WO2010066687A2 - Compositions comprenant une statine stabilisée - Google Patents

Compositions comprenant une statine stabilisée Download PDF

Info

Publication number
WO2010066687A2
WO2010066687A2 PCT/EP2009/066546 EP2009066546W WO2010066687A2 WO 2010066687 A2 WO2010066687 A2 WO 2010066687A2 EP 2009066546 W EP2009066546 W EP 2009066546W WO 2010066687 A2 WO2010066687 A2 WO 2010066687A2
Authority
WO
WIPO (PCT)
Prior art keywords
statin
antioxidants
composition
solution
acid
Prior art date
Application number
PCT/EP2009/066546
Other languages
English (en)
Other versions
WO2010066687A3 (fr
Inventor
De Ben Lange
Den Ronald Uil
Original Assignee
Dsm Ip Assets B.V.
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 Dsm Ip Assets B.V. filed Critical Dsm Ip Assets B.V.
Publication of WO2010066687A2 publication Critical patent/WO2010066687A2/fr
Publication of WO2010066687A3 publication Critical patent/WO2010066687A3/fr

Links

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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to novel compositions comprising a statin and antioxidants and to a method for the preparation of such compositions.
  • Impurities can result from the production process itself but can also occur after isolation of the final product.
  • One particular type of impurity can occur both ways, namely the formation of oxidative degradation products.
  • Such unwanted impurities can occur readily in the class of statins, compounds that are useful as inhibitors of the enzyme 3- hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and are thus useful hypolipidemic and hypocholesterolemic agents.
  • HMG-CoA reductase 3- hydroxy-3-methylglutaryl-coenzyme A reductase
  • oxidative degradation of atorvastatin is known from WO 2006/008091 and the autooxidation of simvastatin has been described by G. B. Smith et al. (Tetrahedron (1993) 49, 4447-4462).
  • the present invention provides a method for isolating a statin comprising spray drying a solution of said statin in an alcohol or precipitating said statin from said solution characterized in that antioxidants are present in said solution or in that said antioxidants are added during said spray drying or during said precipitating. Furthermore there is provided a composition comprising a statin and 0.01 % to 1 % by weight of said composition of antioxidants which are a carbohydrate, a carotenoid, a flavonoid, an isoflavonoid, a hydroxyacid, a phenol, a polyphenol, a sulphite salt, a terpene alcohol, thiourea, an unsaturated acid or a vitamin.
  • statins such as atorvastatin, lovastatin, pravastatin, simvastatin and wuxistatin
  • isolation of the active pharmaceutical ingredients in the presence of small amounts of antioxidants resulted in products that can be isolated in the purity as required by governmental organizations and also retain this degree of purity for long periods of time, such as multiple years.
  • a method for isolating a statin in the presence of antioxidants is carried out by spray drying a solution of said statin in a solvent.
  • a solution of atorvastatin is subjected to spray drying in the presence of antioxidants.
  • Suitable antioxidants are carbohydrates, carotenoids, flavonoids and isoflavonoids, hydroxyacids, phenols, polyphenols, sulphite salts, terpene alcohols, thiourea or derivatives thereof, unsaturated acids and vitamins and derivatives thereof.
  • ascorbic acid ascorbyl palmitate, bis hydroxyanisole, butylated hydroxyanisole, butylated hydroxytoluene, ⁇ -carotene, ⁇ -carotene, ⁇ -carotene, caffeic acid, chlorogenic acid, cinnamic acid, citric acid, coumaric acid, cyanidin, delphinidin, 2,6-diisopropylphenol, 2,6-di-fert-butyl-4-methylphenol, ellagic acid, epicatechin, erythorbic acid, fumaric acid, gallic acid, geraniol, ⁇ -hydroxy ⁇ S ⁇ -tetramethylchroman ⁇ -carboxylic acid, kaempferol, lycopene, malvidin, mannitol, myricetin, peonidin, petunidin, proanthocyanidins, propyl galate,
  • atorvastatin is prepared as its calcium salt, i.e.,
  • compositionsd of statins and a single antioxidant have been reported in US 2003/220343, WO 2003/094923, US 2004/126423 and US 2007/202159.
  • preparation of compositions comprising a statin and two or more antioxidants is novel and furthermore it has now surprisingly been established that combinations of two or more antioxidants display antioxidative effects that surpass those of the individual components.
  • hydroxy acid and a phenol derivative such as for instance the combinations citric acid and bis hydroxyanisole, citric acid and butylated hydroxyanisole, citric acid and butylated hydroxytoluene, citric acid and 2,6-diisopropylphenol, citric acid and 2,6-di-tert-butyl-4- methylphenol, tartaric acid and bis hydroxyanisole, tartaric acid and butylated hydroxyanisole, tartaric acid and butylated hydroxytoluene, tartaric acid and 2,6-diisopropylphenol and tartaric acid and 2,6-di-tert-butyl-4-methylphenol.
  • spray drying refers to a method of drying a liquid feed through a hot gas.
  • this hot gas is air, but sensitive materials such as statins may be processed under oxygen-free conditions and an inert gas such as nitrogen gas is used instead.
  • the liquid feed may be a solution, colloid or suspension.
  • the process of spray drying is a one step rapid process and eliminates additional processing.
  • liquid feed is pumped through an atomizer device that produces fine droplets into the main drying chamber.
  • Atomizers may vary with rotary, single fluid, two-fluid, and ultrasonic nozzle designs. These different styles have different advantages and disadvantages depending on the application of the spray drying required.
  • a spray nozzle may be used in place of an atomizer for a different dispersion rate.
  • the hot drying gas may be passed as a co-current or counter-current flow to the atomizer direction.
  • the co-current flow enables the particles to have a lower residence time within the system and the particle separator (typically a cyclone device) operates more efficiently.
  • the counter-current flow method enables a greater residence time of the particles in the chamber and preferably is paired with a fluidized bed system.
  • the feed solution, colloid or suspension may be sprayed into a partial vacuum. Since the boiling point of a solvent is the temperature at which the vapor pressure of the solvent is equal to the ambient pressure, reducing pressure has the effect of lowering the boiling point of the solvent which may be advantageous for the yield of the spray drying process and/or for the quality of the final product.
  • the solvent in which the statin and/or the antioxidants are dissolved prior to spray drying can be any solvent although preferred solvents are those in which the components in question have a solubility, at 20 Q C, exceeding 0.5 g/L, preferably exceeding 1 g/L, more preferably exceeding 5 g/L, most preferably exceeding 10 g/L, still most preferably exceeding 50 g/L so that a solution can be obtained wherein the concentration of the statin is from 10 g/L to 300 g/L, preferably from 40 g/L to 150 g/L.
  • Preferred solvents are alcohols such as methanol, ethanol, isopropanol and the like.
  • the amount of antioxidants used according to the method of the present invention ranges from 0.005% w/w to 5% w/w relative to the amount of atorvastatin present in the solution prior to spray drying, preferably from 0.01 % w/w to 2% w/w, more preferably from 0.05% w/w to 1 % w/w.
  • the antioxidants may be added to the solution prior to the spray drying process.
  • the antioxidants are added during the spray drying process; the latter approach may have additional advantages, for instance in that, when required, solvents different from the solvent wherein the atorvastatin is dissolved, may be used for dissolving the antioxidants.
  • amorphous atorvastatin could be prepared by precipitation at temperatures not exceeding 50 Q C from a mixture of selected alcohols in the presence of antioxidants.
  • a method for isolating atorvastatin comprising mixing at a temperature not exceeding 50 Q C a solution of atorvastatin in a first solvent which is methanol and/or ethanol and/or n-propanol with a second solvent in which atorvastatin has a lower solubility than in the first solvent.
  • Methanol is particularly suited as a first solvent since it results in atorvastatin of reproducible amorphous consistency, since it is a solvent that is easy to recover and also since it is cheap.
  • Preferred second solvents are alcohols such as isopropanol, n-butanol, sec-butanol, tert-butanol, linear or branched C5-alcohols (such as 1 -pentanol, 2-pentanol, 3-pentanol, 1 -methyl-1 -butanol, 2-methyl-1 -butanol, 3-methyl-1 -butanol, 1 ,1 - dimethyl-1 -propanol, 1 ,2-dimethyl-1 -propanol), linear or branched C6-alcohols (such as 1 -hexanol, 2-hexanol, 3-hexanol, 1 -methyl-1 -pentanol, 2-methyl-1 -pentanol, 3-methyl-1 - pentanol, 4-methyl-1 -pentanol, 3-methyl-2-pentanol, 4-methyl-2-pentanol, 2-methyl-3- pentano
  • the preferred second solvent is isopropanol.
  • the product may be isolated, for instance by centrifugation, filtration, sedimentation and the like.
  • the temperature at which the precipitation is carried out should not exceed 50 Q C.
  • precipitation is carried out at temperatures ranging from 0 Q C to 40 Q C, most preferably ranging from 20 Q C to 30 Q C.
  • the isolated precipitate may be dried using standard drying techniques at temperatures ranging from 20 Q C to 100 Q C, preferably ranging from 30 Q C to 80 Q C, most preferably ranging from 40 Q C to 60 Q C as at this range significant degradation could not be established.
  • the solvents of the present invention have a clear advantage over those suggested in the prior art.
  • a mixture of dichloromethane and diisopropyl ether is suggested and in US 6,613,916 a mixture of alcohols and diethyl ether is suggested. From a safety and environmental point of view these solvents should be avoided, moreover since traces residual solvent are difficult to remove completely and some of the suggested prior art solvents are toxic and/or poisonous.
  • the antioxidants may be added to the solution of atorvastatin in the first solvent, to the second solvent or to the optional third solvent. The latter two approaches may have additional advantages, for instance in that, when required, solvents different from the solvent wherein the atorvastatin is dissolved, may be used for dissolving the antioxidant. Suitable antioxidants are the same as outlined in the first embodiment.
  • the resultant precipitated and isolated or spray dried statin of the method of the present invention is treated with a third solvent.
  • a third solvent Such treatment is referred to as washing and may comprise leading said third solvent over or through a layer of precipitated and isolated statin, or re-mixing the resultant precipitated and isolated statin in said third solvent followed by isolation of the solid materials.
  • the effect of said treatment with a third solvent is that the purity of the end product further increases.
  • Preferred third solvents are the same as mentioned above as second solvent.
  • the third solvent can be a different solvent from the second solvent, which has the advantage that a wide variety of impurities can be removed by choosing from a wide variety of solvents, but can also be the same solvent as the second solvent which has the advantage that it simplifies solvent recovery.
  • the preferred third solvent is isopropanol.
  • statins described above are not limited to atorvastatin but also apply to other statins that are prone to oxidative degradation such as lovastatin, pravastatin, simvastatin and wuxistatin.
  • a composition comprising a statin and at least two antioxidants.
  • the statin is atorvastatin, lovastatin, pravastatin, simvastatin or wuxistatin and the antioxidants are carbohydrates, carotenoids, flavonoids, isoflavonoids, hydroxyacids, phenols, polyphenols, sulphite salts, terpene alcohols, thiourea, unsaturated acids or vitamins or mixtures thereof.
  • ascorbic acid ascorbyl palmitate, bis hydroxyanisole, butylated hydroxyanisole, butylated hydroxytoluene, ⁇ -carotene, ⁇ -carotene, ⁇ -carotene, caffeic acid, chlorogenic acid, cinnamic acid, citric acid, coumaric acid, cyanidin, delphinidin, 2,6-diisopropylphenol, 2,6-di-fert-butyl-4-methylphenol, ellagic acid, epicatechin, erythorbic acid, fumaric acid, gallic acid, geraniol, ⁇ -hydroxy ⁇ S ⁇ -tetramethylchroman ⁇ -carboxylic acid, kaempferol, lycopene, malvidin, mannitol, myricetin, peonidin, petunidin, proanthocyanidins, propyl galate,
  • the amount of antioxidants in the composition of the second aspect ranges from 0.005% w/w to 5% w/w relative to the amount of statin, preferably from 0.01 % w/w to 2% w/w, more preferably from 0.05% w/w to 1 % w/w.
  • said at least two antioxidants are a hydroxy acid such as citric acid or tartaric acid and a phenol derivative such as bis hydroxyanisole, butylated hydroxyanisole, butylated hydroxytoluene, 2,6-diisopropylphenol or 2,6-di-tert-butyl-4- methylphenol.
  • a hydroxy acid such as citric acid or tartaric acid
  • a phenol derivative such as bis hydroxyanisole, butylated hydroxyanisole, butylated hydroxytoluene, 2,6-diisopropylphenol or 2,6-di-tert-butyl-4- methylphenol.
  • the composition comprising two or more antioxidants of the second aspect may be used for the manufacture of a hypocholesterolemic medicament.
  • the antioxidants of the present invention prevent unwanted oxidation of the active ingredient and are of a non-toxic nature.
  • Figure 1 is the XRD spectrum of atorvastatin prepared according to the method of the present invention as detailed in Example 1 (B) and of the crystalline atorvastatin starting material (A).
  • X-axis 2-theta scale
  • Y-axis Lin (counts).
  • Example 1 Spray drying of atorvastatin from methanol
  • Crystalline atorvastatin (14 g) was dissolved in methanol (200 ml_) and spray dried (inlet temperature 66-69 Q C, feed rate 3-4 ml/min, atomization air pressure 0.5-1 .0 kg/cm 2 ) to give 10 g of amorphous atorvastatin with 99.4% HPLC purity (area%).
  • XRD analysis of the product obtained revealed the full amorphous character as confirmed by the XRD spectrum given in Figure 1 . The stability of the resulting product was monitored for a period of three months (see Table 1 ).
  • Crystalline atorvastatin (20 g) was dissolved in methanol (400 mL) and citric acid (0.1 g) and butylated hydroxy anisole (0.1 g) were added. The solution was spray dried under the conditions from Example 1 to give 15 g of amorphous atorvastatin with 99.1 % HPLC purity (area %). The stability of the resulting product was monitored for a period of three months (see Table 2).

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Diabetes (AREA)
  • Organic Chemistry (AREA)
  • Obesity (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
  • Medicinal Preparation (AREA)
  • Food Preservation Except Freezing, Refrigeration, And Drying (AREA)

Abstract

La présente invention concerne un procédé permettant d'isoler une statine comprenant le séchage par atomisation d'une solution de ladite statine dans un alcool ou la précipitation de ladite station de la solution, le procédé se caractérisant en ce que deux antioxydants sont présents dans ladite solution ou en ce que les antioxydants sont ajoutés au cours du séchage par atomisation ou pendant la précipitation. Cette invention porte également sur une composition comprenant une statine et de 0,01% à 1% en poids de la composition de deux antioxydants qui sont un hydrate de carbone, un caroténoïde, un flavonoïde, un isoflavonoïde, un hydroxyacide, un phénol, un polyphénol, un sel de sulfite, un alcool terpénique, un thio-urée, un acide insaturé ou une vitamine.
PCT/EP2009/066546 2008-12-11 2009-12-07 Compositions comprenant une statine stabilisée WO2010066687A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08171325.7 2008-12-11
EP08171325 2008-12-11

Publications (2)

Publication Number Publication Date
WO2010066687A2 true WO2010066687A2 (fr) 2010-06-17
WO2010066687A3 WO2010066687A3 (fr) 2011-03-17

Family

ID=40911098

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/066546 WO2010066687A2 (fr) 2008-12-11 2009-12-07 Compositions comprenant une statine stabilisée

Country Status (1)

Country Link
WO (1) WO2010066687A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8632807B2 (en) 2011-05-20 2014-01-21 Astrazeneca Uk Limited Pharmaceutical composition

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245797B1 (en) * 1997-10-22 2001-06-12 Merck & Co., Inc. Combination therapy for reducing the risks associated with cardio-and-cerebrovascular disease
US20030220343A1 (en) * 2000-10-23 2003-11-27 Sankyo Company, Limited Compositions for improving lipid content in the blood
US6673831B1 (en) * 1996-04-17 2004-01-06 Merck & Co., Inc. Combination therapy for reducing the risks associated with cardiovascular disease
US20040126423A1 (en) * 2002-07-26 2004-07-01 Moore William D. Pharmaceutical formulation
WO2006039441A2 (fr) * 2004-09-30 2006-04-13 Dr. Reddy's Laboratories Ltd. Atorvastatine calcique amorphe
US20060093591A1 (en) * 1999-04-01 2006-05-04 Farmer Sean Methods for reducing cholesterol using Bacillus coagulans spores, systems and compositions
US20070202159A1 (en) * 2006-02-02 2007-08-30 Mathur Rajeev S Pharmaceutical composition comprising stabilized statin particles

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6673831B1 (en) * 1996-04-17 2004-01-06 Merck & Co., Inc. Combination therapy for reducing the risks associated with cardiovascular disease
US6245797B1 (en) * 1997-10-22 2001-06-12 Merck & Co., Inc. Combination therapy for reducing the risks associated with cardio-and-cerebrovascular disease
US20060093591A1 (en) * 1999-04-01 2006-05-04 Farmer Sean Methods for reducing cholesterol using Bacillus coagulans spores, systems and compositions
US20030220343A1 (en) * 2000-10-23 2003-11-27 Sankyo Company, Limited Compositions for improving lipid content in the blood
US20040126423A1 (en) * 2002-07-26 2004-07-01 Moore William D. Pharmaceutical formulation
WO2006039441A2 (fr) * 2004-09-30 2006-04-13 Dr. Reddy's Laboratories Ltd. Atorvastatine calcique amorphe
US20070202159A1 (en) * 2006-02-02 2007-08-30 Mathur Rajeev S Pharmaceutical composition comprising stabilized statin particles

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8632807B2 (en) 2011-05-20 2014-01-21 Astrazeneca Uk Limited Pharmaceutical composition
US10028953B2 (en) 2011-05-20 2018-07-24 Astrazeneca Uk Limited Pharmaceutical composition of rosuvastatin calcium

Also Published As

Publication number Publication date
WO2010066687A3 (fr) 2011-03-17

Similar Documents

Publication Publication Date Title
Jablonsky et al. Valorisation of softwood bark through extraction of utilizable chemicals. A review
EP0618203A1 (fr) O-acylés catechins et procédé pour leur préparation
WO2011128714A1 (fr) Dérivés de polyphénol stabilisés, procédé pour leur fabrication et leurs utilisations
Cuesta-Rubio et al. Chemistry and biological activity of polyisoprenylated benzophenone derivatives
Natolino et al. Supercritical antisolvent precipitation of polyphenols from grape marc extract
JP5162698B2 (ja) ポリフェノール組成物の製造方法
WO2003070263A1 (fr) Procede de production d'un extrait hydrophobe de glycyrrhiza de haute qualite
US20030018222A1 (en) Process of obtaining compositions of stable lutein and lutein derivatives
WO2010066687A2 (fr) Compositions comprenant une statine stabilisée
Awang et al. Comparison of different solvents on the extraction of Melastoma malabathricum leaves using soxhlet extraction method
AU3438499A (en) Process for the obtaining of hmg-coa reductase inhibitors of high purity
TW201350115A (zh) 抗肥胖劑及具有脂肪堆積抑制作用的醫藥品、食品或化妝料
JPWO2003091237A1 (ja) プロアントシアニジン高含有物の製造方法
WO2010066846A2 (fr) Procédé pour isoler de l'atorvastatine
JP2002104985A (ja) フリーラジカル消去活性剤
KR100701798B1 (ko) 해조식물로부터 추출한 콜린에스터라제 활성 억제제를함유하는 알츠하이머성 치매 개선제 및 인지능력 개선제
EP3842413A1 (fr) Procédé de stabilisation d'un composé de sanshool
Tabib et al. Adsorption of polyphenols from almond blanching water by macroporous resin
JP2005082546A (ja) α−グルコシダーゼ阻害剤
Doosthosseini et al. Optimized method for curcumin separation from turmeric oleoresin
JPH06217747A (ja) 抗菌剤
US20080249163A1 (en) Process For Producing Product Containing Proanthocyanidin in High Proportion
KR19990063822A (ko) 알콕실화 지방의 정제 방법
JP2006052184A (ja) 酸化ストレス抑制用の食品
JP2008297230A (ja) コレステロール低下用組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09764537

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09764537

Country of ref document: EP

Kind code of ref document: A2