FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification
(See section 10 and rule 13)
MODIFIED RELEASE RAMIPRIL COMPOSITIONS AND USES THEREOF
PANACEA BIOTEC LIMITED
A COMPANY INCORPORATED UNDER THE LAWS OF INDIA HAVING THEIR
OFFICE AT 104, SAMARPAN COMPLEX, NEW-LINK ROAD, CHAKALA. ANDHERI
(E), MUMBAI 400099, MAHARASHTRA, INDIA

The following specification describes the invention


FIELD OF THE INVENTION:
The present invention relates to method of treating cardiovascular events in mammals comprising administering a pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof. In particular the present invention relates to method of treating hypertension in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof, wherein the composition effectively reduces the blood pressure between dosing intervals and the effect does not diminish towards the end of the dosing interval.
BACKGROUND OF THE INVENTION:
Ramipril, (2S,3aS,6aS)-l[(S)--N--[(S)-l-carboxy-3-phenylpropyl]alanyl]octahydrocycl-
openta[b]pyrrole-2-carboxylic acid, 1-ethyl ester is an angiotensin converting enzyme (ACE) inhibitor.
Ramipril (disclosed in EP 079022) is a long-acting ACE inhibitor. Its active metabolite is the free acid ramiprilat. which is obtained in vivo upon administration of ramipril. In hypertensive patients administration of ramipril is known to cause a reduction in peripheral arterial resistance and thus a reduction of the blood pressure without a compensator)' rise in heart rate. It is being used in the treatment of hypertension and congestive heart failure. Furthermore, ramipril has been shown to reduce mortality in patients with clinical signs of congestive heart failure after surviving an acute myocardial infarction. Ramipril has been suggested to have an added advantage over many other ACE inhibitors due to its pronounced inhibition of ACE in tissues resulting in organ protective effects in e.g. the heart, lung, and kidney.
The recommended initial dose of ramipril for patients having hypertension, not receiving a diuretic, is 2.5 mg once a day. Dosage should be adjusted according to the blood pressure response. The usual maintenance dosage range is 2.5 to 20 mg per day administered as a single dose or in two equally divided doses. It is critical to note that in some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, an increase in dosage or twice daily administration should be considered.
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It is known, in Chronobiologia, Vol. 13, pages 239 to 243, (1986), that blood pressure has within-day rhythmicity, and that the highest pressure values are seen often in the morning hours just after waking by the patient. The rise in blood pressure occurring at waking requires a dosage form that is administered on retiring and delivers its drug after a drug-free interval during sleep. This drug delivery pattern provides the need for therapy at the appropriate time, thereby substantially lessening the incidence of a waking elevated blood pressure.
There exist some more prior arts which relates to the dosage form or delivery systems to curb the problem of waking elevated blood pressure.
United States Patent 5785994 relates to a dosage form provided as an osmotic device comprising means for the rate-programmed delivery of a drug in time-varying patterns to a drug recipient. The patent describes an osmotic drug delivery device comprising means for delivering a pulsed dose of drug to a human, means for providing a drug-free interval, and then providing a recurring pulse dose of drug to the human. The patent discloses osmotic drug delivery device for delivering calcium channel blockers for lessening the incidence of waking elevated blood pressure, when administered at the time of retiring.
United States Patent 6764697 relates to a dosage form that after administration of the dosage form is followed by a drug-free period, which dosage form at this later time delivers a dose of drug for delayed therapy. The patent also relates to a method of delayed-drug therapy by administering a dosage form comprising a drug composition and a second composition (osmotic composition) that delays the onset of drug delivery and after the drug-free interval delivers a drug for its therapeutic effect to produce the effect at morning hours, when administered before retiring. The patent discloses the use of water-soluble non-ionic polymer for providing delayed therapy.
United States Patent 6500459 describes a pharmaceutical compositions that delays the release of drug from a pharmaceutical compositions for a predetermined time or provide a controlled onset after administration of the pharmaceutical compositions and continue releasing the same drug from the pharmaceutical compositions at a predetermined release rate such that the blood levels achieved by such pharmaceutical compositions provide a significant therapeutic benefit to patients suffering from various disease states. The patent discloses the pharmaceutical composition for providing controlled onset and sustained release of verapamil
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using a functional coating membrane for controlled onset and the hydrophilic polymeric matrix for the sustained release.
United States Patent 6267990 relates to the pharmaceutical preparation comprising initial dose of ACE inhibitor in a composition; first delayed release pellets comprising ACE inhibitor and excipients, covered with a coating and a second delayed release pellet comprising ACE inhibitor and excipients, covered with a coating, wherein the amount of coatings on first and second delayed release pellets are present in a ratio, based on weight, within the range of from 1:2 to 1:7. The pharmaceutical preparation permits the controlled release of ACE inhibitor and thus ensures a therapeutically effective blood level over a prolonged period with minimal variations in the blood level concentration.
The prior arts described above used complex and costly technologies to address the need to reduce the problem of waking elevated blood pressure but none of the prior art seem to address the most critical requirement of providing a method of treating cardiovascular events like hypertension in mammals such that the antihypertensive effect does not diminish towards the end of the dosing interval. There, thus exists a critical and presently unfilled need to provide a pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof, which when administered would provide all or either of the following effects; maintain the antihypertensive effect towards the end of dosing interval; effectively reduce the blood pressure between dosing intervals; provide maximum ACE inhibition after 24 hours period.
OBJECTS OF THE INVENTION:
The present invention relates to the method of treating cardiovascular events in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof.
The present invention further relates to the method of treating hypertension in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof, wherein the antihypertensive effect does not diminish towards the end of the dosing interval.
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The present invention also relates to the method of treating hypertension in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof, wherein the composition effectively reduces the blood pressure between dosing intervals.
The present invention also relates to the method of treating hypertension in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof, wherein the composition provides more than 80% ACE inhibition after 24 hours period.
The present invention further relates to a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipient(s). wherein the antihypertensive effect does not diminish towards the end of the dosing interval.
The present invention further relates to a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipient(s), wherein the composition effectively reduces the blood pressure between dosing intervals.
The present invention also relates to a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipient(s). wherein the composition provides more than 80% ACE inhibition after 24 hours period.
The present invention further relates to the method of treating hypertension in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof wherein the composition maintains plasma concentration of ramipril and/or active metabolite(s) thereof in the therapeutic range over the 24 hours period.
The present invention further relates to a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof and pharmaceutically
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acceptable excipient(s), wherein the composition maintains plasma concentration of ramipril and/or active metabolite(s) thereof in the therapeutic range over the 24 hours period.
The present invention further relates to method of reducing cardiovascular morbidity and mortality in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipient(s), wherein the composition effectively reduces the blood pressure between dosing intervals.
DESCRIPTION OF THE INVENTION:
Ramipril is a long-acting ACE inhibitor. Its active metabolite is the free acid ramiprilat, which is formed in vivo upon administration of ramipril. In hypertensive patients administration of ramipril is known to cause a reduction in peripheral arterial resistance and thus a reduction of the blood pressure without a compensatory rise in heart rate.
The present invention provides the method of treating cardiovascular events in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof.
As used herein the term 'cardiovascular events' means, but not limited to, hypertension, myocardial infarction, diabetes, left ventricular dysfunction, heart failure, cardiac insufficiency, stroke, congestive heart failure, worsening of angina, cardiovascular death, overt nephropathy in diabetic patients, peripheral vascular disease or the like.
In one aspect, the present invention relates to the method of treating hypertension in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof, wherein the antihypertensive effect does not diminish towards the end of the dosing interval.
The present invention further relates to a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipient(s). wherein the antihypertensive effect does not diminish towards the end of the dosing interval.
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Ramipril has a dosage regimen of administering once daily, but it has been observed that the antihypertensive effect of ramipril diminishes towards the end of dosing interval. The modified release pharmaceutical composition of the present invention delivers ramipril in such a manner that it maintains the plasma concentration of ramipril and/or active metabolites thereof in therapeutic range over the 24 hours period, resulting in effective reduction of blood pressure between dosing intervals. •
In another aspect the present invention relates to the method of treating hypertension in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof, wherein the composition effectively reduces the blood pressure between dosing intervals.
In another aspect, the present invention relates to a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipient(s), wherein the composition effectively reduces the blood pressure between dosing intervals.
As used here in the term 'modified release, means but not limited to sustained release, controlled release, retarded release, timed release, programmed release, burst release, pulsatile release, prolonged release, delayed release, immediate release, slow release, extended release or combinations thereof.
The modified release formulation of the present invention maintains plasma concentration of ramipril and/or active metabolite(s) thereof in the therapeutic range over the 24 hours period, resulting into lesser fluctuation of blood pressure through out the 24 hours period and after prolonged treatment reduces the cardiovascular morbidity and mortality.
In yet another aspect, the present invention relates to method of reducing cardiovascular morbidity and mortality in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipient(s), wherein the composition effectively reduces the blood pressure between dosing intervals.
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Patient information leaflet of ramipril states that the single dosing of ramipril produces 40-60% inhibition after 24 hrs: however multiple dosing of Ramipril shows 80% inhibition after 24hrs. The pharmaceutical composition of the present invention provides more than 80% ACE inhibition after the 24 hours period and results in effective reduction of blood pressure between dosing intervals.
In yet another aspect the present invention relates to the method of treating hypertension in mammals comprising administering a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof, wherein the composition provides more than 80% ACE inhibition after 24 hours period.
In yet another aspect, the present invention relates to a modified release pharmaceutical composition comprising ramipril or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipient(s), wherein the composition provides more than 80% ACE inhibition after 24 hours period.
The term 'pharmaceutical composition' according to present invention can be any dosage form which can deliver or release the drug in-vitro as well as in-vivo through any route of administration like oral, buccal, sublingual, nasal, transmucosal or the like, preferably by oral route like tablets, capsules, mini-tablets, oral films, sprays, pellets, granules or powder or the like or combinations thereof.
The pharmaceutical composition according to the present invention can be prepared by any suitable process known in the art.
As disclosed herein and as used in the compositions and methods of the present invention, the term 'ramipril', includes ramipril, its pharmaceutically acceptable salts, conjugates, polymorphs, derivatives, complexes, prodrugs and natural and synthetic analogues, solvate, hydrate or anhydrates and combinations thereof. Use of the term 'drug' or 'active ingredient' in context of the present invention refers to ramipril including the forms mentioned herewith.
The term 'pharmaceutically acceptable excipient, according to the present invention means, but not limited to, any inactive ingredient which is required for the formulation of ramipril in a suitable dosage form. Particularly the excipient includes, but not limited to, diluents,
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carriers, fillers, bulking agents, binders, disintegrants, polymer, lubricant, glidant, surface active agents, stabilizers, absorption accelerators, flavoring agents, preservatives, antioxidants, buffering agents, and any other excipient commonly used in the pharmaceutical industry.
Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents used in the composition include diluents commonly used in solid pharmaceutical compositions. Diluents include, but are not limited to, calcium carbonate, calcium phosphate (dibasic or tribasic), calcium sulfate, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, maltose, mannitol, sorbitol, sucrose, starch, pregelatinized starch, talc and the like or combinations thereof.
Carriers for use according to the present invention may include, but are not limited to, hydrophilic or hydrophobic polymers, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, calcium sulphate, kaolin, crystalline cellulose, silicic acid, and the like or combinations thereof.
Binders help to bind the active ingredient and other excipients together. Binders used in the composition include binders commonly used in solid pharmaceutical compositions. Binders include, but are not limited to, acacia, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylceilulose, gelatin, glucose, guar gum, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, maltose, methylcellulose, povidone, starch, gelatin, methylcellulose, polyethylene oxide and the like or combinations thereof.
Disintegrants can increase dissolution. Examples of suitable disintegrants are starch, pregelatinized starch, sodium starch giycolate, sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, clays, microcrystalline cellulose, alginates, gums, surfactants, effervescent mixtures, hydrous aluminum silicate, cross-linked polyvinyl pyrrolidone, and others as known in the art or combinations thereof.
A lubricant can be added to the composition for ease in processing, e.g., to reduce adhesion to the equipment used during processing, and to ease release of the product from a punch or dye during tableting. Lubricants used.in the composition include those commonly used in solid
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pharmaceutical compositions, including, e.g., calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium steady' fumarate, stearic acid, talc, vegetable oil, sodium lauryl sulfate, and zinc stearate or the combinations thereof.
Glidants can be added to improve the flowability of a pharmaceutical composition and improve the accuracy of dosing. Glidants used in the composition include glidants commonly used in solid pharmaceutical compositions, including, e.g., colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate and the like or combinations thereof.
Flavoring agents and flavor enhancers make the dosage farm more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include for example maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl malwl, and tartaric acid and the like or combinations thereof.
Modified release of the drug from the pharmaceutical composition can be achieved by using various polymeric carriers of different viscosity and physical properties or by coating the pharmaceutical composition with release modifying coating material.
Polymeric carriers for modifying the release of the drug from the pharmaceutical composition can be one or more selected from the group comprising natural polymers, synthetic polymers, semi-synthetic polymers, hydrophilic polymers or hydrophobic polymers or combinations thereof, preferably hydrophilic polymers or hydrophobic polymers or combinations thereof.
The hydrophilic polymers constituting the modified release carrier preferably release the active ingredient(s) gradually, slowly, continuously. They swell upon contact with aqueous fluid following administration, resulting in a viscous, drug release regulating gel layer. Hydrophilic polymers suitable for use in this invention are either water soluble or water swellable. and include one or more natural or partially or totally synthetic anionic or nonionic hydrophilic gums, modified cellulosic substances stances or proteinaceous substances. Examples of such polymers are alkylcelluloses, such as, methylcellulose; hydroxyalkylceiluloses, for example, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcelluiose; hydroxyalkyl alkylcelluloses, such as,
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hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; carboxyalkylcelluloses, such as, carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses, such as, sodium carboxymethylcellulose; carboxyalkylalkylcelluloses, such as, carboxymethylethylcellulose: carboxyalkylcellulose esters; other natural, semi-synthetic, or synthetic polysaccharides, such as. alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabicum, guar gum, xanthan gum. starches, pectins, such as sodium carboxymethylamylopectin, chitin derivates such as chitosan, polyfructans, inulin: polyacrylic acids and the salts thereof: polymethacrylic acids and the salts thereof, methacrylate copolymers; polyvinylalcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinylalcohol and polyvinylpyrrolidone; polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.
The hydrophobic polymer suitable for use in the present invention can be selected from the group comprising hydrophobic cellulose derivatives, such as ethyl cellulose, fats, such as glycerol palmitostearate, beeswax, glycowax, castrowax, carnaubawax, glycerol monostearate or stearylalcohol, hydrophobic polyacrylamide derivatives and hydrophobic methacrylic acid derivatives and the like or combinations thereof.
Any coating material which modifies the release of the active ingredient in the desired manner may be used. In particular, coating materials suitable for use in the practice of the invention include but are not limited to polymer coating materials, such as cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, ammonio methacrylate copolymers such as those sold under the Trade Mark Eudragit.RTM. RS and RL, poly acrylic acid and poly acrylate and methacrylate copolymers such as those sold under the tradename Eudragit® (Rohm Pharrha; Westerstadt, Germany), including Eudragit® L30D-55 and LI00-55 (soluble at pH 5.5 and above). Eudragit® L-100 (soluble at pH 6.0 and above), Eudragit® S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and Eudragits® NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability), polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch, and cellulose based cross-linked
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polymers in which the degree of crosslinking is low so as to facilitate adsorption of water and expansion of the polymer matrix, hydoxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, arninoacryl-methacrylate copolymer (Eudragit.RTM. RS-PM, Rohm & Haas), pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers) poiy(hydroxyalkyl methacrylate) (m. wt. .about.5k-5,000k), polyvinylpyrrolidone (m. wt. ,about.10k-360k), anionic and cationic hydrogels, polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (m. wt. .about.30k-300k), polysaccharides such as agar, acacia, karaya, tragacanth, alginates and guar, polyacrylamides, PoIyox.RTM. polyethylene oxides (m. wt. .about.lOOk -5.000k). AquaKeep.RTM. acrylate polymers, diesters of polyglucan, crosslinked polyvinyl alcohol and poly N-vinyI-2-pyrrolidone, sodium starch glucolate (e.g. Explotab.RTM.; Edward Mandell C. Ltd.); hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, polyethylene oxides (e.g. Polyoxe.RTM., Union Carbide), methyl ethyl cellulose, ethylhydroxy ethylcellulose. cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, poiyacrylic acid, copolymers of methacrylic acid or methacrylic acid (e.g. Eudragit.RTM., Rohm and Haas), other acrylic acid derivatives, sorbitan esters, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucan and mixtures and blends thereof. Combinations of different coating materials may also be used. Multi-layer coatings using different polymers may also be applied.
Coating composition may optionally comprise further appropriate ingredients which improve the property of coating layers, such ingredients include but are not limited to fillers, plasticizers, anti-adhesive, pigments, coloring agents, stabilizing agents, surfactants, pore formers and the like.
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Suitable plasticizers include for example acetylated monoglycerides: butyl phthalyl butyl glycolate: dibutyi tartrate: diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; tripropioin; diacetin: dibutyi phthalate; acetyl monoglyceride; polyethylene glycols; castor oil: triethyl citrate; polyhydric alcohols, glycerol acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate. diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyi phthalate. di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate. di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyi sebacate.
The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way, as these examples and other equivalents thereof will become more apparent to those versed in the art in the light of the present disclosure.
Example: 1

S.No. Ingredients Quantity (mg/Tablet)
1. Ramiprii 10.00
2. Calcium sulfate 75.05
3. Hypromellose 37.50
4. Magnesium Stearate 2.45
Total 125.0
Ramiprii was mixed with the inactive ingredients in the geometrical ratio and tablets were compressed in tablet compression machine. The tablets can optionally be coated with a coating composition.
Example: 2

S.No Ingredients Quantity (mg/Tablet)
1. Ramiprii 5.00
2. Compactrol 27.35
3. Starch LM 1500 27.35
4. Magnesium Stearate 0.30
Total 60.00
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Ramipril was mixed with the inactive ingredients in the geometrical ratio and tablets were compressed in tablet compression machine. Tablets were coated with Eudragit S 100. One coated tablet and one uncoated tablet were filled in size # 0 hard gelatin capsule.
Dated this 30thof July 2008

Dr. MAHALAXM1 ANDHERIA)
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FOR PANACEA BIOTEC LIMITED