrups, sachets, tablets and powders that can be reconstituted before usage as a liquid suspension.
In yet another embodiment, the present invention provides a dry powder for oral suspension formulation of Cefditoren Pivoxil which has improved reconstitution time as well as dose uniformity.
In a further embodiment, the present invention provides a taste-masked composition of Cefditoren Pivoxil, wherein the amount of Cefditoren Pivoxil varies from about 1-70% by weight of the dry taste-masked powder for suspension composition. Upon reconstitution, the amount of drug in the oral suspensions ranges from 1 to 100 mg/mL and preferably from 2 to 50 mg/mL.
Still further embodiment provides a method of preparing a dry powder for oral suspension composition of Cefditoren Pivoxil, which is suitable for suspension in water and/ or water miscible suitable solvents to form an orally administrable product.
The details of one or more embodiments are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
DETAIL DESCRIPTION OF THE INVENTION
The present inventors have found that the unpleasant taste and stability problem of Cefditoren Pivoxil may be addressed by employing Cefditoren Pivoxil in taste-masked, dry powder form suitable for suspension. Because of utilization of flavoring and sweetening agents, the external vehicle is pleasantly flavoured, which helps in minimizing the problem of bitterness. Further because of micronized particle size of the active agent, it remains suspended in the suspension and does not come in direct contact with the tongue for longer duration of time and thereby minimizing the discomfort of patients because of bitter taste.
Further, the preparation is reconstituted just prior to usage, its physical and chemical stability is enhanced. The suspension formed is particularly convenient for pediatric and geriatric patients, as it is easily dissolved and quickly dispersed in water during their usages. Further, since the

preparation is presented in the form of granule in suitable container, the caking problem & uneven dosing is avoided.
Typically, the present invention relates to the taste masked dry powder for suspension which is prepared by using non-aqueous granulation method. The compositions include a mixture of Cefditoren Pivoxil or its salts/derivatives and pharmaceutically acceptable excipients selected from suspending agents, viscosity enhancers, coating agents, preservatives, flavouring agents, sweeteners, opacifiers, lubricants, glidants, wetting agents, surfactants, buffering agents, and diluents. Cefditoren Pivoxil may be present at up to about 70% by weight of the dry powder for suspension composition. Upon reconstitution, each mL of oral suspension may contain up to 1 to 100 mg and preferably 2 to 50 mg of Cefditoren.
"Dry powder", as used herein, includes any composition which is dry and flowable such as, for example, granules, powder, flakes, spheroids and other forms which can be readily prepared and when added to an ingestible liquid and mixed, give the desired liquid suspension.
The term "suspending agent" or "viscosity enhancer", as used herein, refers to an agent or a mixture of agents that increases the thickness of a liquid thereby making it slow to flow. For example, in a suspension a viscosity enhancer will help to keep the active ingredient suspended to allow accurate dosing. They may be selected from one or more cellulosic derivatives, gums, polysaccharides, silicates, alginates, acrylic acid copolymers, polyvinyl pyrrolidone, or combinations thereof. Representative suspending agents or viscosity enhancers include, but are not limited to, acacia, alginic acid, bentonite, carbomer, carboxymethylcellulose calcium, carrageenan, colloidal silicon dioxide, dextrin, gelatin, guar gum, magnesium aluminium silicates, hydroxyl ethyl cellulose, hydroxyethylpropylcellulose, hydroxyl propyl cellulose (HPC), hydroxypropyl methylcellulose, methylcellulose, maltodextrin, microcrystalline cellulose (MCC), polydextrose, polyvinyl alcohol, povidone, propylene glycol alginate, sodium alginate, sodium carboxymethylcellulose, starch, tragacanth, xantham gum, and mixtures thereof. The preferred agent is magnesium aluminium silicates. The preferred suspending agent added at a proportion of 1-20% by weight of the total composition.

The term "flavouring agent", as used herein, refers to an agent or a mixture of agents that is natural or artificial in origin and adds flavour to a mixture. Representative flavouring agents include, but are not limited to, banana, black currant, caramel, cherry, chocolate, cream, grenadine, mint, raspberry, strawberry, tuttifrutti flavours, and mixtures thereof. To enhance organoleptic properties, combination of flavours may be used. For example, strawberry and banana flavours may be used together. The preferred flavouring agent added at a proportion of 1-20% by weight of the total composition.
The term "sweetener", as used herein, refers to both bulk (caloric) and intense (non-caloric) sweeteners, which impart sweet taste to the preparation. Examples of bulk sweeteners are dextrose, fructose, glucose, hydrogenated glucose syrup, isomalt, maltitol, maltose, mannitol, sorbitol, sucrose, xylitol, and mixtures thereof. Examples of intense sweeteners are acesulfame, alitame, aspartame, cyclamate, dihydrochalcone sweetener, monellin, neohesperidin, neotame, saccharin, stevioside, sucralose, the pharmaceutically acceptable salts thereof such as sodium or calcium saccharin, acesulfame potassium or sodium cyclamate, and mixtures thereof. Sweetener type, combination and proportion may be varied in various compositions. The preferred sweeteners are selected from sucrose and sucralose and may be added at a proportion of 0-90% by weight of the total composition. Further, these agentsmay be used alone or in combination.
The term "granulating solvent" as used herein refers to a pharmaceutically acceptable nonaqueous granulating solvent selected from the group consisting of acetone, ethanol, isopropyl alcohol and mixtures thereof.While non-aqueous solvents may be employed to prevent aqueous-induced transitions and/or hydrolysis, phase transformation may still occur during processing. Moreover, the use of non-aqueous granulating fluids may also lead to a significant change in granule characteristics, such as fracture strength, bulk density and compatibility.
The term "preservative", as used herein, refers to an agent or mixture of agents that is used to protect a composition against microbes (e.g., yeast, mold; bacteria, etc). Representative preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butyl paraben, chlorobutanol, chlorocresol, chlorhexidine, cresol, ethylenediamine tetraacetic acid, ethyl paraben, imidurea, methyl

paraben, phenol, phenylmercuric salts, potassium sorbate, propylene glycol, propyl paraben, sodium benzoate, sodium citrate, sodium propionate, sorbic acid, thiomerosol, and mixtures thereof. A preferred preservative is sodium benzoate or mixture of parabens, which impart synergistic preservative action.
The term "opacifier", as used herein refers to an agent or a mixture of agents which when added to a preparation make the ensuing system opaque. Representative opacifier agents include, but are not limited to, pharmaceutically acceptable metal oxides, especially titanium dioxide.
The term "lubricant", as used herein refers to an agent or a mixture of agents that lessens or prevents friction. Representative lubricants include, but are not limited to, calcium stearate, colloidal silicon dioxide, corn starch, hydrogenated vegetable oil, magnesium oxide,
magnesium stearate, sodium lauryl stearate, sodium stearylfumarate, stearic acid, talc, zinc
> stearate, and mixtures thereof.
The term "glidant", as used herein, refers to an agent or a mixture of agents that facilitates the flow of powders in the manufacturing process. Representative glidants include, but are not limited to, calcium stearate, colloidal silicon dioxide, fumed silica, magnesium stearate, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, and mixtures thereof.
The term "wetting agent" or "surfactant", as used herein, refers to a surface active agent or a mixture of agents that lower the interfacial tension between a solid & a liquid or two liquids. It may be natural or synthetic in origin. Further, it may be non-ionic, anionic, cationic or amphoteric in nature. Representative examples include, but are not limited to, acacia, poloxamers, polysorbates such as Tween®40, 60 & 80, sodium lauryl sulphate, sodium monolaurate (Span 20), tragacanth, and mixtures thereof.
The term "buffering agent", as used herein, refers to an agent or amixture of agents that can maintain the original acidity or basicity of a composition. Representative buffering agents include, but are not limited to, citric acid, disodium hydrogen phosphate, lactic acid,

monosodium citrate, phosphoric acid, potassium citrate, sodium citrate, sodium hydrogen carbonate, sodium hydroxide, sodium phosphate, succinic acid, tartaric acid, and mixtures thereof. The amount of buffering agent used is dependent on (a) the desired pH; and (b) the amount of Cefditoren Pivoxil per mL of the suspension.
The term "diluent", as used herein, refers to an agent or mixture of agents that when added to a formulation makes that formulation thinner or less concentrated or acts as filler and may also improve manufacturability. Diluents can also serve other functions. For example, a diluent can also act as a sweetener and/or a suspending agent. Representative diluents include, but are not limited to, dextrose, fructose, lactose, maltitol, microcrystalline cellulose, sorbitol, starch, sucrose, xylitol, and mixtures thereof. Preferred diluent issucrose.
The term "antioxidant", as used herein, refers to an agent or a mixture of agents, which are capable of slowing or preventing the oxidation of other molecules or substances. Representative examples include, but are not limited to, ascorbic acid, butylatedhydroxy anisole, butylatedhydroxy toluene, gallic acid, maleic acid, propyl gallate, sodium bisulphate, sodium metabisulphite, tocopherols, and mixtures thereof.
Pharmaceutical compositions as described herein are presented as dry powder suspension composition for constitution with an ingestible liquid such as water before use. The dry powder for suspension composition can be packed in suitable containers to provide multi-dose liquid suspension.
The dry powder after reconstitution with water is set to provide a liquid suspension containing typically 1 to 100 mg of Cefditoren Pivoxil per 5 to 100 mL of liquid suspension. The dry powder for suspension composition is stable on storage and when constituted with an ingestible liquid for administration, the corresponding liquid suspension is stable physically and chemically for the duration in which the therapy is required.
The dry powder for suspension composition is typically prepared by a non aqueous granulation procedure. A typical process involves the following steps:

a) Sieving the Cefditoren Pivoxil and other excipients to obtain the desired particle size range
b) Dry blending the active ingredients with suitable excipients, preferably in geometric mixing sequence
c) Granulating the blend with non-aqueous solvent
d) Drying the granules and sieving them to obtain a desired range
e) Lubricating the granules with lubricant
f) Filling the lubricated granules into suitable containers.
The granules obtained by the above process have certain beneficial features. For example, the composition exhibits enhanced taste-masking capability by non-aqueous granulating method of Cefditoren Pivoxil with sweeteners & flavours. The granules are easy to reconstitute and typically within 2-minutes a stable suspension is formed. Further, the composition has better in-use stability and prolonged shelf life. Further, non-aqueous granulation method provides characteristics features such as fracture strength, bulk density, uniform mixing, uniform size and shape, improve flow property, dose uniformity, comparability, etc. It also provides efficient taste masking of bitter API than dry-mix formulation.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.
EXAMPLES
Example 1: Dry powder for oral suspension
Table 1: Composition of Dry powder for suspension

No. Ingredients Quantity (Wt %)
1 Cefditoren Pivoxil 20-40
2 Sucrose 60-70
3 Xanthan Gum 1-5%
4 Colloidal silicon Dioxide 5-20%
5 Sucralose 0.1-3%

6
Flavour Trusil Orange 3-10%
7 Aluminum Magnesium silicates 1-5%
8 Isopropyl Alcohol q.s.
Example - 2: Stability of the Dry powder for oral suspension Formulation
Three formulations as described above were prepared and developed formulations were evaluated under various conditions of stability testing and data is presented below:
Table 2: Accelerated Stability Study of Dry powder for oral suspension Formulation

Product
Stability Study Type Accelerated Stability Study Data
Stability Condition 40±2°C &75±5 % RH

No Test Formulation 1 Formulation 2 Formulation 3

Initial 1 M 3M 6M Initial IM 3M 6M Initial IM 3M 6M
1.0 Description Off-White to pale yellow colour powder
3.0 pH 5.64 5.76 5.22 5.22 5.66 5.68 5.31 5.40 5.57 5.61 5.19 5.29
4.0 Assay 98.80 99.5 97.9
4 98.57 98.89 99.55 97.7 5 99.4 5 98.16 98.73 97.51 98.68
Table 3: Long term stability for Dry powder for oral suspension Formulation

Product
Stability Study Type Long term stability Data
Stability Condition 30±2°C &75±5 % RH

No Test Formulation 1 Formulation 2 Formulation 3

Initial IM 3M 6M Initial IM 3M 6M Initial IM 3M 6M

1.0
Description Off-White to pale yellow colour powder
3.0 pH 5.64 5.85 5.38 5.31 5.66 5.96 5.45 5.37 5.62 5.71 5.33 5.50
4.0 Assay 98.80 99.81 98.56 99.1 4 98.89 100.46 98.65 99.52 98.58 99.54 99.01 99.46

We claim:
1. An oral taste masked pharmaceutical composition of Cefditoren or pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition of claim 1, which comprises of taste masked granules of Cefditoren or pharmaceutically acceptable salt thereof.
3. The Pharmaceutical composition of claim 2,wherein the composition is provided as dry syrups, sachets, tablets and powders that can be reconstituted to make suspension.
4. The Pharmaceutical composition of claim 2, which is reconstituted with ingestible liquid to prepare the suspension.
5. The Pharmaceutical composition of claim 2, wherein the taste masked granules comprises Cefditoren or pharmaceutically acceptable salt thereofand pharmaceutically acceptable excipients selected from group consisting of sweetening agents, binders, diluents/fillers, suspending agents, glidants, disintegrants, lubricants, structuring agents, wetting agents, solubilizers, buffers, coloring agents, disintegrants, preservatives and pH stabilizers.
6. The pharmaceutical composition of claim 2, wherein the amount of Cefditoren or pharmaceutically acceptable salt is in the range of 1 -70% by weight of the composition.
7. The Pharmaceutical composition of claim 5, wherein the Sweeteners are present in the range of 1 to 20% weight of total composition
8. The Pharmaceutical composition of claim 2, wherein the taste masked granules of Cefditoren pivoxil prepared by using non-aqueous granulation.

9. The pharmaceutical composition of claim 1, wherein Cefditoren pivoxil having an average particle diameter less than 100 μm, preferably less than 50 μm and more preferably less than 20 μm.
10. A process to prepare the pharmaceutical composition of claim 1 comprising:

a) Sieving the Cefditoren Pivoxil and other excipients to obtain the desired particle size range
b) Dry blending the active ingredients with suitable excipients
c) Granulating the blend with non-aqueous solvent
d) Drying the granules and sieving them to obtain a desired range
e) Optionally Lubricating the granules with lubricant
f) Filling the granules into suitable containers.