FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A NOVEL TABLET DOSAGE FORM
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a tablet dosage form comprising a) a layer, comprising a tablet of at least one active ingredient, inlayed in said layer with other pharmaceutically acceptable excipients; b) a layer comprising at least one active ingredient other than mentioned in (a) optionally with other pharmaceutically acceptable excipients.
The following specification particularly describes the invention and the manner in which it is to be performed.
This application is patent of addition of Indian application 1006/MUM/2007.


4. Description
The present invention provides a tablet dosage form comprising a) a layer, comprising a tablet of at least one active ingredient, inlayed in said layer with other pharmaceutically acceptable excipients; b) a layer comprising at least one active ingredient other than mentioned in (a) optionally with other pharmaceutically acceptable excipients.
There is an increasing desire for combination products comprising different active ingredients. However, drug instability causes a major obstacle in combination products in a single dosage form. Drug instability is the phenomenon, which occurs when the effects of one drug are modified by the presence of another drug in the same dosage form. Therefore, combination dosage form which combines the features of pharmacologic efficacy, adequate drug stability, and a reliable and robust method of manufacture has to overcome a number of technical problems to be formulated in a single dosage form. Further, the standard approach of directly mixing the active ingredients with the necessary excipients cannot be applied to combination products of different active ingredients and more sophisticated techniques are needed to separate the different active ingredients in a single dosage form.
There are various types of combination products dosage forms conceivable but it cannot be predicted which of these dosage forms best combines product stability, pharmacological efficacy, and reliable manufacture. It is an object of the present invention to provide a novel tablet dosage form, which can encompass drug of different classes and posing stability issues in a single unit.
There are prior art references, which describes different other techniques/methods/dosage forms combining different drugs in one unit dosage form.


US Patent No. 6,183,779 and 6,287,600 describes a dosage form wherein an NSAID is located in enteric coated granules or particles and prostaglandins, for example in a form of a solid dispersion in HPMC or PVP, is located outside the pellets.
US Application 2005163847 describes a solid dosage form comprising a first portion comprising NSAID; and a coating comprising an anti ulcerative compound, said coating at least partially surrounding the NSAID portion.
US Patent No. 5,601,843 and 5,698,225 describes a tablet having a core of a NSAID selected from diclofenac and piroxicam which core is surrounded by a mantle coating of a prostaglandin such as misoprostol, wherein an intermediate coating can be present between the NSAID core and prostaglandin mantle coating.
US Patent No. 6,511,680 and 6,319,519 describes a dosage form wherein an NSAID is located in coated pellets and misoprostol, for example in a form of a solid dispersion in HPMC or PVP, is located outside the pellets.
International Publication No (PCT) WO 2007/043061 discloses a tablet-in-tablet technology wherein two chemically incompatible anti-malarial compounds are separated by a film coating, wherein the final tablet-in-tablet product is artesunate tablet inside amodiaquine tablet.
The present inventors have overcome the above mentioned problems by designing a novel tablet dosage form wherein one layer comprises of tablet of at least one active ingredient, which is inlayed in said layer along with inert pharmaceutical^ acceptable excipients, and the other layer comprising at least another active ingredient optionally with other pharmaceutically acceptable excipients. This type of tablet dosage form prevents the direct contact of one active ingredient with other ingredient leading to a stable system.


One of the aspects of the present invention provides a tablet dosage form comprising a) a layer, comprising a tablet of at least one active ingredient, inlayed in said layer with other pharmaceutically acceptable excipients; b) a layer comprising at least one active ingredient other than mentioned in (a) optionally with other pharmaceutically acceptable excipients.
The term "active ingredient" refers to a therapeutically active compound, as well as any prodrugs thereof and pharmaceutically acceptable salts, hydrates and solvates of the compound and the prodrugs.
The term "inlayed in said layer" is used herein to mean that the tablet of at least one ingredient may be present at any position in said layer.
The tablet dosage form may include a coating. The tablet may be coated with one or more enteric polymers or pharmaceutically acceptable seal coat polymers. The tablet may form a bilayered tablet.
The active ingredients of the invention may be selected from a group comprising one or more of antiinflammatory drugs, sedatives, hypnotics, antibiotics, antidiabetics, antihypertensives, anti-osteoporosis drugs, antithrombotic drugs, antiviral drugs, antifungal drugs, anticholinergic drugs, anxiolytic drugs, adrenergic drugs, antipsychotic drugs, anti parkinsonism drugs, anticonvulsants, antiepileptic drugs, CNS stimulants, antianginal drugs, antiarrhythmic drugs, antihyperlipidemic drugs, diuretics, antiasthmatic drugs, anticoagulants, antianemia drugs-, vitamins, hormones, antihistamines, anticancer drugs, antomycobacterial drugs, antiallergic drugs, antiarthritis drugs, altialzheimers' drugs, vasopressin antagonists, anticonvulsants, steroids, anesthetics, thrombolytics, antacids, proton pump inhibitors, protease inhibitors, platelet aggregation inhibitors, mucolytics, antimalarials, antiemetics, laxatives, expectorants, enzymes, contraceptives, bronchodilators, antitussives, antimigraines, antidotes, anthelmintics, anorexiants, vasoprotective agents, and the like.


Furthermore, the active ingredient may include one or more of amlodipine, diazepam, paracetamol, aspirin, celecoxib, diclofenac, ibuprofen, indomethacin, ketorolac, tramadolol, divalproex, oxcarbazopine, pioglitazone, rosiglitazone, Miglitol, vildagliptin, sitagliptin, repaglinide, rosiglitazone, voglibose, alprazolam, chlorpromazine, cimetidine, pseudoephedrine, naproxen, piroxicam, atenolol, atorvastatin, benazepril, candesartan, captopril, lisinopril, fosinopril, enalapril, furosemide, indapamide, atenolol, felodipine, verapamil, cartenolol, carvedilol, cerivastatin, diltiazem, fluvastatin, irbesartan, candesartan, methyldopa, reserpine, bupropion, fluoxetine, paroxetine, escitalopram, sertraline, amitryptiline, imipramine, fexofenadine, clopidogrel, entacapone, levodopa, carbidopa, levetiracetam, venlafaxine, duloxetine, lisinopril, losartan, lovastatin, metoprolol, niacin, pravastatin, ramipril, simvastatin, valsartan, sildenafil, tadalafil, vardenafil, esomeprazole, famotidine, omeprazole, pantoprazole, rabeprazole, ranitidine, simethicone, artesunate, amodiaquine, benazepril, misoprostol, metformin, glipizide and the like.
The active ingredient present in both layers of dosage form of present invention may be present as immediate release, delayed release, sustained release, extended release, controlled release or modified release.
The inlayed tablet can be prepared by mixing at least one active ingredient optionally with other inert pharmaceutically acceptable excipients to form a premix, optionally converting the premix into granules and compressing the premix or granules into tablets. The inlayed tablet may include a coating. The tablet may be coated with one or more enteric polymers or pharmaceutically acceptable seal coat polymers.
The pharmaceutically acceptable seal coat polymers may include one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers and the like.


The pharmaceutically acceptable enteric coating polymers may include one or more of methacrylic acid/methyl methacrylate copolymers such as Eudragits or cellulose derivatives such as carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, and the like.
The sustained release or modified release or controlled release can be achieved through hydrophilic or hydrophobic polymers which may be selected from a group comprising one or more of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, a fatty acid ester, an alkyl alcohol, a wax, shellac, rosin, zein (prolamine from corn), a poly(meth)acrylate, microcrystalline cellulose or poly(ethylene oxide), polyuronic acid salts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymers and the like.
The dosage form of the present invention can be made by compressing tablets of at least one active ingredient along with inert pharmaceutically acceptable excipients and the blend of at least one active ingredient other than in the inlayed tablet in such a way that tablet of at least one active ingredient is inlayed at any position in a layer along with inert pharmaceutically acceptable excipients and blend of atleast one active ingredient other than in the inlayed tablet being compressed as another layer resulting in tablet dosage form as shown in figure 1.


The tablet dosage form of the present invention can be in the form of immediate release, sustained release, controlled release or modified release, extended release or delayed release.
The tablet dosage form comprises of inert pharmaceutically acceptable excipients wherein excipients may include binders, fillers, antioxidants, solubilizing agents, disintegrants, surfactants, lubricants and glidants.
Suitable binder may include one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like.
Suitable filler may include one or more of, microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable antioxidant may include one or more of dibutylhydroxy toluene (BHT), propyl gallate, butylhydroxyanisole (BHA), a-tocopherol, citric acid and the like.
Suitable solubilizing agent may include one or more of polyvinyl pyrrolidone, polyvinyl alcohol, hydrophilic derivatives of cellulose like hydroxypropylcellulose, carboxymethylcellulose, maltodextrins, polyethylene glycol, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenated hydrogenated castor oil, sodium dodecyl sulfate, esters of sucrose and of sorbitan, phospholipids, polyethylene glycol stearate, disodium pamoate, polyoxyethylenated oils, polysorbates, cyclodextrins and the like.
Suitable disintegrant may include one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable surfactant may be anionic, non-ionic or cationic and may include one or more of polyoxyethylene hardened castor oil, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, a polyoxyethylene


polyoxypropylene block copolymer, polysorbates, sodium lauryl sulfate, macrogols, sucrose fatty acid ester and the like.
Suitable lubricants may include one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like.
Suitable glidants may inlcude one or more of colloidal silicon dioxide, talc or cornstarch and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
Table 1: Composition of Diclofenac-misoprostol tablet dosage form

No Ingredients % Composition
Misoprostol blend layer
Misoprostol: hypromellose (1:100)
1 Misoprostol 0.01 to 2.0
2 Hypromellose 10 to 99
3 Crospovidone 1 to 10
4 Colloidal silicon dioxide 0.1 to 10
5 Microcrystalline cellulose 10 to 90
6 Hydrogenated castor oil 0.1 to 2.0
Diclofenac sodium tablets in inert excipients layer
7 Diclofenac sodium 5 to 70
8 Microcrystalline cellulose 10 to 90
9 Lactose 10 to 90
10 Sodium starch glycolate 1 to 10
11 Povidone 1 to 10


12 Magnesium stearate 0.1 to 5
Seal coating
13 Hypromellose + PEG 400 1 to 5
14 Purified water q.s.
Enteric coating
15 Methacrylic acid copolymersuspension(Methacrylic acid copolymer, sodiumhydroxide, Talc, triethyl citrate,purified water) 8 to 25
Inert excipients
16 Crospovidone 1 to 10
17 Microcrystalline cellulose 10 to 80
18 Colloidal silicon dioxide 0.1 to 10
19 Hydrogenated castor oil 0.1 to 2.0
Procedure: Misoprostol-hypromellose dispersion was mixed with microcrystalline cellulose, crospovidone, and colloidal silicon dioxide in double cone blender. Above mixture was lubricated with pre-sifted hydrogenated castor oil in double cone blender to form misoprostol blend.
Diclofenac sodium was mixed with microcrystalline cellulose, lactose, povidone, and sodium starch glycollate in double cone blender to form a pre-mix. Pre-mix was further mixed with povidone and converted into flakes by compacting it through roll compactor. Flakes were sized into granules, which were then lubricated with magnesium stearate in double cone blender, and lubricated granules were compressed into tablets using suitable tooling. Compressed tablets were further seal coated with hypromellose polyethylene glycol solution in water. Seal coated diclofenac sodium tablets were coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc, triethyl citrate in water. Inert excipients like crospovidone, colloidal silicon dioxide, sodium starch glycollate, microcrystalline cellulose and hydrogenated castor oil were mixed together in double cone blender.


Enteric-coated diclofenac sodium tablets were compressed along with inert excipients and misoprostol blend in such a way that diclofenac sodium tablet was inlayed at any position in the first layer along with inert excipients and misoprostol blend was compressed as second layer to form bilayered tablet dosage form. Finally the bilayered tablet was further coated with aqueous dispersion of Opadry.
EXAMPLE 2
Table 2: Composition of Benazepril-Amlodipine tablet dosage form

No Ingredients % Composition
Benazepril blend layer
1 Benazepril 0.5 to 25
2 Calcium phosphate dibasic 10 to 99
3 Crospovidone 1 to 10
4 Colloidal silicon dioxide 0.1 to 10
5 Microcrystalline cellulose 10 to 90
6 Talc 0.1 to 2.0
Amlodipine tablets in inert excipients layer
7 Amlodipine 0.01 to 4.0
8 Microcrystalline cellulose 10 to 90
9 Lactose 10 to 90
10 Pregelatinized starch 1 to 10
11 Crospovidone 1 to 10
12 Magnesium stearate 0.1 to 5
Seat-coating
13 Hypromellose + PEG 400 1 to 5
14 Purified water q.s.
Enteric coating
15 Methacrylic acid copolymersuspension(Methacrylic acid copolymer, sodiumhydroxide, Talc, triethyl citrate,purified water) 8 to 25
Inert excipients


16 Crospovidone 1 to 10
17 Microcrystalline cellulose 10 to 80
18 Colloidal silicon dioxide 0.1 to 10
19 Hydrogenated castor oil 0.1 to 2.0
Procedure: Benazepril was mixed with microcrystalline cellulose, crospovidone, and colloidal silicon dioxide in suitable blender. Above mixture was lubricated with talc in suitable blender to form amiodipine blend.
Amiodipine was mixed with microcrystalline cellulose, lactose, pregelatinized starch, in suitable blender to form a pre-mix. Pre-mix was further mixed with crospovidone and converted into flakes by compacting it through suitable compactor. Flakes were sized into granules, which were then lubricated with magnesium stearate in suitable blender, and lubricated granules were compressed into tablets using suitable tooling. Compressed tablets were further seal coated with hypromellose polyethylene glycol solution in water. Seal coated amiodipine tablets were coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc, triethyl citrate in water. Inert excipients like crospovidone, colloidal silicon dioxide, sodium starch glycollate, microcrystalline cellulose and hydrogenated castor oil are mixed together in suitable blender.
Enteric-coated amiodipine tablets were compressed along with inert excipients and benazepril blend in such a way that amiodipine tablet was inlayed at any position in the first layer along with inert excipients and benazepril blend was compressed as second layer to form bilayered tablet dosage form. Finally the bilayered tablet was further coated with aqueous dispersion of Opadry.
EXAMPLE 3
Table 3: Composition of Telmisartan-Amlodipine tablet dosage form

No Ingredients % Composition
Telmisartan blend layer
1 Telmisartan 0.1 to 20.0


2 Hydroxy propyl cellulose 10 to 99
3 Crospovidone 1 to 10
4 Colloidal silicon dioxide 0.1 to 10
5 Microcrystalline cellulose 10 to 90
6 Magnesium stearate 0.1 to 2.0
Amiodipine tablets in inert excipients layer
7 Amiodipine 0.01 to 4.0
8 Microcrystalline cellulose 10 to 90
9 Lactose 10 to 90
10 Pregelatinized starch 1 to 10
11 Crospovidone 1 to 10
12 Magnesium stearate 0.1 to 5
Seal coating
13 Hypromellose + PEG 400 1 to 5
14 Purified water q.s.
Enteric coating
15 Methacrylic acid copolymersuspension(Methacrylic acid copolymer, sodiumhydroxide, Talc, triethyl citrate,purified water) 8 to 25
Inert excipients
16 Crospovidone 1to10
17 Microcrystalline cellulose 10 to 80
18 Colloidal silicon dioxide 0.1 to 10
19 Hydrogenated castor oil 0.1 to 2.0
Procedure: Telmisartan was mixed with microcrystalline cellulose, crospovidone, and colloidal silicon dioxide in suitable blender. Above mixture was lubricated with talc in suitable blender to form telmisartan blend.
Amiodipine was mixed with microcrystalline cellulose, lactose, pregelatinized starch, in suitable blender to form a pre-mix. Pre-mix was further mixed with crospovidone and converted into flakes by compacting it through suitable compactor. Flakes were sized into granules, which were then lubricated with magnesium stearate in suitable blender, and lubricated granules were


compressed into tablets using suitable tooling. Compressed tablets were further seal coated with hypromellose polyethylene glycol solution in water. Seal coated amiodipine tablets were coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc, triethyl citrate in water. Inert excipients like crospovidone, colloidal silicon dioxide, sodium starch glycollate, microcrystalline cellulose and hydrogenated castor oil were mixed together in suitable blender.
Enteric-coated amiodipine tablets were compressed along with inert excipients and telmisartan blend in such a way that amiodipine tablet was inlayed at any position in the first layer along with inert excipients and telmisartan blend was compressed as second layer to form bilayered tablet dosage form. Finally the bilayered tablet was further coated with aqueous dispersion of Opadry.
EXAMPLE 4
Table 4: Composition of Atorvastatin-Amlodipine tablet dosage form

No ingredients % Composition
Atorvastatin blend layer
1 Atorvastatin 0.1 to 20.0
2 Calcium carbonate 1 to 10
3 Croscarmellose sodium 1 to 10
4 Colloidal silicon dioxide 0.1 to 10
5 Microcrystalline cellulose 10 to 90
6 Magnesium stearate 0.1 to 2.0
Amiodipine tablets in inert excipients layer
7 Amiodipine 0.01 to 4.0
8 Microcrystalline cellulose 10 to 90
9 Lactose 10 to 90
10 Pregelatinized starch 1 to 10
11 Crospovidone 1 to 10
12 Magnesium stearate 0.1 to 5
Seal coating
13 Hypromellose + PEG 400 1 to 5


14 Purified water q.s.
Enteric coating
15 Methacrylic acid copolymersuspension(Methacrylic acid copolymer, sodiumhydroxide, Talc, triethyl citrate,purified water) 8 to 25
Inert excipients
16 Crospovidone 1 to 10
17 Microcrystalline cellulose 10 to 80
18 Colloidal silicon dioxide 0.1 to 10
19 Hydrogenated castor oil 0.1 to 2.0
Procedure: Atorvastatin was mixed with microcrystalline cellulose, crospovidone, and colloidal silicon dioxide in suitable blender. Above mixture was lubricated with talc in suitable blender to form atorvastatin blend.
Amiodipine was mixed with microcrystalline cellulose, lactose, pregelatinized starch, in suitable blender to form a pre-mix. Pre-mix was further mixed with crospovidone and converted into flakes by compacting it through suitable compactor. Flakes were sized into granules, which were then lubricated with magnesium stearate in suitable blender, and lubricated granules were compressed into tablets using suitable tooling. Compressed tablets were further seal coated with hypromellose polyethylene glycol solution in water. Seal coated amiodipine tablets were coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc, triethyl citrate in water. Inert excipients like crospovidone, colloidal silicon dioxide, sodium starch glycollate, microcrystalline cellulose and hydrogenated castor oil were mixed together in suitable blender.
Enteric-coated amiodipine tablets were compressed along with inert excipients and atorvastatin blend in such a way that amiodipine tablet was inlayed at any position in the first layer along with inert excipients and atorvastatin blend was compressed as second layer to form bilayered tablet dosage form. Finally the bilayered tablet was further coated with aqueous dispersion of Opadry.


WE CLAIM:
1. A tablet dosage form comprising a) a layer, comprising a tablet of at least one active ingredient, inlayed in said layer with other pharmaceutically acceptable excipients; b) a layer comprising at least one active ingredient other than mentioned in (a) optionally with other pharmaceutically acceptable excipients.
2. The dosage form of claim 1, wherein the dosage form comprises a bilayered dosage form.
3. The dosage form of claim 1, further comprising coating the tablet with one or more enteric polymers or pharmaceutically acceptable seal coat polymers.
4. The dosage form of claim 3, wherein the enteric polymers comprises one or more of methacrylic acid/methyl methacrylate copolymers, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, and cellulose acetate trimellitate.
5. The dosage form of claim 3, wherein the pharmaceutically acceptable seal coat polymers comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and cellulose ethers.
6. The dosage form of claim 1, wherein the at least one active ingredient is formulated in immediate release, delayed release, sustained release, extended release, controlled release or modified release form.
7. The dosage form of claim 1, wherein active ingredient comprises one or more of antiinflammatory drugs, sedatives, hypnotics, antibiotics, antidiabetics, antihypertensives, anti-osteoporosis drugs, antithrombotic drugs, antiviral drugs, antifungal drugs, anticholinergic drugs, anxiolytic


drugs, adrenergic drugs, antipsychotic drugs, anti parkinsonism drugs, anticonvulsants, antiepileptic drugs, CNS stimulants, antianginal drugs, antiarrhythmic drugs, antihyperlipidemic drugs, diuretics, antiasthmatic drugs, anticoagulants, antianemia drugs, vitamins, hormones, antihistamines, anticancer drugs, antomycobacterial drugs, antiallergic drugs, antiarthritis drugs, altialzheimers' drugs, vasopressin antagonists, anticonvulsants, steroids, anesthetics, thrombolytics, antacids, proton pump inhibitors, protease inhibitors, platelet aggregation inhibitors, mucolytics, antimalarials, antiemetics, laxatives, expectorants, enzymes, contraceptives, bronchodilators, antitussives, antimigraines, antidotes, anthelmintics, anorexiants and vasoprotective agents.
8. The dosage form of claim 1, wherein inert pharmaceutically acceptable excipients comprises one or more of binders, fillers, antioxidants, solubilizing agents, disintegrants, surfactants, lubricants and glidants.




Abstract
The present invention provides a tablet dosage form comprising a) a layer, comprising a tablet of at least one active ingredient, inlayed in said layer with other pharmaceutically acceptable excipients; b) a layer comprising at least one active ingredient other than mentioned in (a) optionally with other pharmaceutically acceptable excipients.