FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITION COMPRISING FEXOFENADINE AND PSEUDOEPHEDRINE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition comprising fexofenadine or salts thereof and pseudoephedrine or salts thereof along with pharmaceutical^ acceptable excipients a process for the preparation of said composition wherein the composition is prepared by dry granulation method.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION

The present invention provides a pharmaceutical composition comprising fexofenadine or salts thereof and pseudoephedrine or salts thereof along with pharmaceutically acceptable excipients and process for the preparation of said composition wherein the composition is prepared by dry granulation method.
Fexofenadine hydrochloride is a histamine H-i-receptor antagonist with the
chemical name (±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-
butyl]-a, a-dimethyl benzeneacetic acid hydrochloride (Formula I). Commercially
fexofenadine is marketed by Sanofi Aventis under the trade name as Allegra®
and Allegra-D® wherein Allegra® contains Fexofenadine hydrochloride and
Allerga-D® is a combination of Fexofenadine hydrocloride and Pseudoephedrine
hydrochloride. Fexofenadine, the major active metabolite of terfenadine, is an
antihistamine with selective peripheral H-i-receptor antagonist activity.
Fexofenadine hydrochloride inhibited antigen-induced bronchospasm in
sensitized guinea pigs and histamine release from peritoneal mast cells in rats.

Pseudoephedrine hydrochloride, is an adrenergic (vasoconstrictor) agent with the
chemical name [S-(R*,R*)]-a-[1-(methylamino)ethyl]-benzenemethanol
hydrochloride (Formula II). It is an orally active sympathomimetic amine and
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exerts a decongestant action on the nasal mucosa. Pseudoephedrine hydrochloride is recognized as an effective agent for the relief of nasal congestion due to allergic rhinitis.

U.S Patent Nos. 3,819,706 discloses generically the compound fexofenadine and its salts thereof.
U.S. Patent No. 4,996,061 discloses a pharmaceutical composition in the form of a multiple-compression tablet comprising of two discrete zones.
U.S. Patent No. 4,792,452 discloses a tablet formulation composed of a pH-dependent salt of alginic acid, a pH-independent hydrocolloid gelling agent, binder and excipients.
U.S. Patent 6,039,974 discloses a pharmaceutical composition in the form of a bilayer tablet comprising a sustained release layer decongestant and an immediate release layer of antihistaminic drugs.
U.S. Patent No. 6,267,986 discloses a process for the preparation of a controlled release pharmaceutical composition in the form of a bilayer tablet comprising fexofenadine and pseudoephedrine.
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U.S. Patent No. 6,994,871 discloses controlled release pharmaceutical formulation comprising effective amounts of both an antihistamine and a decongestant.
U.S. Application No. 20050220877 describes a bilayer tablet comprising sustained-release of the sympathomimetic drug or the pharmaceutically acceptable salt thereof, and an immediate-release of the piperidinoalkanol or the pharmaceutically acceptable salt thereof.
Several PCT application WO2002036077, WO2003084510 and WO2006048699 disclose controlled release pharmaceutical formulations comprising an antihistamine and a decongestant.
Fexofenadine is a long acting decongestant with elimination half-life of 14 hr whereas pseudoephedrine is a short acting antihistaminic agent with half-life of 4-6 hr. Therefore the pharmaceutical compositions comprising combination of these two active ingredients contain immediate release fexofenadine and sustained release pseudoephedrine. A number of processes are known in the art for the manufacture of such combination pharmaceutical compositions. However, there is still the need of developing new processes for the manufacture, which can provide the ease of preparation, better compressibility, desired dissolution profile, therapeutic effectiveness, stability and also cost effectiveness. Present inventors while working on the development of pharmaceutical composition comprising fexofenadine and pseudoephedrine have surprisingly found that this combination pharmaceutical composition when prepared by dry granulation method results in a better compressibility, improved stability along with the desired dissolution profile.
In one of the aspects of the present invention, there is provided a pharmaceutical composition comprising fexofenadine or salts thereof and pseudoephedrine or
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salts thereof along with pharmaceutically acceptable excipients wherein the said composition is prepared by dry granulation method.
In yet another aspects of the present invention, there is provided A process for the preparation of a pharmaceutical composition comprising fexofenadine or salts thereof and pseudoephedrine or salts thereof wherein the said process comprises preparation of A) granules of fexofenadine or salts thereof by
i) compacting the blend fexofenadine or salts thereof and
optionally one or more pharmaceutically acceptable excipients
ii) converting compacts of step i) into granules
iii) optionally blending the granules of step ii) with pharmaceutically
acceptable excipients
and B) granules of pseudoephedrine or salts thereof by:
i) compacting the blend of pseudoephedrine or salts thereof and pharmaceutically acceptable rate controlling polymer and optionally one or more pharmaceutically acceptable excipients
ii) converting compacts of step i) into granules
iii) optionally blending the granules of step ii) with pharmaceutically acceptable excipients
The pharmaceutical composition comprising fexofenadine or salts thereof comprises hydrochloride salt of fexofenadine. The pharmaceutical composition comprising pseudoephedrine or salts thereof comprises hydrochloride salt of pseudoephedrine. The pharmaceutical composition contains 10 to 200 mg of fexofenadine HCI and 50 to 300 mg of pseudoephedrine HCI.
The pharmaceutical composition comprising fexofenadine hydrochloride and pseudoephedrine hydrochloride can be prepared in two parts. First part comprises the preparation of immediate release fexofenadine HCI wherein fexofenadine HCI along with intragranular pharmaceutically acceptable excipients is compacted using Roll compactor to form slugs. The slugs can be sized using
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suitable apparatus to get granules of desired size. The granules so obtained can be blended with extragranular pharmaceutically acceptable excipients. In the second phase pseudoephedrine HCI and a pharmaceutically acceptable rate-controlling polymer along with intragranular pharmaceutical excipients can be compacted using a Roll Compactor to form slugs. The slugs can be sized using a suitable apparatus to get granules of desired size. The granules so obtained can be blended with extragranular pharmaceutically acceptable excipients. The granules of first part and second part can be formulated to capsule, tablet, bilayer tablet, granules, minitablets, sachets and the like. The pharmaceutical composition can optionally coated with aqueous dispersion of Opadry.
The dry granulation process offers significant advantages over other method of preparations. The granules of pseudoephedrine HCI with the pharmaceutically acceptable rate-controlling polymer prepared by wet granulation method are hard and exhibit poor compressibility. This further leads to problems in compressing the granules of pseudoephedrine HCI with the granules of fexofenadine HCI. Dry granulation process offers the advantage of being a simple and cost effective method along with ease of preparation.
The pharmaceutical composition of the present invention exhibits a dissolution profile such that after 10 minutes 90% or more of fexofenadine HCI is released and after 10 hr, about 80% or more pseudoephedrine HCI is released in 900 ml of 0.001 N HCI at 50 rpm. The said tablet also exhibits similar dissolution profile as that of Allegra-D® tablet (commercially available fexofenadine and Pseudoephedrine tablets).
The pharmaceutical composition of the present invention contains less than 0.11% of the related impurities after storage for three months at 40°C and 75% relative humidity. Such a high degree of stability of the pharmaceutical compositions of present invention is attributed the dry granulation process of
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preparation. The pharmaceutical composition prepared by dry granulation has considerably low water content, which imparts better stability.
The pharmaceutical composition of the present invention comprises therapeutic effective amounts of fexofenadine or salts thereof and pseudoephedrine or salts thereof. The pharmaceutical composition of the present invention is useful in the of prophylaxis ,and treatment of allergic rhinitis.
The pharmaceutically acceptable rate controlling polymers can be selected from a group comprising of one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers and mixtures thereof. Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties. Suitable polyuronic acid salts include one or more of alkali metal salts of alginic acid or pectic acid and mixtures thereof. Suitable alkali metal salts of alginic acid that may be used include one or more of sodium alginate, potassium alginate, ammonium alginate and other suitable alkali metal salts of alginic acid. Suitable cellulose ethers include one or more of hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and other suitable cellulose ethers. Suitable acrylic acid polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name carbopol.
The intragranular and extragranular pharmaceutically acceptable excipients can be filler, binder, disintegrant, lubricant, glidant, and the like. Suitable binders may be one or more selected from a group of starch, sugars, gums, low molecular weight hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, crosspovidone and hydroxypropyl cellulose and the like. Suitable fillers may be one or more of lactose, dicalcium phosphate, pregelatinized starch, microcrystalline cellulose, mannitol and the like. Suitable disintegrants can be one or more of starch, pregelatinized starch, L-HPC, croscarmellose sodium, crospovidone, sodium
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starch glycolate and the like. Suitable lubricants may be one or more talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate and the like. Suitable glidants may be one or more of microcrystalline cellulose, colloidal silicon dioxide, talc, magnesium stearate and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1
The pharmaceutical composition of fexofenadine hydrochloride and pseudoephedrine hydrochloride is provided in Table 1.
Table 1

Ingredient Name % w/w
Part 1
Intragranular
Fexofenadine HCI 5-50%
Microcrystalline cellulose 10-90%
Croscarmellose sodium 1-20%
Povidone 01-10%
Magnesium stearate 0.1-10%
Extragranular
Microcrystalline cellulose 2-20 %
Croscarmellose sodium 1-20%
Magnesium stearate 0.1-10%
Part II
Intragranular
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Pseudoephedrine HCI 5-50%
Microcrystalline cellulose 2-20%
Hypromellose 10-90%
Iron oxide red 0.05-5%
Colloidal silicon dioxide 0.1-5.0%
Magnesium stearate 0.05-5.0%
Extragranular
Colloidal silicon dioxide 0.1-5.0%
Magnesium stearate 0.05-5.0%
Film Coating
Opadry 1-5%
Purified water q.s.
Procedure:
The pharmaceutical composition is prepared in two parts.
Part I: Fexofenadine HCI, microcrystalline cellulose, croscarmellose sodium,
povidone and magnesium stearate are weighed and blended together. This blend
is compacted in Roll compactor to form slugs. The slugs are passed through
oscillating granulator to obtain the granules. The granules are blended with the
accurately weighed extragranular excipients i.e. microcrystalline cellulose,
croscarmellose sodium and magnesium stearate.
Part II: Pseudoephedrine HCI, microcrystalline cellulose, hydroxy propyl methyl
cellulose, iron oxide, colloidal silicon dioxide and magnesium stearate are
weighed and blended together. This blend is compacted in Roll compactor to
form slugs. The slugs are passed through oscillating granulator to obtain the
granules. The granules are blended with the accurately weighed extragranular
excipients i.e. colloidal silicon dioxide and magnesium stearate.
The granule of Part I and Part II are compressed using appropriate tooling to
form a bilayer tablet. The bilayer tablet is coated with Opadry YS-IR-7006 Clear.
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The dissolution profile of fexofenadine HCI and Pseudoephedrine HCI from the pharmaceutical composition of Example 1 is studied in 900 ml of 0.001 N HCI using USP Type 2 Apparatus at 50 rpm.
Figure 1 Comparative release of fexofenadine HCI from ER tablets of Example 1 and Allegra-D®
Figure 2 Comparative release of pseudoephedrine HCI from ER tablets of Example 1 and Allegra-D®
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We CLAIM:
1. A pharmaceutical composition comprising fexofenadine or salts thereof and pseudoephedrine or salts thereof along with pharmaceutically acceptable excipients wherein the said composition is prepared by dry granulation method.
2. A process for the preparation of a pharmaceutical composition comprising fexofenadine or salts thereof and pseudoephedrine or salts thereof wherein the said process comprises preparation of A) granules of fexofenadine or salts thereof by
i) compacting the blend fexofenadine or salts thereof and optionally one or more pharmaceutically acceptable excipients
ii) converting compacts of step i) into granules
iii) optionally blending the granules of step ii) with pharmaceutically acceptable excipients
and B) granules of pseudoephedrine or salts thereof by:
i) compacting the blend of pseudoephedrine or salts thereof and pharmaceutically acceptable rate controlling polymer and optionally one or more pharmaceutically acceptable excipients
ii) converting compacts of step i) into granules
iii) optionally blending the granules of step ii) with pharmaceutically acceptable excipients
3. The pharmaceutical composition and the process of preparation according to claim 1 and 2, wherein fexofenadine or salts thereof is present as hydrochloride salt of fexofenadine.
4. The pharmaceutical composition and the process of preparation according to claim 1 and 2, wherein pseudoephedrine or salts thereof is present as hydrochloride salt of pseudoephedrine.
5. The pharmaceutical composition and the process of preparation according to claim 1 and 2, wherein the pharmaceutical composition exhibits a dissolution profile such that after 10 minutes 90% or more of
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fexofenadine HCI is released and after 10 hr, about 80% or more pseudoephedrine HCI is released in 900 ml of 0.001 N HCI at 50 rpm.
6. The pharmaceutical composition and the process of preparation according to claim 1 and 2, wherein the pharmaceutical composition contains less than 0.11% of the related impurities after storage for three months at 40°C and 75% relative humidity.
7. The pharmaceutical composition and the process of preparation according to claim 1 and 2, wherein the pharmaceutical composition is useful in the treatment of allergic rhinitis.
8. The pharmaceutical composition and the process of preparation according to claim 1 and 2, wherein pharmaceutically acceptable excipients include filler, binder, disintegrant, glidant and lubricant.
, 9. The pharmaceutical composition and the process of preparation according to claim 1 and 2, wherein the pharmaceutical composition is capsule, tablet, bilayer tablet, granules, minitablets and sachets.
Dated this, 27 th day of April, 2007

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