PHARMACEUTICAL FIXED DOSE COMPOSITIONS
INTRODUCTION TO THE INVENTION
The present invention relates to pharmaceutical fixed dose compositions, processes for preparing the same and methods of use and treatment of hypertension and other cardiovascular disorders.
The present invention further relates to pharmaceutical fixed dose compositions of metoprolol including its pharmaceutically acceptable salts, with ramipril including its pharmaceutically acceptable salts, isomers, racemates, polymorphs, etc., and optionally with amlodipine including its pharmaceutically acceptable salts.
The present invention further relates to pharmaceutical fixed dose compositions of metoprolol including its pharmaceutically acceptable salts and amiodipine including its pharmaceutically acceptable salts.
Combination therapy affords the physician and the patient, the opportunity to more effectively treat diseases that may stem from more than one cause. When used correctly and appropriately combination therapy leads to better outcomes than monotherapy by treating more than one cause of the disease and/or by synergistically enhancing the action of one of the component drugs.
Metoprolol succinate (Formula 1) has a chemical name (±)-1-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1). It is selective betai receptor blocker. It is useful in the treatment of hypertension, angina pectoris and heart failure. It is commercially available as extended release tablets under the brand name TOPROL-XL™ and is manufactured by Astra Zeneca.


Ramipril (Formula II) has a chemical name (2S,3aS,6aS) -1[(S)-A/-[(S)-1-Carboxy-3-phenylpropyl]alanyl]octahydrocyclopenta [b] pyrrole-2-carboxylic acid, 1-ethyl ester. Ramipril is a dicarboxylate-containing angiotensin converting inhibitor. It is useful in the treatment of hypertension and angina. It is commercially available as hard gelatin capsules for oral use under the brand name ALTACE™ and is manufactured by King Pharmaceuticals, Inc.

Formula II Amiodipine besylate (Formula IV) has a chemical name 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3, 5-pyridinedicarboxylate, monobenzenesulphonate. It is a dihydropyridine containing calcium channel blocker. It is useful in the treatment of hypertension and angina. It is commercially available as tablets for oral use under the brand name NORVASC™ and is manufactured by Pfizer.
Formula IV Hypertension and other cardiovascular disorders are frequently inadequately controlled by monotherapy, and hence need treatment involving additional drugs. Among different drugs useful for treating hypertension and

cardiovascular disorders are metoprolol from the beta-blocker class, ramipril from the angiotensin converting enzyme inhibitor class, and amiodipine from the calcium channel blocker class, as commonly used drugs to treat hypertension and other cardiovascular disorders.
All of the above discussed active substances act by different mechanisms of action. The need to use cardiovascular therapeutic agents with different and complementary mechanisms of action frequently arises in the treatment of hypertension and other related cardiovascular diseases due to the progressive nature of the disease with deterioration over time. The use of a single active agent is inadequate for this purpose. Presenting different medications in a single composition promotes patient compliance by avoiding the inconvenience of taking multiple doses of medicines in a single day and reducing the chances of skipping doses.
U.S. Patent Application Publication No. 2005/0032879 describes a combination of metoprolol tartrate and enalapril maleate.
U.S. Patent No. 4,942,040 describes a controlled release preparation containing a combination of metoprolol with a dihydropyridine, such as felodipine or nifedipine.
The development of fixed dose combination pharmaceutical compositions as described in the context of the present invention would be a significant improvement in the field of clinical practice.
SUMMARY OF THE INVENTION The present invention relates to pharmaceutical fixed dose compositions, processes for preparing the same and methods of use and treatment of hypertension and other cardiovascular disorders.
The present invention relates to pharmaceutical fixed dose compositions of metoprolol includingr its pharmaceutically acceptable salts, ramipril including its pharmaceutically acceptable salts, isomers, racemates, polymorphs, etc., and optionally with amiodipine including its pharmaceutically acceptable salts.

The present invention further relates to pharmaceutical fixed dose compositions of metoprolol including its pharmaceutically acceptable salts and amiodipine including its pharmaceutically acceptable salts.
In an embodiment of the invention, immediate or modified release metoprolol is combined with immediate or modified release ramipril and/or amiodipine.
In an embodiment, the invention includes an immediate release layer that comprises one or more active agents.
In another embodiment, the Invention includes an extended release layer that may comprise one or more active agents.
In an embodiment the invention includes pharmaceutical compositions comprising metoprolol and ramipril.
In another embodiment the Invention includes pharmaceutical compositions wherein metoprolol is in a modified release form and ramipril is in an immediate release form.
In an embodiment, the present invention relates to pharmaceutical compositions for once-a-day therapy comprising metoprolol in a modified release form and ramipril in an immediate release form, wherein the composition, after oral administration to a human, results in a tmax of metoprolol from about 5 hours to about 13 hours, or from about 6 hours to about 12 hours.
In an embodiment the present invention relates to pharmaceutical compositions for once-a-day therapy comprising metoprolol in a modified release form and ramipril in an immediate release form, wherein the composition, after oral administration to a human, results in a tmax of ramipril from about 0.3 hour to about 3 hours, or from about 0.4 hour to about 2 hours.
In another embodiment the present invention relates to pharmaceutical compositions for once-a-day therapy comprising metoprolol in a modified release form and ramipril in an immediate release form, wherein metoprolol is released according to the following dissolution profile,

when tested in vitro in 900 ml of pH 6.8 phosphate buffer for up to 20 hours in a USP Type II apparatus at 50 rpm:
a) Not more than 10 % of metoprolol is released in 1 hour.
b) Not more than 50 %, or between 10 % to 50 %, or between 20 % to 50%, of metoprolol is released in 4 hours.
0) Not more than 70 %, or between 30 % and 70 %, or between about 40 % and about 70 %, of metoprolol is released in 8 hours.
d) Not less than 60 %, or not less than 70 %, of metoprolol is released in 20 hours.
In an embodiment, the present invention relates to pharmaceutical compositions for once-a-day therapy comprising metoprolol in a modified release form and ramipril in an immediate release form, wherein release of ramipril after 45 minutes is not less than 80 %, when tested in vitro in 900 ml of 0.1 N HCI in a USP Type II apparatus at 100 rpm.
In an embodiment the invention includes pharmaceutical compositions comprising metoprolol and amiodipine.
In another embodiment, the invention includes pharmaceutical compositions comprising metoprolol in a modified release form and amiodipine in an immediate release form.
In an embodiment, the present invention relates to pharmaceutical compositions for once-a-day therapy comprising metoprolol in a modified release form and amiodipine in an immediate release form, wherein the composition, after oral administration to a human, results in a tmax of metoprolol from about 4 hours to about 13 hours, or from about 5 hours to about 13 hours.
In an embodiment, the present invention relates to pharmaceutical compositions for once-a-day therapy comprising metoprolol in a modified release form and amiodipine in an immediate release form, wherein the composition, after oral administration to a human, results in a tmax of amiodipine from about 5 hours to about 12 hours, or from about 5 hours to about 10 hours.

In an embodiment, the present invention relates to pharmaceutical compositions for once-a-day therapy comprising metoprolol in a modified release form and amiodipine in an immediate release form, wherein release of amiodipine after 45 minutes is not less than about 80 %, when tested in vitro in 900 ml of 0.1N HCI in a USPTypell apparatus at 100 rpm.
In an embodiment, the invention includes pharmaceutical compositions comprising metoprolol or its salts and amiodipine, wherein metoprolol is in a modified release form and amiodipine is in an immediate release form.
In another embodiment, the invention includes pharmaceutical compositions comprising ramipril or its salts and amiodipine, wherein they are either in modified release form or in immediate release form.
In an embodiment, the invention includes processes to prepare pharmaceutical compositions of the present invention.
In yet another embodiment, the invention includes method of treating hypertension or cardiovascular disorders using pharmaceutical compositions of the present invention.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical fixed dose compositions, processes for preparing the same and methods of use and treatment.
The present invention further relates to pharmaceutical fixed dose compositions comprising a combination of a therapeutically effective dose of metoprolol in combination with ramipril and/or amiodipine.
In embodiments of the present invention the individual active substances such as metoprolol, ramipril, amiodipine are presented either in their base forms or as their pharmaceutically acceptable salts, solvates, polymorphs, racemates, enantiomers or mixtures thereof. Mention of the drug name implies the use of any of these compounds that will provide the drug, upon administration of a pharmaceutical preparation containing the compound.

The pharmaceutically acceptable salts of metoprolol include but are not limited to salts which are formed with organic carboxylic acids, such as the succinate, fumarate, benzoate, and tartrate salts, and the like.
Useful pharmaceutically acceptable compounds of ramipril are not particularly limited and include all pharmaceutically acceptable anhydrates, solvates, hydrates, crystalline and amorphous forms, and acid addition salts with organic or inorganic acids. Suitable organic carboxylic acids include salicylic acid, maleic acid, tartaric acid, citric acid, adipic acid, sorbic acid, malonic acid, 1,4-butanedioic acid, malic acid, pivalic acid, succinic acid, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, acetic acid, benzoic acid, fatty acids such as, for example, lauric acid, myristic acid and oleic acid, and suitable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid and phosphoric acid.
Amiodipine may also be used in pharmaceutically acceptable acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, besylate, lactate, citrate, acid citrate, tartarate, bitartarate, succinate, maleate, gluconate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate salts.
In another embodiment of the invention, metoprolol, ramipril, or amiodipine or combinations thereof are presented as immediate, modified, partly immediate and/or partly modified release portions.
In one embodiment of the invention, modified release metoprolol is combined with immediate release ramipril and/or amiodipine.
In another embodiment of the invention pharmaceutical compositions comprise a modified release form of metoprolol in combination with an immediate release form of ramipril.
In an embodiment of the invention, a modified release form of metoprolol is combined with an immediate release form of amiodipine.
Compositions of present invention are formulated as single granular or pellet compositions, or different granular or pellet compositions compressed

as single monolithic tablets, or bilayered or tri layered or multi layered tablets with or without intermediate placebo layers, or filled into capsules, or are tablets in tablets, or inlay tablets, or tablets, or tablets in capsules, or granules or pellets or tablets, or combinations thereof, filled into capsules.
The combination of an immediate release active with a modified release active can be formulated as a tablet formulation containing immediate release and modified release granules, a two or three layer tablet, a tablet with a modified release core surrounded by an immediate release coating, a modified release tablet or granule or pellet coated with a film of Immediate release active, and the like.
In the context of the present invention, different release patterns of active substances are achieved by means of formulating the active substance using matrix or reservoir, or combination of matrix-reservoir, principles and each active may be further presented as monolithic or as multiparticulate compositions-Pharmaceutical fixed dose compositions based on a matrix principle may be prepared by direct blending, dry granulation or wet granulation of active substance with one or more rate modifying substances and they are filled into capsules, or compressed as tablets, or layered on to inert beads and the beads are filled into capsules or compressed into tablets.
Pharmaceutical fixed dose compositions based on a reservoir principle may be prepared by coating powders or granules or pellets or tablets or cores with one or more rate modifying substances, and they may be filled into capsules.
Pharmaceutical fixed dose compositions may also be prepared using matrix-reservoir principles by first preparing the matrix portion as mentioned in the previous paragraphs and subsequently coating the matrix composition with one or more rate modifying substances.
Rate and extent of release of active from the compositions depend on the type and amount of rate modifying substance(s) used, the type of composition used and the processes used to prepare the compositions.

Further in an embodiment, rate modifying substance(s) may be hydrophilic or hydrophobic or a combination thereof.
The ratio of hydrophilic to hydrophobic substances in a coating may range from about 1:10 to about 10:1, or from about 1:4 to about 4:1, or from about 1:2 to about 2:1.
Various useful rate modifying substances comprise, without limitation thereto, cellulose ethers such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC or hypromellose, provided by Dow Chemical Co. under the trade name METHOCEL™, various grades including METHOCEL K4M, METHOCEL K 15M, METHOCEL K 100M, METHOCEL K100M CR, METHOCEL K100LV), hydroxypropyl ethylcellulose (HPEC), carboxymethyl cellulose (CMC), crosslinked carboxymethyl cellulose (croscarmellose) and its alkali salts, ethylhydroxyethylcellulose (EHEC), hydroxyethyl methylcellulose (HEMC), hydrophobically modified hydroxy ethyl cellulose (HMHEC), hydrophobically modified ethylhydroxy ethyl cellulose (HMEHEC), carboxymethyl hydroxyethylcellulose (CMHEC), carboxymethyl hydrophobically modified hydroxyethyl cellulose (CMHMHEC), and the like; vinyl pyrrolidone polymers such as crosslinked polyvinylpyrrolidone or crospovidone, copolymers of vinyl pyrrolidone and vinyl acetate; and alkylene oxide homopolymers such as ethylene oxide, polyethylene oxide, polypropylene oxide, carboxymethyl starch, sodium carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer, polyvinyl alcohols, amylose, cross-linked amylose, starch derivatives, microcrystalline cellulose and cellulose derivatives, alpha-, beta-and gamma-cyclodextrin, dextrin derivatives, chitosan, hydrogenated castor oil and the like.
Examples of gums of plant, animal, mineral or synthetic origin that may be used as rate modifying substances in the present invention comprise agar, alginates, carrageenan, furcellaran derived from marine plants, guar gum, gum arable, gum tragacanth, karaya gum, locust bean gum, pectin derived from terrestrial plants, microbial polysaccharides such as dextran, gellan gum, rhamsan gum, welan gum, xanthan gum, and synthetic or semi-

synthetic gums such as propylene glycol alginate, hydroxypropyl guar and modified starches like sodium starch glycolate, and the like; and an acrylic acid polymer such as cross-linked polymer available under the trade name Carbopol™ or homopolymers and co-polymers of acrylate or methacrylate monomers for example poly methacrylates marketed under the brand names of Eudragit™, particularly Eudragit™ RS and Eudragit™ RL; chitosan; hydrogenated castor oil, and the like.
Examples of fatty compounds that may be used as rate modifying substances in the present invention comprise various waxes such as digestible, long chain (C8-C50, or C12-C40) substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. Other classes of release or rate modifying substances or their mixtures in various ratios as required are also within the purview of this invention without limitation.
In an embodiment the rate modifying substance comprises a cellulose derivative such as hydroxypropyl methylcellulose.
The rate modifying substances in the pharmaceutical composition may be present in concentrations ranging from about 20% to about 60%, by total weight of the composition.
The pharmaceutical fixed dose compositions can further be optionally film coated or enteric coated or seal coated or coated with substances to modify the release of the active. The coating can be done by techniques known to one skilled in the art such as powder coating, spray coating, dip coating, fluidized bed coating and the like.
The dosage forms of the pharmaceutical preparations made in accordance with the invention are solid dosage forms, which include but are not limited to capsules, tablets, caplets, pills, powders, granules, sachets, etc.
Cores that can be used as starting materials include but are not limited to: water-soluble beads such as sucrose spheres, lactose and the like; and water-insoluble beads such as microcrystalline cellulose (including those sold as CELPHERE™ by Asahi Kasei Chemicals Corporation, Tokyo,

Japan), silicon dioxide, calcium carbonate, dicalcium phosphate anhydrous, dicalcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like. Active substance may be layered on to an inert core or mixed with core forming materials and made as a drug containing core.
The compositions of the present invention further comprise one or more excipients such as diluents, binders, disintegrants, glidants, lubricants, colorants, flavouring agents, solvents, film forming polymers, plasticizers, opacifiers, antiadhesives, polishing agents. Diluents:
Various useful diluents include but are not limited to starches, lactose, mannitol, cellulose derivatives and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™ (available from Meggle Products), Pharmatose™ (available from DMV) and others. Different grades of starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation) and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products) and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801. Avicel™ PH 101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose 114, and microcrystalline cellulose 112, silicified microcrystalline cellulose (PROSOLV ™). Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol, sorbitol and xylitol, destrates, dextrin, maltodextrin. dextrose, calcium carbonate, magnesium carbonate, magnesium oxide, dibasic calcium phosphate, and tribasic calcium phosphate, and the like.

Binders:
Various useful binders include but are not limited to hydroxypropylcellulose (Klucel™-LF), hydroxypropyl methylcellulose (Methocel™), polyvinylpyrrolidone or povidone (PVP-K25. PVP-K29, PVP-K30, PVP- K90D), powdered acacia, gelatin, guar gum, alginic acid carbomer (e.g. carbopol), methylcellulose, polymethacrylates, and starch and the like. DIsintegrants:
Various useful disintegrants include but are not limited to carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co.. Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (available as Ac-Di-Sol®, Primellose®), crospovidone. examples of commercially available crospovidone products including but not being limited to crosslinked povidone, Kollidon™ CL [manufactured by BASF (Germany)], Polyplasdone™ XL, XI-10, and INF-10 [manufactured by ISP Inc. (USA)], 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 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate (type A or type B) e.g. Explotab®, colloidal silicon dioxide (different grades which are commercially available such as Syloid™ 244), polacrilin potassium, starch, pregelatinized starch, and the like. Surfactants:
Useful surfactants include but are not limited to: anionic surfactants such as chenodeoxycholic acid, 1-octanesulfonic acid sodium salt, sodium deoxycholate, glycodeoxycholic acid sodium salt, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, sodium chelate hydrate, sodium lauryl sulfate (SLS) and sodium dodecyl sulfate (SDS); cationic surfactants such as cetylpyridinium chloride monohydrate and hexadecyltrimethylammonium bromide; nonionic surfactants such as poloxamers (such as Poloxamer 188, Poloxamer407), N-decanoyl-N-methylglucamine, octyl a-D-glucopyranoside, n-Dodecyl b-D-maitoside (DDM), polyoxyethylene glycol, and

polyoxypropylene glycol, polyoxyethylene sorbitan esters like polysorbates, polyglycolized glycerides grades such as GELUCIRE 40/14, GELUCIRE 42/12, GELUCIRE 50/13 and the like. Solvents:
Various useful solvents for making the compositions include but are not limited to water, lower alcohols like methanol, ethanol, and isopropanol, hydroalcoholic mixtures, acidified ethanol, acetone, polyols, polyethers, oils, esters, alky! ketones, methylene chloride, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, dimethylformamide, and tetrahydrofuran. pH Modifiers:
Various useful pH modifiers include but are not limited to citrates, phosphates, carbonates, tartrates, fumarates, acetates, amino acid salts, and meglumine. Lubricants:
Various lubricants that can be used include but are not limited to magnesium stearate. sucrose esters of fatty acid, polyethylene glycol, talc, stearic acid, sodium stearyl fumarate, zinc stearate, and castor oils. Flavors:
Flavoring agents, which can be used in the present invention, include but are not limited to natural or synthetic or semi-synthetic flavors like menthol, fruit flavors, citrus oils, peppermint oil, spearmint oil, and oil of wintergreen (methyl salicylate). Colorants:
Various useful colorants include but are not limited to Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, and the like, food lake colorants , ferric oxide, and sunset yellow FCF. Stabilizers:
Various stabilizers include but are not limited to magnesium oxide (light magnesium oxide, heavy magnesium oxide) disodium edetate, tocopherol, cyclodextrins and the like.

Film-forming Agents:
Various useful film-forming agents include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyethyl cellulose, hydroxypropyl methylcellulose. sodium carboxymethyl cellulose, etc., acidic cellulose derivatives such as cellulose acetate phthalate, cellulose acetate trimellitate and methylhydroxypropylcellulose phthalate, polyvinyl acetate phthalate, etc., insoluble cellulose derivatives such as ethylcellulose and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinylalcohol, polyvinyl acetate, polyvinylpyrrolidone, polymethacrylates and derivatives thereof (Eudragit™), chitosan and derivatives thereof, shellac and derivatives thereof, and waxes and fat substances.
In the case of polymethacrylates, cationic copolymehzates of dimethylaminoethyl methacrylate with neutral methacrylic esters (Eudragit™ E), copolymerizates of acrylic and methacrylic esters having a low content of quaternary ammonium groups (described in "Ammonio Methacrylate Copolymer Type A or Type B" USP/NF, Eudragit™ RL and RS, respectively), and copolymerizates of ethyl acrylate and methyl methacrylate with neutral character (in the form of an aqueous dispersion, described in "Polyacrylate Dispersion 30 Per Cent" Ph. Eur, Eudragit™ NE 30 D) are useful.
Anionic copolymerizates of methacrylic acid and methyl methacrylate (described in "Methacrylic Acid Copolymer, Type C" USP/NF, Eudragit™ L and S, respectively, or in the form of the Eudragit™ L 30 D aqueous dispersion), acidic cellulose derivatives such as cellulose acetate phthalate, cellulose acetate trimellitate and methylhydroxypropylcellulose phthalate, polyvinyl acetate phthalate, etc. may be used for film coatings. Plasticizers:
Various useful plasticizers include but are not limited to castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin.

polyethylene glycol, ethers of polyethylene glycol propylene glycol, triacetin, triethyi citrate, acetyltributyl citrate, phosphate esters, phthalate esters, amides, mineral oils, fatty acids and esters, glycerin, triacetin or sugars, fatty alcohols such as cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, myristyl alcohol.
Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. A plasticizer is normally present in an amount ranging from 5% (w/w) to 30 (w/w) based on the total weight of the film coating.
An opacifier like titianium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating. When coloured tablets are desired then the colour is normally applied in the coating. Consequently, colouring agents and pigments may be present in the film coating. Various colouring agents include but are not limited to ferric oxides, which can either be red, yellow, black or blends thereof.
Anti-adhesives are normally used in the film coating process to avoid sticking effects during film formation and drying. An example of an anti-adhesive for this purpose is talc. The anti-adhesive such as talc is present in the film coating in an amount of about 5% (w/w) to 15% (w/w) based upon the total weight of the coating.
Suitable polishing agents include polyethylene glycols of differing molecular weights or mixtures thereof, talc, surfactants (e.g. glycerol mono-stearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax). In an embodiment, polyethylene glycols having molecular weights of 3,000-20,000 are employed.
In addition to above the coating ingredients, sometimes ready mixed coating materials such as Opadry (supplied by Colorcon) are used, such as Opadry YS-1-7003 white. These compositions require only mixing with a liquid before application.

In certain embodiments, pharmaceutical compositions of the present invention can be manufactured as described below. The granules or cores can be prepared by sifting the active and excipients through a desired mesh size sieve and then mixed using a rapid mixer granulator, planetary mixer, mass mixer, ribbon mixer, fluid bed processor or any other suitable device. The blend can be granulated by dry or wet granulation. In wet granulation, the granulate can be dried using a tray drier, fluid bed drier, rotary cone vacuum drier and the like. The dried granulate particles are sieved and then mixed with lubricants and disintegrants and compressed into tablets or filled into capsules.
Further, the manufacture of granules may be done by direct compression with the use of directly compressible excipients using a suitable device, such as a multi-station rotary machine, to form compressed slugs or by roller compaction to form slugs, which are passed through a multimill, fluid energy mill, ball mill, colloid mill, roller mill, hammer mill and the like, equipped with a suitable screen. The milled slugs are then lubricated and compressed into tablets or pellets and are coated with a rate controlling substance. Coated pellets are further filled into capsules or compressed as tablets.
In another embodiment, the invention includes use of packaging materials such as containers including lids, composed of polyethylene and or polypropylene and/or glass, and blisters or strips composed of aluminium or high-density polypropylene or polyvinyl chloride, or polyvinyl chloride coated with polyvinylidene chloride, generally termed as PVC/PVDC. Different grades of PVC/PVDC are available as PVC/PVDC 40 gsm, PVC/PVDC 60 gsm, PVC/PVDC 90 gsm, etc. PVC/PVDC 40 gsm means 40 grams of PVDC coating per square meter of PVC foil. Similarly 60 gsm means 60 grams of PVDC coating per square meter of PVC foil, 90 gsm means 90 grams of PVDC coating per square meter of PVC foil, etc.
Dissolution testing can be carried out in accordance with Test 711 "Dissolution" in United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 ("USP"), and

dissolved drug concentrations determined using techniques such as high-performance liquid chromatography.
The pharmaceutical compositions disclosed in the context of the present invention are useful in the treatment of hypertension.
The following examples are provided only to further illustrate certain specific aspects and embodiments of the invention in greater detail and are not intended to limit the scope of the invention.



Celphere™ CP507* is supplied by Asahi Kasei Chemicals Corporation, Tokyo, Japan., Celphere™ CP507 is microcrystalline cellulose spheres which has diameter in the range of 500-710 micrometer. Manufacturing process:
I. Preparation of ramipril blend:
1) Ramipril, pregelatinized starch and light magnesium oxide were sifted
through a ASTM # 40 mesh sieve.
2) Sifted materials from step 1 were blended in a double cone blender for
20 minutes.
3) The blended material was kept aside for filling into empty hard gelatin
capsules of size "2".
II. Preparation of metoprolol extended release pellets:
A. Drug loading stage:
1. Water was heated to 70 °C-80 °C.
2. Metoprolol succinate was dissolved in the water with stirring at 1400
rpm.
3. HPMC 3 cps was dispersed in step 2 with stirring until it formed a
clear solution.
4. Celphere CP-507 was sifted through a ASTM #20 mesh sieve.
Material passing through the sieve was collected and sifted through a
ASTM #40 mesh sieve. Material retained on the sieve was collected
for use.
5. Celphere CP 507 (retained on a ASTM #40 mesh sieve) was coated
using drug-loaded solution prepared in step 3 using a fluidized bed
coater with the following process parameters:

Inlet temperature: 45°C-50°C Spray rate: 3-15 g/minute Atomizing air: 2-2.5 kg/cm2. 6. Drug loaded pellets were dried for 10 minutes.
B. Subcoating stage:
1. Drug loaded pellets were sifted through a ASTM #18 mesh sieve and material passing through was sifted through a ASTM #24 mesh sieve, then the material retained was collected.
2. Hydroxypropyl methylcellulolse (6 ops) was dissolved in water under stirring to form a clear solution, with stirring at 1400 rpm for 15-30 minutes.
3. Sifted drug loaded pellets (ASTM #24 mesh sieve retained fraction) prepared in step B(1) were subcoated with subcoating solution prepared in step 8(2) using a fluidized bed coater with the following process parameters:
Inlet temperature: 45°C-50°C Spray rate: 1-10g/min Atomizing air: 1.5-4 kg/cm2.
4. Subcoated pellets were dried for 10 to 15 minutes.
C. Extended release coating stage:
1) Subcoated pellets were sifted through a ASTM #18 mesh sieve and material passing through was sifted through a ASTM #24 mesh sieve, and the retained material was collected.
2) Ethyl cellulose was dissolved in isopropyl alcohol under stirring at 1400 rpm for 15-30 minutes.
3) Hydroxypropyl methylcellulolse (3 cps) was dissolved in water under stirring to form a clear solution, with stirring at 1200-1500 rpm for 15 minutes.
4) Added step 3 liquid to step 2 liquid under stirring at 1000-1500 rpm for 10 minutes.

5) Triethyl citrate was added to the dispersion of step 4 under stirring at 800-1500 rpm for 15 minutes.
6) Sifted subcoated (retained on ASTM #24 mesii sieve) were coated using coating solution prepared in step 5 using fluidized bed coater with the following process parameters:
Inlet temperature: 40°C-45^C
Spray rate: 1-10 g/min
Atomizing air: 1.5-4 kg/cm2. 7). Extended release coated pellets were dried for 15-30 minutes. 8) Dried extended release pellets were sifted through a ASTM #18 mesh sieve, then material passing through was sifted through a ASTM #24 mesh sieve and the retained material was collected. III. Preparation of the final dosage form:
1) The metoprolol pellets prepared in step C(5) and ramipril blend of step I are loaded into their respective hoppers of an automated capsule filling machine AFT-LAB
2) Ramipril blend and metoprolol pellets were filled into size '2' hard gelatin capsules.
EXAMPLE 2: Metoprolol and ramipril capsules. Composition for ramipril:

Pregelatinized starch (PCS PC10) is supplied by Signet Chemical Corporation private limited.
Pregelatinized starch (National 78-1551) is supplied by Essex Grain Products Composition for metoprolol:


Manufacturing process:
I. Preparation of ramipril blend
1) Ramipril, pregelatinized starch (PCS-PC10), and light magnesium
oxide were sifted through a ASTM #40 mesh sieve.
2) Pregelatinized starch (National 78-1551) was mixed with above
step 1 sifted material by geometric dilution.
3) Loaded above step 2 materials into a blender and blended for 20
minutes.
II: Preparation of metoprolol pellets.: similar to procedure of Example 1.

Ill: Preparation of final dosage form: similar to procedure of Example 1.
Capsules were subjected to dissolution testing in the following manner:
Dissolution for ramipril:
Apparatus: USP APPARATUS II (Paddle)
RPM:100 Medium: 0.1N HCI Volume: 900 ml
Temperature: 37°C ± 0.5°C Reference product: Tritace™ 5

Dissolution for metoprolol
Apparatus: USP APPARATUS II (Paddle)
RPM: 50 Medium: pH 6.8 phosphate buffer.
Volume: 900 ml Temperature: 37°C ± 0.5°C
Reference product: Seloken™ XL50.

EXAMPLE 3: Metoprolol and amiodipine capsules. Composition for amiodipine:


Manufacturing process:
I: Preparation of amiodipine formulation:
1) Amiodipine besylate, microcrystalline cellulose, dibasic calcium
phosphate diydrate, crospovidone, and colloidal silicon dioxide were
sifted through a ASTM #40 mesh sieve.
2) Magnesium stearate was sifted through a ASTM # 80 mesh sieve, was added to step 1 and the blend was mixed.
3) Step 2 materials were blended in blender for 25 minutes.
4) The blended materials were compressed into tablets using 5 mm
normal concave punches.
5) Opadry White was added to water with stirring, and stirring continued
for 45 minutes.
6) The coating solution was filtered through a nylon cloth of 200-mesh aperture size to remove oversized matter.
7) Tablets were film coated using coating solution prepared in Step 6 using a conventional coating pan with the following process parameters:
Inlet temperature: 60°C -75°C Spray gun distance: 20-26 cm Atomization pressure: 2-4 Kg/cm2. II. Preparation of metoprolol extended release pellets:

Composition and manufacturing process were similar to that of
Example 2. III. Encapsulation: Preparation of the final dosage form:
The metoprolol pellets prepared in Part II were blended with the amiodipine formulation of Part I and filled into capsules of size "2" using an automated dual capsule filling machine.
Capsules prepared were subjected to dissolution in the following manner: Dissolution of amiodipine
Apparatus: USP APPARATUS I
Medium: 0.01 N HCI, 900 ml, 100 rpm.
Temperature: 37°C ± 0.5X

EXAMPLE 4: Biopharmaceutical performance of compositions prepared according to Example 2.
Capsules were evaluated in a randomized, open label, balanced, two treatment, two period, two sequence, single dose, crossover bioequivalence study involving administration to 24 healthy human volunteers (plus 2 standby) under fasting conditions to determine plasma levels. Volunteers were administered a capsule of the present invention after an overnight fasting. Washout period during the study was 7 days.
Plasma samples were withdrawn at 0, 0.25, 0.5, 0.75, 1, 1.25, 1.50, 1.75,2.2.5,3,3.5,4, 5,6,7,8, 10, 12, 14. 16 and 24 hours post-dosing.

The pharmacokinetic parameters for metoprolol and ramipril were calculated using WinNonlin™ Professional software version 4.1. (Pharsight Corporation, USA). The following parameters were calculated:
AUCo-t = the area under plasma concentration versus time curve, from time zero to the last measurable concentration.
AUCo-~ = area under the plasma concentration versus time curve, from time zero to infinity.
Cmax = maximum plasma concentration.
Tmax = tTime of the maximum measured plasma concentrations.
The results of these pharmacokinetic parameters (log transformed data) calculated from the study are given in Table 1.

EXAMPLE 5: Biopharmaceutical performance of compositions prepared according to Example 4.
Capsules were evaluated in a randomized, open label, balanced, two treatment, two-period, two sequence, single dose, crossover bioequivalence study involving administration to 24 healthy human volunteers (+2 standby) under fasting conditions to determine plasma levels. Volunteers were administered a capsule of the present invention after an overnight fasting.
Plasma samples were withdrawn at 0, 0.5, 1, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16. 24, 36, 48, 72, 96, 120, and 144 hours post-dosing.
Wash out period during the study was 21 days.

The pharmacokinetic parameters for metoprolol and amiodipine were calculated using WinNonlin™ Professional software version 4.1. (Pharsight Corporation, USA). Parameters as discussed in Example 5 were calculated.
The log transformed data for least square mean ratio for Cmax (ng/ml), AUCo-t (ngh/ml), AUCo- (ngh/ml) values calculated from the study are given in Table 2.

CLAIMS:
1. A pharmaceutical composition comprising at least one beta blocker and at least one of an angiotensin converting enzyme inhibitor and a calcium channel blocker.
2. A pharmaceutical composition of claim 1 comprising a beta blocker and an angiotensin converting enzyme inhibitor.
3. A pharmaceutical composition of claims 1 or 2 wherein an angiotensin converting enzyme inhibitor comprises a dicarboxylate.
4. A pharmaceutical composition of any of claims 1-3 wherein an angiotensin converting enzyme inhibitor comprises ramipril.
5. A pharmaceutical composition of any of claims 1-4 wherein a beta blocker comprises metoprolol.
6. A pharmaceutical composition of any of claims 1-4 wherein a beta blocker comprises metoprolol, and a release rate of metoprolol is modified.
7. A pharmaceutical composition of any of claims 1-4 wherein a beta blocker comprises metoprolol, combined with a rate-modifying substance comprising hydroxypropyl methylcellulose.
8. A pharmaceutical composition of any of claims 1-7, comprising a capsule comprising pellets containing metoprolol, and granules or a blend or a tablet or tablets containing ramipril.
9. A pharmaceutical composition of any of claims 1-8, comprising a calcium channel blocker.
10. A pharmaceutical composition of any of claims 1-8, comprising amlodipine.