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WO2008133537A1 - Composition pharmaceutique à stabilité améliorée comprenant un inhibiteur de l'ace ou un de ses sels pharmacocompatibles, et leurs méthodes de fabrication - Google Patents

Composition pharmaceutique à stabilité améliorée comprenant un inhibiteur de l'ace ou un de ses sels pharmacocompatibles, et leurs méthodes de fabrication Download PDF

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Publication number
WO2008133537A1
WO2008133537A1 PCT/PL2008/000031 PL2008000031W WO2008133537A1 WO 2008133537 A1 WO2008133537 A1 WO 2008133537A1 PL 2008000031 W PL2008000031 W PL 2008000031W WO 2008133537 A1 WO2008133537 A1 WO 2008133537A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
group
manufacturing
pharmaceutically acceptable
Prior art date
Application number
PCT/PL2008/000031
Other languages
English (en)
Inventor
Anna Kaminska
Jaroslaw Mazgalski
Original Assignee
Zaklady Farmaceutyczne Polpharma Sa
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 Zaklady Farmaceutyczne Polpharma Sa filed Critical Zaklady Farmaceutyczne Polpharma Sa
Priority to EP08753858A priority Critical patent/EP2150240A1/fr
Publication of WO2008133537A1 publication Critical patent/WO2008133537A1/fr

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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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • composition exhibiting improved stability comprising ACE inhibitor or pharmaceutically acceptable salt thereof and method for manufacturing thereof.
  • the subject of the invention includes a pharmaceutical composition exhibiting improved stability comprising ACE inhibitor or pharmaceutically acceptable salt thereof and method for manufacturing thereof.
  • Inhibitors of angiotensin convertase belong to a group of compounds used in the treatment of cardiovascular system and, particularly, arterial hypertension.
  • the group of these compounds consists of, for example, perindopril, quinapril, ramipril.
  • These compounds were first disclosed in patents EP 049658B, EP 049605B and EP 079022B.
  • the problem associated with ACE inhibitors is that they are prone to degradation process due to cyclization, hydrolysis or oxidation. Being a degradation product of ACE inhibitors, the form of diketopiperazine produced in the cyclization process may be of particular disadvantage due to its toxicity.
  • the prior art disclosed various solutions to this problem.
  • the patent EP 280999B describes a pharmaceutical composition comprising ACE inhibitor as the active ingredient whereby the instability problem was overcome by using alkaline earth metal carbonate in combination with saccharide.
  • the method for manufacturing of the composition includes wet granulation and tableting of the obtained granulate.
  • the patent EP 108393 IB describes a pharmaceutical composition comprising ACE inhibitor as the active ingredient whereby the instability problem was overcome by using magnesium oxide in combination with a suitable amount of saccharide.
  • the method for manufacturing of the composition includes wet granulation and tableting of the obtained granulate.
  • the patent EP 468929B describes a pharmaceutical composition comprising a compound prone to degradation process as the active ingredient, in particular ACE inhibitor stabilized by a hydrochloric acid donor selected from among e.g. glycine hydrochloride or glutamic acid hydrochloride.
  • the international patent application WO 2005/094793 described the method for manufacturing of the pharmaceutical composition comprising perindopril, or the salt thereof, consisting in the dry mixing of excipients mixture with at least one inorganic carbonate, and dry processing of the mixture obtained.
  • the objective of the present invention is to develop a new, pharmaceutical composition exhibiting improved stability comprising inhibitor of angiotensin convertase (ACE) or pharmaceutically acceptable salt thereof as the active ingredient.
  • ACE angiotensin convertase
  • the pharmaceutical composition according to the present invention preferably comprises alkali copolymer of butyl methacrylate in the form of a powder, known under the trade name as Eudragit E PO. Additionally, the weight ratio of the content of alkali copolymer of butyl methacrylate to the content of the active ingredient should preferably be within 1 :2.5 to 2: 1.
  • the pharmaceutical composition according to the present invention preferably comprises ACE inhibitor selected from a group consisting of perindopril, quinapril, ramipril or combination thereof.
  • the pharmaceutical composition according to the present invention preferably comprises the pharmaceutically acceptable excipients selected from a group consisting of fillers, disintegrants, glidants and/or lubricants.
  • the pharmaceutical composition according to the present invention preferably takes the form of a tablet, capsule or powder for oral use.
  • the pharmaceutical composition according to the present invention preferably comprises fillers selected from a group consisting of lactose, microcrystalline cellulose, powdered cellulose, microcrystalline cellulose co- processed with silica colloidal, sucrose, dextrose, fructose, dibasic calcium phosphate, tribasic calcium phosphate, starch and modified starch.
  • the pharmaceutical composition according to the present invention preferably comprises disintegrants selected from a group consisting of croscarmellose sodium, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium starch glycolate, sodium alginate, starch, modified starch, microcrystalline cellulose and powdered cellulose.
  • the pharmaceutical composition according to the present invention preferably comprises glidants selected from a group consisting of colloidal anhydrous silica, talk, magnesium stearate, starch.
  • the pharmaceutical composition according to the present invention preferably comprises lubricants selected from a group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, glycerol behenate, glycerol monostearate, glycerol palmitostearate, polyethylene glycol, stearic acid.
  • lubricants selected from a group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, glycerol behenate, glycerol monostearate, glycerol palmitostearate, polyethylene glycol, stearic acid.
  • the pharmaceutical composition according to the present invention may be comprised of the pharmaceutically acceptable excipients which simultaneously act as fillers, disintegrants, glidants and/or lubricants.
  • the invention includes a method for manufacturing of a pharmaceutical composition exhibiting improved stability comprising inhibitor of angiotensin convertase (ACE) or pharmaceutically acceptable salt thereof as the active ingredient.
  • ACE angiotensin convertase
  • the method for manufacturing of the pharmaceutical composition according to the present invention consists in the mixing of the active ingredient, alkali copolymer of butyl methacrylate and pharmaceutically acceptable excipients in appropriate weight ratio, and, subsequently, tableting of the mixture using direct tableting method.
  • the method for manufacturing of the pharmaceutical composition according to the present invention is preferably carried out using alkali copolymer of butyl methacrylate in the form of a powder. Additionally, the weight ratio of the content of alkali copolymer of butyl methacrylate to the content of the active ingredient in the pharmaceutical composition should preferably be within 1 :2.5 to 2:1.
  • the method for manufacturing of the pharmaceutical composition according to the present invention is carried out using ACE inhibitor selected from a group consisting of perindopril, quinapril, ramipril or combination thereof.
  • the method for manufacturing of the pharmaceutical composition according to the present invention is carried out using the substances selected from a group consisting of fillers, disintegrants, glidants and lubricants as pharmaceutically acceptable excipients.
  • the method for manufacturing of the pharmaceutical composition according to the present invention is carried out preferably using the fillers selected from a group consisting of lactose, microcrystalline cellulose, powdered cellulose, microcrystalline cellulose co-processed with silica colloidal, sucrose, dextrose, fructose, dibasic calcium phosphate, tribasic calcium phosphate, starch and modified starch.
  • the fillers selected from a group consisting of lactose, microcrystalline cellulose, powdered cellulose, microcrystalline cellulose co-processed with silica colloidal, sucrose, dextrose, fructose, dibasic calcium phosphate, tribasic calcium phosphate, starch and modified starch.
  • the method for manufacturing of the pharmaceutical composition according to the present invention is carried out preferably using the disintegrants selected from a group consisting of croscarmellose sodium, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium starch glycolate, sodium alginate, starch, modified starch, microcrystalline cellulose and powdered cellulose.
  • the disintegrants selected from a group consisting of croscarmellose sodium, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium starch glycolate, sodium alginate, starch, modified starch, microcrystalline cellulose and powdered cellulose.
  • the method for manufacturing of the pharmaceutical composition according to the present invention is carried out preferably using the glidants selected from a group consisting of colloidal anhydrous silica, talk, magnesium stearate, starch.
  • the method for manufacturing of the pharmaceutical composition according to the present invention is carried out preferably using the lubricants selected from a group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, glycerol behenate, glycerol monostearate, glycerol palmitostearate, polyethylene glycol, stearic acid.
  • the method for manufacturing of the pharmaceutical composition according to the present invention is carried out preferably using the pharmaceutically acceptable excipients which simultaneously act as fillers, disintegrants, glidants and/or lubricants.
  • the weighed quantities of perindopril ter/-erbumine, micronised crospovidone, Eudragit E PO, mannitol are mixed for about 30 min. Magnesium stearate is added to the obtained mixture, and the contents are thoroughly mixed.
  • the resulting tablet mass is tableted using direct tableting method using Korsch XL200 rotary tablet press. The resulting tablets have a weight of 180 mg.
  • Magnesium stearate 2.7 Procedure is identical to that in Example 1.
  • the resulting tablets have a weight of 180 mg.
  • Example 2 Procedure is identical to that in Example 1 except that micronised crospovidone is replaced with maize starch.
  • the resulting tablets have a weight of 180 mg.
  • the resulting tablets of the examples 1, 2, 3 and 4 were stored for 3 weeks at 50 0 C and 75% relative humidity.
  • the same storage conditions are applied to Prestarium ® tablets - currently available on the market - containing 8 mg of perindopril tert-erbumine and excipients such as lactose monohydrate, colloidal anhydrous silica, lake and magnesium stearate. All of the tablets are tested for impurities content using an analytical method by high performance liquid chromatography (HPLC). The test is performed for storage intervals of 0, 1 and 3 weeks.
  • the tablets of the example 1 are stored for 12 months at 30 0 C and 60% relative humidity.
  • Prestarium ® tablets - currently available on the market - containing 8 mg of perindopril tert-erbumine and excipients such as lactose monohydrate, colloidal anhydrous silica, lake and magnesium stearate were stored under the same storage conditions. Both batches of the tablets are tested for impurities content using an analytical method by high performance liquid chromatography (HPLC). The test is performed for storage intervals of 0, 3, 6 and 12 months. The results for the content of total impurities and a separately determined form of perindopril diketopiperazine, also known as impurity F, are given in the table below.
  • the pharmaceutical composition according to the invention is less toxic for patients.
  • the pharmaceutical composition according to the invention can be considered to be of practical use for the entire group of ACE inhibitors, preferably perindopril, quinapril and ramipril.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur une composition pharmaceutique à stabilité améliorée comprenant: un inhibiteur de l'ACE ou l'un de ses sels pharmacocompatibles comme principe actif, un copolymère alcalin de méthacrylate de butyle, et des excipients pharmacocompatibles. L'invention porte également une méthode de fabrication de la composition pharmaceutique à stabilité améliorée comprenant l'inhibiteur d'ACE comme principe actif, consistant: à mélanger le principe actif, le copolymère alcalin de méthacrylate de butyle et les excipients pharmacocompatibles dans des rapports pondéraux appropriés, puis à former des comprimés par la méthode directe.
PCT/PL2008/000031 2007-04-27 2008-04-24 Composition pharmaceutique à stabilité améliorée comprenant un inhibiteur de l'ace ou un de ses sels pharmacocompatibles, et leurs méthodes de fabrication WO2008133537A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08753858A EP2150240A1 (fr) 2007-04-27 2008-04-24 Composition pharmaceutique à stabilité améliorée comprenant un inhibiteur de l'ace ou un de ses sels pharmacocompatibles, et leurs méthodes de fabrication

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL382311A PL382311A1 (pl) 2007-04-27 2007-04-27 Kompozycja farmaceutyczna o polepszonej stabilności zawierająca inhibitor acetylocholinoesterazy lub farmaceutycznie dopuszczalną jego sól oraz sposób jej wytwarzania
PLP.382311 2007-04-27

Publications (1)

Publication Number Publication Date
WO2008133537A1 true WO2008133537A1 (fr) 2008-11-06

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/PL2008/000031 WO2008133537A1 (fr) 2007-04-27 2008-04-24 Composition pharmaceutique à stabilité améliorée comprenant un inhibiteur de l'ace ou un de ses sels pharmacocompatibles, et leurs méthodes de fabrication

Country Status (3)

Country Link
EP (1) EP2150240A1 (fr)
PL (1) PL382311A1 (fr)
WO (1) WO2008133537A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011034513A1 (fr) 2009-08-17 2011-03-24 Mahmut Bilgic Granules à solubilité et stabilité améliorées

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5442008A (en) * 1987-11-24 1995-08-15 Hoechst Aktiengesellschaft Stabilized polymer film coated compounds and stabilized formulations in compressed from using same
WO2002089775A1 (fr) * 2001-05-09 2002-11-14 Ethypharm Granules enrobes a base d'inhibiteur de l'enzyme de conversion de l'angiotensine
US20050186274A1 (en) * 2004-02-20 2005-08-25 Boehringer Ingelheim International Gmbh Multilayer tablet
WO2007090721A1 (fr) * 2006-02-03 2007-08-16 Evonik Röhm Gmbh Compositions pharmaceutiques contenant des mélanges de polymères et d'agents actifs peu solubles dans l'eau

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5442008A (en) * 1987-11-24 1995-08-15 Hoechst Aktiengesellschaft Stabilized polymer film coated compounds and stabilized formulations in compressed from using same
WO2002089775A1 (fr) * 2001-05-09 2002-11-14 Ethypharm Granules enrobes a base d'inhibiteur de l'enzyme de conversion de l'angiotensine
US20050186274A1 (en) * 2004-02-20 2005-08-25 Boehringer Ingelheim International Gmbh Multilayer tablet
WO2007090721A1 (fr) * 2006-02-03 2007-08-16 Evonik Röhm Gmbh Compositions pharmaceutiques contenant des mélanges de polymères et d'agents actifs peu solubles dans l'eau

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011034513A1 (fr) 2009-08-17 2011-03-24 Mahmut Bilgic Granules à solubilité et stabilité améliorées

Also Published As

Publication number Publication date
EP2150240A1 (fr) 2010-02-10
PL382311A1 (pl) 2008-11-10

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