FORM 2
THE PATENTS ACT, 1970 (39 OF 1970) & THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)


TITLE OF THE INVENTION "NOVEL DISPERSIBLE TABLET COMPOSITIONS OF LORATADINE"
We, BA RESEARCH INDIA LIMITED, of BA Research House, Opposite "Pushparaj Towers", Nr. Judges Bungalows, Bodakdev, Ahmedabad-380-054, Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed:


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FIELD OF INVENTION
The present invention relates to a novel dispersible tablet composition of Loratadine, which rapidly disperses in water to produce a homogeneous dispersion that ensures uniformity of dose and desired therapeutic outcome. BACKGROUND OF INVENTION
Loratadine or ethyl 4-(8-chloro-5,6-dihydro-l lH-benzo[5,6] cyclohepta [1,2-b] pyridin-1 l-ylidene)-l-piperidine carboxylate is useful as an antihistamine and is disclosed in U.S. Pat. No. 4,282,233.
Loratadine is particularly advantageous for use of an antihistamine compared to other drugs of the same class as it is administered only once daily and has little or no sedative effects.
It is therefore preferred for use by patients who have to perform mental or physical tasks requiring a high level of concentration. Loratadine however poses problems to the formulator as it has low solubility in water and therefore shows poor bioavailability characteristics.
Pharmaceutical suspensions are uniform dispersions of solid drug particles in a vehicle in which the drug has minimum solubility. These are usually formulated to improve chemical stability of drug, mask the unpleasant taste etc.
Solid oral dosage forms are most convenient from patient as well as from, manufacturing chemist's perspective. They ensure uniformity of dosage, are more robust, have less microbiological issues compared to liquid dosage forms. However immediate release tablets cannot act as a substitute for suspension. Thus, there is a need for a formulation, which overcomes the problems associated with the swallowing of solid dosage forms and act as a viable substitute for suspensions. One such dosage form is dispersible tablet. Dispersible tablets as defined in Ph. Eur. are uncoated or film coated tablets intended to be dispersed in water before administration giving a homogeneous dispersion. Typically a dispersible tablet is dispersed in about 5-15 ml of water and the resulting dispersion is administered to the patient. Dispersible tablets are required to disintegrate within 3 minutes in water at 15-25 °C. Also the dispersion produced from a dispersible tablet should pass through a sieve screen with a nominal mesh aperture of 710 microns. The dosage form provides advantages of both tablets and liquid formulations. These are convenient to carry, easy to manufacture and more stable.
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OBJECTS OF INVENTION
It is an object of the present invention to provide a composition of Loratadine in the form of a dispersible tablet.
It is a further object of the present invention to provide a dispersible tablet composition of Loratadine which rapidly disintegrate in water.
It is another object of the present invention to provide a composition of Loratadine which, when dispersed in water gives a homogeneous dispersion with a low rate of sedimentation. SUMMARY OF INVENTION
According to a preferred aspect of the present invention, there is provided a water-dispersible tablet comprising - Loratadine and-at least one excipient, which reduces the sedimentation rate of Loratadine. According to another aspect of the present invention there is provided a process for the preparation of a dispersible tablet of Loratadine. DETAILED DESCRIPTION
Typically suspensions have problem of settling of insoluble pharmacologically active ingredient like Loratadine resulting in non-uniformity of dosage. This problem has been addressed by addition of flocculating agents, wetting agents, viscolizers etc. However no such attempts of maintaining uniformity of dosage have been made in the case of dispersion formed using dispersible tablets as these agents may adversely affect the dispersibility of the formulation. It was surprisingly found that the dispersible tablet of Loratadine prepared in accordance with present invention not only achieves rapid disintegration and dispersion but also ensures dosage uniformity.
The composition of the present invention mainly includes - Loratadine and-at least one excipient, which reduces sedimentation rate of pharmacologically active ingredient.
The pharmaceutical unit may include along with Loratadine other functional components presented for the purpose of modifying the physical, chemical or taste properties of the pharmaceutical. For example the pharmaceutical unit may be in the form of ion-exchange or cyclodextrin complexes or the pharmaceutical unit may be included as a mixture or dispersion with various additives such as waxes, lipids, dissolution inhibitors, taste-masking or-suppressing agents, carriers or excipients, and fillers In certain embodiments of the present invention, one or a combination of more than one pharmacologically active ingredients can also be employed.
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Other important components of the instant invention are the excipients that reduce the sedimentation rate of the active ingredient. Such excipients may include polymers, waxes, wetting agents or others that interact ionically with the active ingredient. The preferred excipients for reducing sedimentation rate are hydrophilic polymers.
They increase the viscosity of the medium and maintain the wetted particles of the active substance(s) in homogeneous suspension, leading to reduction in their sedimentation rate. These polymers may be used alone or in combination.
Examples of polymers which can be used include but are not limited to: polyalkylene oxides such as polyethylene oxide; cellulose ethers such as hydroxypropylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose; gums such as gum arabic alginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, karaya, whelan; polyols such as propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol (PEG), sorbitol and glycerol; starch and starchbased polymers such as pregelatinized starch, acrylic acid and methacrylic acid polymers, and esters thereof, maleic anhydride polymers; polymaleic acid; poly(acrylamides); poly(olefinic alcohol)s; poly(N-vinyl lactams); polyoxyethylated saccharides; polyoxazolines; polyviny (amines; polyvinylacetates; polyimines; povidone vinylpyrrolidone/vinyl acetate copolymer and polyvinyl acetate, mixture of polyvinyl acetate and polyvinylpyrrolidone, chitin, cyclodextrin, gelatin, chitosan, and combinations thereof The preferred hydrophilic polymers are polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, microcrystalline cellulose, guar gum, xanthan gum, alginates and combinations thereof. The weight percent of the hydrophilic polymer in the dosage form is about 5 to 75 weight percent, preferably about 10 to 60 weight percent.
The present invention may also include a wetting agent which acts to reduce the surface tension between the aqueous media and the insoluble active, thereby facilitating the active's maintenance in the aqueous media. The wetting agent may be chosen from the broad classes of surfactants, including nonionic, cationic. anionic, and zwitterionic surfactants known in the art. These can include, for example, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters (Tween(R)), polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypropylene copolymers and block copolymers.
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Disintegrants are particularly important excipients of the present invention as they ensure the rapid dispersibility of the formulation. A careful selection of type and concentration of both hydrophilic polymer and disintegrants ensures rapid disintegration of the tablet with reduced sedimentation rate. The disintegrating agent can be selected from a group including but not limited to the following: starch, sodium starch glycolate, pregelatinised starch, crosslinked polyvinyl pyrrolidone, cross linked calcium or sodium carboxy methyl cellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, ion exchange resin, cross-linked polyacrylic acid, alginates, colloidal magnesium-aluminum silicate, calcium silicate and the like. The most preferred being cross linked polyvinyl pyrollidone and calcium silicate. The disintegrant may be present in an amount ranging from about 0.25% to about 50%, more preferably about 0.5 to about 30.0%) and most preferably about 1-20%) by weight based on the total weight of the composition.
The composition of the invention also typically includes other pharmaceutically acceptable excipients, usually incorporated to ease the manufacturing process as well as to improve the performance of the dosage form. Common excipients include diluents, lubricants, granulating aids, colorants, flavorants, surfactants, pH adjusters, anti-adherents and glidants etc. Such excipients may. routinely be incorporated in the dosage forms of this invention.
The present invention may additionally include one or more fillers or excipients in an amount within the range of from about 0 to about 90% by weight and preferably from about 1 to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose.
The present invention may additionally include one or more stabilizers. Stabilizers may include anti-oxidants, pH modulators etc. As used herein, "antioxidant" refers to a substance known to inhibit oxidation. Among preferred antioxidants suitable for use in accordance with the present invention include tocopherol, tocopherol acetate, tocopherol acid succinate, n-carotene, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin B, ascorbic acid, sodium ascorbate, calcium ascorbate and the like, including pharmaceutically acceptable salts and esters of these compounds. pH modifiers or buffers may also be used to maintain the pH of the final composition within a certain desired range.
As the composition is in the form of a tablet, it may include one or more table-ting lubricants in an amount within the range of from about 0.2 to about 8% and preferably from
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about 0.5 to about 2% by weight of the composition, such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, polyethylene glycol, colloidal silicon dioxide, sodium stearyl fumarate, carnauba wax and the like and mixtures thereof.
A coloring agent may be selected from any colorant used in pharmaceuticals which is approved and certified by the FDA. It may include Lake of Tartrazine, Lake of Quinoline Yellow, Lake of Sunset Yellow and Lake of Erythrosine, Lack of Carmosine Ponceau. Allura Red, iron oxide red. ion oxide yellow.
The dispersible solid oral dosage forms according o the present invention can be in the form of tablets, capsules, pellets, granules, powders, coated granules, coated pellets etc. The preferred dosage form of the present invention is a tablet. The coated granules or pellets can be filled in capsules or compressed into a tablet.
Tablets of Loratadirie in accordance with this invention may be manufactured using conventional tableting techniques like: 1) Direct compression 2) Wt granulation 3) Dry granulation 4) Extrusionl melt granulation The invention is also applicable to orally disintegrating tablets, which disintegrates rapidly in the oral cavity.
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.
The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations. Examples: Example 1: Dispersible tablets of Loratadine

Ingredients A B C D
mg/tablet mg/tablet mg/tablet mg/tablet
Loratadine 10 10 10 10
Copovidone 10 10 10 10 ..
Microcrystalline 25 25 25 25
cellulose (Avicel
PH 102)
Sodium starch 20 20 20 20
glycol ate
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Crospovidone 10 10 10 10
HPMC (MethocelKl00) 25
Hydroxy ethyl cellulose 25 50
Aerosil 4 4 4 4
Talc 4 4 4 4
Magnesium stearate 2 2 2 2
Procedure:
Loratadine, Copovidone and Avicel PH 102 were mixed thoroughly and the blend was roll compacted. A fraction of granules between 30 and 40# was collected and mixed with Sodium starch glycolate. Crospovidone, and the polymer. This mixture was then lubricated using magnesium stearate. Aerosil and talc and compressed into tablets. The formulations also pass the dispersibility test mentioned in Ph. Eur. (4th Edition). Pharmacokinetic study:
In vivo dissolution differences between said between the aforesaid two preparations were
demonstrated in a single dose, crossover, randomized comparative pharmacokinetic study
performed in 30 healthy volunteers.
it was found that
38 % subjects achieved Tmax earlier in test product compare to reference product;
38 % of subjects have higher Cmax compare to ref product
Thus, it was found that among the test population, 31 % of subjects had earlier Tmax
and higher Cmax in test product compare to reference product thereby demonstrating that the
absorption rate of the present formulation has significantly improved over the test product.
While the invention has been described by way of examples and in terms of the preferred
embodiments, it is to be understood that the invention is not limited to the disclosed
embodiments. On the contrary, it is intended to cover various modifications as would be apparent
to those skilled in the art. Therefore, the scope of the appended claims should be accorded the
broadest interpretation so as to encompass all such modifications.
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Claim:
1. A novel dispersible tablet comprising (i) of Loratadine and (ii) at least one excipient, which reduces the sedimentation rate of the pharmacologically active ingredient.
2. The novel dispersible tablet composition as claimed in claim I wherein the said excipient is selected from the group of polymers, waxes and wetting agents.
3. The novel dispersible tablet composition as claimed in claim 2 wherein the said excipient is a polymer.
4. The novel dispersible tablet composition as claimed in claim 3 wherein the said polymer is selected from polyalkylene oxides such as polyethylene oxide; cellulose ethers such as hydroxypropylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose; gums such as gum arabic alginates, agar, guar gum, locust bean, carrageenan, tara, gum arable, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic. inulin, karaya. whelan; polyols such as propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol (PEG), sorbitol and glycerol; starch and starchbased polymers such as pregelatinized starch, acrylic acid and methacrylic acid polymers, and esters thereof, maleic anhydride polymers; polymaleic acid; poly(acrylam ides); poly(o!efmic alcohol)s; poly(N-vinyl lactams); polyoxyethylated saccharides; polyoxazolines; polyvinylamines; polyvinylacetates; polyimines; povidone vinylpyrrolidone/vinyl acetate copolymer and polyvinyl acetate, mixture of polyvinyl acetate and polyvinylpyrrolidone, chitin, cyclodextrin, gelatin, chitosan, and combinations thereof The preferred hydrophilic polymers are polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose. hydroxyethyl cellulose, sodium carboxy methylcellulose, microcrystalline cellulose, guar gum, xanthan gum, alginates and combinations thereof.
5. The novel dispersible tablet composition as claimed in claim 4 wherein the said polymer is polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulos, sodiun carboxy methylcellulose microcrystalline cellulose, guar gum. xanthan gum, alginates and combinations thereof
6. The novel dispersible tablet composition as claimed in claim 3 wherein the hydrophilic polymer is present in an amount of about 2 to about 75 % by weight of the total composition.
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7. The novel dispersible tablet composition as claimed in any preceding claim further comprising pharmaceutically acceptable excipients selected from disintegrants. fillers, pH modifiers, stabilizers, taste modifying agents, flavors, and colorants.
8. The novel dispersible tablet composition as claimed in claim 7 wherein the said disintegrant is selected from sodium starch glycolate, pregelatinised starch, crosslinked polyvinyl pyrrolidone, cross linked calcium or sodium carboxy methyl cellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, ion exchange resin, cross-linked polyacryiic acid, alginates, colloidal magnesium-aluminum silicate, calcium silicate.
9. The novel dispersible tablet composition as claimed in claim 8 wherein the said disintegrant is cross linked polyvinyl pyrrolidone and calcium silicate.
10. A process of preparation of the pharmaceutical composition containing Loratadine as claimed in claim 1.
11. A dispersible tablet of Loratadine as hereinbefore described and claimed.
Dated this the 21st day of July 2008

H. SUBRAMANIAM
Of Subramaniam, Nataraj & Associates
Attorneys for the Applicants
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