PHARMACEUTICAL COMPOSITIONS COMPRISING RAMIPRIL AND INDAPAMIDE

INTRODUCTION TO THE INVENTION
The present invention relates to pharmaceutical compositions comprising ramipril or its pharmaceutically acceptable salts, enantiomers, racemates, etc., and indapamide or its pharmaceutically acceptable derivatives. The invention further relates to processes to prepare such compositions and method of using such compositions in treating hypertension. Further the invention includes stabilized pharmaceutical compositions comprising ramipril and indapamide.
Ramipril is a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance, soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°C and 112°C.
Ramipril has a chemical name (2S, 3aS, 6aS)-1[(S)-N-[(S)-1-carboxy-3-phenylpropyl]alanyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid, 1-ethyl ester. It has an empirical formula C23H32N2O5 and a molecular weight of 416.5. It has structural formula (1).

(1)
Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group. Ramipril is currently marketed in the U.S. as ALTACE® capsules, available in the strengths 1.25 mg, 2.5 mg, 5 mg, or 10 mg of ramipril. It is indicated for reduction in risk of myocardial infarction, stroke, and death from cardiovascular causes, hypertension, heart failure and post myocardial infarction.
Ramipril is also available in a tablet dosage form under the trademark TRITACE® containing 1.25 mg, 2.5 mg, or 5 mg of ramipril, and a capsule containing 10 mg of ramipril. CARDACE™ tablets are sold by Aventis in a range of ramipril strengths.
Indapamide is an oral antihypertensive/diuretic. The molecule contains both a polar sulfamoyl chlorobenzamide moiety and a lipid-soluble methylindoline moiety. It differs chemically from the thiazides in that, it does not possess the thiazide ring system and contains only one sulfonamide group. It has a chemical name 1-(4-chloro-3-sulfamoylbenzamido)-2-methylindoline, and its molecular weight is 365.84. The compound is a weak acid, pKa=8.8, and is soluble in aqueous solutions of strong bases. It is a white to yellow-white crystalline (tetragonal) powder. Its structural formula is (2).

(2)
Indapamide is currently available in a tablet form having the brand name LOZOL® and containing 1.25 mg or 2.5 mg of indapamide. LOZOL® is indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs. LOZOL® is also indicated for the treatment of salt and fluid retention associated with congestive heart failure. Sustained release tablets containing 1.5 mg of indapamide hemihydrate are sold by Servier Laboratories as NATRILIX™ SR.
Indapamide acts at a proximal segment of the distal tubule. Indapamide appears to have natriuretic properties (sodium and chloride being excreted in equivalent amounts) with less effect on kaliuresis or uric acid excretion.
Ramipril is disclosed in U.S. Patent No 5,061,722. U.S. Patent No. 5,403,856 discloses a method of treating cardiac insufficiency using ramipril.
U.S. Patent Nos. 4,793,998; 6,653,336; 5,256,687; 4,830,853, U.S. Patent Application Publication Nos. 2004/0219208; 2003/0216384, and International Application Publication Nos. WO/2001/15674, WO 2005/067887, WO 2005/065639, WO 2003/059330 WO 2004/012699, WO 2005/074927, WO 2003/059388, WO 2005/011737, and WO 2001/80895 disclose pharmaceutical compositions of ACE inhibitors and diuretics.
Ramipril is an ACE Inhibitor, inhibiting angiotensin-converting enzyme. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decrease aldosterone secretion. The latter decrease may result in increase of serum potassium resulting in hyperkalemia. Indapamide is a diuretic. As ramipril and indapamide act by different mechanisms, the combination produces a synergistic effect for antihypertensive action.
Indapamide being a diuretic, increases sodium delivery, this increases potassium loss. Thus the potassium ion concentration increase due to the ramipril is balanced by decreasing of potassium ion concentration by indapamide thus reducing side effects of hyperkalemia, which can be caused by ramipril. Hence the compositions of ramipril and indapamide produce diminished side effects.

SUMMARY OF THE INVENTION
The present invention relates to fixed dose pharmaceutical compositions of ramipril or its pharmaceutically acceptable salts, enantiomers, racemates etc and indapamide or its pharmaceutically acceptable derivatives. The invention further includes processes for preparing the pharmaceutical compositions of the present invention and method of using the compositions. The dosage forms prepared in the present invention are intended for oral administration.
In embodiments, the invention includes ramipril or its salt in an immediate release form and indapamide or its derivative in an extended release form.
In embodiments, the invention includes ramipril or its salt in an extended release form and indapamide or its salt in an immediate release form.
In embodiments, the invention includes pharmaceutical compositions, which are solid oral dosage forms.
In embodiments, the invention includes pharmaceutical compositions wherein a solid oral dosage form may be a multilayered, coated, or capsule dosage form.
In embodiments, the invention includes pharmaceutical compositions wherein an extended release form may be in the form of matrix or multiple unit particles, such as spheres, pellets, beads, granules, etc.
In embodiments, the invention includes compositions comprising ramipril in the form of a powder, granules, spheres, beads, pellets, or one or more tablets, and indapamide in the form of a tablet, minitablets, granules, beads, or pellets.
In embodiments, the invention includes ramipril in a powder or granular form, and indapamide as a tablet, together filled into capsules.
In embodiments, the invention includes stabilized pharmaceutical compositions comprising ramipril and indapamide.
An embodiment of the invention provides a pharmaceutical dosage form comprising:
a composition comprising ramipril, a stabilizer, and a hydrolysis-minimizing agent; and
a controlled release composition comprising indapamide.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to fixed dose pharmaceutical compositions of ramipril or its pharmaceutically acceptable salts, enantiomers, racemates etc and indapamide or its pharmaceutically acceptable derivatives. The invention further includes processes for preparing the pharmaceutical compositions of the present invention and method of using the compositions. The dosage forms prepared using the pharmaceutical compositions of present invention are intended for oral administration.
In an embodiment, the invention includes pharmaceutical compositions, which are in a solid oral dosage form.
In another embodiment, the invention includes pharmaceutical compositions wherein a solid oral dosage form is in the form of a multilayered or coated, or a capsule, dosage form.
In another embodiment, the invention includes pharmaceutical compositions wherein a modified release portion is in the form of matrix or multiple unit particles, such as spheres, pellets, beads, granules, etc.
In an embodiment, the invention includes stabilized pharmaceutical compositions comprising ramipril and indapamide.
The chemical form of the ramipril and/or a pharmaceutical acceptable salt thereof is not particularly limited and includes 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 or oleic acid, and suitable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid and/or phosphoric acid. When the term “ramipril” is used herein, it is intended to encompass the compound and any of the chemical forms.
The pharmaceutically acceptable derivatives of indapamide include but are not limited to salts, solvates and other derivatives. When the term “indapamide” is used herein, it is intended to encompass the compound and any of its derivatives.
Ramipril and indapamide act by different mechanisms: ramipril, being an angiotensinogen converting enzyme inhibitor, and indapamide, being a diuretic. Ramipril, as it decreases aldosterone secretion, it would result in an increase of serum potassium levels leading to hyperkalemia.
Hyperkalemia means an abnormally elevated level of potassium in the blood. The normal potassium level in the blood is about 3.5-5 milliequivalents per liter (mEq/L). Potassium levels between 5.1 mEq/L and 6 mEq/L are considered to indicate mild hyperkalemia. Potassium levels in the range of 6.1 mEq/L to 7 mEq/L indicate moderate hyperkalemia, and levels above 7 mEq/L indicate severe hyperkalemia. Symptoms of hyperkalemia include nausea, fatigue, muscle weakness, or tingling sensations. More serious symptoms of hyperkalemia include slow heartbeat and weak pulse. Severe hyperkalemia can result in fatal cardiac arrest (heart stoppage). Generally, a slowly rising potassium level (such as with chronic kidney failure) is better tolerated than an abrupt rise in potassium levels.
Indapamide, being a diuretic, increases sodium delivery, this increases potassium loss. Thus the potassium ion concentration increase due to the ramipril is balanced by decreasing of potassium ion concentration by indapamide, thus reducing side effects of hyperkalemia of ramipril. Hence, administering the compositions of ramipril and indapamide results in a synergistic antihypertensive effect and also produces diminished side effects.
In one embodiment, the invention includes ramipril or its salt in an immediate release form and indapamide or its derivative in a controlled release form.
In an embodiment, the invention includes ramipril or its salt in a controlled release form and indapamide or its salt in an immediate release form.
Indapamide is sparingly soluble, but can be toxic or produce discomforting symptoms, such as central nervous system disorders such as muscle cramps, blurred vision, nervousness, and fatigue. In addition, indapamide can produce gastrointestinal problems when taken in immediate release compositions administered several times daily. Hence to minimize the side effects of indapamide, it may be formulated in modified release forms.
In an embodiment, the invention includes unit doses of ramipril in the pharmaceutical composition ranging from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to 12.5%, of the final composition.
In an embodiment, the invention includes a concentration of indapamide ranging from 1% to about 25%, or from about 1% to about 15%, or from about 1% to 10% of the composition. All of the ingredient percentages stated herein are weight percentages based on total composition weight, unless otherwise stated.
In embodiments the present invention includes solid oral dosage forms such as tablets, capsules, granules, sachets, etc.
ACE inhibitors, such as ramipril, on contact with some of the commonly used pharmaceutical excipients, undergo degradation at accelerated rates due to one or more of:
i) Cyclization via internal nucleophilic attack to form substituted diketopiperazines.
ii) Hydrolysis of the side chain ester group.
iii) Oxidation to form products having unwanted coloration.
Various known impurities for ramipril are described below:
1) Impurity “A” (ramipril methyl ester) has a chemical name (2S,3aS,6aS)-1-[(S)-2-[[(S)-1-(methoxycarbonyl)-3-phenylpropyl]amino]propanoyl]octahydro-cyclopenta[b]pyrrole-2-carboxylic acid, and is represented by structural formula (3) where R=CH3.
2) Impurity “B” (ramipril isopropyl ester) has a chemical name: (2S,3aS,6aS)-1-[(S)-2-[[(S)-1-[(1-methylethoxy)carbonyl]-3- phenylpropyl]amino]propanoyl] octahydrocyclopenta [b]pyrrole-2-carboxylic acid is represented by structural formula (3) where R=CH(CH3) 2.

(3)
3) Impurity “C” (hexahydroramipril) has a chemical name (2S,3aS,6aS)-1-[(S)-2-[[(S)-3-cyclohexyl-1-(ethoxycarbonyl)propyl]amino]propanoyl]octahydro-cyclopenta[b]pyrrole-2-carboxylic acid and is represented by structural formula (4).

(4)
4) Impurity “D” (ramipril diketopiperazine) has a chemical name ethyl (2S)-2-[(3S,5aS,8aS,9aS)-3-methyl-1,4-dioxodecahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoate and is represented by (5)

(5)
5) Impurity “E” (ramipril diacid) has a chemical name (2S,3aS,6aS)-1-[(S)-2-[[(S)-1-carboxy-3-phenylpropyl]amino] propanoyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid and is represented by structural formula (6).

(6)
6) Impurity “F” has a chemical name (S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino ] propanoic acid is represented by structural formula (7).

(7)
7) Impurity “G” ((R,S-S,S,S) isomer of ramipril) has a chemical name (2S,3aS,6aS)-1-[(R)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid and is represented by structural formula (8).

(8)
8) Impurity “H” ((S,R-S,S,S) isomer of ramipril) has a chemical name (2S,3aS,6aS)-1-[(S)-2-[[(R)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid and is represented by structural formula (9).

(9)
9) Impurity “I” ((R,R-R,R,R) isomer of ramipril) has a chemical name (2R,3aR,6aR)-1-[(R)-2-[[(R)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid and is represented by structural formula (10).

(10)
10) Impurity “J” (ramipril diketopiperazine acid) has a chemical name (2S)-2-[(3S,5aS,8aS,9aS)-3-methyl-1,4-dioxodecahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoic acid and is represented by structural formula (11).

(11)
11) Impurity “K” (ramipril hydroxydiketopiperazine) has a chemical name ethyl (2S)-2-[(3S,5aS,8aS,9aS)-9a-hydroxy-3-methyl-1,4-dioxodecahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoate and is represented by structural formula (12).

(12)
12) Impurity “L” (dibenzoyltartric acid) has a chemical name (2R,3R)-2,3-di(benzoyloxy)butanedioic acid and is represented by structural formula (13).

(13)
13) Impurity “N” ((S,S-R,R,R) isomer of ramipril) has a chemical name (2R,3aR,6aR)-1-[(S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino] propanoyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid and is represented by structural formula (14).

(14)
Hence the compositions comprising ramipril should be stabilized using various stabilizers. Useful stabilizers include metal oxides such as magnesium oxide to prevent a cyclization reaction, and hydrolysis minimizing agents such as saccharrides.
The degradation of ramipril occurs mainly via two pathways: the hydrolysis to ramipril diacid (impurity E) and the cyclization to ramipril diketopiperazine (impurity D).
The following two impurities are known impurities of indapamide:
1) Impurity “X” has a chemical name (2RS)-2-methyl-1-nitroso-2, 3-dihydro-1H-indole, and is represented by structural formula (15).

(15)
2) Impurity “Y” has a chemical name 4-chloro-N-(2-methyl-1H-indol-1-yl]-3-sulphamoylbenzamide and is represented by structural formula (16).

(16)
In an embodiment the invention includes stabilized pharmaceutical compositions comprising ramipril and indapamide.
Stabilizers:
Various useful stabilizers include, without limitation thereto, metal oxides, disodium edetate, tocopherol, cyclodextrins and derivatives, and alkalizing agents such as alkali or alkaline earth metal bicarbonates and carbonates. Metals such as sodium, magnesium, calcium are commonly used. Combinations of stabilizers are useful.
Magnesium oxide is available in many commercial grades, all of which are within the scope of the present invention. Two commercially available forms of magnesium oxide are a very bulky form termed "Light" and a dense form termed "Heavy." Either of these forms, any other form, or combinations thereof can be used as stabilizers in the present invention.
In embodiments of the present invention, weight ratios of ramipril to stabilizer range from about 1:0.001 to about 1:1, or from about 1:0.002 to about 1:0.5, or from about 1:0.02 to about 1:0.2.
In embodiments the invention includes particular concentrations of magnesium oxide used as a stabilizer in the invention. Magnesium oxide is used in the concentration ranges of about 0.01% to less than 0.5%, or about 0.02% to about 0.4%, or about 0.05% to about 0.3%, of the total weight of a pharmaceutical composition.
Hydrolysis-Minimizing Agents:
A hydrolysis-minimizing agent of the present invention acts to protect the ACE inhibitor from hydrolytic degradation. The hydrolysis-minimizing agents to be used in the pharmaceutical products and methods of the invention are substances, which are compatible with magnesium oxide or other stabilizer so that they do not interfere with the stabilizer’s function in the composition. Generally, they are substances that do not contain groups that could significantly interfere with the function of either the metal-containing component or the drug component. Non-limiting examples of hydrolysis-minimizing agents of the present invention are saccharides such as starch, and mannitol, lactose, and other sugars that have a hydrolysis minimizing effect on the ACE inhibitors. Starches like pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon) and fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products) can be used. Different useful grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tabletting), lactose anhydrous, Flowlac™ (available from Meggle Products), and Pharmatose™ (available from DMV), etc. Combinations of hydrolysis-minimizing agents can be used.
Generally, the quantity of the hydrolysis-minimizing agent present will be from about 5% to about 99%, or from about 5% to about 90%, of the total weight of the composition.
In embodiments of the present invention weight ratios of ramipril to the hydrolysis-minimizing agent ranges from about 1:1 to about 1:400, or from about 1:1 to about 1:200, or from about 1:10 to about 1:100.
Compositions in controlled release form comprise at least one rate controlling excipient that reduces and/or delays onset of the rate of release of drug from the dosage form. Usually, the rate controlling excipient is a polymer or a fatty compound, or a mixture thereof. It may also comprise an ion-exchange resin. Examples of rate controlling polymers that may be used in the present invention include, but are not limited to: cellulose ethers such as methylcellulose (MC), ethyl cellulose (EC), hydroxy ethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (hypromellose or HPMC, provided by Dow Chemical under the trade name METHOCEL™, various grades including METHOCEL K 4M, METHOCEL K 15M, METHOCEL K 100M, METHOCEL K100M CR, and METHOCEL K100LV), hydroxypropyl ethylcellulose (HPEC), carboxymethyl cellulose (CMC), cross linked carboxymethyl cellulose (croscarmellose) and its alkali salts, ethylhydroxyethylcellulose (EHEC), hydroxyethyl methylcellulose (HEMC), hydrophobically modified hydroxyethyl cellulose (HMHEC), hydrophobically modified ethylhydroxyethylcellulose (HMEHEC), carboxymethyl hydroxyethylcellulose (CMHEC), carboxymethyl hydrophobically modified hydroxyethyl cellulose (CMHMHEC), and the like; vinylpyrrolidone polymers such as crosslinked polyvinylpyrrolidone or crospovidone, copolymers of vinylpyrrolidone and vinyl acetate; and alkylene oxide homopolymers such as polypropylene oxide, such as ethylene oxide homopolymers.
Other rate controlling excipients include super disintegrant polymers such as cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, 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 and dextrin derivatives such as cross-linked carboxymethylcellulose;
Useful rate controlling excipients also include gums of plant, animal, mineral or synthetic origin such as (i) agar, alginates, carrageenan, furcellaran derived from marine plants, (ii) guar gum, gum arabic, gum tragacanth, karaya gum, locust bean gum, pectin derived from terrestrial plants, (iii) microbial polysaccharides such as dextran, gellan gum, rhamsan gum, welan gum, xanthan gum, and (iv) synthetic or semi-synthetic gums such as propylene glycol alginate, hydroxypropyl guar and modified starches like sodium starch glycolate, and the like; and acrylic acid polymers such as cross-linked polymers available under the trade name CARBOPOL™ or homopolymers and co-polymers of acrylate or methacrylate monomers for example polymethacrylates marketed under the brand names of EUDRAGIT™, particularly EUDRAGIT RS and EUDRAGIT RL.
Examples of fatty compounds that may be used as rate controlling excipients in the present invention include various waxes such as digestible, long chain (C8-C50, especially C12-C40), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. Hydrocarbons having a melting point of between 25° and 90°C are useful.
In an embodiment of the present invention, a release rate controlling excipient is a hydrophilic swellable polymer. In an embodiment the hydrophilic swellable polymer comprises polyethylene oxide. Polyethylene oxide is a nonionic homopolymer of ethylene oxide, containing 2,000 to over 100,000 repeating oxyethylene groups. The molecular weight of polyethylene oxide ranges between 100,000 Daltons and 7,000,000 Daltons. It is commercially available as POLYOX™ from Union Carbide. The higher molecular weight polyethylene oxide grades (molecular weight 3,000,000 to 7,000,000 Daltons), such as POLYOX WSR coagulant with an approximate molecular weight of 5,000,000 Daltons, are used in certain embodiments of the present invention to provide delayed, sustained or controlled drug release. The polymer swells upon contact with aqueous fluid from the environment of use to form a hydrophilic gel matrix. This matrix expands with time and causes diffusion of the drug at a predetermined rate, depending upon the concentration and grade of the polymer used.
The amount of rate controlling excipient to be used varies widely according to the properties of the particular excipient, or combination of excipients, chosen, and the desired drug release profile to be obtained. Typically, a series of formulations will be prepared with varying amounts of the excipient or excipients, and the drug dissolution rates are determined using a standard method, as will be discussed more fully below. The dissolution data will assist with optimizing formulation parameters.
The pharmaceutical compositions of the present invention further comprise one or more of various pharmaceutically acceptable excipients which include but are not limited to diluents, binders, disintegrants, surfactants, glidants, lubricants, colorants, opacifiers, rate controlling polymers, film coating polymers, plasticizers, etc.
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 tabletting), 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. Other useful diluents include but are not limited to croscarmellose, sugar alcohols such as mannitol, sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.
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 (FMC-Asahi Chemical Industry Co., Ltd.), crospovidone, examples of commercially available crospovidone products including but not being limited to crosslinked povidone, Kollidon™ CL (manufactured by BASF (Germany)), Polyplasdone™ XL, Xl-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), colloidal silicon dioxide, and starch.
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, and PVP-K90D), powdered acacia, gelatin, guar gum, carbomer (e.g. carbopol), methylcellulose, polymethacrylates, and starch.
Surfactants:
Various useful surfactants include but are not limited to sodium lauryl sulfate, polysorbate 80, poloxamer 188, poloxamer 407, sodium carboxy methylcellulose hydrogenated oil, polyoxyethylene glycol, and polyoxypropylene glycol, Polyoxyethylene sorbitan fatty acid esters, polyglycolized glycerides grades such as GELUCIRE 40/14, GELUCIRE 42/12, GELUCIRE 50/13 and so on.
Glidants:
Various glidants or anti-sticking agents include but are not limited to talc, silica derivatives, colloidal silicon dioxide.
Solvents:
Various useful solvents for processing into pharmaceutical dosage forms include but are not limited to water, lower alcohols like methanol, ethanol, and isopropanol, acidified ethanol, acetone, polyols, polyethers, oils, esters, alkyl 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, tartarates, 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:
The 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.
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, xanthins, 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 copolymerizates 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, commercial products including 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" European Pharmacopea., e.g., EUDRAGIT™ NE 30 D) are useful.
Anionic copolymerizates of methacrylic acid and methyl methacrylate (described in "Methacrylic Acid Copolymer, Type C" USP/NF, e.g., 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 plasticizers for coatings include but are not limited to castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Also mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. A plasticizer is frequently 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 colored 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 and especially 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 weight 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 pre-mixed coating products such as those sold under the OPADRY trademark (supplied by Colorcon) may conveniently be used. These may require only dispersion in a liquid, before use.
In an embodiment the invention includes filling of ramipril and indapamide in the form of pellets, granules, or powders into empty hard gelatin capsule shells.
In another embodiment the invention includes one of ramipril or indapamide in the form of pellets, granules, powders, and the other of ramipril or indapamide compressed into minitablets, and filling into empty hard gelatin capsule shells.
The following examples illustrate certain specific aspects and embodiments of invention and demonstrate the practice and advantage thereof. It is to be understood that the examples are provided only for purposes of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLE 1: Ramipril 5 mg and indapamide 1.5 mg capsules.
Ingredient mg/Capsule
Ramipril Blend
Ramipril 5
Partially pregelatinized starch 103.3
Fully gelatinized starch 11.5
Light magnesium oxide 0.2
Indapamide Tablet
Indapamide 1.5
Mannitol 17
Hydroxypropyl methylcellulose (HPMC) K 100M 22.8
Microcrystalline cellulose 114 (MCC 114) 14.7
Hydroxypropyl cellulose LF (HPC LF) 0.75
Water* 20
Zinc stearate 0.25
Tablet Coating
HPMC (Hydroxypropyl methylcellulose) 3 cps 2
Water* 18
* Evaporates during processing.
Manufacturing process:
A. Ramipril blend:
1) Ramipril, partially pregelatinized starch, fully gelatinized starch, and light magnesium oxide were sifted through an ASTM 30 mesh sieve.
2) Above sifted materials were placed into a blender and blended for 20 minutes.
B. Indapamide tablet:
1) Indapamide, MCC 114, mannitol, and HPMC K 100M were sifted through a ASTM #40 mesh sieve, then were placed into a rapid mixer granulator and dry mixed for 10 minutes.
2) HPC LF was added to the first quantity of water with stirring to form a granulating medium.
3) Step 1 dry mixed materials were granulated using granulating medium of step 3.
4) Wet mass of step 3 was dried in a fluid bed dryer at 60 °C until loss on drying was 2-3% w/w at 105°C.
5) Dried granules were sifted through an ASTM #30 mesh sieve, and the retained fraction was milled through a 1 mm screen so that all granules passed through the sieve.
6) Zinc stearate was sifted through an ASTM #40 mesh sieve.
7) Sifted zinc stearate was added to sifted granules of step 5 and blended in a blender for 10 minutes.
8) Final blend from step 7 was compressed using 5 mm punches and dies using a compression machine.
9) HPMC 3 cps was dissolved in the second quantity of water to form a coating solution.
10) Indapamide tablets from step 8 were coated using the coating solution prepared in step 9.
C. Encapsulation:
Ramipril blend and an indapamide tablet were encapsulated in size 2 hard gelatin capsule shells, using a capsule-filling machine.
Comparative dissolution profiles were determined using Test 711 “Dissolution” from United States Pharmacopeia 29, United States Pharmacopeia Convention, Inc., Rockville, Maryland, 2005 (“USP 29”), with the following conditions:
Dissolution medium: 0.1 N HCL for 1 hour followed by pH 6.8 buffers.
Volume: 900 ml.
Stirring: 50 rpm.
Apparatus: USP apparatus II with sinkers.
Reference for ramipril: CARDACE™ 5 mg capsules.
Reference for indapamide: NATRILIX™ SR tablets.
Comparative average dissolution profiles for ramipril are tabulated in Table 1, and comparative average release profiles for indapamide are tabulated in Table 2, wherein the values are percentages of contained drug that dissolved as determined using high performance liquid chromatography.

Table 1
Time (minutes) Example 1 CARDACE
10 92 98
15 94 98
30 95 98
45 96 98
60 96 98

Table 2
Time (hours) Example 1 NATRILIX SR
1 4 4
4 20 21
8 39 37
12 54 47
16 67 62
20 76 72
24 86 80
30 94 90
36 97 100

EXAMPLE 2: Ramipril 2.5 mg and indapamide 1.5 mg capsules.
Ingredient mg/Capsule
Ramapril Blend
Ramipril 2.5
Partially pregelatinized starch 105.8
Fully gelatinized starch 11.5
Light magnesium oxide 0.2
Indapamide Tablet
Indapamide 1.5
Mannitol 17
Microcrystalline cellulose 14.7
HPMC K 100M 22.8
Hydroxypropyl cellulose LF 0.75
Water* 20
Zinc stearate 0.25
Tablet Coating
HPMC 3 cps 2
Water* 18
* Evaporates during processing.
Manufacturing process: same as that of Example 1.

EXAMPLES 3-5: Ramipril 5 mg and indapamide 1.5 mg capsules.
Ingredient mg/Capsule
Example 3 Example 4 Example 5
Ramipril Blend
Ramipril 5 5 5
Partially pregelatinized starch 103.3 103.3 103.3
Fully gelatinized starch 11.5 11.5 11.5
Light magnesium oxide 0.2 0.2 0.20
Indapamide Tablet
Indapamide 1.5 1.5 1.5
Mannitol 47 23 10
Microcrystalline cellulose - 20.1 10.46
HPMC K 100M 7.5 11.4 34.2
Hydroxypropyl cellulose LF 0.75 0.75 0.6
Water* 20 20 20
Zinc stearate 0.25 0.25 0.25
Tablet Coating
HPMC 3 cps 1 2 2
Water* 18 18 18
HPMC K 100M in Tablet 13.15% 20% 60%
* Evaporates during processing.
Manufacturing process: same as that of Example 1.

EXAMPLE 6: Ramipril 5 mg and indapamide 1.5 mg capsules.
Ingredient mg/Capsule
Ramipril Blend
Ramipril 5
Partially pregelatinized starch 103.3
Fully gelatinized starch 11.5
Light magnesium oxide 0.2
Indapamide Tablet
Indapamide 1.5
Mannitol 9.65
Microcrystalline cellulose 10
HPMC K 100M 33
Hydroxypropyl cellulose LF 0.6
Water* 10
Isopropyl alcohol* 10
Zinc stearate 0.25
Tablet Coating
HPMC 3 cps 2
Water* 18
* Evaporates during processing.
Manufacturing process: Same as that of Example 1, except that the solvent for granulating also contains isopropanol.

EXAMPLE 7: Comparative release profiles of indapamide from Examples 3-6.
Test method: USP 29.
Dissolution parameters:
Dissolution medium: 0.1N HCL for 1 hour followed by pH 6.8 buffers.
Volume: 900 ml.
Apparatus: USP type II apparatus with sinkers.
RPM: 50.
Release profiles are tabulated in Table 3.

Table 3
Time (hours) Cumulative Percent of Indapamide Dissolved
Example 3 Example 4 Example 5 Example 6
1 9 10 3 6
4 33 49 16 24
8 55 79 30 43
12 69 96 44 59
16 80 101 55 72
20 90 105 66 84
24 97 106 76 92
30 - - 86 100
36 - - 95 101

EXAMPLES 8 and 9: Ramipril 5 mg or 2.5 mg, and indapamide 1.5 mg capsules.
Ingredient mg/Capsule
Example 8 Example 9
Ramipril Blend
Ramipril 5 2.5
Partially pregelatinized starch (PCS-PC10) $ 103.3 105.6
Fully gelatinized starch 11.5 11.7
Light magnesium oxide 0.2 0.2
Indapamide Tablet
Indapamide 1.5
Lactose monohydrate 14.7
Microcrystalline cellulose 114 5
Hydroxypropyl cellulose EF (HPC EF) 0.35
Water* 3.33
Hydroxypropyl methylcellulose (“HPMC”) K100M 33
Colloidal silicon dioxide 0.2
Zinc stearate 0.25
Tablet Coating
Hydroxypropyl methylcellulose (HPMC) 3 cps 1.7
Talc 0.1
Titanium dioxide 0.1
Glycerin 0.1
Water* 11.3
* Evaporates during processing.
$ PCS-PC10 was supplied by Signet Chemical Corporation.
Manufacturing process:
A: Ramipril blend:
1) Partially pregelatinized starch (PCS-PC10) was divided into four equal parts for geometric mixing with the drug.
2) PCS-PC10 part I, ramipril, magnesium oxide, and fully gelatinized starch were loaded into a double cone blender and mixed for 10 minutes.
3) Step 2 blend was sifted through a ASTM #30 mesh sieve.
4) PCS-PC10 part II and material of Step 3 were co sifted through a ASTM #30 mesh sieve.
5) PCS-PC10 part III was sifted through a ASTM #30 mesh sieve.
6) PCS-PC10 Part IV was sifted through a ASTM #30 mesh sieve.
7) Step 4), step 5) and step 6) materials were placed into a double cone blender and blended for 20 minutes.
B: Indapamide tablet:
1) Indapamide, microcrystalline cellulose and lactose monohydrate were sifted separately through a ASTM #40 mesh sieve.
2) Step 1) materials were placed into a rapid mixer granulator and dry mixed for 10 minutes.
3) HPC EF was dissolved in water with constant stirring to form a binder solution.
4) Step 2) was granulated with step 3).
5) The wet mass obtained from step 4) was dried at 105 °C until the loss on drying was 1.5-2.5 % w/w.
6) Step 5) was sifted through a ASTM #40 mesh sieve to obtain granules.
7) HPMC K 100M CR and colloidal silicon dioxide were sifted through a ASTM #40 mesh sieve and uniformly blended with step 6) for 20 minutes.
8) Zinc stearate was co-sifted through a ASTM # 40 mesh together with step 7) product and blended for 5 minutes.
9) Step 8 was compressed into tablets using 5 mm punches and dies with a compression machine.
10) HPMC 3 cps, glycerin, talc and titanium dioxide were dispersed in water with constant stirring for 45 minutes. The suspension was filtered through a ASTM # 200 mesh nylon cloth.
11) The compressed tablets of step 9) were coated with coating suspension of step 10) until a 2 mg buildup was obtained.
C. Encapsulation:
Ramipril blend and an indapamide tablet were encapsulated in size 2 hard gelatin capsule shells, using a capsule-filling machine.

EXAMPLE 10: Comparative release profiles of indapamide from Examples 8 and 9.
Test method: USP 29.
Dissolution parameters:
Dissolution medium: pH 6.8 buffer.
Volume: 900 ml.
Apparatus: USP type II apparatus with sinkers.
RPM: 50.
Release profiles are tabulated in Table 4.

Table 4
Time (hours) Cumulative Percent of Indapamide Dissolved
NATRILIX SR Example 8 Example 9
4 21 15 16
12 47 45 47
24 80 78 79
36 100 99 100

EXAMPLE 11: Stability study.
Example 8 capsules( 6 capsules) were packaged in a blister package strip formed from two sheets of 0.04 mm aluminum foil and stored at 40 °C and 75 % relative humidity (“RH”) for 2 months, and samples were analyzed at intervals using high performance liquid chromatography. Results are shown below, where the values given for impurities are percentages of the drug content.

Parameter Ramipril Indapamide
Initial 1 Month 2 Months Initial 1 Month 2 Months
Drug Assay, % of label 104.5 105.4 103.9 99.6 98.9 99
Impurity Y - - - 0.1 0.1 0.11
Impurity D 0.26 0.27 0.31 - - -
Impurity E 0.08 0.11 0.28 - - -
Highest Unidentified Impurity 0.04 0.05 0.02 - - -
Total Impurities 0.43 0.48 0.62 0.1 0.1 0.11

EXAMPLE 12: Stability study.
Capsules of Example 9 were packaged, stored, and analyzed as in preceding Example 11, and the analysis results are shown below.
Parameter Ramipril Indapamide
Initial 1 Month 2 Months Initial 1 Month 2 Months
Drug Assay, % of label 101.1 101.5 101.8 99.3 100.5 0.11
Impurity Y - - - 0.09 0.1 0.11
Impurity D 0.26 0.3 0.32 - - -
Impurity E 0.07 0.13 0.25 - - -
Highest Unidentified Impurity 0.04 0.06 0.09 - - -
Total Impurities 0.45 0.53 0.65 0.09 0.1 0.11

CLAIMS:

1. A pharmaceutical dosage form comprising:
a composition comprising ramipril, a stabilizer, and a hydrolysis-minimizing agent; and
a controlled release composition comprising indapamide.
2. The pharmaceutical dosage form of claim 1, wherein ramipril is in an immediate release form.
3. The pharmaceutical dosage form of either of claims 1 or 2, wherein a stabilizer comprises a metal oxide, disodium edetate, tocopherol, a cyclodextrin or derivative thereof, an alkalizing agent, or a combination of any two or more thereof.
4. The pharmaceutical dosage form of either of claims 1 or 2, wherein a stabilizer comprises magnesium oxide.
5. The pharmaceutical dosage form of any of claims 1-4, wherein a weight ratio of ramipril to stabilizer is about 1:0.001 to about 1:1.
6. The pharmaceutical dosage form of any of claims 1-5, wherein a hydrolysis-minimizing agent comprises a saccharide, a starch, or a mixture thereof.
7. The pharmaceutical dosage form of any of claims 1-5, wherein a hydrolysis-minimizing agent comprises a mixture of starches.
8. The pharmaceutical dosage form of any of claims 1-7, wherein a weight ratio of ramipril to hydrolysis-minimizing agent is about 1:1 to about 1:400.
9. The pharmaceutical dosage form of any of claims 1-8, wherein a composition comprising ramipril is a powder or granules.
10. The pharmaceutical dosage form of any of claims 1-9, wherein a composition comprising indapamide is a tablet.
11. The pharmaceutical dosage form of any of claims 1-10, wherein a controlled release composition comprises a rate controlling polymer.
12. The pharmaceutical dosage form of any of claims 1-10, wherein a controlled release composition comprises a hydroxypropyl methylcellulose rate controlling polymer.
13. The pharmaceutical dosage form of any of claims 1-12, wherein compositions are filled into a capsule.