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WO2008068577A2 - Compositions pharmaceutiques - Google Patents

Compositions pharmaceutiques Download PDF

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Publication number
WO2008068577A2
WO2008068577A2 PCT/IB2007/003705 IB2007003705W WO2008068577A2 WO 2008068577 A2 WO2008068577 A2 WO 2008068577A2 IB 2007003705 W IB2007003705 W IB 2007003705W WO 2008068577 A2 WO2008068577 A2 WO 2008068577A2
Authority
WO
WIPO (PCT)
Prior art keywords
diuretic
pharmaceutical composition
ace
inhibitor
indapamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2007/003705
Other languages
English (en)
Other versions
WO2008068577A3 (fr
Inventor
Nilendu Sen
Sunil Mirajkar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glenmark Pharmaceuticals Ltd
Original Assignee
Glenmark Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Pharmaceuticals Ltd filed Critical Glenmark Pharmaceuticals Ltd
Publication of WO2008068577A2 publication Critical patent/WO2008068577A2/fr
Publication of WO2008068577A3 publication Critical patent/WO2008068577A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates generally to a pharmaceutical composition containing a diuretic; and an angiotensin-converting enzyme (ACE) inhibitor, a process for its preparation and a method for the treatment of arteriolo-capillary microcirculatory disorders.
  • ACE angiotensin-converting enzyme
  • ACE inhibitors are known.
  • an Ace inhibitor is perindopril erbumine, also known as (2S,3aS,7aS)-l-[(S)-N-[(S)-l-Carboxy-butyl]alanyl]hexahydro- 2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1), can be represented by the structure of Formula I:
  • perindopril also known as perindopril erbumine
  • the tert-butylamine salt of perindopril is the form commercially sold under the trade name Aceon ® .
  • Perindopril is the free acid form of perindopril erbumine and is an ethyl ester of a non-sulfhydryl ACE inhibitor.
  • Perindopril is a pro-drug and is metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite.
  • Perindopril is ordinarily used to treat hypertension.
  • ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II.
  • Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion.
  • Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with a small increase of serum potassium.
  • Indapamide also known as 4-chloro-N-(2-methyl-l-indolinyl)-3- sulfamoylbenzamide, has a molecular weight of 365.84.
  • Indapamide can be represented by the structure of Formula II:
  • Indapamide is an oral antihypertensive/diuretic. Its 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.
  • Indapamide contains both a polar sulfamoyl chlorobenzamide moiety and a lipid- soluble methylindoline moiety. Indapamide bears a structural similarity to the triazide diuretics which are known to decrease vascular smooth muscle reactivity. However, it differs chemically from the thiazides in that it does not possess the thiazide ring system and contains only one sulfonamide group. Indapamide appears to cause vasodilation, probably by inhibiting the passage of calcium and other ions (sodium, potassium) across membranes. This same effect may cause hypokalemia in susceptible individuals.
  • indapamide has also been shown to cause uterine myometrial relaxation in experimental animals. Overall, indapamide has an extra-renal antihypertensive action resulting in a decrease in vascular hyper reactivity and a reduction in total peripheral and arteriolar resistance.
  • U.S. Patent No. 6,653,336 discloses the use of a combination of an angiotensin converting enzyme inhibitor (CEI) and of a diuretic for producing pharmaceutical compositions intended for the treatment of arteriolo-capillary microcirculatory disorders. It would be desirable to provide improved to provide improved solid pharmaceutical composition is provided comprising (a)a diuretic; and (b) an angiotensin-converting enzyme (ACE) inhibitor.
  • CEI angiotensin converting enzyme inhibitor
  • ACE angiotensin-converting enzyme
  • U.S. Patent No. 6653336 ('336 Patent), herein incorporated by reference, invention relates to the use of a combination of an angiotensin converting enzyme inhibitor (CEI) and of a diuretic for producing pharmaceutical compositions intended for the treatment of arteriolo- capillary microcirculatory disorders.
  • CEI angiotensin converting enzyme inhibitor
  • This patent in example 1 and 2 discloses the innovator's composition.
  • the 90 % Confidence Intervals for Cmax, AUC (0-t) and AUC - ⁇ 0- ⁇ ) are (95.38 - 131.31) %, (100.45 - 122.12) % and (100.63 - 121.88) % respectively, Perindopril fasting study data under fasting conditions of the study, the ratio of means for the Perindopril Ln-transformed parameters Cmax, AUC (0-t), AUC ⁇ (O- ⁇ ) and tl/2 of means are 80.43 %, 83.51 %, 83.76 % and 100.58 % respectively.
  • the 90 % Confidence Intervals for Cmax, AUC (0-t) and AUC -(0- ⁇ ) are (69.42 - 93.18) %, (73.42 - 94.99) % and (73.64 - 95.27) % respectively .
  • the ratio of means for the Perindoprilate Ln-transformed parameters Cmax, AUC (0-t), AUC -(0- ⁇ ) and tl/2 of means are 91.98 %, 92.86 %, 96.18 % and 106.75 % respectively.
  • the 90 % Confidence Intervals for Cmax, AUC (0-t) and AUC - (O- ⁇ ) are (81.75 - 103.49) %, (87.85 - 98.16) % and (85.69 - 107.94) % respectively.
  • test product is not bioequivalent to the Innovator's marketed product with respect to both Perindopril and Indapamide at the same time surprisingly the inventors of this application found that when the particle size of Indapamide is increased by roll compaction technique, the resultant product is expected to be bioequivalent to the 'Coversyl Plus'.
  • a solid pharmaceutical composition comprising (a) a diuretic; and (b) an angiotensin- converting enzyme (ACE) inhibitor; wherein about 100% of the particle size of the diuretic pass through a standard 60# mesh screen.
  • ACE angiotensin- converting enzyme
  • a process for preparing a pharmaceutical composition comprising combining a diuretic and a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor in solid form.
  • ACE non-sulfhydryl angiotensin-converting enzyme
  • a solid pharmaceutical composition comprising (a) indapamide and (b) perindopril, wherein about 100% indapamide particle passing through 60# mesh or at least about 75% indapamide particles are retained on 100# or at most about 25% indapamide particles are retained on 80#.
  • a tablet composition comprising perindopril as one active ingredient and indapamide as another active ingredient, wherein the composition is a physicochemically stable composition.
  • treating means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
  • the term "therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
  • the term "delivering” as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.
  • salts and esters as used herein means those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulphate salts and the like.
  • Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts, and the like.
  • the combination of (a) and (b) of the pharmaceutical composition of the present invention is believed to be clinically more effective due to the synergistic effects than the existing products alone or in combinations in the market.
  • the pharmaceutical composition of the present invention is believed to be a bioequivalent product to Coversyl Plus.
  • the pharmaceutical composition of the present invention is believed to be a bioequivalent product to Coversyl Plus when the 100% of the particle size of the diuretic indapamide pass through a 60# mesh screen or at least about 75% of the particle size of the diuretic are retained on a 100# mesh screen or at most about 25% of the particle size of the diuretic are retained on s 80# mesh screen wherein the present particle size is achieved by using roll compaction technique (Mini Roll compactor machine of Make: Chamunda Pharma machinery pvt.ltd. (Clit) and Model: CPMMRC- 100/25 is used for roll compaction.).
  • roll compaction technique Mini Roll compactor machine of Make: Chamunda Pharma machinery pvt.ltd. (Clit) and Model: CPMMRC- 100/25 is used for roll compaction.
  • the present invention is directed to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising (a) a diuretic; and (b) an angiotensin-converting enzyme (ACE) inhibitor; wherein 100% of the particle size of the diuretic pass through a standard 60# mesh screen.
  • ACE angiotensin-converting enzyme
  • 100% of the particle size of the diuretic pass through a standard 60# mesh screen.
  • at least about 75% of the particle size of the diuretic are retained on 100# mesh screen.
  • at most about 25% of the particle size of the diuretic are retained on a 80# mesh screen.
  • the particle size can be achieved using a roll compaction technique (e.g., Mini Roll compactor machine (Chamunda Pharma machinery pvt.ltd. (Clit) and Model CPMMRC-100/25)).
  • Suitable diuretics for use herein include indapamide and the like. Suitable
  • ACE inhibitors for use herein include perindopril, captopril, enalapril, lisinopril, delapril, fosinopril, quinapril, ramipril, spirapril, imidapril, trandolapril, benazepril, cilazapril, temocapril, pharmaceutically acceptable salts thereof and their addition salts with a pharmaceutically acceptable acid or base and the like and mixtures thereof.
  • a preferred ACE inhibitor is perindopril or perindopril erbumine.
  • the pharmaceutical composition of the present invention can contain one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients include diluents, glidants, lubricants and the like and mixtures thereof.
  • glidant as used herein is intended to mean a substance that acts as filler in the formulation. Suitable diluents include, by way of example, microcrystalline cellulose, starch, lactose monohydrate, dicalcium phosphate, starch and the like and combinations thereof and other material known to those of ordinary skill in the art.
  • glidant can be any glidant typically used in the pharmaceutical art for oral solid dosage forms. Examples include colloidal silicon dioxide, talc alone and magnesium stearate and the like and combinations thereof. The amount of glidants varies widely and will ordinarily ranges from about 0.1 % to about 5.0 % by weight, based on the total weight of the composition.
  • lubricant can be any lubricant typically used in the pharmaceutical art for oral solid dosage forms.
  • Example include stearate salts such as calcium stearate, magnesium stearate, zinc stearate and the like, stearic acid, talc, hydrogenated vegetable oil, vegetable oil derivatives, silica, silicones, high molecular weight polyalkyllene glycol and saturated fatty acids and the like and mixtures thereof.
  • the amount of lubricant varies widely and will ordinarily ranges from about 0.1 % to about 5.0 % by weight, based on the total weight of the composition.
  • compositions of the present invention may also contain other optional ingredients that are also typically used in pharmaceutical compositions such as, for example, coloring agents, preservatives, flavorings, and the like.
  • a pharmaceutical composition is a combination product of perindopril or a salt thereof and indapamide or a salt thereof in the form a stable pharmaceutical tablet formulation wherein about 100% indapamide particle passes through 60# or at least about 75% indapamide particles are retained on 100# or at most about 25% indapamide particles are retained on 80#.
  • compositions of the present invention in solid form are preferably tablets. Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors.
  • the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art.
  • Suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
  • the pharmaceutical compositions can be prepared using dry/wet granulation technique or any other suitable technique that is known to the person skilled in the art to obtain a tablet.
  • the process can involve Roll Compaction of indapamide API compacted through a Roll- Compactor.
  • the compacted mass of indapamide API is passed through a #80 mesh followed by dry mixing of pharmaceutically acceptable excipients with the drugs followed by lubrication and compression.
  • step (c) was sifted through a #40 mesh screen, again reloaded into the blender and mixed for 10 minutes.
  • step (c) microcrystalline cellulose followed by the mixtures of (a) and (b) were loaded in a blender and mixed for 3 minutes, (d) the blend of step (c) was sifted through a #40 mesh screen, again reloaded into the blender and mixed for 10 minutes.
  • Lubrication Magnesium stearate (Previously sifted through a # 60 mesh screen) was added to the blend of step (d) and mixed for 5 minutes.
  • Compression The lubricated blend was compressed into tablets using suitable punch and die set.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition pharmaceutique solide comprenant (a) un diurétique ; et (b) un inhibiteur de l'enzyme de conversion de l'angiotensine (ECA), environ 100 % des tailles de particules du diurétique passant dans un tamis présentant un maillage standard de 60#.
PCT/IB2007/003705 2006-12-01 2007-11-30 Compositions pharmaceutiques Ceased WO2008068577A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1987/MUM/2006 2006-12-01
IN1987MU2006 2006-12-01
US87387506P 2006-12-08 2006-12-08
US60/873,875 2006-12-08

Publications (2)

Publication Number Publication Date
WO2008068577A2 true WO2008068577A2 (fr) 2008-06-12
WO2008068577A3 WO2008068577A3 (fr) 2009-04-23

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ID=39492669

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2007/003705 Ceased WO2008068577A2 (fr) 2006-12-01 2007-11-30 Compositions pharmaceutiques

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WO (1) WO2008068577A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ309820B6 (cs) * 2021-04-23 2023-11-08 Pro.Med.Cs Praha A.S. Způsob přípravy pevné lékové formy obsahující kompozici s nízkým obsahem účinné látky

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2771010B1 (fr) * 1997-11-19 2003-08-15 Adir Utilisation d'une combinaison d'un inhibiteur de l'enzyme de conversion de l'angiotensine et d'un diuretique pour le traitement des desordres microcirculatoires
LT1729739T (lt) * 2004-03-29 2016-11-10 Les Laboratoires Servier Kietos farmacinės kompozicijos gamybos būdas

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ309820B6 (cs) * 2021-04-23 2023-11-08 Pro.Med.Cs Praha A.S. Způsob přípravy pevné lékové formy obsahující kompozici s nízkým obsahem účinné látky

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Publication number Publication date
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