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
"CAPSULES OF LORATADINE WITH STABLE OUTER HYDROPHILlC LAYER FOR RAPID BUCCAL DISINTEGRATION"

We BA RESEARCH IlfDIA LIMITED, of BA Research House, Opposite "Pushparaj Towers", Judges Bungalows, Boclakdev, 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 the Invention
The present invention relates to capsules of Loratadine including at least one hydrophobic inner core layer and at least one hydrophilic outer layer. Such capsules experience minimal or no degradation under accelerated stability conditions. Background and Prior Art:
Loratadine or ethyl 4-(8-chloro-5,6-dihydro-l lH-benzo[5,6] cyclohepta [1,2-b] pyridin-ll-ylidene)-l-piperidine carboxylate is useful as an antihistamine and is disclosed in U.S. Patent 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.
Oral dosage forms may be designed to disintegrate in the buccal cavity. Such dosage forms desirably disintegrate in the buccal cavity of a consumer with pleasing attributes or the dosage form will not be acceptable. Desirably, disintegrating dosage forms will disintegrate in the mouth in a rapid manner, provide a pleasing taste and not leave a residue behind.
Capsules may be manufactured to disintegrate in the buccal cavity. Typically, a film forming or gelling agent is used in an outer layer of a capsule. Gelatin is one such gelling agent: however, gelatin alone does not provide desirable attributes for a fast disintegrating dosage form because the gelatin may not rapidly disintegrate in the buccal cavity and consequently may leave a residue in the mouth for an unacceptable period of time. Additives may be added to enhance the disintegration of an outer layer that contains gelatin. However, these additives may cause unacceptable degradation to an outer capsule layer as evidenced in stressed conditions such as those required by stability testing for a product containing an active pharmaceutical agent.
Accordingly, it is desirable to provide a capsule of Loratadine designed to rapidly disintegrate in the buccal or oral cavity with pleasing attributes to a consumer and is stable even under stressed stability type conditions. Summary of the invention:
In several embodiments of the present invention there are provided capsules of Loratadine including at least one hydrophobic inner core and at least one hydrophilic outer
layer; where the at least one outer layer includes at least one hygroscopic polyol and at least
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one polyol with a low hygroscopicity. In several embodiments of the present invention there are provided capsules of Loratadine including a hydrophobic inner core, a middle hydrophihc layer and at least one hydrophihc outer layer; where the outer layer includes at least one hygroscopic polyol and at least one polyol with a low hygroscopicity. A capsule of Loratadine may have a seamless outer layer, also known as a seamless capsule. In other embodiments, the at least one outer layer may include at least one film or gel forming agent, at least one hygroscopic polyol and at least one polyol with a low hygroscopicity. An outer layer may include gelatin, glycerin and isomalt. In various embodiments of the present invention, the outer appearance of the capsule is stable and experiences minimal or no degradation in stressed conditions such as those in accelerated stability conditions where the temperature and/or relative humidity is increased. Such stability conditions include 30 °C/65% relative humidity or 45 °C/75% relative humidity. Detailed Description:
Various embodiments of the present invention provide for capsules of Loratadine in which at least one outer layer that is considered to be hydrophihc also known as water soluble layer. In various embodiments the at least one outer layer of a capsule may include at least one hygroscopic polyol and at least one polyol with a low hygroscopicity. The at least one outer layer may include at least one film forming agent, at least one gel forming agent or a combination thereof.
Useful gel or film forming agents include, but is not limited to, gelatin. Gelatin may be used in the at least one outer layer which may also be the outer hydrophihc layer. Gelatin often takes some time to disintegrate in the oral cavity and may leave an undesirable residue in the oral cavity. Sugar alcohols also known as polyols may be added to the outer layer to help improve disintegration speed and mouth feel of a capsule. Useful sugar alcohols, also known as polyols, include hygroscopic polyols and include but are not limited to glycerin, sorbitol, mannitol, xylitol, maltitol, lactitol, erythritol and the like and combinations thereof. A useful polyol includes glycerin also known as glycerol. Polyols may be highly hydroscopic. If hygroscopic polyols are used in a hydrophihc outer layer of a capsule, then the outer layer may absorb large amounts of moisture. Consequently, the capsule may degrade and lose its integrity and may leak or become gooey or appear to melt. Such degradation can be seen under stressed conditions such as accelerated stability conditions. To minimize the degradation of a hydrophihc layer of a capsule, it has been found that adding at least one non-hygroscopic polyol or a polyol with low hygroscopicity to the hydrophihc layer increases the stability of an outer hydrophihc layer while maintaining the desirable 'mouth
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feel' for the orally disintegrating dosage form of Loratadine. During accelerated stability studies such as at 30 °C/65% relative humidity, hydrophilic outer layers of the capsule of Loratadine experience minimal or no degradation. By adding a hygroscopic polyol such as glycerin and polyol with a low hygroscopicity such as isomalt to a hydrophilic outer layer, the outer layer is stable. Capsules of Loratadine with an outer layer that includes a polyol that has a low hygroscopicity maintains its integrity, e.g. the capsule does not leak, become gooey or appear to melt. Additionally, a capsule of Loratadine with an outer layer including a hygroscopic polyol and a polyol with a low hygroscopicity has a feel in the oral cavity is highly pleasing and disintegrates quickly without leaving undesirable residues.
A hygroscopic polyol refers to a polyol that absorbs water readily from its surroundings. A non-hydgroscopic polyol refers to a polyol that does not readily absorb water from its surroundings. A polyol with a low hygroscopicity absorbs minimal water from its surroundings.
Useful non-hygroscopic polyols or polyols with low hygroscopicity include but are not limited to isomalts. Isomalt has a low hygroscopicity and absorbs virtually no moisture at a temperature of 25 °C and relative humidities up to 85 %. Isomalt' s hygroscopicity is lower than that of almost all of the other polyols and even sugar itself. Without wishing to bound by any particular theory, it is believed that isomalt helps provide for the high stability of the capsules. This may be noticed particularly at accelerated stability conditions especially those at high temperatures and high relative humidity.
Capsules of Loratadine may be formulated to disintegrate and/or dissolve directly in the buccal cavity or in the GI tract or stomach area, preferably useful capsule of Loratadine includes a fast disintegrating capsule that disintegrates in the buccal cavity.
In various embodiments, the capsule of Loratadine is capable of disintegrating or breaking apart in an oral cavity from about 1 second to about 60 seconds or from about 1 second to about 45 seconds or from about 1 second to about 30 seconds or from about 1 second to about 15 seconds or in less than about 20 seconds or less than about 10 seconds.
The capsule of Loratadine may have a diameter from about 0.1 mm to about 10 mm. The at least one hygroscopic polyol may be present in an amount from about 1% to about 50% by weight or from about 10% to about 30% by weight. The at least one polyol with a low hygroscopicity may be present in an amount from about 1% to about 50% by weight or from about 10% to about 50% by weight. The film or gel forming agent may be present in an amount from about 40% to about 95% by weight or from about 50% to about 80% by weight.
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An embodiment of the present invention provides for a fast disintegrating capsule of Loratadine with a single inner hydrophobic core layer and a single hydrophilic outer layer, wherein the capsule is stable and does not experience any cracking or breaking in the outer layer. This type of capsule may be advantageous for several reasons. Depending on the materials utilized in the capsule, a capsule of Loratadine having multiple hydrophilic or water soluble outer layers may affect the desired disintegration performance of the capsule. For instance, a capsule with a hydrophobic core layer and two or more outer water soluble layers may not disintegrate as quickly as a capsule that has a single core layer and a single outer water soluble layer.
Additionally, having a single core hydrophobic layer and a single outer water soluble layer may be advantageous from a manufacturing efficiency point of view.
Other embodiments of the present invention include capsules of Loratadine with more layers such as an additional layer between the core and shell layer and/or an additional layer on the outside of the outer shell layer. Several embodiments of the present invention provide for a capsule of Loratadine that has 2, 3, 4, 5 phases or layers. The thickness of each layer may be adjusted by varying the ratio of the various solutions. Suitable enteric agents include pectin, alginic acid, cellulose such as carboxyl methyl cellulose, cellulose acetate phthalate, and the like, Eudragit(R) which is one of an acrylic copolymer and the like and combinations thereof.
Useful film or gel forming agents for the at least one outer layer include but are not limited to gelatins, proteins, polysaccharides, starches, celluloses and combinations thereof.
Useful film or gel forming agents, such as those suitable for the at least one outer layer include, but are not limited to, gelatin, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymers, carboxyvinyl polymers, amylose, high amylose starch, hydroxypropylated high amylose starch, dextrin, chitin, chitosan, soy protein isolate, whey protein isolate, casein and combinations thereof.
Useful agents for hydrophilic, water soluble outer coatings or shell layers include but are not limited to, gelatin, albumin, pectin, guar gum, carboxymethyl starches, carboxymethyl celluloses, carrageenan. agar and the like, hydroxypropylcellulose, ethycellulose, hydroxypropylmethyl cellulose, such as Aquacoat(R), polyvinyl alcohol, polyvinyl pyrrolidone, and combinations thereof. When the material for forming the coating layer contains protein or polysaccharide, useful amounts include an amount from about 100 parts
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by weight to about one part by weight. Other useful materials in the outer, coating or shell layer include an enteric material, a plasticizer. a preservative and a colorant and the like and combinations thereof.
To adjust the hardness of the shell, a material that increases the hardness of the shell material after hardening, such as sorbitol, can be added to the shell material along with the plasticizer. Furthermore, by adding a thickening polysaccharide, a gelling agent, a proteolytic agent or the like, it is possible to improve the long-term stability of the shell.
The shell material can be colored to any arbitrary color tone by a pigment, and flavorings, sweeteners, souring agents or the like can be added. Sorbitol, thickening polysaccharides, gelling agents, proteolytic agents and the like are added at 10% by mass or less with respect to the total amount of the shell material, and preferably at 5% by mass or less.
Useful materials in a water soluble phase include plasticizers, which include polyhydric alcohols, such as sorbitol, glycerin, polyethylene glycol and the like and combinations thereof. A water-soluble polyvalent alcohol or water-soluble derivative thereof may also be used in water soluble outer or coating layer. Useful examples of polyvalent alcohol or water soluble derivatives thereof include but are not limited to, glycerin, polyglycerin, sorbitol, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, ethylene oxide-propylene oxide copolymer, oligosaccharide, sugar ester, glyceride, sorbitan ester and the like. Useful preservatives and colorants include benzoic, acid, para-oxybenzoate, caramel colorant, gardenia colorant, carotene colorant, tar colorant and the like and combinations thereof.
A film substance may be used on the water soluble outer or shell layer and may be formed by treating a capsule with a film forming substance. Suitable film formers include but are not limited to albumin, pectin, guar gum, carrageenan, agar and the like, hydroxypropylcellulose, ethycellulose, hydroxypropylmethyl cellulose, such as Aquacoat(R), pullulan and combinations thereof.
Useful amounts of additives include 2 parts by weight to 98-parts by weight, based on 100 parts by weight of gelatin in the coating layer.
A water-soluble layer or phase may also contain an acid or an acid salt thereof, to minimize or prevent the capsule from insolubilizing. Useful acids or acid salt thereof include a water-soluble organic acid, an inorganic acid, or an acid salt thereof (for example, sodium salt). Suitable organic acid include acids having 2 to 6 carbon atoms, including, for example, citric acid, malic acid, tartar acid, fumaric acid, lactic acid, butyric acid, succinic acid and the
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like, an acid salt thereof (for example, sodium malate, potassium succinate, calcium citrate and the like); and combinations thereof. Useful inorganic acids include phosphoric acid, polyphosphoric acid, carbonic acid, an acid salt thereof (for example, dibasic sodium phosphate) and combinations thereof. Useful amounts of an acid or acid salt thereof to a water-soluble layer is generally from about 0.01 to about 50% by weight, or from about 0. 05 to about 20% by weight, based on 100% by weight of a water soluble layer or phase.
The inner or core solution or phase of a capsule may include a fatty acid such as a unsaturated fatty acid or a derivative thereof. Suitable materials for the inner core include but are not limited to, vegetable fats and oils, animal fats and oils and mineral oils and combinations thereof. Suitable materials for the inner core include fish oils and a purified material thereof, liver oils, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid, prostaglandin and a derivative thereof, sucrose fatty acid ester, propylene glycol fatty acid ester, glycerin fatty acid ester, long chain fatty acid triglyceride, medium chain fatty acid triglyceride, ampho-ionic emulsifiers, lecithin, sesame oil, coffee oil, rapeseed oil, brown rice oil, liquid paraffin and combinations thereof.
To prepare an emulsified core liquid, well-known conventional methods can be used in which the main component, including an emulsifying agent, and an oil component are emulsified using a homogenizer to obtain an oil-in-water emulsion. Other useful materials for the core or inner phase include, but are not limited to, various types of a stabilizers for unsaturated fatty acid or a derivative thereof including antioxidants, such as vitamin E, vitamin C, p-carotene, eucalyptol, menthol, flavorings, sweeteners, wheat germ oil and the like and combinations thereof.
Useful amounts of the inner or core phase is from about 10% to 95% by weight, or from about 40% to about 90% by weight, based on the totaj weight of the capsule.
The inner or outer layer may include other material^ including APIs, foods, cosmetics, flavors, industrial chemicals and the like.
In various embodiments of the present invention, the dosage forms may be administered orally. Useful inactive ingredients that may be included in the various phases or solutions of the capsule, may include but are not limited to, binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavorings and flavor enhancer agents, taste-masking agents, preservatives, buffers, wetting agents, anti-oxidants, colorants or coloring agents, pharmaceutically acceptable carriers, clisintegrants, salivary stimulating agents, cooling agents, co-solvents (including oils), pH adjusting agents, effervescent agents, emollients, bulking agents, anti-foaming agents, surfactants, soluble organic salts,
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permeabilizing agents, glidants and other excipients and combinations thereof. Desirably, the agents are chemically and physically compatible with the API.
Examples of useful substantially water soluble carriers or filling agents include, but are not limited to, various starches, celluloses, carbohydrates compression sugars or soluble fillers. More particularly, useful fillers include but are not limited to lactose, lactose monohydrate, lactose anhydrous, sucrose, amylose. dextrose, mannitol, inositol, maltose, maltitol, sorbitol, glucose, xylitol, erythritol, fructose, maltodextrins; microcrystalline cellulose, calcium carboxy methyl cellulose; pregelatinized starch, modified starches, potato starch, maize starch; clays, including kaolin and polyethylene glycols (PEG) including PEG 4000; or combinations thereof. Useful amount of fillers include the range of about 1 to about 99 weight percent, or about 25 to about 95 weight percent or about 40 weight percent to about 95 weight percent of the compositions of this invention.
Compositions of the present invention may include a sweetener. Useful sweeteners include, but are not limited to, sugars such as sucrose, glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof; acid saccharin and its various salts such as the sodium or calcium salt; cyclamic acid and its various salts such as the sodium salt; the dipeptide sweeteners such as aspartame and alitame. Suitable sugar alcohols useful as sweeteners include, but are not limited to, sorbitol, xylitol, mannitol, galactitol, maltitol, isomalt and mixtures thereof The exact amount of sugar alcohol employed is a matter of preference subject to such factors as the degree of cooling effect desired. Thus, the amount of sugar alcohol may be varied in order to obtain the result desired in the final product and such variations are within the capabilities of those skilled in the art without the need for undue experimentation.
One embodiment of the invention provides for a controlled or extended release composition.
Optionally, one or more flavors such as those described in U.S. Patent No. 6,596,298 which is incorporated herein. Any amount of flavor can be used and will depend on characteristics of the active pharmaceutical ingredient(s); preferred concentration of flavoring is between about 0.01% to about 10% w/w of a composition.
In one embodiment, capsules are provided in blister packaging which is believed to limit the amount of oxygen that may interact with the capsule and as such may also increase or enhance the stability of the drug product containing the API. Another embodiment contemplates a method of dispensing a capsule from a blister pack by forcing the drug product through a foil back on a blister pack.
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The capsule of the present invention may be formed into a desirable particle size of 0.1 mm to 20 mm, preferably 0.3 to 8 mm. The water-soluble outer layer may have a thickness from about 0.001 to about 5.00 mm, or from about 0.01 to 1 mm. EXAMPLES Table 1: The formulations in Table 1 are mixed to prepare the respective layers of a capsule.

Outer Layer Capsule 1 % weight Capsule 2 % weight Capsule 3 % weight Capsule 4 % weight
Gelatin 58.5% 58.5% 58.5% 58.5%.
Glycerin 20.0% 20.0% 20.0% 20.0%.
Isomalt 20.0% 20.0% 20.0% 20.0%)
Sucralose 1.5% 1.5% 1.5% 1.5%

Weight of outer shell 6mg 6mg 6 mg 6mg
Middle-layer
Hydrogenated vegetable oil 95% 95%
Soybean Lecithin 5% 5%
Weight of middle layer 82.67 mg 82.67 mg

Core layer
Hydrogenated vegetable oil 80.84% 80.84% 80.84% 78.16%
Sucralose NF 1.88 % 1.88 % 1.88%) 1.88%
Menthol 8.75% 8.75% 8.75% 8.75%
Eucalyptol 0.31% 0.31% 0.31% 0.31%
Loratadine 6.25 % 6.25 % 6.25 % 6.25 %
Orange flavoring 1.31 % 1.31 % 1.31 % 1.31 %
Silicon dioxide 0.66% 0.66% 0.66% 0.66%

Weight of core 160mg 160mg 160 mg 160 mg
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Total Weight of capsule 248.7 mg 166 mg 248.7 mg 166 mg
The hydrophilic outer layer liquid is prepared by adding purified water in a suitable size container with glycerin, isomalt, sucralose while mixing at 30 °C+/-5 °C until the ingredients completely dissolve. Gelatin is then added and the mixture is heated to 60 °C+/-5 °C while mixing for about 1 to 2 hours to dissolve all ingredients. Mixing is stopped and the temperature kept at 60 °C +/-5 °C for one to two hours to remove air bubbles. The solution is transferred to an encapsulation tank while maintaining the temperature at 60 °C +/-5 °C. The protective layer is prepared by melting hydrogenated vegetable oil in an oven at 50 °C +/-5 °C and mixing with lecithin while maintaining the temperature for 2-5 hours to allow the Lecithin to dissolve. The mixture is maintained for about 30 minutes at 40 °C +/-5 °C without stirring to remove air bubbles. The core liquid phase is prepared by melting hydrogenated vegetable oil in an oven at a temperature from about 40 °C to about 55 °C and mixing in menthol until it dissolves. Eucalyptol and orange flavor are added while continuing to mix at a temperature from about 30 to about 45 °C for about 1hour.
Loratadine and silicon dioxide, sucralose are added while maintaining the temperature and mixing. The mixture is homogenized for about 20 minutes while mixing with a stirring speed from about 2500 to about 8500 rpm while maintaining the temperature from about 30 °C to about 45 °C.
To form capsule, the materials are extruded through a triple nozzle arranged concentrically and released into a cooling solution (vegetable oil) to produce capsules in form of a triple structure.
While the invention has been described in detail and with reference to specific examples thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof of the invention.
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Claim:
1. A capsule of Loratadine comprising a hydrophobic inner core and at least one hydrophilic outer layer wherein said outer layer comprises at least one hygroscopic polyol and at least one polyol with a low hygroscopicity.
2. The capsule as claimed in claim 1. wherein said at least one hydrophilic outer layer further comprises at least one film or gel forming agent.
3. The capsule as claimed in claim 1 or 2 wherein said polyol with a low hygroscopicity comprises isomalt.
4. The capsule as claimed in any preceding claim wherein said hygroscopic polyol is selected from the group consisting of glycerin, sorbitol, mannitol, xylitol, maltitol, lactitol, erythritol and the like and combinations thereof.
5. The capsule as claimed in claim 2, wherein said at least one film or gel forming agent is selected from the group consisting of gelatin, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol and combinations thereof.
6. The capsule as claimed in any preceding claim wherein said hydrophobic inner core comprises Loratadine in a pharmaceutically effective amount.
7. The capsule as claimed in any preceding claim wherein wherein said capsule is a standalone product that is capable of disintegrating completely in an oral cavity of a consumer.
8. The capsule as claimed in claim 8, wherein said capsule disintegrates in an oral cavity in less than about 20 seconds.
9. A capsule of Loratadine comprising a hydrophobic inner core and at least one hydrophilic outer layer; said outer layer comprises at least one film or gel forming agent, at least one hygroscopic polyol and at least one polyol with a low hygroscopicity; said hydrophobic inner core comprises Loratadine in a pharmaceutically effective amount and said at least one outer layer experiences minimal degradation at 30 °C/65% relative humidity.
10. A formulation comprising Loratadine substantially as hereinbefore described.
Dated this the 21st day of July 2008
H. SUBRAMANIAM
Of Subramaniam, Nataraj & Associates Attorneys for the Applicants
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