TASTE MASKED H2 ANTAGONIST PHARMACEUTICAL FORMULATIONS

INTRODUCTION

Aspects of the present application relate to taste masked film-coated tablets containing a H2 antagonist drug, and to processes for their preparation. Aspects of the present application relate to the uses of taste masked film-coated H2 antagonist drug tablets for providing relief to a patient who is suffering from disorders causing heartburn and related symptoms.

Coated pharmaceutical tablets are commonly used in the art. Pharmaceutical dosage forms may be coated for a variety of reasons, including protecting unstable core compositions, providing a barrier to prevent coating interactions, providing protection to dosage forms in the stomach (e.g., using enteric coatings), masking unpleasant taste or mouth feel, improving general appearance, improving ease of swallowing, and the like. A common film coating is one using slightly water soluble film forming polymers, particularly cellulose derivatives. Thin film coatings, which do not alter the dissolution characteristics of the substrate, may be readily formed using standard film-coating processes. The coating compositions may incorporate other additives to provide additional properties to the formulation.

U.S. Patent No. 5,098,715 teaches that aqueous film coatings, such as hydroxypropyl methyl cellulose coatings, particularly Opadry® ™ coatings, can be used to deliver volatile flavoring and cooling agents in thin film coatings, particularly for use on core ingredients having unpleasant taste, to enhance a taste-masking effect.

Heartbunvalso known as dyspepsia or acid indigestion, is a burning sensation in the chest, just behind the breastbone or in the epigastrium. Heartburn is usually associated with regurgitation of gastric acid (gastric reflux) which is the major symptom of gastro esophageal reflux disease (GERD). The chest pain caused by GERD has a distinct 'burning' sensation, occurs after eating or at night, and worsens when a person is lying down or bending over. It also is common in pregnant women; and may be triggered by consuming food in large quantities, or specific foods containing certain spices, high fat content, or high acid content. The treatment of heartburn depends on the underlying cause. Medicines such as H2 receptor antagonists or proton pump inhibitors are effective for gastritis and GERD, the two most common causes of heartburn.

The H2 receptor antagonists are a class of drugs used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells. H2 antagonists used in the treatment of heartburn are competitive antagonists of histamine at the parietal cell H2 receptor.

In the United States, four regulatory-approved members of the H2 antagonist group (cimetidine, ranitidine, famotidine, and nizatidine) are available as over-the-counter medicines. One of the popular compounds of this group is ranitidine.

Ranitidine is commonly used as the ranitidine hydrochloride salt, having chemical names:dimethyl[(5-{[(2-{[(E)-1 -(methylamino)-2-nitroethenyl]amino}ethyl)sulfanyl]methyl}furan-2-yl)methyl]amine hydrochloride; or1,1 -ethenediamine, N-[2-(((5-((dimethylamino)methyl)-2-furanyl)methyl)thio)ethyl]-N'-methyl-2-nitro-, hydrochloride; and the structural formula below.

U.S. Patent No. 4,128,658 discloses ranitidine and its pharmaceutically acceptable salts.

Ranitidine hydrochloride ("ranitidine HCI") is widely available in several dosage forms including tablets, effervescent tablets, capsules, injections, and syrups as prescription medications as well as over-the-counter (OTC) formulations. Ranitidine HCI is a white to pale yellow, granular substance that is soluble in water. It has.a slightly bitter taste and sulfur-like odor. Hence, it is important that an OTC product containing ranitidine should be suitably taste masked for patient acceptance and compliance. Over-the-counter ranitidine preparations are widely available as ZANTAC® products from Boehringer Ingelheim, in different strengths. One product is Maximum Strength Zantac 150® Cool Mint Tablets, a nonprescription acid reducer available for the relief and prevention of heartburn associated with acid indigestion and sour stomach brought on by certain foods and beverages. This product contains 168 mg of ranitidine hydrochloride (equivalent to 150 mg of ranitidine) and the inactive ingredients carrageenan; FD&C blue no. 1, flavors, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate, sucralose, and titanium dioxide.

A flavoring agent in Maximum Strength Zantac 150® Cool Mint Tablets, hereinafter called Zantac Cool Mint, is N,2,3-trimethyl-2-isopropylbutamide (WS-23; CAS no. 51115-67-4) known by the trade name of WINSENSE which is an amide compound coolant of the type described in GB Patent 1,421,744. It is available as white crystals having a mild cooling mentholic minty odor. However there are several disadvantages when this coolant is used in formulating dosage forms. A major problem associated with this excipient is the difficulty in handling this compound during processing as it causes irritation to eyes; therefore it requires the use of protective equipment during handling and storage. Further this ingredient also poses several health hazards if inhaled.

U.S. Patent No. 5,098,715 describes a pharmaceutical tablet comprising an unpleasant tasting, solid core and a flavored, pharmaceutically acceptable, thin film coating, where the coating increases the weight of the tablet by an average of about 5%, said coating comprising a water-soluble, film-forming polymer, a volatile flavoring agent and a sweetening agent, said coating being capable of masking the unpleasant taste of the core, and said coating having a flavor that is retained in the coating for at least about 24 months during storage and that provides a taste perception of said flavor for at least five seconds after oral administration of said tablet and a method for preparing the same.

U.S. Patent Application Publication No. 2008/0131467 discloses a film-coated solid oral dosage form comprising a solid core and a film coating comprising at least two separately applied coating or layers. The first layer, which is a seal coat, contains a swellable polymer, such as hydroxypropyl methyl cellulose. The second • layer. which is a Telease coat, contains carrageenan, microcrystalline cellulose, hydroxypropyl methylcellulose, and taste modifying agents. The outer coating contains readily releasable volatile and non-volatile flavoring and cooling agents together with sweeteners, to provide an intense cooling effect which is instantly perceived by the consumer upon placing the dosage form in the oral cavity. In this publication, the flavors and the coolants or mixtures thereof comprise in an amount from about 40% to 75% by weight of said second layer, considered to be high concentrations of the taste modifying agents.

U. S. Patent No. 5,244,670 discloses ingestible pharmaceutical compositions comprising pharmaceutical actives useful for treating upper gastrointestinal tract distress (e.g., antacid agents) and 3-(1-menthoxy)-propane-1,2-diol(CAS No. 195863-84-4,commonly known as "cooling agent 10")in amounts effective for providing a cooling sensation to the throat.

U.S. Patent No. 5,827,582 describes a pharmaceutical composition that has been coated with a volatile aromatic compound selected from the group consisting of 3-1-menthoxy propane-1, 2-diol, N-substituted-p-menthane-3-carboxamides, acyclic carboxamides, and mixtures thereof.

U.S. Patent No. 6,592,887 describes compositions containing therapeutic agents and/or breath freshening agents for use in the oral cavity. The compositions comprise carriers of water soluble polymers, in combination with ingredients that provide cosmetic and/or therapeutic effects. In an example, a film coating comprising ingredients such as sorbitol, glycerol, polysorbate 80, Brij™ 35, lemon mint flavor, aspartame, menthol, and citric acid is disclosed. These ingredients are made into a clear solution by dissolving in solvents such as ethanol and water, and hydroxypropyl methylcellulose is added with stirring until a clear homogeneous solution is formed. The solution is then cast into films which are coated into suitable carrier materials for use in the oral cavity.

European Patent No. 0 679 391B1 relates to a solid, swallowable pharmaceutical dosage form for temporary relief of cough and sore throat. The dosage form contains a solid core with a therapeutically effective amount of an analgesic and an antitussive. A menthol-flavored film coating is applied to the core in an amount sufficient to provide sensory stimulation of the throat and nasal passageways when the dosage form is placed in the oral cavity and swallowed.

The currently known taste masked film coated ranitidine tablets utilize large ' ^quantities of taste "modifying agents for their preparation. The currently marketed formulations also utilize cooling agents that are synthetic in nature and expensive. Thus, there remains a need for simple and economical taste masked film coated ranitidine tablets and processes for preparing the same.

SUMMARY

Aspects of the present application relate to taste masked film coated pharmaceutical formulations comprising H2 antagonist drugs and their uses in the treatment of heartburn.

Embodiments of the present application provide taste masked film-coated H2 antagonist tablets having a drug in a core tablet, a film coating over the core tablet, and a flavor coating applied over the film coating comprising: (i) carrageenan; (ii) microcrystalline cellulose; (iii) hydroxypropyl methylcellulose; and (iv) one or more taste modifying agents in amounts from about 1% to about 30% by weight of the flavor coating.

Aspects of the present application relate to taste masked film-coated tablets comprising ranitidine or pharmaceutically acceptable salts, esters, hydrates, solvates, derivatives, or single enantiomers thereof, and processes for preparing the same.

Aspects of the present application provide taste masked film-coated ranitidine tablets comprising a film coating over a drug-containing core tablet, a flavor coating applied thereupon, and processes for preparing the same.

Aspects of the present application provide processes of preparing taste masked film-coated ranitidine tablets of the present application.

Aspects of the present application provide methods for relieving heartburn associated with acid indigestion and sour stomach, brought on by certain foods and beverages, using taste masked film-coated ranitidine tablets to provide a perceptible cooling sensation to the patient's mouth during administration.

An aspect of the present application relates to taste masked film coated tablets comprising ranitidine or its pharmaceutically acceptable salt, wherein ranitidine is present in amounts about 25mg to about 300mg.

Aspects of the present application provide taste masked film coated ranitidine tablets comprising flavoring agents and sweeteners.

Aspects of the present application relate to coating on tablets comprising ranitidine or ptrarmaceutically acceptable salts thereof, wherein the coatings comprise any one or more of flavoring agents, sweeteners, cooling agents, and colorants.

Aspects of the application provide taste masked film-coated ranitidine tablets that do not have unpleasant medicinal tastes, such as that associated with ranitidine and pharmaceutically acceptable salts thereof, due to the presence of small quantities of flavoring agents in combination with a sweetening agent.

Aspects of the application also provide taste masked film-coated ranitidine tablets comprising one or more layers, wherein an unpleasant taste of an ingredient in a core tablet is masked by the film coating, wherein the film coating hides an unpleasant taste.

Aspects of the application provide taste masked film-coated ranitidine tablets, wherein a flavoring agent and/or sweetener is present within a drug-containing core tablet.

An aspect of the present application relates to coating core tablets comprising ranitidine or pharmaceutically acceptable salts thereof with one or more film coatings, wherein atleast one film coating comprises a taste modifying agent. In embodiments, a taste modifying agent is present in an outer layer and separated by another film coating from a core tablet containing ranitidine or pharmaceutically acceptable salts thereof.

An aspect of the present application relates to taste masked film-coated ranitidine tablets comprising a taste modifying agent that is a flavoring agent, cooling agent, sweetener, etc., in a tablet coating and which provides a perceptible cooling sensation in a patient's mouth.

An aspect of the present application relates to taste masked film coated ranitidine tablets, prepared by processes including one or more of the steps of mixing, dry granulation, direct compression, wet granulation, fluidized bed granulation, drying, sifting, blending, compression, and coating.

An aspect of the present application provides taste masked film-coated ranitidine tablets, comprising ranitidine hydrochloride having polymorphic crystalline Form I and/or Form II.

An aspect of the present application provides taste masked film coated ranitidine tablets, wherein ranitidine is chemically stable during the preparation of the composition and also during the normal shelf-life of the product. as pecfttrf the present application relates to taste masked film coated ranitidine tablets, wherein the release of ranitidine or its pharmaceutically acceptable salt into an aqueous fluid is atleast 70% within 45 minutes, when the tablets are subjected to an invitro dissolution study using a USP test method.

An aspect of the present application relates to taste masked film coated ranitidine tablets wherein the release of ranitidine or its pharmaceutically acceptable salts is from about 40% to about 60% within 10 minutes, and atleast 80% within 30 minutes and atleast 90% within 45 minutes in an invitro dissolution study conducted using 900ml of degassed water in USP apparatus 2 (paddle) with 50rpm stirring, and at a temperature 37°C.

Embodiments of taste masked film-coated ranitidine tablets of the present application are stable during manufacturing and storage for commercially relevant times, provide the taste masked active agent for relief of heartburn along with a perceptible cooling sensation, and provide a desired therapeutic concentration of the active agent for the intended duration.

DETAILED DESCRIPTION

Aspects of the present application relate to taste masked film coated pharmaceutical formulations comprising H2 antagonist drugs and their uses in the treatment of heartburn. Useful drugs include cimetidine, ranitidine, famotidine, and nizatidine, including any of the various pharmaceutical^ acceptable salts and other derivatives thereof. For convenience, the discussion herein uses ranitidine hydrochloride as a representative of the entire class of drugs, but it is to be understood that the scope of the disclosure is not limited to this particular compound.

As used herein, 'ranitidine' refers to all compounds of ranitidine including pharmaceutically acceptable salts, esters, hydrates, solvates, derivatives or single enantiomers thereof. In embodiments of the present application, the hydrochloride salt of ranitidine is employed.

Aspects of the present application provide taste masked film-coated ranitidine tablets comprising ranitidine or its pharmaceutically acceptable salts together with one or more pharmaceutically acceptable excipients.

Aspects of the present application provide processes for preparing taste masked film-coated tablets comprising ranitidine and its pharmaceutically acceptable salts.

Aspects of the present application provide methods of providing relief from heartburn associated with acid indigestion and sour stomach brought on by certain foods and beverages, using taste masked film-coated ranitidine tablets that can be easily ingested by patients.

Aspects of the present application provide methods of relieving heartburn and associated with acid indigestion and sour stomach brought on by certain foods and beverages, by administering taste masked film-coated ranitidine tablets, wherein a perceptible cooling sensation is experienced by a patient before swallowing the tablet. When a tablet is placed in the oral cavity, an unpleasant taste of the drug may be avoided, as taste modifying agents are released immediately to provide a rapid taste masking effect.

An aspect of the present application relates to taste masked film-coated tablets comprising ranitidine or a pharmaceutically acceptable salt thereof, wherein a ranitidine content of a tablet is about 25mg to about 300mg.

In embodiments, ranitidine or its pharmaceutically acceptable salt comprises from about 1% to about 99% or from about 20% to about 80% or from about 25% to about 75%, by weight of a pharmaceutical formulation of the present application.

In embodiments, the present application provides taste masked film-coated ranitidine tablets comprising taste modifying agents to provide a ranitidine taste masking effect.

In embodiments, the present application provides taste masked film-coated ranitidine tablets, wherein a taste modifying agent is included within a tablet core.

In embodiments, the present application provides taste masked film-coated ranitidine tablets, wherein a taste modifying agent is included in a coating over a tablet core.

In embodiments, the present application provides taste masked film-coated ranitidine tablets, wherein a core tablet has a single layer or multilayer coating.

In embodiments, the present application provides taste masked film-coated ranitidine tablets, wherein a taste modifying agent is present within a single coating layer applied over a core tablet.
vita embodiments, the present application provides taste masked film-coated ranitidine tablets, wherein a flavoring agent, cooling agent, and sweetening agent are present in more than one layer applied over a core tablet. In embodiments, a sweetening agent and a flavoring agent are present in an outer coating layer. In embodiments, a sweetening agent is present in an inner coating layer.

In embodiments, a core tablet may be coated with an inert layer, followed by a coating layer comprising a flavoring agent, cooling agent, and sweetening agent.

In embodiments, the inert layer applied over a core tablet comprises a film coating with a polymer such as a hydroxypropyl methylcellulose.

Embodiments of the present application may be in the form of tablets granules, pellets, spheroids, extrudates, or mini-tablets, comprising ranitidine or any pharmaceutically acceptable salts thereof. Core tablets may contain any one or more pharmaceutically acceptable excipients, such as inert carriers, binders, diluents, disintegrants, lubricants, glidants, wetting agents, etc.

In embodiments of the present application, film-coated ranitidine tablets are prepared by methods of formulating tablet dosage forms which are commonly known in the art, and which include one or more of the steps of mixing, dry granulation, direct compression, wet granulation, fluidized bed granulation, drying, sifting, blending, compression, and coating.

The term 'stability' is the propensity of a drug substance or formulated drug product to remain within established specifications to maintain its identity, strength, quality, and purity during manufacturing and in storage at normal ambient conditions, in original packaging, until its expiration date. The term 'chemical stability' means the tendency of drug to resist degradation or decomposition due to internal reactions, or due to the effects of external conditions such as oxygen, heat, light, pressure, etc. and includes maintaining acceptable concentrations of drug-related impurities.

The term 'product shelf life' is the recommendation of time that finished products can be stored, during which the defined quality of a specified proportion of the product remains acceptable under expected (or specified) conditions of distribution, storage, and display.

An aspect of the present application relates to taste masked film coated ranitidine tablet iamerein the release of ranitidine or its pharmaceutically acceptable salt into an aqueous fluid is atleast 70% within 45 minutes, when the tablets are subjected to an invito dissolution study using a USP test method.

An aspect of the present application relates to taste masked film coated ranitidine tablets wherein the release of ranitidine or its pharmaceutically acceptable salts is from about 40% to about 60% within 10 minutes, and atleast 80% within 30 minutes and atleast 90% within 45 minutes in an invitro dissolution study conducted using 900ml of degassed water in USP apparatus 2 (paddle) with 50rpm stirring, and at a temperature 37°C.

Embodiments of the present application relate to taste masked film-coated ranitidine tablets comprising ranitidine or its pharmaceutically acceptable salt, wherein the tablets are packaged into closed HDPE bottles or blister packages having a cold-formable base foil and a paper-backed peelable foil.

Embodiments of the present application provide taste masked film-coated ranitidine tablets comprising ranitidine or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

Ranitidine and its pharmaceutically acceptable salts are bitter-tasting drug substances. In order to promote patient compliance, bitterness masking of ranitidine is important in dosage forms of the present application. Various methods are available to mask undesirable tastes of drugs, some of which are described below.

Taste masking may be achieved by formation of inclusion complexes. In inclusion complex formation, a drug molecule fits into the cavity of a complexing agent, i.e., forms a stable complex. The complexing agent can mask the taste of the drug by either decreasing its oral solubility during ingestion or decreasing the amount of drug particles exposed to taste buds, thereby reducing the perception of taste. Beta-cyclodextrin is a widely used complexing agent for inclusion type complexes. It is a sweet, nontoxic, cyclic oligosaccharide obtained from starch.

The solubility and adsorption of a drug can be modified by formation of molecular complexes. Consequently lowering drug solubility through molecular complex formation can decrease the intensity of taste of a drug.

Solid xlispersions using insoluble matrices or bland matrices may be used to mask the taste of drugs. Also absorbing drugs on various carriers may increase the stability of certain drugs. Solid dispersions are dispersions of one or more active ingredients in an inert carrier or matrix in the solid state, prepared using techniques such as melting (fusion), solvent, and melting-solvent methods.

Microencapsulation is a means of applying a relatively thin coating to small particles of solids, droplets of liquid, and dispersions. This process can be used for masking the taste of drugs by microencapsulating drug particles with various coating agents. Coating agents employed include materials such as gelatin, povidone, HPMC, ethyl cellulose, beeswax, carnauba wax, acrylics, and shellac. Drugs can first be encapsulated to produce free flowing microcapsules, which can then be blended with other excipients and compressed into tablets. Microencapsulation can be accomplished by a variety of methods including air suspension, coacervation, phase separation, spray drying and congealing, pan coating, solvent evaporation, and multi-orifice centrifugation techniques.

Another popular approach for taste masking uses ion exchange resins. Ion exchange resins are solid and suitably insoluble high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding medium. The resulting ion exchange is reversible and stoichiometric with the displacement of one ionic species by another. The drugs are adsorbed onto synthetic ion exchange resins to achieve a taste masking effect.

The term "excipient" means a component of a pharmaceutical product that is not an active ingredient, such as a diluent, binder, disintegrant, lubricant, etc. The excipients that are useful in preparing pharmaceutical formulations are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutical^ acceptable excipient" as used herein includes both one and more than one such excipient. Specific examples of pharmaceutically acceptable excipients that can be used to formulate the dosage form may be found in standard reference works, including: Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, Washington, D.C. (1986); Pharmaceutical Dosage Forms: Tablets, 2nd Ed. (edited by Lieberman et al.), Vols. 1-3, published by Marcel Dekker, Inc., New York M9$9y, and Remington's Pharmaceutical Sciences, 1&h Ed. (edited by A. L. Gennaro), Mack Publishing Co., Easton, PA, Chapter 89 (1990).

The diluents include, but are not limited to, calcium sulfate, cellulose acetate, dextrates, dextrin, dextrose, fructose, kaolin, lactitol, maltitol, maltodextrin, maltose, polymethacrylates, sodium chloride, sucrose, talc, starches, lactose, cellulose derivatives, and the like. Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac® Pharmatose®, and others. Different grades of starches include, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starch and Starch 1500, Starch 1500 LM grade (low moisture content grade), fully pregelatinized starch, and others. Different cellulose compounds that can be used include crystalline cellulose, powdered cellulose, and cellulose acetate. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801, Avicel® ™ PH101, PH102, PH301, PH302 and PH-F20, PH112, PH114 and silicified microcrystalline cellulose. Other useful diluents include, but are not limited to, carmellose, sugar alcohols such as mannitol, sorbitol, and xylitol, calcium carbonate, magnesium carbonate, sodium carbonate, sodium bicarbonate, light magnesium oxide, heavy magnesium oxide, sodium hydrogen phosphate, calcium sulfate, disodium hydrogen phosphate, basic calcium phosphate, and tribasic calcium phosphate.

Useful binders include, but are not limited to, carboxymethylcellulose, hydroxyethyl cellulose, dextrin, gelatin, maltodextrin, polyethylene oxides, sodium alginate, hydroxypropyl celluloses, hydroxypropylmethyl celluloses, polyvinyl pyrrolidones or povidone (PVP-K25, PVP-K29, PVP-K30, PVP-K90D), powdered acacia, gelatin, guar gum, carbomers (e.g. Carbopol® products), methyl celluloses, polymethacrylates, and starches.

Further, disintegrants can also be present, such as carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidone, examples of commercially available crospovidone products including but not being limited to cross linked povidone, Kollidon® CL, Polyplasdone® XL, XI-10, and INF-10 and low-substituted hydroxypropylcellulose. Examples of low-substituted hydroxypropylcellulose include, but are not limited to, low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33. Other useful disintegrants include sodium starch glycolate (type A or type B), "cottoidal silictfrtiiioxide, and starches.

Lubricants can also be present as excipients, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, talc, glyceryl behenate, glyceryl monostearate, palmitic acid, talc, carnauba wax, calcium soaps, zinc stearate, polyoxyethylene monostearate, calcium silicate, silicon dioxide, macrogol, or any mixtures of two or more thereof.

The term "taste modifying agent" should be understood to include excipients that are flavors and sweeteners. The term "flavors" should be understood to include flavoring agents, cooling agents, and the like, as described herein. A flavoring agent may also provide a cooling effect. In addition to a flavoring agent, one or more sweeteners may also be included in the composition.

Flavors may be present in amounts up to 30% by weight of a flavor-containing coating. A suitable formula could contain from about 2% to 20% by weight of a flavoring agent. The flavoring agents that may be used in embodiments of the present application may be obtained from natural sources or artificial sources.

Flavoring agents that can be used include those known to the skilled artisan, such as natural and artificial flavoring agents. These flavorings may be chosen from synthetic flavor oils, flavoring aromatics, and/or oils, oleoresins and extracts derived from plants, leaves, flowers, fruits, etc., including any combinations thereof. Representative flavor oils include: spearmint oil, cinnamon oil, peppermint oil, wintergreen, eucalyptus clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds.

Also useful are artificial, natural or synthetic flavors such as vanilla, chocolate, coffee, cocoa, and citrus oils, including lemon, orange, grape, lime, and grapefruit, fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc., flavoring agents such as eucalyptol, thymol, camphor, methyl salicylate, benzaldehyde, ginger, and the like, and acidulants such as citric acid, malic acid, and the like. Flavorings such as aldehydes and esters, including cinnamyl acetate, cinnamaldehyde, citral, diethylacetal, dihydrocarvyl acetate, eugenyl formate, p-methyl anisole, etc. may also be used. Generally, any flavoring or food additive, such as those described in Chemicals Used in Food Processing, • ■^Publication 1274*1*? the National Academy of Sciences, pages 63-258, may be used. These flavorings can be used individually or in any combinations.

Excipients useful as cooling agents include, but are not limited to, menthol, substituted p-menthanes, e.g., hydroxymethyl and hydroxyethyl derivatives, menthyl succinate (PHYSCOOL®), menthyl lactates (e.g. FRESCOLAT®), N, N-dimethyl menthyl succinamide; substituted-p-menthane-3-carboxamides, such as N-ethyl-p-menthane-3-carboximide, (WS-3), N,2,3-trimethyl-2-isopropyl butamide (WS-23); acyclic carboxamides, substituted cyclohexanamides, substituted cyclohexane carboxamides, substituted ureas and sulphonarnides, substituted menthanols, 3-(1-menthoxy) propan-1,2-diol, menthoxy propane diol, menthone glycerol ketals, p- menthane-3,8-diols, 2-mercapto-cyclo-decanone, 2-isopropanyl-5-methylcyclohexanol(ISOPREGOL); isopulegol, cubebol, incilin, xylitol, and other substances.

In embodiments of the present application, combinations of a flavoring agent and a sweetening agent are employed.

Excipients acting as sweeteners may be sugars or sugar substitutes, or mixtures thereof. Useful sweeteners include, but are not limited to: sugars such as sucrose, glucose (com syrup), dextrose, invert sugar, fructose, and mixtures thereof; saccharin and its various salts such as the sodium or calcium salt; cyclamic acid and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame, alitame, and neotame; sucralose; natural sweeteners such as dihydrochalcone compounds; glycyrrhizin; Stevia rebaudiana (Stevioside); sugar alcohols such as sorbitol, sorbitol syrup, mannitol, xylitol, and the like; synthetic sweeteners such as acesulfame-K and sodium, calcium salts thereof, and the like; hydrogenated starch hydrolysate (lycasin); protein based sweetening agents such as talin (thaumaoccous danielli); and any other pharmacologically acceptable sweeteners known in the state of the art, including any mixtures of two or more thereof.

In embodiments, a sweetener is a high intensity sweetener such as sucralose.

In embodiments of the present application, coloring agents or opacifying agents may be used to impart a pleasing appearance to the formulation.

Coloring or opacifying agents useful in the present application include pigments sucka&JJtanium dioxide and iron oxides, and natural food colors and dyes suitable for food, drug and cosmetic applications. These colorants are known as FD&C dyes and lakes. A full recitation of all FD&C and D&C dyes and their corresponding chemical structures may be found in the current edition of Kirk-Othmer Encyclopedia of Chemical Technology, and in other works.

In embodiments of the present application, taste masked film-coated ranitidine tablets may be coated with one or more layers of film forming polymers. In embodiments, tablets are coated with two or more polymeric film-forming layers.

A film forming agent can be a water soluble or swellable film forming polymer, such as a hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxypropyl cellulose, povidone, etc. The film coating may optionally contain a plasticizer, such as a polyethylene glycol, propylene glycol, or glycerin, and a coloring or opacifying agent. For example, blends of a hydroxypropyl methylcellulose, a plasticizer, and a colorant are commercially available from Colorcon Inc. as Opadry® products. Opadry® Blue 03F505007 contains a hydroxypropyl methylcellulose, titanium dioxide, Macrogol 6000, FD&C Blue#1/ Brilliant Blue FCF Aluminum Lake, iron oxide yellow and FD&C Yellow#6/ Sunset Yellow FCF Aluminum Lake. Opadry® White 03F580011 contains a hydroxypropyl methylcellulose, titanium dioxide, and Macrogol 6000.

Other commercially available film coating formers such as Lustre Clear® (from FMC) can be used in a coating. Lustre Clear® will generally contain carrageenan in the range of about 5% to 25% by weight and microcrystalline cellulose in a range of from about 15% to 60% by weight. Other components such as plasticizers may be present in ranges of from 10% to 40% by weight. Lustre Clear ® 103, for example, is a commercially available combination of carrageenan, microcrystalline cellulose, and polyethylene glycol. Other Lustre Clear® formulations may contain carrageenan, microcrystalline cellulose, polyethylene glycol, a hydroxyethyl cellulose, and maltodextrin.

In embodiments of the present application, a core tablet comprises ranitidine or a pharmaceutically acceptable salt thereof, any number of excipients such as inert carriers, fillers, binders, lubricants, etc, flavoring agents, and sweeteners.

In embodiments of the present application, formulations are prepared by processes in which: the active agent ranitidine is blended with suitable excipients; '^optionally, theMend is granulated to form granules; the blend or granules are mixed with a lubricant; and the lubricated material is compressed to form tablets. Flavoring agents and sweeteners may be included within the granules or the blend which is to be compressed. Finally, the tablets are film-coated.

In embodiments of the present application, a taste masking agent is included in a coating dispersion which is coated over the core tablets containing the active agent. In embodiments, a taste masking agent is present in an outer coating layer that is applied over an inner "protective layer" or "barrier layer" coating, which is present on core tablets.

As described herein, there may be one or more coating layers applied over core tablets. In embodiments, a protective or barrier coating that does not contain a flavoring agent is applied over core tablets, followed by a second coating layer. The second coating layer comprises a flavoring agent and sweetener, which are dispersed in the coating composition.

In embodiments of the present application, taste masked film-coated ranitidine tablets comprise a swellable polymer in a first coating layer. A polymer such as a hydroxypropyl methylcellulose is a useful swellable polymer. Embodiments of taste masked film-coated ranitidine tablets comprise hydroxypropyl methylcellulose in amounts from about 40% to about 80% by weight of the coating layer. This coating may further contain a plasticizer such as a polyethylene glycol and the like.

In embodiments, there is applied over the first coating layer an outer layer that contains a taste masking agent. The use of a first coating, particularly of the type containing a polymer such as hydroxypropyl methylcellulose, acts as a barrier between the core tablet and the outer layer. The use of this first coating helps to prevent interactions of the flavoring and/or cooling agents of a subsequently applied outer layer with the core tablets.

In embodiments of the present application, a first coating layer may suitably comprise a commercial film-coating product designed for aqueous film coating, such as those comprising the polymer hydroxypropyl methylcellulose. Suitable products are commercially available under the trade name Opadry®. In embodiments, a coating dispersion that is used to form the first coating layer comprises about 40% to ,jtiabort'«©% by weight hydroxypropyl methylcellulose, optionally 10% to about 40% by weight colorant and/or opacifying agent, and optionally from 10% to about 30% by weight plasticizer.

In embodiments of the present application, a barrier coating layer comprises from about 1% to about 10% by weight of a finished dosage form, and about 25% to about 50% of the entire coating layers.

In embodiments of the present application, an outer coating is applied over a barrier coating, and comprises a flavoring agents and a sweetening agent.

In embodiments of the present application, taste masked film-coated tablets of ranitidine comprising volatile flavoring agents are provided. It is observed that when the taste masked film coated ranitidine tablets comprising the volatile agents present in the outer layer are stored for prolonged periods of time, they tend to lose the flavoring effect, perhaps due to losses of these agents through evaporation.

In embodiments of the present application, taste masked film-coated ranitidine tablets comprising coating compositions that include "gummy" excipients are used, which are able to improve retention of volatile flavoring agents within the formulation. In embodiments of the present application, taste masked film-coated tablets of ranitidine comprising coatings including carrageenan materials are used. The "gummy" nature of such coating components retains the flavoring agents within the composition.

In an embodiment of the present application, it has been found that by combining a hydroxypropyl methylcellulose with carrageenan and microcrystalline cellulose in an outer coating provides a robust coating that does not lead to undesirable losses of flavoring agents, and at the same time provides a rapid release of taste modifying agents while ingesting a tablet.

In embodiments of the present application, taste masked film-coated tablets of ranitidine comprising carrageenan and microcrystalline cellulose in an outer coating layer are provided. Lustre Clear® products can provide the microcrystalline cellulose and carrageenan. The outer coating layer may also comprise a hydroxypropyl methylcellulose in combination with Lustre Clear products®. Opadry® products can provide the hydroxypropyl methyl cellulose for the outer coating layer. Such combinations of film forming agents provides an ease of swallowing and good taste ^masking effect, which gives a clear advantage in consumer preference and patient compliance. The coating compositions for an outer layer may comprise a combination of Lustre Clear® and Opadry® products in weight ratios from about 0.3:1 to about 0.9:1, or from about 0.4:1 to about 0.7:1, respectively.

In embodiments of the present application, taste masked film-coated ranitidine tablets comprise carrageenan in an outer coating layer in amounts from about 1 % to about 10% by weight of said layer.

In embodiments of the present application, taste masked film-coated ranitidine tablets comprise microcrystalline cellulose in an outer coating layer in amounts from about 6% to about 15% by weight of said layer.

In embodiments of the present application, weight ratios of microcrystalline cellulose to carrageenan in an outer coating layer are suitably in the range of from about 65:35 to about 90:10, or about 70:30 to about 85:15.

In embodiments of the present application, taste masked film-coated ranitidine tablets comprise a hydroxypropyl methylcellulose in an outer coating layer, wherein a hydroxypropylmethyl cellulose is present in amounts from about 10% to about 50% by weight of said layer.

In embodiments of the present application, an outer coating layer further contains a plasticizer. Examples include, but are not limited to, polyethylene glycols, polyvinyl pyrrolidones, polypropylene glycols, polyvinyl alcohols, polyvinyl acetates, polyhydric alcohols, such as glycerol, sorbitol, mannitol, and propylene glycol, esters of polyhydric alcohols, such as glycerol triacetate, triacetin, glycerol tricaprylate, monacetin and diacetin, and the like, including any mixtures thereof. The plasticizer is generally used in amounts sufficient to provide the desired degree of flexibility and toughness to the coating being applied and to facilitate processing. The plasticizer, when used, is present in amounts in the range of from about 2% to about 15%, or 3% to 8%, by weight.

A coating over core tablets may range from about 2% to about 10% by weight of the taste masked film-coated ranitidine tablets. The first film coating applied over core tablets and comprising a swellable polymer constitutes about 1.5% to about 5% of the weight of a taste masked film-coated ranitidine tablet. The outer coating applied over the film coated tablets constitutes about 1% to about 10% by weight of r fltesteinasked fHm-coated ranitidine tablet. In all cases, the amounts of coating herein are expressed on a dry basis, since the coating solutions or dispersions will be dried after they are applied.

In embodiments of the present application, taste modifying agents, namely the flavors, sweeteners, and/or coolants, are present in the outermost layer of taste masked film-coated ranitidine tablets, and the amounts of taste modifying agents comprise about 0.1 to about 2% by weight of the finished dosage forms. They may also comprise from about 1% to about 30% by weight of the outer coating layer or the flavor coating.

In embodiments of the present application, taste masked film-coated ranitidine tablets comprise a flavor agent in the outer layer, present in amounts from about 1% to about 30% by weight of said layer.

In embodiments of the present application, taste masked film-coated ranitidine tablets comprise a sweetener in the outer layer, present in amounts from about 0.1% to about 5% by weight of said layer.

Embodiments of the present application provide taste masked film-coated ranitidine tablets comprising a drug-containing core tablet, a film coating over the core tablet, and a flavor coating applied over the film coating comprising: (i) carrageenan; (ii) microcrystalline cellulose; (iii) a hydroxypropyl methylcellulose; and (iv) a taste modifying agent in amounts from about 1% to about 30% by weight of the flavor coating.

An example of a method for applying a coating comprises aqueous spray-coating techniques, wherein core tablets are continuously spray-coated with a coating solution or dispersion. Core tablets are placed in a coating chamber and the coating material is sprayed into the coating chamber until the coated tablets have a desired weight gain, or until a desired quantity of the coating material has been used.

The listings of excipients herein are illustrative members of the various classes and are not intended to be exhaustive or limiting. Those skilled in the art will be aware of many other substances that will be useful, and their uses are specifically contemplated herein.

The different physicochemical properties of ranitidine or its pharmaceutically 'acceptable sattr thereof as well as of excipients are to be considered, as these properties affect processing and formulation parameters. Various important physicochemical properties include, but are not limited to, particle sizes and distributions, density (bulk density and tapped density), compressibility index, Hausner's ratio, angle of repose, etc. Particle sizes of active pharmaceutical ingredient can affect the solid dosage form in numerous ways. For example, content uniformity (CU) of pharmaceutical dosage units can be affected by particle sizes and size distributions. Also, particle sizes can play an important role in the dissolution of active agent from finished dosage forms, because of their solubility. Hence, these physicochemical properties not only affect the processes of preparing the pharmaceutical compositions but also affect the performance of the pharmaceutical product, both in vitro and in vivo.

In embodiments, compositions of the present application are in the form of multiple particulates such as granules, pellets, or powder blends that are further made into suitable dosage forms, wherein the particles have bulk densities of about 0.3g/ml to about 0.6g/ml and tapped densities of about 0.5g/ml to about 0.8g/ml.

In embodiments, compositions of the present application are in the form of multiple particulates such as granules, pellets, or powder blends that are further made into suitable dosage forms, wherein the particles have Carr's indices in the range of about 1-40%. Flowability of materials can be measured and represented using the Carr's index. The Carr's index is the percent ratio of the difference between tapped density and bulk density to tapped density, mathematically described as:
Carr's index = [(Tapped density - Bulk density) + Tapped density] * 100.

Densities can be determined using test method 616 "Bulk Density and Tapped Density" of United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, U.S.A., 2005. Carr's Index values below about 15% represent materials with very good flow properties and values above about 40% represent materials with very poor flow properties.

In embodiments of the present application, taste masked film-coated ranitidine tablets have hardness values of about 12kiloponds (KP) to about 17KP.

In embodiments of the present application, taste masked film-coated ranitidine <■:, tablets have friability not more than 0.8%, or not more than 0.5%, or not more than 0.1%.

In embodiments of the present application, tablet compositions exhibit a 'loss-on-drying' (LOD) of not more than 2.5%w/w, when heated to 105°C.

In embodiments of the present application, taste masked film-coated ranitidine tablets are prepared using direct compression, dry granulation, wet granulation, fluidized bed granulation, or any combination of such methods.

In embodiments of the present application, a direct compression method is employed in which ranitidine or a pharmaceutically acceptable salt thereof and desired excipients are blended and compressed.

In embodiments of the present application, granulation methods for formulating core tablets are used. As an example, a wet granulation method is used in which a binder and a solvent are added to a powder mixture and granulation is carried out, a dry granulation method is used in which granulation is carried out by compacting and decompacting or slugging and deslugging a powder mixture, or a molten granulation method is used in which a substance that melts upon heating is added and heating and granulation are carried out. Other techniques also are useful, as will be recognized by those skilled in the art.

There are no particular limitations on the scope of granulation solvents, which may be water, any of various organic solvents, for example, lower alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as methylene chloride, hydrocarbons, and any mixtures of two or more thereof.

Furthermore, in connection with granulation methods, equipment such as a planetary mixer, screw mixer, Henschel mixer, super mixer, cylindrical granulator, rotary granulator, screw extruding granulator, pellet mill type granulator, and the like, may be used. Wet high-shear granulation methods include a fluidized-bed granulation method, a compression granulation method, a crushing granulation method, and a spray granulation method.

After granulation, drying using a dryer, e.g., a fluidized bed dryer or gravity oven, and sieving can be conducted to obtain granules or fine granules for further use. Moreover, a granulation solvent may be used when preparing a composition according to the present application.

In embodiments of the present application, core tablets may be prepared by sifting the active ingredient, the filler, and diluents, blending the mixture, and then adding sifted lubricants and/or glidants to form a final blend, which is then compressed into desired shapes and coated.

Equipment suitable for processing the pharmaceutical compositions include any one or more of rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, mechanical sifters, blenders, roller compacters, extrusion-spheronizers, compression machines, capsule filling machines, rotating bowls or coating pans, tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like, multi-mills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, and the like, equipped with a suitable screen.

Embodiments of dosage forms of the present application are intended for oral administration to a subject in need thereof.

In embodiments of the present application, the application provides methods of prophylaxis, amelioration, or treating diseases and/or disorders, by administering a therapeutically effective amount of a formulation.

The term 'related substances' or 'impurities' mean the degradation impurities or API process related impurities of drug materials.

In embodiments of the present application, taste masked film coated ranitidine tablets can comprise low concentrations of ranitidine-related degradation substances or impurities, such as Impurity A, Impurity B, Impurity C, Impurity D, Impurity E, Impurity F, and Impurity G.

In embodiments of the present application taste masked film coated ranitidine tablets comprise not more than 0.2% of maximum unknown individual impurity.

In embodiments of the present application, taste masked film coated ranitidine tablets comprise not more than 1.2% of total impurities.

Impurity A is 5-[[(2-aminoethylthio] methyl]-N,N-dimethylfuranmethanamine.

Impurity B is N, N- bis(2-{[(5-Dimethylamino) methyl]-2 furanyl] methyl] -thio] ethyl-2- nitro 1,1- ethenediamine.

Impurity C is N-[2-[[[5-[(Dimethyamino)methyl]-2-furanyl]methyl]sulfinyl]ethyl]-Nmethyl-2-nitro-1, 1-ethenediamine.

Impurity D is [5-[(dimethylamino) methyl)-furan-2yl] methanol.
Impurity E is 3- (methyl amino)- 5,6- dihydro- 2H-1, 4- thiazin-2- one oxime.
Impurity F is N-methyl-2- nitroacetamide.
Impurity G is N-[2-[[[5-[(Dimethyamino) methyl]-2-furanyl] methyl] thio] ethyl]-2- nitroacetamide.

The dosage forms can be subjected to in vitro dissolution testing, such as according to Test 711 "Dissolution" in United States Pharmacopeia 29, United States Pharmacopoeial Convention, Inc., Rockville, Maryland, 2005, to determine the rate at which the active agents are released from the dosage forms, and the content of active agents can be determined in dissolution media using techniques such as high performance liquid chromatography (HPLC).

Embodiments of the present application provide taste masked film-coated ranitidine tablets wherein the release of ranitidine or its pharmaceutically acceptable salt is not less than about 80% within about 45 minutes, when performed in USP type II (paddle) apparatus at 50rpm and in 900ml_ of degassed water.

Embodiments of the present application provide taste masked film-coated ranitidine tablets which exhibit a substantially comparable release of ranitidine to the commercial product Maximum Strength Zantac 150® Cool Mint Tablets

Embodiments of the present application provide taste masked film-coated ranitidine tablets which have a strong mint flavor and sweet taste, which is desired for patient acceptability.

Embodiments of the present application provide taste masked film-coated ranitidine tablets which have a strong mint flavor and sweet taste which is comparable in flavor intensity with the commercial product Maximum Strength Zantac 150® Cool Mint tablets.

Embodiments of the present application provide taste masked film-coated ranitidine tablets which are packaged into closed HDPE bottles. They may also be packaged in blister packages comprising a cold-formable base foil and a paper-wy tacked-peeMMelpp foil.

In embodiments of the present application, tablets can be formed in any shapes and sizes, such as round, oval, elongated, capsule-shaped, etc.

In embodiments of the present application, tablets can be embossed or debossed with identifying information. To form tablets, compression punches can be plain, concave, or convex in shape.

Embodiments of the present application provide taste masked film-coated ranitidine tablets, which can be administered once daily, twice daily, three times daily, or four times daily to a subject in need thereof.

The following examples further describe certain specific aspects and embodiments of the application. These examples are provided solely for the purpose of illustration, and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLE 1

* Evaporates during processing. Manufacturing procedure: Core Tablets

1. Sift Ranitidine HCI and microcrystalline cellulose through a 40mesh sieve, and blend.
2. Sift magnesium stearate through a 60mesh sieve and blend with the step 1 — materials.
3. Compress the lubricated blend into tablets.

Film Coating

1. Disperse Opadry® Blue and PEG 6000 in water.
2. Coat the core tablets with the dispersion of step 1 to produce a weight gain of 2.5±0.5% (after drying), and dry the coated tablets.

EXAMPLE 2

Film coated tablets prepared according to the procedure of Example 1 are coated with flavor coatings having different compositions.

* Evaporates during processing.

Manufacturing procedure:
Flavor Coating
1. Dissolve menthol in isopropyl alcohol.
2. Dissolve sucralose in water, then sequentially, with stirring, add peppermint flavor, wintergreen, Luster Clear® 103, and Opadry® Blue and PEG 6000, and continue stirring for 1 hour.
3. Combine the step 1 solution and step 2 dispersion, with continuous stirring.
4. Coat the film coated tablets using the dispersion of step 3 to produce a weight gain of 4.5±0.5% (after drying), and dry the coated tablets.

Packaging

Coated tablets are packaged in closed heavy weight HDPE bottles, or in blister packages comprising a cold-formable base foil and a peelable paper-backed foil.

We claim:

1. A taste masked film coated ranitidine tablet comprising a core tablet, a film coat over the core and a flavor coat applied to the film coat comprising (i) carrageenan (ii) microcrystalline cellulose (iii) hydroxy propyl methyl cellulose and (iv) taste modifying agents in an amount from about 1% to about 30% by weight of the said flavor coat.

2. The core tablets of claim 1 comprise pharmaceutical^ acceptable excipients, such as diluents and lubricants.

3. The taste modifying agents of preceding claims are selected from flavors, cooling agents and sweeteners or mixtures thereof.

4. The taste masked film coated tablets of the preceding claims wherein the flavors comprise about 10 to about 20% by weight of the flavor coat.

5. The taste masked film coated tablet of the preceding claims wherein the cooling agents comprise about 5% to about 15% by weight of the flavor coat.

6. The taste masked film coated tablets of the preceding claims wherein the sweetener comprises about 0.1% to about 5% by weight of the flavor coat.

7. A taste masked film coated ranitidine tablet as described and illustrated in examples herein.