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WO2009091346A2 - Formulation pharmaceutique stable et procédés de préparation - Google Patents

Formulation pharmaceutique stable et procédés de préparation Download PDF

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Publication number
WO2009091346A2
WO2009091346A2 PCT/TR2009/000002 TR2009000002W WO2009091346A2 WO 2009091346 A2 WO2009091346 A2 WO 2009091346A2 TR 2009000002 W TR2009000002 W TR 2009000002W WO 2009091346 A2 WO2009091346 A2 WO 2009091346A2
Authority
WO
WIPO (PCT)
Prior art keywords
potassium
sodium
pharmaceutical composition
monovalent
cation
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/TR2009/000002
Other languages
English (en)
Other versions
WO2009091346A3 (fr
Inventor
Ramazan Sivasligil
Serap Odabasi
F . Bilgehan Perveli
Nalan Sarikas
Selen Ural
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.)
Bilim Ilac Sanayi Ticaret A S
Original Assignee
Bilim Ilac Sanayi Ticaret A S
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 Bilim Ilac Sanayi Ticaret A S filed Critical Bilim Ilac Sanayi Ticaret A S
Publication of WO2009091346A2 publication Critical patent/WO2009091346A2/fr
Publication of WO2009091346A3 publication Critical patent/WO2009091346A3/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

Definitions

  • the present invention relates to pharmaceutical compositions and more particularly to pharmaceutical composition containing bis[(E) - 7 - [4 - ( 4 - fluorophenyl)- 6 - isopropyl - 2 - [ methyl ( methylsulfonyl) amino] pyrimidin - 5 - yl ] - (3 R, 5S) - 3,5- dihydroxyhept - 6 - enoic acid] or pharmaceutically acceptable salt thereof ( and referred to hereinafter as " the Formula I "), in particular the sodium and calcium salts, and especially the calcium salt, bis [( E) - 7 - [4 - (4 - fluorophenyl) - 6 - isopropyl - 2 - [methyl( methylsulfonyl ) amino] pyrimidin - 5 - yl] - ( 3 R, 5 S) - 3,5 - dihyroxyhept - 6 - enoic acid] calcium salt ( of the Formula I
  • the Formula I is disclosed as and inhibitor of 3 - dihyroxy - 3 methylglutaryl CoA reductase (HMG Co A reductase ) in European Patent Application, Publication No. 051471 and Bioorganic and Medicinal Chemistry, (1997), 5 (2), 437 - 444 and is useful in treatment of hypercholesterolemia, hyperlipidproteinemia and atherosclerosis.
  • Pharmaceuticals formulations of HMG CoA reductase inhibitors eg. Atorvastatin,
  • EP 1 148 872 uses different kinds of buffering agent to stabilize the pharmaceutical compositions of HMG CoA reductase inhibitors, and adjust the pH range is between 7-11.
  • the invention of patent EP 1 223 918, Formula I comprises a stable pharmaceutical composition comprising the Agent and tribasic phosphate salt in which the cation is multivalent as stabilizing agent.
  • Formula I is obtained by using the methods of chemical syntesis which is a white to off-white amorphous powder. It is sparingly soluble in water and methanol, and slightly soluble in ethanol. It is a hydrophilic compound with a partition cofficients is 0.13 (octanol/water) at pH of 7.0.
  • statins have bad flow rate and compressibility.
  • Formula I has bad flow rate and compressibility characteristics as other statins.
  • the present invention aims that formulating Formula I into a pharmaceutical composition which has good flow properties, homogeneous and compressible.
  • the Formula I shows polymorphism which has different crystalline forms and amorphous form.
  • compositions mentioned in this invention and preperation methods of these formulations enclose all forms polymorphs, solvates and pharmaceutically acceptable salts of Formula I, especially enclose stable without degradation pharmaceutical formulations of amorphous form of Formula I with adequate storage life.
  • This present invention comprises all polymorphic forms of Formula I and especially for amorphous form since it's hard to formulate amorphous form into a pharmaceutical composition.
  • a problem associated with the Formula I is that it undergoes degradation under certain conditions. This makes it difficult to formulate the product and provide a pharmaceutical composition with adequate storage life.
  • the major degradation products formed are the corresponding (3R, 5S) lactone (hereinafter referred to as “the lactone”), and related (3R,5R) (hereinafter referred to as "anti”). If this degradation happens drug product will not be efficate and patients will not be cured. It is therefore important to find a pharmaceutical composition of the Formula I which remains stable over a prolonged period. It is also preferable that such a composition has a good flow rate to assist processing into until dosage forms for oral administration, for example into tablets, and good disintegration and dissolution characteristics when processed into tablets are of a convenient size for ease of administration for all strengths of the drug product.
  • formulations require the presence of an alkaline medium (such as a carbonate or bicarbonate) capable of imparting a pH of at least 8 to an aqueous solution or dispersion of the composition.
  • an alkaline medium such as a carbonate or bicarbonate
  • a first aspect of the invention comprises a stable pharmaceutical composition comprising Formula I and the buffering agent in which the cation is monovalent.
  • a second aspect of the invention comprises a stable pharmaceutical composition comprising Formula I and the use of one or more buffering agents in which the cation is monovalent.
  • the present invention encloses buffering agents in which the cation is monovalent which are described in Remington: The Science and Practice of Pharmacy 20 th Edition (2000) University of Sciences in Philadelphia; USP (United States Pharmacopeia) 30-NF25; BP (British Pharmacopeia) 2007 ve Handbook of Pharmaceuticals Excipients 5 th Edition (2006) The Pharmaceutical Press and The American Pharmacists Association.
  • Buffering agents in which the cation is monovalent can be exemplified as citrate (anhydrous and/or hydrate), carbonate, bicarbonate, acetate, tribasic phosphate, dibasic phosphate, monobasic phosphate, hydroxide, borate salts without limiting the present invention.
  • the ratio of total amount of buffering agent to Formula I in the pharmaceutical composition is for example within the range of 1:70 to 70:1 by weight, for example within the range of 1:45 to 45:1 by weight, such as 1:10 to 10:1 by weight, more particularly 1:3 to 3:1 by weight.
  • the pharmaceutical composition of the present invention is formulated into an oral dosage form, such as a tablet.
  • a further aspect of the invention comprises a pharmaceutical composition of Formula I, one or more buffering agent in which the cation is monovalent, one or more fillers, one or more binders, one or more disintegrants and/or one or more lubricants.
  • a further aspect of the invention comprises manufacturing of the pharmaceutical composition and related processes steps for this production to produce the pharmaceutical composition for oral administration comprising Formula I, one or more buffering agent in which the cation is monovalent, one or more fillers, one or more binders, one or more disintegrants, one or more lubricants and/or one or more glidants.
  • the present invention encloses fillers which are included in Remington: The Science and Practice of Pharmacy 20 th Edition (2000) University of Sciences in Philadelphia; USP
  • Suitable fillers include, for example; lactose, sugar, starch, modified starch, mannitol, sorbitol, anorganic salts, cellulose derivatives (eg microcrystalline cellulose, cellulose) other filler materials which are used with cellulose derivatives.(eg the mixture of lactose and microcrystalline cellulose is called Cellactose®).
  • the present invention encloses binders which are included in Remington: The Science and Practice of Pharmacy 20 th Edition (2000) University of Sciences in Philadelphia; USP (United States Pharmacopeia) 30-NF25; BP (British Pharmacopeia) 2007 ve Handbook of Pharmaceuticals Excipients 5 th Edition (2006) The Pharmaceutical Pres and The American Pharmacists Association.
  • Suitable binders include, for example, polyvinylpyrrolidone, lactose, starchs, modified starchs, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, copolyvidone, gelatin and sodium alginate.
  • the present invention encloses disintegrants which are included in Remington: The
  • Suitable disintegrants include, for example, crospovidone, crosscarmellose sodium, polyvinylpyrorolidone, sodium starch glycollate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose.
  • the present invention encloses lubricants which are included in Remington: The
  • Suitable lubricants include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycols and sodium stearyl fumarate.
  • Formula I will be present in an amount within the range of 1 to 50 %, and preferably from 1 to 20 % (especially 3 to 15 %) by weight of the composition.
  • the buffering agent or the total amount of buffering agents which the cation is monovalent will be present in an amount within the range of 1 to 40 %, such as 1 to 20 % and particularly 5 to 15 % by weight.
  • fillers will be presented in amount of 20 to 80 % by weight.
  • binders will be presented in amount of 20 to 80 % by weight.
  • disntegrants will be presented in amount of 0.5 to 20 % by weight.
  • lubricants will be presented in amount of 0.1 to 5 %, and especially 0.5 to 2 % by weight.
  • the pharmaceutical composition of the invention may be prepared, using standard techniques and manufacturing processes generally known in the art, for example by dry blending the components.
  • Formula I one or more buffering agent in which the cation is monovalent, one or more fillers, one or more binders and one or more disintegrants, as well as other additional excipients if desired are blended together.
  • the components of the blend prior the blending, or the blend itself, may be passed through a mesh screen, 400 - 1000 ⁇ m mesh screen.
  • a lubricant which may also be screened, is then added to the blend and blending continued until a homogeneous mixture is obtained.
  • the mixture is then compressed into tablets.
  • a wet granulation technique can be employed.
  • the Formula I one or more buffering agents in which the cation is monovalent, one or more fillers, one or more binders and a portion of a disintegrant, as well as other additional excipients if desired, are blended together, for example by using granulator, and the powder blend is granulated with a some volume of purified water and/or ethanol, wet granules may be screened before drying or can be dried wihthout screening. Oven or fluid bed dryer can be used for drying processes. Granulate is dried and passed through a mill. The remainder of the disintegrant and a lubricant are added to the milled granulation and after blending the resultant homogeneous mixture is compressed into tablets.
  • Formula I In an another manufacturing technique; Formula I, one or more buffering agents in which the cation is monovalent, one or more fillers, one or more binders, one or more disintegrants and other excipients if desired are put into fluid bed granulator and granulated wiht a some volume of purified water and/or ethanol and dried at the same time. Dry granules are sieved; remainder of disintegrants, lublicants is added. Powder blend is mixed until homogeneous mixture is obtained then tablets are pressed.
  • a tablet coating may then be applied, for example by spray-coating with a water- based film coating formulation.
  • the coating may comprise, for example, polyvinyl alcohol, cellulose derivates, lactose, hydroxypropyl methylcellulose, triacetin, titanium dioxide and ferric oxides. Coating ingredient combinations can be commercially available.
  • the coating may comprise, for example, 0.5 to 10 % by weight of the tablet composition, particularly 1 to 6 %, and preferably 2 to 5 %. Coatings containing ferric oxides are especially preferred as they reduce the rate of formation of photodegradation products of the Formula I.
  • the following pharmaceutical compositions, where in the Formula I is the calcium salt Formula I are to illustrate the invention without being limitative in any way.
  • Formula I microcrystalline cellulose, lactose (monohydrate), sodium carbonate and crospovidone are blended together for 10 minutes. If desired, the mixture may be screened through 800 ⁇ m screen. Magnesium stearate is passed through a 300 ⁇ m screen and added to the blend and the mixture is blended for a further 3 minutes. The resulting homogeneous mixture is compressed into tablets.
  • Tablets obtained from Example 1, formulation of Example 1 without Sodium carbonate, Formula I and Crestor® 40 mg film coated tablets including tribasic calcium phosphate as explained in EP 1 223 918 were kept in open and closed glass bottles at 40+2 0 C 75+5 % RH and 70 ⁇ 5°C conditions for four weeks. The samples were analyzed on weekly basis and the results of the 4 th week analysis are given below.
  • Example 4 th WEEK 70 ⁇ 5°C //OPEN After evaluation of impurity results of Example 1 tablets; the present invention formulation which includes sodium carbonate is stable formulation for 'lactone' and 'anti' degradation products.
  • Formula I microcrystalline cellulose, lactose (monohydrate), sodium bicarbonate and crospovidone are blended together for 10 minutes. If desired, the mixture may be screened through 800 ⁇ m screen. Magnesium stearate is passed through a 300 ⁇ m screen and added to the blend and the mixture is blended for a further 3 minutes. The resulting homogeneous mixture is compressed into tablets.
  • Formula I microcrystalline cellulose, lactose (monohydrate), sodium carbonate, sodium bicarbonate and crospovidone are blended together for 10 minutes. If desired, the mixture may be screened through 800 ⁇ m screen. Magnesium stearate is passed through a 300 ⁇ m screen and added to the blend and the mixture is blended for a further 3 minutes. The resulting homogeneous mixture is compressed into tablets.

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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)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques, en particulier un acide bis[(E)-7-[4-(4- fluorophényl-6-isopropyl-2-[méthyl(méthylsulfonyl)amino]pyrimidin-5-yl]-(3R, 5S)-3,5- dihydroxyhept-6-énoïque] ou des sels pharmaceutiquement acceptables (désignés ci-après par la formule I) de ce dernier, en particulier des sels de sodium et de calcium, caractérisées en ce qu'elles renferment un agent de tamponnage dans lequel le cation est monovalent.
PCT/TR2009/000002 2008-01-15 2009-01-14 Formulation pharmaceutique stable et procédés de préparation Ceased WO2009091346A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2008/00269 2008-01-15
TR2008/00269A TR200800269A2 (tr) 2008-01-15 2008-01-15 Stabil farmasötik formülasyon ve hazırlama yöntemleri

Publications (2)

Publication Number Publication Date
WO2009091346A2 true WO2009091346A2 (fr) 2009-07-23
WO2009091346A3 WO2009091346A3 (fr) 2009-10-01

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2009/000002 Ceased WO2009091346A2 (fr) 2008-01-15 2009-01-14 Formulation pharmaceutique stable et procédés de préparation

Country Status (2)

Country Link
TR (1) TR200800269A2 (fr)
WO (1) WO2009091346A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016079162A (ja) * 2014-10-14 2016-05-16 日本ジェネリック株式会社 安定なロスバスタチンカルシウム錠剤

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2648897B2 (ja) * 1991-07-01 1997-09-03 塩野義製薬株式会社 ピリミジン誘導体
US8987322B2 (en) * 2003-11-04 2015-03-24 Circ Pharma Research And Development Limited Pharmaceutical formulations for carrier-mediated transport statins and uses thereof
EP1905424A3 (fr) * 2006-02-02 2008-04-30 Ranbaxy Laboratories Limited Procédé de preparation d'une composition pharmaceutique comprenant des particules de statine stabilisées
HU227610B1 (en) * 2006-09-18 2011-09-28 Richter Gedeon Nyrt Pharmaceutical compositions containing rosuvastatin potassium
WO2008062476A2 (fr) * 2006-10-31 2008-05-29 Glenmark Pharmaceutical Limited Composition pharmaceutique comprenant de la rosuvastatine ou un sel de qualité pharmaceutique de cette substance

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016079162A (ja) * 2014-10-14 2016-05-16 日本ジェネリック株式会社 安定なロスバスタチンカルシウム錠剤

Also Published As

Publication number Publication date
WO2009091346A3 (fr) 2009-10-01
TR200800269A2 (tr) 2009-08-21

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