WO2010030201A2 - Composition pharmaceutique orale stable contenant un sel pharmaceutiquement acceptable de l'acide [(e)-7-[4-(4-fluorophényl)-6-isopropyl-2-[méthyl(méthylsulfonyl)amino]pyrimidin-5-yl]-(3r,5s)-3,5-dihydroxyhept-6-énoïque - Google Patents

Composition pharmaceutique orale stable contenant un sel pharmaceutiquement acceptable de l'acide [(e)-7-[4-(4-fluorophényl)-6-isopropyl-2-[méthyl(méthylsulfonyl)amino]pyrimidin-5-yl]-(3r,5s)-3,5-dihydroxyhept-6-énoïque Download PDF

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Publication number
WO2010030201A2
WO2010030201A2 PCT/PL2009/000084 PL2009000084W WO2010030201A2 WO 2010030201 A2 WO2010030201 A2 WO 2010030201A2 PL 2009000084 W PL2009000084 W PL 2009000084W WO 2010030201 A2 WO2010030201 A2 WO 2010030201A2
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
oral pharmaceutical
composition according
stable oral
magnesium
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/PL2009/000084
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English (en)
Other versions
WO2010030201A3 (fr
Inventor
Anna Madanecka
Aleksandra Tukalska
Magdalena Grabowska
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Zaklady Farmaceutyczne Polpharma SA
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Zaklady Farmaceutyczne Polpharma SA
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Publication of WO2010030201A2 publication Critical patent/WO2010030201A2/fr
Publication of WO2010030201A3 publication Critical patent/WO2010030201A3/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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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

Definitions

  • Stable oral pharmaceutical composition containing a pharmaceutically acceptable salt of [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-
  • the present invention relates to a stable oral pharmaceutical composition containing the pharmaceutically acceptable calcium salt of [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3R, 5S) - 3,5 dihydroxyhept-6-enoic acid.
  • 6-heptenoic acids substituted at the 7-position are active components of pharmaceutical compositions, there arises the problem of maintaining stability of the pharmaceutical composition. Therefore various methods are applied to preserve stability of the pharmaceutical composition.
  • salts of 3,5-dihydroxy-6-heptenoic acid substituted at the 7-position are susceptible to degradation under influence of pH below about 8, light or heat.
  • Pharmaceutical compositions containing these salts require the presence of an alkaline agent that is capable of maintain a pH of at least 8.
  • an alkaline agent that is capable of maintain a pH of at least 8.
  • composition in which the active ingredient is an amorphous form of the calcium salt of [(E)7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5- yl] (3 R, 5S) - 3,5-dihydroxyhept-6-enoic acid.
  • the high purity calcium salt of [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3R, 5S) - 3,5-dihydroxyhept-6-enoic acid is obtained through conversion of crystalline ammonium salt of this acid. Subsequently, the calcium salt obtained by this method is used to produce the pharmaceutical composition.
  • the many excipients that might be used in the production of a pharmaceutical composition include calcium carbonate, magnesium carbonate or magnesium oxide, used as fillers, magnesium aluminosilicate as an example of a binder or magnesium trisilicate being an lubricant.
  • the aim of the present invention is development of a new stable oral pharmaceutical composition containing a pharmaceutically acceptable salt of [(E)-7-[4- (4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3R, 5S) - 3,5-dihydroxyhept-6-enoic acid, especially a calcium salt of [(E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3R, 5S) - 3,5-dihydroxyhept-6-enoic acid.
  • compositions containing the calcium salt of [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino] pyrimidine-5-yl] (3R, 5S) - 3,5-dihydroxyhept-6-enoic acid can be stabilized by substances like magnesium carbonate, magnesium oxide, magnesium trisilicate, magnesium aluminosilicate and calcium lactate.
  • particularly preferable agents that stabilize pharmaceutical compositions containing calcium salt of [(E)-7-[4-(4-fluorophenyl)-6- isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3R, 5S) - 3,5-dihydroxyhept-6-enoic acid are magnesium carbonate and magnesium oxide.
  • magnesium carbonate used as a stabiliser
  • an increase the amount of the magnesium carbonate in a pharmaceutical composition results in significant increase the stability of the pharmaceutical composition, with a maintain the disintegration time set for this type of pharmaceutical composition.
  • the proportion of the amount of magnesium carbonate to that of the calcium salt of [(E)-7- [4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidine-5- yl] (3R, 5S) - 3,5-dihydroxyhept-6-enoic acid is within the range 0.75:1 up to 3:1.
  • the most preferable proportion of magnesium carbonate to the calcium salt of [(E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3R, 5S) - 3,5-dihydroxyhept-6-enoic acid is 2:1.
  • a single stabilizer or a mixture of stabilizers chosen from the group comprising magnesium carbonate, magnesium oxide, magnesium trisilicate, magnesium aluminosilicate and calcium lactate, with the whole content of stabilizing agents preferably within the range of 5-20% by weight of the tablet core.
  • composition according to the present invention containing the calcium salt of [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-
  • pharmaceutically acceptable fillers were chosen from the group comprising lactose, microcrystalline cellulose, and calcium hydrogen phosphate. Lactose monohydrate or microcrystalline cellulose are preferably used as fillers in the pharmaceutical composition of the invention.
  • the content of a filler or a mixture of two or more fillers ranges from 70 to 90% by weight of the tablet core.
  • compositions according to the present invention pharmaceutically acceptable disintegrants were chosen from the group comprising crospovidone, sodium croscarmellose and sodium carboxymethyl starch.
  • the preferable disintegrant in the pharmaceutical composition of the invention is crospovidone.
  • the content of a disintegrant or a mixture of two or more disintegrants is preferably 5% by weight of the tablet core.
  • pharmaceutically acceptable lubricants were chosen from the group comprising magnesium stearate, calcium stearate, stearic acid and stearyl fumarate.
  • the preferable lubricant in the pharmaceutical composition of the invention is magnesium stearate.
  • the content of a lubricant or a mixture of two or more lubricants is preferably 1.5% by weight of the tablet core.
  • the pharmaceutically acceptable coating agent used is known under the trade name of Opadry®.
  • the coating contains hypromelose, lactose monohydrate, titanium dioxide, iron oxide, polyethylene glycol, and triacetin and is known under the trade name of Opadry® II.
  • composition of the invention has a solid form and is intended for oral administration as a tablet or capsule, preferably a tablet.
  • the invention ensures the stable oral pharmaceutical composition containing the pharmaceutically acceptable calcium salt of [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3R, 5S) - 3,5-dihydroxyhept-6-enoic acid, which is characterized by advantageous composition stability properties and a simple way of preparation.
  • the invention is illustrated with the following examples that do not limit the invention in any way.
  • compositions where the active ingredient is calcium salt of [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3R, 5S) - 3,5-dihydroxyhept-6-enoic acid.
  • Specific doses (5 mg, 10 mg, 10 mg, 40 mg) of the composition are proportional to each other, Le. they are prepared from the same tablet mass.
  • Preparation procedure of the tablet core for examples 1-6 is as follows: a) the active ingredient, fillers, disintegrants and stabilizers are sieved; b) the sieved ingredients are mixed in the stirrer; c) lubricants are added to the mixture obtained in point b) and the mixture is stirred until a uniform tablet mass is obtained; d) the tablet mass obtained in point c) is subjected to tabletting in a rotary tablet press. AU percentages are expressed by weight of the tablet core.
  • Tablet cores obtained in examples 1-6 are covered with a layer of coating.
  • the coating is performed in a coating machine loaded with uncoated tablet cores prepared according to the procedure described above, which are subsequently coated with aqueous solution of a mixture of hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol, triacetin, lactose monohydrate, and iron oxide - commercially available under the trade name of Opadry ® II.
  • the coating accounts for about 3% of the tablet core weight.
  • Coated tablets in aluminum blister packs were subjected to accelerated stability tests. They were seasoned for one month at 50 0 C and relative humidity 75%.
  • a comparative pharmaceutical composition was prepared, where the stabilizer was tribasic calcium phosphate disclosed in the patent application No. WO 01/54669 (composition of the original preparation CRESTOR ® ). The amount of tribasic calcium phosphate in the composition was the same as the amount of the stabilizer used in respective examples.
  • the stability test of the pharmaceutical composition comprised the determination of impurities level (main decomposition products of salts of [(E)-7- [4-(4-fluorophenyl)-6- isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3R, 5S) -
  • 3,5-dihydroxyhept-6-enoic acid are diastereoisomer and lactone) .
  • magnesium oxide As a stabilizer, impurity 2 was not detected and total impurities decreased by half, which indicates that magnesium oxide particularly positively affects stability of the pharmaceutical composition.
  • magnesium trisilicate As a stabilizer, a similar level of impurities was observed as with the use of tribasic calcium phosphate as a stabilizer, which indicates that magnesium trisilicate has similar stabilizing properties to tribasic calcium phosphate.
  • the test revealed a similar amount of impurity 1 and a lower amount of impurity 2 than with the use of tribasic calcium phosphate as a stabilizer, which indicates that magnesium aluminosilicate has better stabilizing properties then tribasic calcium phosphate.
  • compositions containing the same stabilizing agents as those in examples 1-5 were prepared; their content in the tablet core was: - variant a) 5% - variant b) 20%.
  • composition of the original preparation CRESTOR ® was also prepared in which the stabilizing agent was tribasic calcium phosphate disclosed in patent application No. WO 01/54669 (composition of the original preparation CRESTOR ® ).
  • Coated tablets in aluminum blister packs (AVPVC foil) were subjected to accelerated stability tests. They were seasoned for 9 days at 50 0 C and relative humidity 75%.
  • the obtained results indicate that among all the stabilizing agents the largest influence on the stability of the pharmaceutical composition depending on the amount of the stabilizer is exerted by magnesium carbonate.
  • 20% of magnesium carbonate by weight of the tablet core
  • total impurities were almost 2.5 times lower than in the case of using 5% of magnesium carbonate (by weight of the tablet core).
  • magnesium carbonate is compared with tribasic calcium phosphate (both substances used in the amount of 20% by weight of the tablet core), total impurities were almost 4 times lower. This indicates that magnesium carbonate particularly positively influences the stability of the pharmaceutical composition.

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

Abstract

La présente invention concerne une composition pharmaceutique orale stable contenant, en tant que principe actif, de l'acide [(E)-7-[4-(4-fluorophényl)-6-isopropyl-2-[méthyl(méthylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-énoïque ou un sel pharmaceutiquement acceptable de celui-ci, ainsi qu'un ou plusieurs agents diluants, un ou plusieurs agents désintégrants, un ou plusieurs agents lubrifiants, des agents d'enrobage, et un ou plusieurs agents stabilisants.
PCT/PL2009/000084 2008-09-09 2009-09-02 Composition pharmaceutique orale stable contenant un sel pharmaceutiquement acceptable de l'acide [(e)-7-[4-(4-fluorophényl)-6-isopropyl-2-[méthyl(méthylsulfonyl)amino]pyrimidin-5-yl]-(3r,5s)-3,5-dihydroxyhept-6-énoïque Ceased WO2010030201A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP-386051 2008-09-09
PL386051A PL386051A1 (pl) 2008-09-09 2008-09-09 Stabilna doustna kompozycja farmaceutyczna zawierająca farmaceutycznie dopuszczalną sól kwsu [(E)-7-[4-(4-fluorofenylo)-6-izopropylo-2-[metylo(metylosulfonylo)amino]pirymidyn-5-ylo] (3R,5S)-3,5-dihydroksyhept-6-enowego

Publications (2)

Publication Number Publication Date
WO2010030201A2 true WO2010030201A2 (fr) 2010-03-18
WO2010030201A3 WO2010030201A3 (fr) 2010-07-22

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PCT/PL2009/000084 Ceased WO2010030201A2 (fr) 2008-09-09 2009-09-02 Composition pharmaceutique orale stable contenant un sel pharmaceutiquement acceptable de l'acide [(e)-7-[4-(4-fluorophényl)-6-isopropyl-2-[méthyl(méthylsulfonyl)amino]pyrimidin-5-yl]-(3r,5s)-3,5-dihydroxyhept-6-énoïque

Country Status (2)

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PL (1) PL386051A1 (fr)
WO (1) WO2010030201A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010140992A1 (fr) * 2009-06-03 2010-12-09 Mahmut Bilgic Compositions pharmaceutiques stables contenant du calcium rosuvastatine
WO2012064306A3 (fr) * 2010-11-11 2012-08-09 Bilgic Mahmut Formulations effervescentes de rosuvastatine
US20140179712A1 (en) * 2012-12-21 2014-06-26 Astrazeneca Ab Pharmaceutical formulation of n-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl]benzamide
JP2016135782A (ja) * 2015-01-20 2016-07-28 日本ケミファ株式会社 ロスバスタチンカルシウム製剤及びレーザー照射によるフィルムコーティング錠の印字方法
US10398694B2 (en) 2014-11-11 2019-09-03 Shionogi & Co., Ltd. Multi-layered tablet containing drug unstable to light

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5180589A (en) * 1988-03-31 1993-01-19 E. R. Squibb & Sons, Inc. Pravastatin pharmaceuatical compositions having good stability
GB0001621D0 (en) * 2000-01-26 2000-03-15 Astrazeneca Ab Pharmaceutical compositions
WO2007071357A2 (fr) * 2005-12-20 2007-06-28 Lek Pharmaceuticals D.D. Composition pharmaceutique
HU227610B1 (en) * 2006-09-18 2011-09-28 Richter Gedeon Nyrt Pharmaceutical compositions containing rosuvastatin potassium
WO2009112870A1 (fr) * 2008-03-11 2009-09-17 Belupo-Lijekovi I Kozmetika D.D. Composition pharmaceutique comprenant de la rosuvastatine calcique et de l'hydroxyde de carbonate de magnésium pentahydraté comme stabilisant

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010140992A1 (fr) * 2009-06-03 2010-12-09 Mahmut Bilgic Compositions pharmaceutiques stables contenant du calcium rosuvastatine
WO2012064306A3 (fr) * 2010-11-11 2012-08-09 Bilgic Mahmut Formulations effervescentes de rosuvastatine
US20140179712A1 (en) * 2012-12-21 2014-06-26 Astrazeneca Ab Pharmaceutical formulation of n-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl]benzamide
JP2016503782A (ja) * 2012-12-21 2016-02-08 アストラゼネカ アクチボラグ Ｎ−［５−［２−（３，５−ジメトキシフェニル）エチル］−２ｈ−ピラゾール−３−イル］−４−［（３ｒ，５ｓ）−３，５−ジメチルピペラジン−１−イル］ベンズアミドの医薬製剤
US10420764B2 (en) 2012-12-21 2019-09-24 Astrazeneca Ab Pharmaceutical formulation of N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-YL]-4-[(3R,5S)-3 ,5-dimethylpiperazin-1-YL] benzamide
US10398694B2 (en) 2014-11-11 2019-09-03 Shionogi & Co., Ltd. Multi-layered tablet containing drug unstable to light
JP2016135782A (ja) * 2015-01-20 2016-07-28 日本ケミファ株式会社 ロスバスタチンカルシウム製剤及びレーザー照射によるフィルムコーティング錠の印字方法

Also Published As

Publication number Publication date
WO2010030201A3 (fr) 2010-07-22
PL386051A1 (pl) 2010-03-15

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