Field of the invention The present invention relates to novel buccal dosage form compositions of preferably poorly bioavailable drug (s), or drug (s) which undergo extensive presystemic metabolism, to provide extended release of the drug, and process of preparation thereof. The compositions of the present invention are preferably in the taste masked form.

Background of the invention Migraine is a significant disorder, due to its high prevalence and disabling severity. The total sum of suffering caused by migraine is probably higher than that with any other kind of headache. Nearly 15% of the population suffer from this recurrent debilitating attacks of headache associated with anorexia, nausea, vomiting and photo/or phonophobia (Dechant, K. L. et al.; Drugs 43 (5) 776-798,1992). Migraine had not been clearly defined or classified until 1988, and its subforms had not been studied individually until very recently.

Migraine could be two types namely, migraine without aura (common migraine) and migraine with aura (classic migraine), respectively. First, migraine without aura is characterised by headache attacks lasting 4 to 72 hours. This headache is usually severe, unilateral pulsating aggravated by physical activity and accompanied by nausea, vomiting, photophobia and phonophobia. In the second type, the attacks are initiated by neurological symptoms called aura (visual, sensory, speech or motor symptoms).

5-HT (serotonin) has long been implicated in its pathophysiology. Probably 5-HT is released from platelets at the onset of attack, this release is associated with increase in free 5-HT in the plasma. Later stage of the attack are characterized by lower levels of 5- HT, because 5-HT acts on many different receptors mainly 5-HT1D/5-HT2 receptors. It may induce vasodilation or vasoconstriction, depending on the type of receptor dominated in particular blood vessels.

Two subtypes of receptors have a particular importance in migraine therapy. 5-HT1D receptors located on cerebral blood vessels which are dilated and distended during migraine headache (Dechant, K. L. et al. ; Drugs 43 (5) 776-798, 1992). 5-HT1D agonists are potent cerebral vasoconstrictors able to close arteriovenous anastomoses (AVAs) and also inhibit release of neurotransmitter acting on presynaptic 5-HT1D receptors. 5-HT1D receptors mediate vasconstriction and platelet aggregation but also depolarize serotonergic neurons of brain stem..

Sumatriptan is a novel 5-HT1D receptor agonist which is effective in the acute treatment of migraine headache. The antimigraine activity has been attributed to the selective vasoconstriction of cranial blood vessels which are dilated and distended during migraine headache and/or from inhibition of neurogenically mediated inflammation in dura mater.

Besides this, Sumatriptan is also reported to have affinity for 5-HT1A and 5-HT1B <BR> <BR> receptors (Dechant, K. L. et al. ; Drugs 43 (5) 776-798,1992, Ghelardini et al. , J, Pharmacol. Exp. Ther 279: 884-890,1996).

Peak plasma concentration of Sumatriptan reached at a median of 10 min (range 5 to 20 min) after 6 mg subcutaneous dose and median of 1.5 hour (range 0.5 to 4.5 hours) after a 100 mg oral dose. The mean bioavailability of Sumatriptan was 96% after subcutaneous administration but only 14% after oral, due to extensive presystemic metabolism (metabolized predominantly by the'A'isoenzyme of monoamine oxidase).

Protein binding is approximately 14 to 21%. The terminal elimination half life is 2 hours.

Like Sumatriptan, newer congeners zolmitriptan, avitriptan and naratriptan have affinity for both 5-HT1B and 5-HT1D receptor. Zolmitriptan showed similar pharmacology as compared to Sumatriptan with better potency, oral bioavailability and increased lipophilicity with central as well as peripheral synapses.

The advantages of controlled release products are well-known in the pharmaceutical field and include the ability to maintain a desired level of medicament over a desired period of time while increasing patient compliance by reducing the number of administrations necessary to achieve the same level.

U. S. Pat. No. 4,948, 580 describes a bioadhesive composition which may be employed as an oral drug delivery system and includes a freeze-dried polymer mixture formed of the copolymer poly (methyl vinyl ether/maleic anhydride) and gelatin dispersed in an ointment base. This composition is said to be useful to deliver active ingredients such as steroids, antifungal agents, and antibacterial agents, to the oral mucosa.

U. S. Pat. No. 4,915, 948 describes a tablet which is said to have improved adhesion to mucous membranes. The tablet includes a water soluble biopolymer selected from xanthan gum, a pectin and mixtures thereof, and a solid polyol having a solubility at room temperature in water greater than about 20 g/100 g solution.

U. S. Pat. Nos. 4,994, 276,5, 128, 143, and 5,135, 757, describe a controlled, release <BR> <BR> excipient comprised of synergistic heterodisperse polysaccharides (e. g. , a heteropolysaccharide, such as xanthan gum in combination with a polysaccharide gum capable of cross-linking with the heteropolysaccharide, such as locust bean gum) that is capable of processing into oral solid dosage forms using either direct compression, following addition of drug and lubricant powder, conventional wet granulation, or a combination of the two. Release of the medicament from the formulations is reported to proceed according to zero-order or first-order mechanisms.

U. S. Pat. No. 4,059, 686 describes a pharmaceutical preparation for oral cavity administration characterized by being a mixture of a pharmacologically active agent, a pharmaceutical carrier, and sodium polyacrylate in conventional dosage form. It adheres strongly to a local site and dissolves gradually over a prolonged period of time, releasing appropriate amounts of the active agent. The preparation is designed to adhere to mucosal membranes.

U. S. Pat. No. 3,972, 995 describes a dosage form for buccal administration of a drug, and which is directly applicable to the interior surfaces of the mouth. The dosage form is comprised of a support member which is water-insoluble, waterproof and flexible, a moisture-activated adhesive precursor applied to one surface of the support member, and an active ingredient applied to the central portion of the support member, either directly or dispersed in a matrix. The dosage form is applied directly to the interior surface of the

mouth. Contact with saliva activates the adhesive and causes the support member to adhere to the interior surface of the mouth, thereby exposing the active ingredient to a limited area of the oral mucosa while isolating the active ingredient from the remainder of the oral environment.

U. S. Pat. No. 5,330, 761 describes a controlled release bioadhesive tablet which includes a locally active agent, a heterodisperse gum matrix, and a pharmaceutically acceptable diluent. The final product adheres to mucous membranes and releases the locally active agent over a desired period of time.

U. S. Pat. No. 4,900, 554 describes an adhesive device for application to body tissue having an adhesive layer and a backing layer positioned over one side of the adhesive layer. The adhesive layer includes one or more acrylic acid polymers having adhesive properties upon dissolution or swelling in water and at least one water-insoluble cellulose derivative. The backing layer is water-insoluble or sparingly water-soluble.

This patent discloses a composition comprising the active agent in an admixture that also includes a bioadhesive. Further, it includes a backing layer so that the adhesive does not adhere to adjacent areas. Further, the patent does not teach the use of a sustained release composition which can be attached to a tooth or other dental surface by a separate adhesive.

Oral controlled release delivery systems should ideally be adaptable so that release rates and profiles can be matched to physiological and chronotherapeutic requirements. The art describes free forms, such as sublingual tablets, troches, and buccal dosage forms. In addition to oral sustained or controlled release forms, other forms are designed to adhere to the oral mucosa and deliver an active pharmaceutical agent either directly into the oral mucosa, or into the saliva. Ointments and other sticky adhering compositions also have been used. The active ingredient in all these forms can act locally or systemically.

Furthermore, each of the above-cited references further discusses sustained release compositions, many of which can be used to release a pharmaceutically active agent in the oral cavity.

Several problems are associated with controlled release or sustained release formulations in the oral cavity. A major problem is providing prolonged release at effective concentrations. For example, fungal infections beginning in the mouth and then entering other parts of the body are life-threatening to immuno-compromised patients. It is thus desirable to release antifungal agents on an ongoing basis. However, it is very difficult to achieve the same.

Buccal tablets and sublingual tablets are pharmaceutical preparations primarily intended for systemic effect. These tablets are placed between the cheek and gingival or under the tongue and allowed to dissolve slowly. The drugs absorbed through the oral mucous membrane enter directly, not through the portal circulation but through the systemic circulation. An advantage of these tablets is in the efficient absorption of the drug, because the drug is not decomposed by the liver. However, if the disintegration and dissolution of the tablet are too rapid, the object of this method of administration is not achieved.

A problem with these sustained release devices involves the area of comfort coupled with taste. Patients often reject these oral sustained release devices because they have a "foreign"feeling or, the composition has a bitter or unpleasant taste. As a result, these devices are often dislodged by the patient. Hence the bitter taste of such buccal compositions arising essentially due to the bitter taste of the active ingredient (s) present therein needs to be properly masked in order to make it patient compliant.

Hence, there still exists an unmet need for developing taste masked buccal form compositions which can provide extended release of the active ingredient (s).

Summary of the invention It is an objective of the present invention to provide novel extended release buccal dosage form composition comprising at least one active agent or its tautomeric forms, analogues, isomers, polymorphs, solvates, or salts thereof ; one or more ion exchange

resin (s); one or more sustaining material (s); one or more release modifying agent (s); optionally with other pharmaceutically acceptable excipients.

It is also an objective of the present invention to provide novel extended release buccal dosage form compositions of preferably poorly bioavailable drugs, more preferably triptan (s), its salts, esters or hydrates, most preferably Sumatriptan succinate.

It is another objective of the present invention to provide novel taste masked buccal dosage form compositions of poorly bioavailable drugs, preferably triptan (s), its salts, esters or hydrates, more preferably Sumatriptan succinate, which provides extended release of the active ingredient.

It is yet another objective of the present invention to provide process for preparation of a composition which comprises of the following steps: i) complexation of active agent with ion exchange resin (s), ii) addition of one or more release modifying agent (s), and one or more sustaining material (s), iii) formulation of the mixture into a suitable dosage form.

Detailed description of the invention The present invention relates to novel extended release buccal dosage form composition comprising at least one active agent or its tautomeric forms, analogues, isomers, polymorphs, solvates, or salts thereof; one or more ion exchange resin (s); one or more sustaining material (s); one or more release modifying agent (s); optionally with other pharmaceutically acceptable excipients.

The present invention relates to novel extended release buccal dosage form composition comprising at least one active agent preferably triptan (s), its tautomeric forms, analogues, isomers, polymorphs, solvates, or salts, more preferably Sumatriptan succinate ; one or more ion exchange resin (s), one or more sustaining material (s), one or

more release modifying agent (s), optionally with other pharmaceutically acceptable excipients.

In an embodiment of the present invention, the active ingredient is selected from but not limited to a group comprising carvedilol, olanzapine, ondansetron, L-cardinipine, zolpidem, fluoxetine, etc. or its tautomeric forms, analogues, isomers, polymorphs, solvates, or salts thereof.

Sumatriptan succinate is bitter tasting drug and is expected to provide unpleasant taste when formulated as extended release buccal dosage form. It was however surprisingly found that when the drug was formulated as extended release buccal tablet composition according to the present invention, the bitter taste of Sumatriptan succinate was not evident.

In an embodiment of the present invention, the novel extended release buccal dosage form composition of the present invention comprises Domperidone or its salts, esters or hydrates thereof as the active ingredient.

In an embodiment, the ion exchange resin (s) of the present invention is selected from a group comprising cross-linked polyacrylic copolymer resins (manufactured by Ion Exchange (India) Ltd. ) such as Indion 204, Indion (D 214, Indionl) 224, Indiong 234 ; Amberlite resins such as IRP-64@, Polacrilin potassium, and the like, or mixtures thereof.

The sustaining materials are selected from the group including cellulose and cellulose derivatives, waxes, carbomers, polyalkylene polyols, polycarbophils, methacrylate derivatives, gelatins, gums, polyethylene oxides, and the like.

The sustaining materials comprise materials which are non-toxic and pharmaceutically acceptable. These may be natural, semi-synthetic, synthetic or man-modified. Suitable materials include cellulose and cellulose derivatives like microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate, cellulose acetate butyrate,

cellulose acetate propionate, cellulose acetate trimellitate, cellulose carboxymethyl ethers and their salts, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, Polyethylene; Polyquaternium-1 ; Polyvinyl acetate (homopolymer); Polyvinyl acetate phthalate ; Propylene glycol alginate; PVM/MA (polyvinylmethylether/maleic anhydride) copolymer; Polyvinyl pyrrolidone (PVP)/ dimethiconylacrylate/polycarbamyl/polyglycolester ; Polyvinyl pyrrolidone (PVP) /dimethyl aminoethyl methacrylate copolymer; Polyvinyl pyrrolidone (PVP)/dimethylaminoethylmethacrylate/polycarbamyl polyglycol ester; Polyvinyl pyrrolidone (PVP)/polycarbamyl polyglycol ester; Polyvinyl pyrrolidone (PVP)/VA copolymer; PVP/VA/Vinyl propionate copolymer ; PVP/VA/Itaconic acid copolymer; PVP/Hexadecene copolyme; PVP/Eicosene copolyme; PVP/ Dimethylaminoethylmethacrylate copolyme; PVP/Dimethylaminoethylmethacrylate/ Polycarbamyl polyglycol ester; PVP/Dimethiconylacrylate/polycarbamyl/polyglycol ester; PVP/Decene copolyme; PVM/MA Decadiene crosspolymer; Cross-linked polyacrylic copolymer resins (manufactured by Ion Exchange (India) Ltd. ) such as IndionO 204, Indiong 214, Indion 224, Indion 234 ; Amberlite resins such as IRP- 64X, Polacrilin potassium, and the like ; used either alone or in combination thereof.

In an embodiment of the present invention, the ion exchange resin (s) is used as a sustaining material.

The release modifying agent (s) of the present invention is selected from the group comprising pore formers, pH modifiers and tonicity adjusting agents, or mixtures thereof. Such release modifying agents are selected from the group including pore formers, pH modifiers and tonicity adjusting agents. Examples of pH modifiers include citric acid, tartaric acid, fumaric acid, malic acid, maleic acid, ascorbic acid, and the like.

Examples of pore forming agents include sodium chloride, potassium chloride and the like. Examples of tonicity adjusting agents include sodium chloride, potassium chloride, dextrose, lactose, povidone, and the like.

In an embodiment of the present invention, the release modifying agent (s) preferably are hydrophilic in nature and present in a blend of fast and slow hydrating polymers.

Pharmaceutically acceptable excipients as used in the composition are selected from the group of excipients generally used by persons skilled in the art e. g. diluents, disintegrants, binders, fillers, bulking agent, organic acid (s), colorants, stabilizers, preservatives, lubricants, glidants, chelating agents and the like.

In another embodiment of the present invention, the composition further comprises of a taste masking agent selected from but not limited to a group comprising Ion exchange resins, Acrylic and methacrylic acid polymers, Carbopols, and the like.

In an embodiment of the present invention, the ion exchange resin (s) functions as a taste masking agent.

The pharmaceutical compositions of the present invention may be formulated as an oral dosage form such on tablets, capsules, patches and the like. The compositions may be in the form of compressed tablets, moulded tablets, products prepared by extrusion or film cast technique, and the like.

In an embodiment, the composition of the present invention is in the form of tablets. The tablets can be prepared by either direct compression, dry compression (slugging), or by granulation.

The granulation technique is either aqueous or non-aqueous. Preferably, the tablets of the present invention are prepared by non-aqueous granulation technique. The non-aqueous solvent used is selected from a group comprising ethanol or isopropyl alcohol.

In an embodiment of the present invention is provided a process for preparation of a composition which comprises complexation of active agent with ion exchange resin (s), addition of one or more release modifying agent (s), and one or more sustaining material (s), and formulation of the mixture into a suitable dosage form.

In a further embodiment, the process of preparation of the composition of the present invention involves complexation of sumatriptan succinate with ion exchange resin (s), addition of release modifying agent such as an organic acid to break the complex and

sustaining material to provide for gradual release of the drug into oral cavity primarily by erosion process; addition of one or more pharmaceutically acceptable excipients as described herein, and formulating into tablets.

The active ingredient is primarily released by erosion or diffusion process. The said compositions provide a taste masked dosage form, which can be retained in the oral cavity for long period of time. Moreover the said composition is not expected to compromise the absorption of the poorly bioavailable drug, such as Sumatriptan from the oral cavity.

In an embodiment of the present invention, sumatriptan succinate was complexed with ion exchange resin (s), the process being reversible under acidic conditions. Such complexation would result in liberation of free drug in the stomach resulting in reduced bioavailability due to first pass metabolism. During experimentation, it was observed that if an organic acid is added to the composition, the release of the drug from the taste masked formulation increases significantly at pH of the oral cavity. Moreover, this release is not accompanied by increase in bitter taste of the drug. The organic acid added to the formulation alters the pH in the microenvironment of the complex resulting in the gradual breakdown of the complex. The uncomplexed drug is then slowly released into the oral cavity. The release rate of the drug from the dosage form can be modified using one or more sustaining materials as described herein.

In an embodiment of the present invention, the sumatriptan succinate complex along with organic acid is embedded in a matrix of sustaining materials such as controlled release polymers which form a diffusion layer around the tablet when it comes in contact with the fluid of oral cavity. This diffusion layer controls the penetration of fluid into the tablet which, in turn controls the gradual breakdown of the complex. It also controls the release of the uncomplexed drug out of the tablet and into the oral cavity.

The examples given below serve to illustrate embodiments of the present invention.

However, they do not intend to limit the scope of present invention.

Example 1 Ingredients mg/tablet i) Sumatriptan succinate 25.0 ii) Ion exchange resin (Cross-linked polyacrylic copolymer resin ; Indion 204) 75.0 iii) Maltodextrin 48.0 iv) Sucrose 30.0 v) Carboxymethyl cellulose 18.0 vi) Hydroxypropyl methyl cellulose 8.0 vii) Hydroxypropyl cellulose 8.0 viii) Citric acid 15.0 ix) Sodium chloride 5.0 x) Povidone 3.0 xi) Isopropyl alcohol Lost in processing xii) Magnesium stearate 3.0 xiii) Water Lost in processing Procedure: 1. Dissolve (i) in (xiii) and add (ii) while stirring continuously for about 1-3 hours.

Adjust the pH to about 4-6.

2. Filter the slurry of step 1 and dry. Sift the dried mass.

3. Separately sift (iii), (iv), (v), (vi), (vii), (viii) and (ix). Blend with dried mass of step 2.

4. Dissolve (x) in (xi) and granulate the blend of step 3. Dry and sift the granules.

5. Sift (xii) and blend with granules of step 4. Compress the blend into tablets.

Example 2 Ingredient mg/tablet i) Sumatriptan succinate 25.0 ii) Ion exchange resin (Cross-linked polyacrylic

copolymer resin; Indion 204) 75. 0 iii) Lactose 48.0 iv) Locust bean gum 10.0 v) Xanthan gum 8.0 vi) Povidone 3.0 vii) Isopropyl alcohol Lost in processing viii) Magnesium stearate 3.0 ix) Water Lost in processing Procedure: 1. Dissolve (i) in (ix) and add (ii) while stirring continuously for about 1-3 hour Adjust the pH to about 4-6.

2. Filter the slurry of step 1 and dry. Sift the dried mass.

3. Separately sift (iii), (iv) and (v). Blend with dried mass of step 2.

4. Dissolve (vi) in (vii) and granulate the blend of step 3. Dry and sift the granules.

5. Sift (viii) and blend with granules of step 4. Compress the blend into tablets.

Example 3 Ingredients mg/tablet i) Domperidone maleate (equivalent to Domperidone 10 mg) 12.72 ii) Ion exchange resin (Cross-linked polyacrylic copolymer resin; IndionW 204) 75.00 iii) Maltodextrin 48.00 iv) Sucrose 30.00 v) Carboxymethyl cellulose 18.00 vi) Hydroxypropyl methyl cellulose 8.00 vii) Hydroxypropyl cellulose 8.00 viii) Citric acid 15.00 ix) Sodium chloride 5.00 x) Povidone 3. 00

xi) Isopropyl alcohol Lost in processing xii) Magnesium stearate 3.00 xiii) Water Lost in processing Procedure: 1. Dissolve (i) in (xiii) and add (ii) while stirring continuously for about 1-3 hours.

Adjust the pH to about 4-6.

2. Filter the slurry of step 1 and dry. Sift the dried mass.

3. Separately sift (iii), (iv), (v), (vi), (vii), (viii) and (ix). Blend with dried mass of step 2.

4. Dissolve (x) in (xi) and granulate the blend of step 3. Dry and sift the granules 5. Sift (xii) and blend with granules of step 4. Compress the blend into tablets.

Example 4 Ingredient mg/tablet i) Domperidone maleate (equivalent to Domperidone 10 mg) 12.72 ii) Ion exchange resin (Cross-linked polyacrylic copolymer resin; Indion 204) 75.00 iii) Lactose 48.00 iv) Locust bean gum 10.00 v) Xanthan gum 8.00 vi) Povidone 3.00 vii) Isopropyl alcohol Lost in processing viii) Magnesium stearate 3.00 ix) Water Lost in processing Procedure : l. Dissolve (i) in (ix) and add (ii) while stirring continuously for about 1-3 hours.

Adjust the pH to about 4-6.

2. Filter the slurry of step 1 and dry. Sift the dried mass.

3. Separately sift (iii), (iv) and (v). Blend with dried mass of step 2.

4. Dissolve (vi) in (vii) and granulate the blend of step 3. Dry and sift the granules.

5. Sift (viii) and blend with granules of step 4. Compress the blend into tablets.

Example 5 Ingredients mg/tablet i) Olanzapine 10.00 ii) Ion exchange resin (Cross-linked polyacrylic copolymer resin; Indion 214) 75.00 iii) Maltodextrin 48.00 iv) Sucrose 30.00 v) Carboxymethyl cellulose 18.00 vi) Hydroxypropyl methyl cellulose 8.00 vii) Hydroxypropyl cellulose 8.00 viii) Citric acid 15.00 ix) Sodium chloride 5.00 x) Povidone 3.00 xi) Isopropyl alcohol Lost in processing xii) Magnesium stearate 3.00 xiii) Water Lost in processing Procedure: 1. Dissolve (i) in (xiii) and add (ii) while stirring continuously for about 1-3 hours.

Adjust the pH to about 4-6.

2. Filter the slurry of step 1 and dry. Sift the dried mass.

3. Separately sift (iii), (iv), (v), (vi), (vii), (viii) and (ix). Blend with dried mass of step 2.

4. Dissolve (x) in (xi) and granulate the blend of step 3. Dry and sift the granules.

5. Sift (xii) and blend with granules of step 4. Compress the blend into tablets.

Example 6 Ingredient mg/tablet i) Ondansetron 8. 00 ii) Polacrilin potassium 75.00 iii) Lactose 48.00 iv) Locust bean gum 10.00 v) Xanthan gum 8.00 vi) Povidone 3.00 vii) Isopropyl alcohol Lost in processing viii) Magnesium stearate 3.00 ix) Water Lost in processing Procedure: 1. Dissolve (i) in (ix) and add (ii) while stirring continuously for about 1-3 hours.

Adjust the pH to about 4-6.

2. Filter the slurry of step 1 and dry. Sift the dried mass.

3. Separately sift (iii), (iv) and (v). Blend with dried mass of step 2.

4. Dissolve (vi) in (vii) and granulate the blend of step 3. Dry and sift the granules.

5. Sift (viii) and blend with granules of step 4. Compress the blend into tablets.

Example 7 Ingredients mg/tablet i) Zolpidem tartrate 10.0 ii) Ion exchange resin (Cross-linked polyacrylic copolymer resin; Indion 234) 75.0 iii) Maltodextrin 48.0 iv) Sucrose 30.0 v) Carboxymethyl cellulose 18.0 vi) Hydroxypropyl methyl cellulose 8.0

vii) Hydroxypropyl cellulose 8.0 viii) Citric acid 15.0 ix) Sodium chloride 5.0 x) Povidone 3.0 xi) Isopropyl alcohol Lost in processing xii) Magnesium stearate 3.0 xiii) Water Lost in processing Procedure: 1. Dissolve (i) in (xiii) and add (ii) while stirring continuously for about 1-3 hours.

Adjust the pH to about 4-6.

2. Filter the slurry of step 1 and dry. Sift the dried mass.

3. Separately sift (iii), (iv), (v), (vi), (vii), (viii) and (ix). Blend with dried mass of step 2.

4. Dissolve (x) in (xi) and granulate the blend of step 3. Dry and sift the granules.

5. Sift (xii) and blend with granules of step 4. Compress the blend into tablets.