CLIAMS:1. A process of preparing bilayer tablet dosage form; wherein process comprises steps of:
(a) preparing aspirin enteric coated tablets;
(b) preparing aspirin immediate release granules;
(c) preparing omeprazole immediate granules; and
(d) compressing the immediate release granules of aspirin and omeprazole along with the enteric coated aspirin tablet to form a bilayer tablet, such that the enteric coated aspirin tablet is inlayed in any of the two layers.

2. The process of claim 1, wherein the enteric coated tablets of aspirin or salts are prepared by a process which comprises steps of:
(i) preparing granules of aspirin or salts thereof by mixing and granulating aspirin, light magnesium oxide & crospovidone with hydroxypropyl cellulose in isopropyl alcohol;
(ii) drying the granules of (i) in fluidized bed dryer followed by milling & sizing;
(iii) mixing the granules of (ii) with hydroxy propyl cellulose;
(iv) lubricating the granules of (iii) with magnesium stearate & sodium stearyl fumarate;
(v) compressing the granules of (iv) to form a tablet;
(vi) applying a seal coat over the tablets of (v); and
(vii) applying an enteric coat over the seal coated tablets of (vi).

3. The process of claim 1, wherein the immediate release granules of aspirin or salts thereof are prepared by a process which comprises steps of:
(i) mixing aspirin, microcrystalline cellulose, maize starch & croscarmellose sodium, polyvinyl pyrrolidone and granulating with purified water;
(ii) drying the granules of (i) in fluidized bed dryer followed by milling & sizing;
(iii) mixing the granules of (ii) with microcrystalline cellulose & croscarmellose sodium; and
(iv) optionally, lubricating the granules of (iii) with magnesium stearate.

4. The process of claim 1, wherein the immediate release granules of omeprazole or salts thereof are prepared by a process which comprises steps of:
(i) dispersing omeprazole in molten hydrogenated castor oil, cooling and passing through sieve to form granules;
(ii) re-granulating the granules of (i) with polyvinyl pyrrolidone solution in purified water;
(iii) drying the granules of (ii) in fluidized bed dryer;
(iv) mixing the granules of (iii) with lake brilliant blue and microcrystalline cellulose; and
(v) optionally, lubricating the granules of (iv) with magnesium stearate.

5. The process of claim 1 or 2, wherein the enteric coat comprises one or more methacrylic acid/methyl methacrylate copolymers, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate and cellulose acetate trimellitate polymers.

6. The process of claim 1, wherein the ratio of the amount of aspirin or salt thereof in the first layer to the amount of aspirin in the inlayed tablet ranges from about 1:0.4 to 1:0.01.
,TagSPECI:Description

The present invention relates to a process of preparing novel tablet dosage forms, which can be used for different classes of pharmaceutical active ingredients posing stability issues in a single unit system. The dosage form includes a first layer that includes a tablet of one or more active pharmaceutical ingredients, which is inlayed in the first layer along with other pharmaceutically acceptable excipients, and a second layer that includes one or more active pharmaceutical Ingredients 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 product 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.

U.S. 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 prostaglandin, for example in a form of a solid dispersion in HPMC or PVP, is located outside the pellets.

U.S. Patent Application No. 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.

U.S. 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.

U.S. 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 pharmaceutically 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.

In one general aspect the present invention provides a bilayer 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.

In another general aspect the present invention provides a bilayer tablet dosage form wherein the active ingredient present in both layers of dosage form may be present as immediate release, delayed release, sustained release, extended release, controlled release or modified release.

In another general aspect the present invention provides a bilayer tablet dosage form wherein 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 inlayed tablet may be coated with one or more pharmaceutically acceptable seal coat polymers or pharmaceutically acceptable enteric polymers.

In another general aspect the present invention provides a bilayer tablet dosage form wherein the pharmaceutically acceptable seal coat polymers may include one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers and the like.

In another general aspect the present invention provides a bilayer tablet dosage form wherein the pharmaceutically acceptable enteric coating polymers may include one or more of methacrylic acid/methyl methacrylate copolymers such as Eudragit 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.

In another general aspect the present invention provides a bilayer tablet dosage form wherein 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.

In another general aspect the present invention provides a bilayer tablet dosage form wherein the dosage form 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 at least one active ingredient other than in the inlayed tablet being compressed as another layer resulting in tablet dosage form as shown in figure 1.

In another general aspect, there is provides a process of preparing a bilayer tablet dosage form, which process comprises steps of:
(a) preparing aspirin enteric coated tablets;
(b) preparing aspirin immediate release granules;
(c) preparing omeprazole immediate granules; and
(d) compressing the immediate release granules of aspirin and omeprazole along with the enteric coated aspirin tablet to form a bilayer tablet, such that the enteric coated aspirin tablet is inlayed in any of the two layers.

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 active 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 bilayer tablet.

The active ingredients of the invention may be selected from a group comprising one or more of anti-inflammatory drugs, sedatives, hypnotics, antibiotics, anti-diabetics, anti-hypertensives, anti-osteoporosis drugs, anti-thrombotic drugs, antiviral drugs, antifungal drugs, anti-cholinergic drugs, anxiolytic drugs, adrenergic drugs, antipsychotic drugs, anti parkinsonism drugs, anticonvulsants, antiepileptic drugs, CNS stimulants, anti-anginal drugs, anti-arrhythmic drugs, anti-hyperlipidemic drugs, diuretics, anti-asthmatic drugs, anticoagulants, anti-anemia drugs, vitamins, hormones, antihistamines, anticancer drugs, anti-mycobacterial drugs, anti-allergic drugs, anti-arthritis drugs, anti-alzheimer drugs, vasopressin antagonists, anticonvulsants, steroids, anesthetics, thrombolytics, antacids, proton pump inhibitors, protease inhibitors, platelet aggregation inhibitors, mucolytics, antimalarials, anti-emetics, 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, aceclofenac, diclofenac, ibuprofen, indomethacin, ketorolac, tramadol, divalproex, oxcarbazepine, 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.

In one embodiment the invention provides a bilayer tablet dosage form comprising a) a first layer comprising at least one active ingredient optionally with one or more pharmaceutically acceptable excipients; b) a second layer comprising at least one active ingredient optionally with one or more pharmaceutically acceptable excipients; c) an inlayed tablet comprising at least one active ingredient other than mentioned in (a) optionally coated with one or more seal coats and one or more enteric coats; d) active ingredient mentioned in (a) and (b) may be same or may be different.

In another embodiment the invention provides a bilayer tablet dosage form comprising a) a first layer comprising aspirin or salts thereof optionally with one or more pharmaceutically acceptable excipients; b) a second layer comprising aspirin or salts thereof optionally with one or more pharmaceutically acceptable excipients; c) an inlayed tablet comprising omeprazole or salts thereof.

In another embodiment the invention provides the tablet dosage form in the form of immediate release, sustained release, controlled release or modified release, extended release or delayed release.

In another embodiment the invention provides the tablet dosage form comprising 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 include one or more of colloidal silicon dioxide, talc or cornstarch and the like.

The invention further provides a process of preparing a bilayer 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, which process comprises steps of:
(a) preparing aspirin enteric coated tablets;
(b) preparing aspirin immediate release granules;
(c) preparing omeprazole immediate granules; and
(d) compressing the immediate release granules of aspirin and omeprazole along with the enteric coated aspirin tablet to form a bilayer tablet, such that the enteric coated aspirin tablet is inlayed in any of the two layers.

In an embodiment, the process of preparing the enteric coated tablets of aspirin or salts thereof comprises steps of:
(i) preparing granules of aspirin or salts thereof by mixing and granulating aspirin, light magnesium oxide & crospovidone with hydroxypropyl cellulose in isopropyl alcohol;
(ii) drying the granules of (i) in fluidized bed dryer followed by milling & sizing;
(iii) mixing the granules of (ii) with hydroxy propyl cellulose;
(iv) lubricating the granules of (iii) with magnesium stearate & sodium stearyl fumarate;
(v) compressing the granules of (iv) to form a tablet.
(vi) applying a seal coat over the tablets of (v); and
(vii) applying an enteric coat over the seal coated tablets of (vi),

In an embodiment, the process of preparing the immediate release granules of aspirin or salts thereof comprises steps of:
(i) mixing aspirin, microcrystalline cellulose, maize starch & croscarmellose sodium, polyvinyl pyrrolidone and granulating with purified water;
(ii) drying the granules of (i) in fluidized bed dryer followed by milling & sizing;
(iii) mixing the granules of (ii) with microcrystalline cellulose & croscarmellose sodium; and
(iv) optionally, lubricating the granules of (iii) with magnesium stearate.

In an embodiment, the process of preparing the immediate release granules of omeprazole or salts thereof comprises steps of:
(i) dispersing omeprazole in molten hydrogenated castor oil, cooling and passing through sieve to form granules;
(ii) re-granulating the granules of (i) with polyvinyl pyrrolidone solution in purified water;
(iii) drying the granules of (ii) in fluidized bed dryer;
(iv) mixing the granules of (iii) with lake brilliant blue and microcrystalline cellulose; and
(v) optionally, lubricating the granules of (iv) with magnesium stearate.

In an embodiment, the process of preparing the bilayer tablet dosage form comprises a step of compressing the aspirin, omeprazole immediate release granules and aspirin enteric coated tablet to form a bilayer tablet.

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: Composition of Aspirin-Omeprazole tablet dosage form

Table 1
Sr. No. Ingredients Qty/Unit (mg)
Aspirin CR Core Tablets
1 Aspirin 285
2 Mannitol 31
3 Light Magnesium Oxide 40
4 Crospovidone 6
5 Hydroxy propyl cellulose 1
6 Isopropyl alcohol q. s.
7 Hydroxy propyl cellulose 10
8 Magnesium Stearate 0.5
9 Sodium stearyl fumarate 1
a) Seal Coating I
1 Instacoat IC-S-1643 2
2 Methylene chloride q. s.
3 Isopropyl alcohol q. s.
b) Seal Coating II
1 Opadry clear 1R-7006 4
2 Methylene chloride q. s.
3 Isopropyl alcohol q. s.
c) Enteric Coating
1 Insta EN (IC-EN-670) Pink 12
2 Methylene chloride q. s.
3 Isopropyl alcohol q. s.
Aspirin IR Granules
1 Aspirin 40
2 hydroxy propyl cellulose 190
3 Maize starch 50
4 Croscarmellose sodium 6
5 Polyvinyl pyrrolidone 35
6 Purified Water q. s.
7 Croscarmellose sodium 6
8 Microcrystalline cellulose 30
9 Magnesium Stearate 2.5
Omeprazole IR Granules
1 Omeprazole 40
2 Hydrogenated Castor Oil 30
3 Polyvinyl pyrrolidone 4
4 Purified Water q.s.
5 Microcrystalline cellulose 44.30
6 Lake brilliant blue 0.20
7 Magnesium Stearate 1.50

Procedure:
Manufacturing of aspirin enteric coated tablets:
(a) Manufacturing of aspirin core tablets:
Aspirin, magnesium oxide light, mannitol and crospovidone was mixed and granulated with hydroxy propyl cellulose in isopropyl alcohol. The granules were then dried in the fluidized bed dryer followed by milling and sizing. The sized granules were then mixed with hydroxy propyl cellulose and lubricated with magnesium stearate and sodium stearyl fumarate followed by compression to achieve tablet of specified weight, hardness and thickness.

(b) Seal coating of aspirin core tablets:
The aspirin core tablets were then seal coated with Instacoat IC-S-1643 followed by coating with Opadry clear 1R-7006 in suitable coating pan.

(c) Enteric coating of aspirin seal coated tablets:
The seal coated aspirin tablets were then enteric coated with Insta EN (IC-EN-670) pink in suitable coating pan.

Manufacturing of aspirin IR granules:
The mixture of aspirin, microcrystalline cellulose, maize starch and croscarmellose sodium was granulated with solution of polyvinyl pyrrolidone in purified water. The granules were then dried in the fluid bed dryer followed by milling and sizing. The sized granules were then mixed with microcrystalline cellulose and croscarmellose sodium followed by lubrication with magnesium stearate.

Manufacturing of omeprazole IR granules:
Omeprazole was dispersed and granulated using molten hydrogenated castor oil and the wet mass was then allowed to cool at room temperature. The mass was passed through multimill to ensure that all the material passed through # 20 sieve.

Above granules were re-granulated with polyvinyl pyrrolidone solution in purified water. The granules were then dried in the fluid bed dryer. The dried granules were mixed with lake brilliant blue with one-fourth quantity of microcrystalline cellulose followed by lubrication with magnesium stearate.

Compression of bilayer tablet in tablet: Compression of the lubricated blend of aspirin enteric coated tablets and immediate release aspirin and omeprazole granules into tablets with tablet press:
The hopper was filled with aspirin immediate release blend and omeprazole immediate release blend and the vibratory hopper was filled with aspirin enteric coated tablets. The weight of first layer i.e. aspirin immediate release layer was set. The aspirin enteric coated tablet feeder plate was set to insert this tablet in to the die containing aspirin immediate release layer blend such that it drops at the centre. The pre-compression pressure was set such that there will not be any upper punch embossing impression on aspirin enteric coated tablet. The weight of second layer i.e. omeprazole immediate release layer was set along with the final compaction pressure, such that there will be no cracks on aspirin enteric coated tablet.

Example 2: Composition of Benazepril-Amlodipine tablet dosage form

Table 2
Sr. 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
Seal coating
13 Hypromellose + PEG 400 1 to 5
14 Purified water q. s.
Enteric coating
15 Methacrylic acid copolymer suspension(Methacrylic acid copolymer, sodium hydroxide, 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 amlodipine blend.

Amlodipine 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 amlodipine 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 amlodipine tablets were compressed along with inert excipients and benazepril blend in such a way that amlodipine tablet was inlayed at any position in the first layer along with inert excipients and benazepril blend was compressed as second layer to form bilayer tablet dosage form. Finally the bilayer tablet was further coated with aqueous dispersion of Opadry.

Example 3: Composition of Telmisartan-Amlodipine tablet dosage form

Table 3
Sr. 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
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
Seal coating
13 Hypromellose + PEG 400 1 to 5
14 Purified water q. s.
Enteric coating
15 Methacrylic acid copolymer suspension(Methacrylic acid copolymer, sodium hydroxide, 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:
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.

Amlodipine 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 amlodipine 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 amlodipine tablets were compressed along with inert excipients and telmisartan blend in such a way that amlodipine tablet was inlayed at any position in the first layer along with inert excipients and telmisartan blend was compressed as second layer to form bilayer tablet dosage form. Finally the bilayer tablet was further coated with aqueous dispersion of Opadry.

Example 4: Composition of Atorvastatin-Amlodipine tablet dosage form

Table 4
Sr. 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
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
Seal coating
13 Hypromellose + PEG 400 1 to 5
14 Purified water q. s.
Enteric coating
15 Methacrylic acid copolymer suspension(Methacrylic acid copolymer, sodium hydroxide, 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.

Amlodipine 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 amlodipine 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 amlodipine tablets were compressed along with inert excipients and atorvastatin blend in such a way that amlodipine tablet was inlayed at any position in the first layer along with inert excipients and atorvastatin blend was compressed as second layer to form bilayer tablet dosage form. Finally the bilayer tablet was further coated with aqueous dispersion of Opadry.