Title of Invention


Abstract The present invention discloses a stable liquid oral formulation comprising synthetic H1 receptor antagonist, fexofenadine in the form of acid addition salts, hydrates, polymorphs or mixture thereof, suitable to be encapsulated in soft gelatin capsule. The present invention also provides methods of preparing the same.
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1. TITLE OF THE INVENTION: "Liquid oral formulation containing
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: No. 201, 'Devavrata' Sector 17, Vashi, Navi Mumbai - 400
703, Maharashtra, India
The following specification particularly describes the invention.

Technical field:
This invention relates to a liquid oral formulation containing antihistamine such as fexofenadine and a process for preparation of the same.
Background of the Invention:
Fexofenadine is a water soluble, antihistamine drug with the chemical name: (±)-4-[l-hydroxy-4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-butyl]-(a),(a)-dimethyl benzeneacetic acid hydrochloride. Fexofenadine binds to histamines and prevents them from carrying out their function. Therefore, Fexofenadine is known as a Hi- receptor antagonist, since Fexofenadine can block the histamines in the body, it is used as a treatment for allergies. Fexofenadine hydrochloride is a white to off-white crystalline powder; it is freely soluble in methanol and ethanol, slightly soluble in chloroform and water, and insoluble in hexane.
Fexofenadine was first mentioned in US 4254129. It is acknowledged in the art and is commercially available, in particular as an oral tablet or capsule, under the trade name Allegra, RTM.
US6723348 discloses orodispersible tablets containing fexofenadine as coated granules.
US2001051613 relates to a pharmaceutical formulation of fexofenadine where in the excipient used to enhance solubility in water, is cyclodextrin.
WO03075829 provides a process of making a bitter tasting drug to a tasteless drug and
their dosage forms. Specifically fexofenadine is produced as a fast dissolving carbomer
US 2004062801 provide a dual release dosage form containing a neuraminidase inhibitor
and an antihistaminic antagonist (which could be fexofenadine).
US6248363, US6294192 US6383471, US6451339 disclose compositions for improved delivery of active ingredients which include fexofenadine as well. But none of them provide fexofenadine or any of its form as a preferred embodiment.

US20040157928 provides a formulation for acidic actives (which could be fexofenadine) with poor solubility using a pharmaceutically acceptable cation along with other excipients.
US20040247666 relates to prompt-release oral pharmaceutical compositions containing active (which could be fexofenadine) in an amphiphilic matrix for improving bioavailability with a component based on cyclodextrin and other excipients.
CA2396145 provides an osmotic device which controls the release of pseudoephidrine in the core in combination with a rapid release Hi antagonist (which could be fexofenadine) in the external coat.
Oral administration of fexofenadine is highly active. One particular draw back of the oral compositions of Fexofenadine is its unpleasant, strong bitter taste and after taste.
Another drawback of the oral formulations of fexofenadine is its low solubility, especially in gastric conditions.
It is therefore highly desirable to develop soft gelatin capsules, containing fexofenadine, which have taste-masking properties due to the encapsulation of the active ingredient while permitting release and absorption of the active substance from the matrix in the body after oral administration. It is a known fact that compared to tablets and hard gelatin capsules the bioavailability of the drug is better with soft gelatin capsules. These capsules are also aimed for better patient compliance because of its soft and elastic characteristics making it easier to swallow when compared to conventional tablets or hard gelatin capsules.
Summary of the Invention:
In one aspect, the present invention provides a stable liquid oral formulation comprising synthetic Hi receptor antagonist, fexofenadine in the form of acid addition salt, preferably fexofenadine hydrochloride, which is encapsulated in soft gelatin capsule.

In another aspect, the invention provides a process for preparation of liquid soft gel fill formulation of fexofenadine hydrochloride.
Detailed description of Invention:
The present invention describes an orally administered stable liquid pharmaceutical formulation containing Fexofenadine and a preferred method of its preparation. The liquid formulation of Fexofenadine is encapsulated into soft gelatin capsule.
In the present patent application, the term "fexofenadine" is employed for designating anyone of the specific forms such as salt, hydrate, ester or any of its polymorphic form. The compositions of the present invention essentially comprise suspended/solubilized fexofenadine in a total concentration of 18 to 35% by weight of the total liquid.
In one preferred embodiment of the present invention, there is provided a fill formulation wherein fexofenadine hydrochloride is present in the solubilized form along with the solubilizers, cosolvents and viscosity imparting agents
One or more solubilizers are suitable for use herein, provided that the solubilizing system is suitable to solubilize the active and other excipients which are compatible with softgel shell wall and also suitable for encapsulation within soft gel capsules.
Examples of suitable solubilizers used in the present invention are selected from a group comprising of, but not limited to, Diethylene glycol monoethyl ether (Transcutol®) and polyethylene glycols, preferably PEG-400. It could be used alone or in combination thereof. The compositions of the present invention comprise solubilizers in a variable concentration of 35 % to 85%.
The co-solvents are selected from a group comprising of aliphatic alcohols like ethylene glycol, propylene glycol, or mixture thereof, and glycerine or combinations thereof. The concentration of the co-solvents used in the present invention may be in the range of 5 % to 15%.

Viscosity imparting agent is selected from polyvinyl pyrrolidones, preferably K-30. The composition comprise viscosity agent, preferably in a concentration of 7% to 18%.
In another embodiment, the present invention provides a suitable process for preparation of stable fill formulation, which comprises the steps of:
a) mixing of propylene glycol or glycerin or a mixture of both, Polyethylene glycol 400, and diethylene glycol monoethyl ether;
b) heating the above mixture;
c) adding and dissolving the polyvinyl pyrrolidone with continuous stirring and heating;
d) adding and dissolving Fexofenadine HC1 with continuous stirring and heating to get the clear solubilized fill.
Further, this clear solubilized fill was encapsulated into soft gelatin capsules
In another preferred embodiment, there is provided a fill formulation, wherein fexofenadine hydrochloride is present in suspension form along with surfactants, viscosity imparting agents and a suitable vehicle.
Examples of suitable surfactants includes, but not limited to lecithin, glyceryl monostearate, soyalecithin and the other surfactants or a combination thereof known in the art. The surfactant preferably present in an amount of 1 to 2%.
Example of suitable viscosity imparting agents used in the present invention are selected from a group comprising of, but not limited to saturated fatty acid esters, glycerylmonostearate, cetostearyl alcohol, waxes like bees wax, hard wax and preferably glyceryl monostearate. The viscosity imparting agent preferably present in an amount of 5 to 6%.

Suitable lipophilic vehicles used in the present invention are selected from a group comprising, but not limited to fatty oils which could be either of animal or vegetable origin such as fish oil or, sesame oil, or synthetic fatty acid esters, like, ethyl oleate or triglycerides. In the present invention, one preferred vehicle is vegetable oil such as refined peanut oil. The compositions comprise lipophilic vehicle in an amount of 50 to 70%.
Yet, in another embodiment, the invention provides a process for preparation of a stable liquid suspension formulation, which comprises the steps of:
a) heating to melt glyceryl monostearate in refined peanut oil;
b) adding and dispersing lecithin;
c) adding and dispersing Fexofenadine HC1 in the above mixture and
d) mixing well the above mix to obtain suspended fill formulation.
Further, the above prepared fill formulation is encapsulated into a soft gelatin capsule.
The following example will serve to illustrate the practice of the invention however this is by no means a limiting disclosure.
Example 1

Ingredients Amount per Capsule (mg)
Fexofenadine hydrochloride (active ingredient) 180
Propylene glycol 5-15%
PVP-K30 7-18 %
Transcutol 40-50 %
PEG-400 10-20%

Process of Preparation:
1) The propylene glycol, PEG-400 and transcutol were taken in a beaker and heated up to 70 to 80°C;
2) Once the solution is hot then the PVP-K30 was added to it and stirred with the help of a glass rod till a clear solution is formed
3) Then the active ingredient was incorporated in the solution slowly with continuous stirring till a clear solution is formed.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative example and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Dated this 5th day of April 2006
Dr. Gopakumar G. Nair Agent for the Applicant






538-MUM-2006-CLAIMS(MARKED COPY)-(11-6-2012).pdf

538-MUM-2006-CLAIMS(MARKED COPY)-(18-3-2011).pdf







538-mum-2006-description (provisional).pdf


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538-MUM-2006-FORM 18(3-10-2008).pdf

538-mum-2006-form 2(3-4-2007).pdf

538-mum-2006-form 2(title page)-(3-4-2007).pdf

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538-MUM-2006-REPLY TO EXAMINATION REPORT(18-3-2011).pdf

538-MUM-2006-REPLY TO HEARING(11-6-2012).pdf

Patent Number 253721
Indian Patent Application Number 538/MUM/2006
PG Journal Number 34/2012
Publication Date 24-Aug-2012
Grant Date 17-Aug-2012
Date of Filing 05-Apr-2006
Applicant Address NO. 201, 'DEVAVRATA" SECTOR 17, VASHI, NAVI MUMBAI
# Inventor's Name Inventor's Address
1 KATAGERI, SHIVARAJ BASAVARAJ STAR Bldg., Bilekahalli, Bannerghatta Road, Banglore - 560 076
2 IYER, VENKAT SUBRAMANIAM STAR Bldg., Bilekahalli, Bannerghatta Road, Banglore - 560 076 Karnataka, India.
PCT International Classification Number A61K9/00;A61K31/445
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA