CN1805741A - Stable compositions of atorvastatin prepared with wet granulation - Google Patents

Stable compositions of atorvastatin prepared with wet granulation Download PDF

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CN1805741A
CN1805741A CNA2004800163910A CN200480016391A CN1805741A CN 1805741 A CN1805741 A CN 1805741A CN A2004800163910 A CNA2004800163910 A CN A2004800163910A CN 200480016391 A CN200480016391 A CN 200480016391A CN 1805741 A CN1805741 A CN 1805741A
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atorvastatin
wet granulation
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CN100434069C (en
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肯尼思·C·沃特曼
迈克尔·B·弗吉奥恩
巴巴拉·A·约翰逊
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Warner Lambert Co LLC
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Abstract

A wet granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof with less than about 5 weight% of an alkaline earth metal salt additive with a disintegrant which provides the atorvastatin with not more than about 3% atorvastatin lactone based on the ratio of lactone peak area compared to the total drug-related peak integrated areas, as well as said wet granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof in combination with at least one other active drug, methods for preparing said compositions, kits for containing such compositions, and a method of treating hypercholesterolemia and/or hyperlipidemia, osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease using a therapeutically effective amount of the pharmaceutical compositions.

Description

Utilize the stable compositions of atorvastatin of wet granulation preparation
The cross reference of related application
Ask No.60/478,119 priority in the interim patent of the U.S. that the application requires to submit on June 12nd, 2003.
Invention field
The present invention relates to pharmaceutical composition, comprise atorvastatin (atorvastatin) and its officinal salt, the method for preparing said composition, contain the test kit of this based composition, and use this based composition treatment to suffer from the experimenter's of hypercholesterolemia and/or hyperlipemia and osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer method.
Background of invention
3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) is an early stage rate-limiting step in the cholesterol biosynthesis pathway to the conversion of mevalonic acid.This step is subjected to the catalysis of HMG-CoA reductase.Statins suppresses this transformation of HMG-CoA reductase catalysis.Therefore, Statins is strong lipid lowering agent generally.
Atorvastatin calcium is disclosed in U.S. Patent No. 5,273, in 995, is incorporated herein by reference, at present as Lipitor List marketing, chemical name are [R-(R *, R *)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles-1-Calcium salt enanthate (2: 1) trihydrate, have following formula
Figure A20048001639100051
Atorvastatin and officinal salt thereof are selectivity, the competitive inhibitors of HMG-CoA reductase.Therefore, Atorvastatin calcium is strong blood fat reducing chemical compound, thereby can be used as blood fat reducing and/or hypocholesterolemic agents, and is used for the treatment of osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer.
A large amount of patent disclosures of having issued are crossed the preparation of atorvastatin, atorvastatin and the process and the key intermediate of preparation atorvastatin.They comprise: U.S. Patent No. 4,681,893,5,273,995,5,003,080,5,097,045,5,103,024,5,124,482,5,149,837,5,155,251,5,216,174,5,245,047,5,248,793,5,280,126,5,397,792,5,342,952,5,298,627,5,446,054,5,470,981,5,489,690,5,489,691,5,510,488,5,686,104,5,998,633,6,087,511,6,126,971,6,433,213 and 6,476,235, be incorporated herein by reference.
Atorvastatin can exist crystallization, liquid crystal and noncrystalline and amorphous form.
The crystal form of Atorvastatin calcium is disclosed in U.S. Patent No. 5,969, in 156 and 6,121,461, is incorporated herein by reference.Further the atorvastatin crystal form is disclosed in U.S. Patent No. 6,605, in 729, is incorporated herein by reference.
In addition, the international patent application of having announced in a large number disclosed the process of the crystal form and the preparation amorphous atorvastatin of atorvastatin.They comprise: WO 00/71116, WO 01/28999, WO01/36384, WO 01/42209, WO 02/41834, WO 02/43667, WO 02/43732, WO02/051804, WO 02/057228, WO 02/057229, WO 02/057274, WO 02/059087, WO 02/083637, WO 02/083638, WO 03/011826, WO 03/050085, WO03/070702 and WO 04/022053.
Disclosed, and compared with crystal form, there is different dissolving characteristics in the amorphous form in the high amount of drug, has different bioavailability pattern (Konno, T., Chem.Pharm.Bull., 1990 in some cases; 38:2003-2007).With regard to some treatment indication, a kind of bioavailability pattern may be better than another kind.
Difference on the rate of dissolution can help the atorvastatin preparation of production crystallization or amorphous form.For example, and with regard to some potential use of atorvastatin (paralytic's acute treatment for example, as Takemoto, M.; Node, K.; Nakagami, H.; Liao, Y.; Grimm, M.; Takemoto, Y.; Kitakaze, M.; Liao, J.K., Journal of Clinical Investigation, 2001; 108 (10): 1429-1437 is described), active rapid onset may be a significant benefit to the effect that improves medicine.
The preparation of solid atorvastatin preparation is described in U.S. Patent No. 5,686, in 104 and 6,126,971.In the described therein process,, re-use water and surfactant (tween with atorvastatin and the additive with Stabilization such as alkali salt and excipient merging TW80) wet granulation is carried out in combination.Because the alkaline-earth metal salt additives can influence the bioavailability of atorvastatin, still need to provide the wet granulation compositions of atorvastatin, wherein said compositions is substantially free of the alkaline-earth metal salt additives.Similarly, may need to reduce the use of any basifier (alkalizing agent) additive in compositions of atorvastatin,, avoid when this medicine is used in the combination dosage forms and the interaction of other medicines to avoid potential bioavailability problem.
The U.S. Patent application that the applicant submits to simultaneously, attorney docket are PC25684, serial number _ _ a kind of unit dosage form without the granulation step preparation is disclosed, it comprises atorvastatin or its officinal salt; Attorney docket PC25686 discloses the pharmaceutical composition of non-slurry pelletizing, comprises atorvastatin or its officinal salt.
In the preparation and storage of atorvastatin dosage form, importantly provide the active medicine of respective pure form.And, need to utilize simple as far as possible preparation to reach this high-purity and stability.Still need to provide the simple formulations and the preparation process of atorvastatin unit dosage form, this dosage form has low-level impurity.And, still need to provide the atorvastatin that is suitable for unit dosage form preparation, adding minimum basifier thus can provide sufficient pharmaceutical purity, stability and required rate of dissolution and bioavailability.
A kind of preferred atorvastatin unit dosage form is a tablet.With regard in case swallow in the tablet that is promptly absorbed rapidly with regard to the active medicine, generally importantly these tablets in a single day to be exposed to gastrointestinal tract body fluid be rapid disintegrate.Meanwhile, importantly these tablets are sufficiently rigid, so that they can be not broken or cracked at manufacturing, processing or lay up period.Adding disintegrating agent to compositions can satisfy these and appear the demand of contradiction.The disintegrating agent that is used for compositions of atorvastatin in a large number is open in the prior art, comprises carboxymethylcellulose calcium, starch and cross-linking sodium carboxymethyl cellulose (referring to U.S. Patent No. 5,686,014 and 6,126,971).When alkalization additive that uses atorvastatin and floor level or alkaline-earth metal salt additives, we are surprised to find that, utilize the wet granulation process of standard, only have some disintegrating agent to provide acceptable purity for the atorvastatin sheet.This is especially unexpected, because find to be used in disintegrating agent (cross-linking sodium carboxymethyl cellulose) in the commodity preparation for adding the alkalization additive of floor level to amorphous atorvastatin or the wet granulation of alkaline-earth metal salt additives is unacceptable.And even when atorvastatin is amorphous form, this stability also unexpectedly is maintained.Except the improvement of preparation, we have also developed the wet granulation process of mixing disintegrating agent to preparation, and it provides high-purity to atorvastatin, even provide the disintegrating agent of weak stability also can provide high purity in standard procedure.
We further find, when utilizing the wet granulation of atorvastatin (especially amorphism atorvastatin), add the purity that volatility alkali can improve medicine to the pelletize solvent.These volatility alkali improve the purity of medicine in dosage form, and itself are not present in the final dosage form, therefore can not influence bioavailability.
Therefore, the purpose of this invention is to provide stable atorvastatin dosage form, it has good disintegration rate and bioavailability.Another object of the present invention provides stable and pure compositions of atorvastatin, and it contains the alkaline-earth metal salt additives of floor level or other and is added in basifier in the said composition.
Summary of the invention
Therefore, a first aspect of the present invention is the atorvastatin pharmaceutical composition of wet granulation, and it contains the alkaline-earth metal salt additives that is less than about 5 weight %, and said composition comprises:
(a) atorvastatin or its officinal salt; With
(b) combination of disintegrating agent or disintegrating agent, the pharmaceutical composition of wherein said wet granulation contain based on the atorvastatin lactone that utilizes HPLC gained lactone peak area with the ratio of total medicine relevant peaks integral area no more than about 3%.
A second aspect of the present invention is the atorvastatin pharmaceutical composition of wet granulation, and it contains the alkaline-earth metal salt additives that is less than about 5 weight %, and said composition comprises:
(a) combination of atorvastatin or its officinal salt and at least a other active medicine; With
(b) combination of disintegrating agent or disintegrating agent, the pharmaceutical composition of wherein said wet granulation contain based on the atorvastatin lactone that utilizes HPLC gained lactone peak area with the ratio of total medicine relevant peaks integral area no more than about 3%.
A third aspect of the present invention is the method for the compositions of atorvastatin of preparation wet granulation, and it comprises:
(a) merge (combining) atorvastatin or its officinal salt and primojel, starch, sodium alginate, Powderd cellulose, hydroxypropyl cellulose, Magnesiumaluminumsilicate or bohr Acree woods potassium (polacrilinpotassium) or their combination and other optional excipient;
(b) under shearing, in the atorvastatin admixture that obtains by step (a), add water, isopropyl alcohol, ethanol or their mixture of capacity, generate granule;
(c) randomly mill or sieve described wet granular;
(d) dry described granule;
(e) the described granule of randomly milling, grind or sieve;
(f) randomly sneak into other excipient; With
(g) randomly make resultant composition form unit dosage form.
A fourth aspect of the present invention is the method for the compositions of atorvastatin of preparation wet granulation, and it comprises:
(a) merge atorvastatin or its officinal salt and contain the diluent that is less than 2 weight % disintegrating agents;
(b) under shearing, in the atorvastatin admixture that obtains by step (a), add water, isopropyl alcohol, ethanol or their mixture of capacity, generate granule;
(c) the described wet granular of randomly milling, grind or sieve;
(d) dry described granule;
(e) the described granule of randomly milling, grind or sieve;
(f) mix disintegrating agent and other optional excipient; With
(g) randomly make resultant composition form unit dosage form.
A fifth aspect of the present invention is the method for the compositions of atorvastatin of preparation wet granulation, and it comprises:
(a) merge atorvastatin or its officinal salt and one or more excipient;
(b) solution of volatility alkali in water, isopropyl alcohol or ethanol or their mixture of adding capacity under shearing generates granule;
(c) the described wet granular of randomly milling, grind or sieve;
(d) dry described granule;
(e) the described granule of randomly milling, grind or sieve;
(f) randomly sneak into other excipient as required, make final compositions; With
(g) randomly make described compositions form unit dosage form.
A sixth aspect of the present invention is the method for the compositions of atorvastatin of preparation wet granulation, and it comprises:
(a) combination of merging atorvastatin or its officinal salt and at least a active medicine and primojel, starch, sodium alginate, Powderd cellulose, hydroxypropyl cellulose, Magnesiumaluminumsilicate or bohr Acree woods potassium or their combination and other optional excipient;
(b) under shearing, in the atorvastatin admixture that obtains by step (a), add solution in water, isopropyl alcohol, ethanol or their mixture of capacity, generate granule;
(c) randomly mill or sieve described wet granular;
(d) dry described granule;
(e) the described granule of randomly milling, grind or sieve;
(f) randomly sneak into other excipient; With
(g) randomly make described compositions form unit dosage form.
A seventh aspect of the present invention is the method for the compositions of atorvastatin of preparation wet granulation, and it comprises:
(a) merge the combination of atorvastatin or its officinal salt and at least a active medicine and contain the diluent that is less than 2 weight % disintegrating agents;
(b) under shearing, in the atorvastatin admixture that obtains by step (a), add water, isopropyl alcohol, ethanol or their mixture of capacity, generate granule;
(c) the described wet granular of randomly milling, grind or sieve;
(d) dry described granule;
(e) the described granule of randomly milling, grind or sieve;
(f) mix disintegrating agent and other optional excipient; With
(g) randomly make resultant composition form unit dosage form.
A eighth aspect of the present invention is the method for the compositions of atorvastatin of preparation wet granulation, and it comprises:
(a) combination and one or more excipient of merging atorvastatin or its officinal salt and at least a active medicine;
(b) solution of volatility alkali in water, isopropyl alcohol or ethanol or their mixture of adding capacity under shearing generates granule;
(c) the described wet granular of randomly milling, grind or sieve;
(d) dry described granule;
(e) the described granule of randomly milling, grind or sieve;
(f) randomly sneak into other excipient as required, make final compositions; With
(g) randomly make described compositions form unit dosage form.
A ninth aspect of the present invention is the test kit that reaches therapeutic effect in mammal, comprise tablet or the capsule and the container that contains described dosage form by atorvastatin wet granulation preparation of compositions of treatment effective dose, wherein tablet or capsule are to be prepared by the form of described compositions with unit dosage form.
A tenth aspect of the present invention is to use this medicine composite for curing to suffer from the experimenter's of hypercholesterolemia and/or hyperlipemia, osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer method.
Detailed description of the invention
As U.S. Patent No. 4,681,893,5,273,995 and 5,969,156 is described, and atorvastatin can easily prepare, and above-mentioned document is incorporated herein by reference.Half calcium salt of atorvastatin (hemicalsium salt) is at present as Lipitor List marketing.
Atorvastatin exist a large amount of from the highly crystalline form to morphologic form with different unordered degree forms.Some ordered form still possesses some structures, shown in powder x-ray diffraction.For purposes of the present invention, all atorvastatin forms are all benefited from the present invention, all comprise within the scope of the invention.Not too orderly atorvastatin form, especially amorphous or main unbodied form special benefit are in the present invention.This class form for example can be disclosed in U.S. Patent No. 6,087 from the crystalline material utilization, and the technology in 511 is prepared, and the document is incorporated herein by reference.Select as an alternative, the amorphous atorvastatin material can be prepared according to the method that is disclosed in the U.S. Patent application that attorney docket is the applicant of PC-25825 (serial number _ _ _).With regard to enforcement of the present invention, amorphism and crystallinity atorvastatin can be by any means preparations known in the art.It is to disclose the patent of atorvastatin form preferred for this invention and the nonexcludability tabulation of published below: United States Patent (USP) 5,969,156, United States Patent (USP) 6,121,461, United States Patent (USP) 6,605,729, International Patent Application WO 01/36384, International Patent Application WO 02/41834, International Patent Application WO 02/43732, International Patent Application WO 02/051804, International Patent Application WO 02/057229, International Patent Application WO 03/011826, International Patent Application WO 03/050085, International Patent Application WO 03/070702 and International Patent Application WO 04/022053.All above-mentioned patents and application all are incorporated herein by reference.
Atorvastatin can use its prepared form, the processing of method that perhaps can be through changing the particle physics attribute.For example, can be by the arbitrary process known in the art raw material of milling.The nonexcludability example of this class process comprises that mechanical disruption and injection mill.That directly obtain from the method that forms the amorphism atorvastatin or after the operation of milling resulting average particle size in the scope of 1-200 μ m, more preferably 5 and 150um between.
The pharmaceutically acceptable base addition salts of atorvastatin is formed with metal or amine such as alkali metal and alkaline-earth metal or organic amine.Example as cationic metal has sodium, potassium, magnesium, calcium etc.The example of the amine that is fit to has N, and N-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, hexanamine, ethylenediamine, N-methyl glucoside amine and procaine (for example referring to Berge, S.M., et al., " PharmaceuticalSalts ", J.Pharm.Sci., 1977; 66:1).
The base addition salts of atorvastatin is to prepare by free acid form being contacted with the required alkali of capacity generate salt.Free acid form is to regenerate by making salt form contact also separated free acid with acid in a usual manner.Some is different with their salt forms separately on some physical property for free acid form, the dissolubility in polar solvent for example, but for purposes of the present invention, salt is equivalent to their free acids separately.
In addition, atorvastatin can comprise that hydrated form exists with not solvation form and solvation form.Generally speaking, the solvation form is contained in scope of the present invention, and this solvation form comprises hydrated form.
At least some the unordered atorvastatin form or the crystallization of atorvastatin and the mixture of ordered form are benefited from the present invention the most significantly.Some unordered live width (peak width at half peak height place) of utilizing the measured any peak of powder x-ray diffraction (PXRD) that means has greater than 2 about 2 ° θ values.Especially the amorphous or main amorphous form of benefiting from atorvastatin of the present invention is to be feature with no characteristic peak with non-constant width.Should be noted that the crystallinity of atorvastatin and the combination of some ordered form at least are showing that spike (promptly 2 θ are less than 2 °) and broad peak (promptly greater than 2 °) are feature, the present invention is benefited from the combination of this class form.
Even have been found that atorvastatin is than also being effective medicine under the low dosage.In fact,, might reduce side effect, still keep efficacy of drugs simultaneously by given patient is kept low dosage.Therefore need provide the atorvastatin that the form of low dosage can be provided to the patient.For purposes of the present invention, by the dosage that final dosage form provided of atorvastatin preferably 0.5 and 120mgA between (wherein mgA represents the milligram number of said medicine based on free acid); More preferably 5 and 80mgA between.
With the easy adaptability that improves the patient, most drug is sent with the form of unit dosage form for convenience.With regard to the solid drugs material, these unit dosage forms generally are the forms of tablet and capsule.In the present invention, the dosage form form of capsule or tablet preferably; The form of tablet most preferably.The preparation of these dosage forms relates to powder fills punch die or capsular steps necessary.For make dosage unit have can allow in the limit identical effectiveness (relative standard deviation RSD less than 6% with satisfy the I phase, less than 7.8% to satisfy the requirement of II phase American Pharmacopeia USP guide), formulation components must be without any significant separation.For this reason, especially when under low dosage, using this medicine, may need the atorvastatin pelletize.Wet granulation is bonded together medicine and excipient, reduces any isolating trend thus.
The invention discloses processes for wet granulation and preparation, described preparation provides atorvastatin with pure with stable form.Term " impurity " is meant material and any material based on medicine that is generated that is present in purification process in the drug substance by synthetic in the preparation of unit dosage form.Any material that (in the pot-life of dosage form) generated after the preparation of unit dosage form of term " catabolite " expression based on medicine.The analysis of impurity and catabolite is to utilize as known in the art the hplc rp-hplc technology to carry out at the sample that is extracted.The calculating of the amount of impurity and catabolite represents divided by the integral area percentage ratio at all peaks with the integral area percentage ratio at all peaks except that the medicine peak, perhaps if possible, and based on the response factor of the integration at credible material sample peak.
As known in the field, in the atorvastatin preparation of wet granulation, use the combination of diluent, binding agent, disintegrating agent, lubricant and other additive known in the art to provide unit dosage form required character.For example, with regard to the preparation of tablet, this combination is provided at behind the tabletting tablet hardness fully, and disintegrate in the body is provided rapidly simultaneously.Although broad scope is arranged on the preparation atorvastatin for satisfying these conditions, but this class tablet contains the 1-40% weight of having an appointment usually: (w: w) medicine, about 1-15% disintegrating agent, about 0-10% binding agent and about 0.5-2% lubricant, all the other comprise diluent and/or other component to weight.Preferred adhesive comprises carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, dextrin, gelatin, guar gum, hydroxypropyl emthylcellulose, maltodextrin, methylcellulose, polyoxyethylene, polymethacrylates and sodium alginate; Concrete preferred adhesive is a hydroxypropyl cellulose.Preferred lubricant is a magnesium stearate.Preferable absorbent comprises calcium phosphate, calcium sulfate, cellulose acetate, dextrates, dextrin, glucose, fructose, Kaolin, lactose, lactose, maltose alcohol, maltodextrin, maltose, microcrystalline Cellulose, polymethacrylates, Powderd cellulose, silicified microcrystalline cellulose, sodium chloride, Sorbitol, sucrose and Talcum.
In enforcement of the present invention, the preferably about 0-5% (w: w) of the level of alkaline-earth metal salt additives in compositions; 0-3% more preferably from about; 0-2% most preferably from about.The level of other basifier additive in compositions also is preferably about 0-5% (w: w); 0-3% more preferably from about; 0-2% most preferably from about.Amine polymer and amide polymer be preferably preparation less than about 0-5% (w: w); 0-3% more preferably from about; 0-2% most preferably from about.The example of this base polymer is disclosed among the International Patent Application WO 01/76566A1.
Basifier is additive or the excipient that has the character that increases this class preparation pH when adding preparation in water.The example of basifier comprises inorganic and organic base (buffer agent).The example of inorganic basifier comprises citrate, carbonate, bicarbonate, phosphate, sulfate, benzoate and the Ascorbate of sodium or potassium, and calcium carbonate and magnesium carbonate.Latter two example is also represented alkali salt.The example of organic basifier comprises amine.The instantiation of amine comprises N-methyl glucoside amine, guanine and arginine.
In the preparation of the compositions of atorvastatin that passes through wet granulation, any wet granulation technology known in the art may be used to purpose of the present invention.An important elements of these processes is to add granulation solution to compositions of atorvastatin when fusion powder under shearing.The effect of smashing the initial stage agglomerate is played in shearing, and more uniform pelletize is provided thus.The limiting examples of shear history comprises high shear wet granulation, fluidized bed prilling, extruding pelletization and the low wet granulation (for example blender, mixer and blender comprise box blender) of shearing.The amount of the wet granulation solvent that is added depends on moistening fully, with bonding most of fine particles.The adding of wet granulation solvent can utilize any technology known in the art to carry out.For example, liquid can be added, be sprayed onto the bed that stirs powder by single or multiple rapidly and goes up, directly is pumped on the powder or is incorporated in the fluidizing gas.General through optimizing with the time of liquid mixing, so that most of minuteness particle is bonded in the granule, and granule itself can overvulcanization.
As known in the field, in case form granule, milling, grind or sieve when taking advantage of its moistening (soft) is favourable sometimes.Dry moistening compositions before being used to prepare unit dosage form preferably.This class drying can utilize any means known in the art to finish.That the limiting examples of these methods comprises is air-dry, fluid bed drying, microwave drying, oven drying, radio-frequency seasoning, vacuum drying oven drying and convection oven drying.We have found that baking temperature is important for control provides low-level atorvastatin impurity.Preferably, baking temperature is no more than about 60 ℃; More preferably, this temperature is no more than about 50 ℃; Most preferably, this temperature is no more than about 40 ℃.As known in the field,, need sometimes by milling, grind or sieving and dwindle particle diameter in case granule is exsiccant.Then, add lubricant usually, mix with the short time (about 1-10 minute) afterwards, carry out low the shearing in the blender usually, blender for example rolls.The example of described rolling blender comprises box blender, V-type blender and Turbula TMBlender.Preferred lubricant is a magnesium stearate.In case make admixture, by prepared unit dosage form known in the art.Preferred unit dosage form comprises tablet and capsule.Tablet is prepared with the drift compacting of coupling then by filling punch die with the compositions that contains atorvastatin.Capsule is by being filled into the capsule shells of molding, seals then and prepares.This generic operation preferably utilizes rotary tablet machine or commodity capsule filling machine to carry out.The nonexcludability example of commodity rotary tablet machine comprises the machine of being produced by following company: Niro Pharma Systems (Columbia, MD), Kilianand Company (Horsham, PA), Korsch (Berline, Germany) and Elizabet-HataInternational (North Huntingdon, PA).The nonexcludability example of commodity capsule pad device comprise the equipment of making by following company: Capsugel (Morris Plains, NJ) and CapPlus Technologies (Phoenix, AZ).Tablet can randomly carry out coating then, and coating is through design, provide easily swallow, the protection of proprietary or distinctive outward appearance and/or dosage form.Utilize the final unit dosage form of technology packing known in the art then.For the present invention, pack the bubble of aluminium foil preferably eye, plastic blister eye or contain the form of the air-tight bottle of desiccant.Randomly, packing can contain just like EP 1243524A2 or the disclosed active oxygen absorbing material of EP1241110A1, and above-mentioned document is incorporated herein by reference.
Two kinds of main degradation pathway of atorvastatin experience: lactonize and oxidation.Lactone is the hexatomic ring that is generated by inside condensation (dehydration) pure and carboxylic acid.This is in the wet granulation and the main degradation products of tablet after forming, especially do not have alkali salt in the presence of.We have found that, the selection of excipient and the combination of processes for wet granulation can significantly reduce by wet granulation preparation, contain and be less than 5% (w: w) the lactone level in the tablet of alkaline-earth metal salt additives.
When atorvastatin is made into tablet form, need disintegrating agent that the rapid disintegrate of tablet in gastrointestinal tract is provided, guarantee that thus medicine can be used for rapidly absorbing.Prior art openly is used for the disintegrating agent of atorvastatin excessively in a large number.For example, international patent application No.WO 03/011283A1 discloses the following disintegrating agent that makes up with the basifier and second active pharmaceutical ingredient: carboxymethylcellulose calcium, sodium carboxymethyl cellulose, silicon dioxide, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, guar gum, Magnesiumaluminumsilicate, methylcellulose, bohr Acree woods potassium, cellulose, pregelatinized starch, sodium alginate, primojel and starch.In a large amount of patents, a large amount of examples concentrate on the use (for example referring to U.S. Patent No. 5,686,014,6,126,971,6,531,507B1 and the European patent application EP 1336405A1 that has announced) of cross-linking sodium carboxymethyl cellulose.This disintegrating agent also is used in commodity Lipitor In.Although much these disintegrating agents provide sufficient disintegrate character, but be less than 5% (w: w) in the atorvastatin wet granulation of basifier additive containing, we unexpectedly measure, and only have some that sufficient pharmaceutical purity is provided in a lot of possible disintegrating agents.In fact, be surprised to find that the disintegrating agent (sodium carboxymethyl cellulose) that is used in most of examples provides relatively poor pharmaceutical purity.
Preferred disintegrating agent provides following atorvastatin preparation, in wet granulation and dried atorvastatin lactone level less than about 3% (based on area percentage of HPLC integration gained lactone peak and all medicine relevant peaks); Preferred disintegrating agent provides the lactone level less than about 1%; And then preferred disintegrating agent provides the lactone level less than about 0.5%.
Be suitable for disintegrating agent of the present invention and also provide preferably disintegration time less than 30 minutes for the tablet of being produced; And then be more preferably less than 15 minutes; And then be more preferably less than 8 minutes.Disintegration time utilizes pH6.8 phosphate buffered solution and commercial available disintegrate measuring device to measure.
The preferred disintegrating agent of the compositions that can use in containing the atorvastatin wet granulation that is less than about 5 weight % basifier additives or alkali salt comprises starch, primojel, sodium alginate, Powderd cellulose, hydroxypropyl cellulose, Magnesiumaluminumsilicate and bohr Acree woods potassium.Particularly preferred starch comprises corn starch and pregelatinized starch.The level of these disintegrating agents in compositions of atorvastatin is preferably about 1 and about 10% (w: w) of all preparations; More preferably about 3 and about 8% (w: w).
Preferred wet granulation solvent has bring out adherent character between the particle under the situation of significantly not dissolving atorvastatin, and wherein the remarkable dissolving of atorvastatin may cause medicine to change morphologic form.In addition, preferably this kind solvent is volatile and hypotoxic, so that any trace residue will not be deleterious.Therefore, the preferred pelletize solvent of atorvastatin institute is water and alcohols.Particularly preferred alcohols is ethanol and isopropyl alcohol.Under many circumstances, the combination of solvent may be favourable.Preferably, this class combination relates to water and ethanol or isopropyl alcohol.In addition, as known in the field, it may be favourable adding disintegrating agent to the pelletize solvent.For example, can mix binding agent, wetting agent and the stabilizing agent part as the pelletize solvent, this also within the scope of the invention.
We have found that a kind of concrete pelletize solvent additive, i.e. wetting agent tween TM80 (polyoxyethylene sorbitan monoleates) are deleterious to the stability of atorvastatin.This discovery is surprising, because this additive generally is used in the atorvastatin preparation of most prior art (for example referring to U.S. Patent No. 5,686,104 and 6,126,971).Therefore, be used in the level of the Tween 80 in the compositions of atorvastatin of wet granulation preferably less than 0.5% (w: w); Be more preferably less than 0.2%; And then be more preferably less than 0.1%.
The preferred for preparation method that contains the wet granulation of the atorvastatin that is less than 5 weight % basifier additives or alkali salt and preferred disintegrating agent comprises the following step:
(a) fusion atorvastatin and preferred disintegrating agent and optional all the other required excipient of some or all final compositions.These other excipient can comprise diluent, binding agent and other this class material, they be unit dosage form processing, flow, stability or form necessary;
(b) raw material that is obtained by step (a) is in and shears down, add the pelletize solvent.Preferred pelletize solvent comprises water, ethanol, isopropyl alcohol and their combination.As known in the field, can add other composition to the pelletize solvent.The example of this class additive has binding agent, wetting agent, stabilizing agent and buffer agent.This solvent can be applied by any technology known in the art.The method for optimizing of solvent-applied comprises high shear pelletize, low shear granulation, fluidized bed prilling and extruding pelletization when giving shearing;
(c) randomly, can mill, grind or sieve from the raw material of step (b).Then with this moist wood drying, preferably adopt air-dry, fluid bed drying, oven drying or microwave drying.Preferred baking temperature is no more than about 60 ℃, more preferably no more than about 50 ℃, is most preferably not exceeding about 40 ℃ and carries out drying;
(d) randomly, mill then or sieve this raw material;
(e) this raw material of fusion and other excipient then;
(f) randomly compositions is made unit dosage form, preferred tablet or capsule.
We also find, even during the disintegrating agent of lactonize at induce drug during the wet granulation when using (do not having alkali in the presence of), also might mix this class excipient by changing the method that adds this disintegrating agent.More specifically, we have found that add disintegrating agent to compositions after wet granulation step, promptly granule adds outward, the accident that has obtained medicine stability improves.Preferred step comprises in this method:
(a) fusion atorvastatin and the required excipient of at least some final compositions, but the disintegrating agent of not fusion significant quantity.The significant quantity of disintegrating agent is regarded as the about 2% (w: w) greater than preparation.Other excipient can comprise diluent, binding agent and other this class material, they be unit dosage form processing, flow, stability or form necessary;
(b) raw material that is obtained by step (a) is in and shears down, add the pelletize solvent.Preferred pelletize solvent comprises water, ethanol and isopropyl alcohol and their combination.As known in the field, can add other composition to the pelletize solvent.The example of this class additive has binding agent, wetting agent, stabilizing agent and buffer agent.This solvent can be applied by any technology known in the art.The method for optimizing of solvent-applied comprises high shear pelletize, low shear granulation, fluidized bed prilling and extruding pelletization when giving shearing;
(c) randomly, can mill, grind or sieve from the raw material of step (b).Then with this moist wood drying, preferably adopt air-dry, fluid bed drying, oven drying or microwave drying; Preferred baking temperature is no more than about 60 ℃, more preferably no more than about 50 ℃, is most preferably not exceeding about 40 ℃ and carries out drying;
(d) randomly, this raw material of milling then, grind or sieve;
(e) this compositions of fusion and one or more disintegrating agents and other optional excipient then preferably include lubricant;
(f) randomly final composition is made unit dosage form, preferred tablet or capsule.
We have found the another kind of method that improves the pharmaceutical purity of atorvastatin wet granulation, even it also can improve the pharmaceutical purity of atorvastatin wet granulation in the presence of the disintegrating agent that shows relatively poor pharmaceutical purity.More specifically, we are surprised to find that, only have a kind of alkali during wet granulation and dry run in compositions, even this alkali is not present in the end product, also can provide atorvastatin the anti-Stabilization that lactonizes.Particularly, do not have other alkali that is added in the presence of, find that volatility alkali provides than the purity that has higher degree that does not have this class volatility alkali for the wet granulation of atorvastatin.The example of this class preferred volatile alkali comprises alkyl and arylamine, diethanolamine and the monoethanolamine of ammonium hydroxide, tetra-alkyl ammonium hydroxide, secondary and three grades.Particularly preferred volatility alkali comprises ammonium hydroxide and TBAH.Can add these alkali with pelletize solvent (preferred water, isopropyl alcohol, ethanol or their combination), select the adding level of this alkali to make it provide good purity and stability, and they itself can induce drug degraded or preparation variable color for final atorvastatin dosage form.We have found that the concentration that is used in the volatility alkali in the pelletize water is preferably about 0.001 and about 50% (w: w); More preferably about 0.1 and about 40% (w: w).The amount of the granulation solution of the alkali that adds to granule is preferably at the about 100% (w: between solid material w) of about 40-.
The invention provides the compositions of atorvastatin, because disintegrating agent of the present invention gives atorvastatin bigger stability, so said composition specifically is applicable to the combination product with the other medicines material.Especially all the more so when second kind of medicine (excipient associating with it) can make atorvastatin unstable.The limiting examples that can benefit from the medicine of the combination of compositions of atorvastatin of the present invention and method comprises torcetrapib and amlodipine and officinal salt thereof.
Can unite the formation unit dosage form with at least a other active medicine according to compositions of atorvastatin of the present invention.Preferred unit dosage form comprises tablet and capsule.Unite when forming unit dosage form at compositions of atorvastatin and at least a other active medicine, the possible option of this class unit dosage form has been described in following non-limiting tabulation: (a) admixture of the atorvastatin of wet granulation and other active medicine itself (being that other medicines add outside the granule of the atorvastatin of wet granulation), as with the admixture (being that other medicines and excipient add outside the granule of the atorvastatin of wet granulation) of excipient, perhaps, form tablet or capsule as granule (being the combination of the atorvastatin of other medicines granule and wet granulation); (b) the single wet granulation of atorvastatin and other medicines forms tablet or capsule; (c) double-layer tablet comprises the atorvastatin of wet granulation in its one deck, comprise other medicines and optional excipient in its another layer.
The present invention relates to treat disease and disease in the experimenter, for example hyperlipemia and/or hypercholesterolemia, osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer, aforesaid atorvastatin or its officinal salt that can carry out administration with unit dosage form used in this treatment, and this dosage form has low-level catabolite and/or the impurity that is included in therapeutic packing or the test kit.This test kit comprises this unit dosage form and container.Usually, test kit comprises the administration guidance of dosage form.Container can be any conventional shape known in the art or form, for example carton, glass or plastic bottle or blister, and it can extrude single dosage form according to therapeutic scheme from packing.
Following non-limiting examples is set forth inventor's preferred manufacturing procedure and is used the method for pharmaceutical composition of the present invention.
Embodiment 1
The usual method of preparation amorphous atorvastatin
Amorphous atorvastatin, the example of the unordered atorvastatin that uses as previously described and in the following embodiments, be according to attorney docket be the applicant of PC25825 U.S. Patent Application Serial Number of submitting to simultaneously _ _ _ _ disclosed process preparation, at first with Atorvastatin calcium (U.S. Patent No. 5,273,995) be dissolved in methanol, make 5% (w: w) solution.This solution is 170 gram/minute (g/min), uses nitrogen to be sprayed onto in the NiroPSD-1 spray dryer as atomization gas with speed.Inlet temperature is 195 ℃, and outlet temperature is 60 ℃.After the spray drying,, obtain amorphous atorvastatin with powder tray dried 12 hours in 40 ℃ of baking ovens.
Embodiment 2
Use the amorphous atorvastatin calcium sheet of the no disintegrating agent of wet granulation preparation
Will be as amorphous atorvastatin calcium (1.3g), 39.0g microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 50.7g lactose hydrous (Foremost Farms USA, Rothschild, WI) and 2.0g hydroxypropyl cellulose (Klucel EXF TM, Hercules Incorporated, Aqualon Division, Wilmington DE) is incorporated in the 500cc bottle, utilizes Turbula vibration mixer (Willy A.Bachofen AG Maschinenfabrik, Basel Switzerland) mixed 10 minutes.(Pro-C-epT n.v., B-9060Zelzate Belgium) use the cylinder of 0.9L will form the thing pelletize to utilize Pro-C-epT Mi Mi Pro high shear wet granulator then.Change per minutes (rpm) in impeller speed 400, under the cutting knife speed 1000rpm, with preparation dry mixed 2 minutes.Moistening mixing is carried out under 600rpm impeller speed and 1000rpm cutting knife speed.Utilize standard 60cc syringe to add the water that amounts to 45g by 20-30g/min with the 10-30g increment.Make the moistening hash total of raw material 2.5 minutes.With hands that granule is moistening by the #10 mesh sieve, to reach more homogeneous granules size, dry then.The dried machine of forced heated air (Gruenberg Forced Hot Air Oven, GruenbergOven Co., Williamsport, PA) in, granule is reached 16 hours 50 ℃ of following pallet dried overnight.Utilize then Fitzpatrick L1A mill (Fitzpatrick Co., Elmhurst IL) use 0.040 " Conidur filing board, the rotating speed 500rpm granule of milling.The atorvastatin lactone level of following analysis raw material (based on the ratio that utilizes HPLC gained lactone peak integration with total peak integral area), (v: v) 0.05M ammonium citrate buffer (pH7.4): acetonitrile added the 400mg granule, vibrates 20 minutes to 50mL 1: 1.Then prepared using Gelman Acrodisc poly tetrafluoroethylene (0.45 μ m aperture) is filtered, utilize high performance liquid chromatography (HPLC) to analyze (Pheomenex, Ultremex C18 post, 5 μ m particle diameters, 25.0cm * 4.6mm, HPLC Waters 2690D, Waters Corp., Milford, MA, 20 μ l volume injected, flow velocity 1.5mL/min, mobile phase 53: 27: 20 (v: v: v) 0.05M ammonium citrate (pH4.0): acetonitrile: oxolane, utilize Waters 2487 detectors under 244nm, to detect).The result is reported in the table 1.Tablet is made by handwork to utilize single station Manesty F-Press (Manesty, Liverpool, United Kingdom).Utilize 13/32 " recessed (SRC) drift of standard round and punch die production tablet, every heavy 450mg.The target tablet hardness is 12kP, and its scope is 10-14kP (utilizing Schleuniger tablet hardness tester, Dr.Schleuniger Pharmatron AG, Solothurn, Switzerland test tablet hardness).
Embodiment 3
Use the wet granulation preparation to contain the amorphous atorvastatin calcium of cross-linking sodium carboxymethyl cellulose
Will be as amorphous atorvastatin calcium (1.3g), 39.0g microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 50.7g lactose hydrous (Foremost Farms USA, Rothschild, WI), 3.0g cross-linking sodium carboxymethyl cellulose (Ac-Di-Sol TM, FMC Biopolymer, Philadelphia is PA) with 2.0g hydroxypropyl cellulose (KlucelEXF TM, Hercules Incorporated, Aqualon Division, Wilmington DE) is incorporated in the 500cc bottle, utilizes Turbula vibration mixer (Willy A.Bachofen AGMaschinenfabrik, Basel Switzerland) mixed 10 minutes.(Pro-C-epT n.v., B-9060Zelzate Belgium) use the cylinder of 0.9L will form the thing pelletize to utilize Pro-C-epT Mi MiPro high shear wet granulator then.Change per minutes (rpm) in impeller speed 400, under the cutting knife speed 1000rpm, with preparation dry mixed 2 minutes.Moistening mixing is carried out under 600rpm impeller speed and 1000rpm cutting knife speed.Utilize standard 60cc syringe to add the water that amounts to 60g by 20-30g/min with the 10-30g increment.Make the moistening hash total of raw material 5.5 minutes.With hands that granule is moistening by the #10 mesh sieve, to reach more homogeneous granules size, dry then.The dried machine of forced heated air (Gruenberg Forced HotAir Oven, Gruenberg Oven Co., Williamsport, PA) in, granule is reached 16 hours 50 ℃ of following pallet dried overnight.Utilize Fitzpatrick L1A to mill then and use 0.040 " Conidur filing board, the rotating speed 500rpm granule of milling.As analysis raw material as described in the embodiment 2, the result is reported in the table 1.
Embodiment 4
Use the wet granulation preparation to contain the amorphous atorvastatin calcium of primojel
Will be as amorphous atorvastatin calcium (1.3g), 39.0g microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 50.7g lactose hydrous (Foremost Farms USA, Rothschild, WI), 3.0g primojel (Explotab TM, Penwest Pharmaceuticals Co., Cedar Rapids is IA) with 2.0g hydroxypropyl cellulose (KlucelEXF TM, Hercules Incorporated, Aqualon Division, Wilmington DE) is incorporated in the 500cc bottle, utilizes Turbula vibration mixer (Willy A.Bachofen AGMaschinenfabrik, Basel Switzerland) mixed 10 minutes.(Pro-C-epT n.v., B-9060Zelzate Belgium) use the cylinder of 0.9L will form the thing pelletize to utilize Pro-C-epT Mi MiPro high shear wet granulator then.Change per minutes (rpm) in impeller speed 400, under the cutting knife speed 1000rpm, with preparation dry mixed 2 minutes.Moistening mixing is carried out under 600rpm impeller speed and 1000rpm cutting knife speed.Utilize standard 60cc syringe to add the water that amounts to 55g by 20-30g/min with the 10-30g increment.Make the moistening hash total of raw material 5.5 minutes.With hands that granule is moistening by the #10 mesh sieve, to reach more homogeneous granules size, dry then.The dried machine of forced heated air (Gruenberg Forced HotAir Oven, Gruenberg Oven Co., Williamsport, PA) in, granule is reached 16 hours 50 ℃ of following pallet dried overnight.Utilize Fitzpatrick L1A to mill then and use 0.040 " Conidur filing board, the rotating speed 500rpm granule of milling.As analysis raw material as described in the embodiment 2, the result is reported in the table 1.
Embodiment 5
Use the wet granulation preparation to contain the amorphous atorvastatin calcium of corn starch
Will be as amorphous atorvastatin calcium (1.3g), 39.0g microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TMFMC Biopolymer, Philadelphia, PA), 50.7g lactose hydrous (Foremost Farms USA, Rothschild, WI), (National Starchand Chemical Corp., Bridgewater is NJ) with 2.0g hydroxypropyl cellulose (Klucel EXF for 3.0g corn starch-purity 21 TM, Hercules Incorporated, Aqualon Division, Wilmington DE) is incorporated in the 500cc bottle, utilizes Turbula vibration mixer (Willy A.Bachofen AG Maschinenfabrik, Basel Switzerland) mixed 10 minutes.(Pro-C-epT n.v., B-9060Zelzate Belgjum) use the cylinder of 0.9L will form the thing pelletize to utilize Pro-C-epTMi Mi Pro high shear wet granulator then.Change per minutes (rpm) in impeller speed 400, under the cutting knife speed 1000rpm, with preparation dry mixed 2 minutes.Moistening mixing is carried out under 600rpm impeller speed and 1000rpm cutting knife speed.Utilize standard 60cc syringe to add the water that amounts to 45g by 20-30g/min with the 10-30g increment.Make the moistening hash total of raw material 2.5 minutes.With hands that granule is moistening by the #8 mesh sieve, to reach more homogeneous granules size, dry then.The dried machine of forced heated air (Gruenberg Forced Hot Air Oven, Gruenberg OvenCo., Williamsport, PA) in, granule is reached 16 hours 50 ℃ of following pallet dried overnight.Utilize Fitzpatrick L1A to mill then and use 0.040 " Conidur filing board, the rotating speed 500rpm granule of milling.As analysis raw material as described in the embodiment 2, the result is reported in the table 1.
Embodiment 6
Use the wet granulation preparation to contain the amorphous atorvastatin calcium of pregelatinized starch
Will be as amorphous atorvastatin calcium (1.3g), 39.0g microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 50.7g lactose hydrous (Foremost Farms USA, Rothschild, WI), (Starch 1500 for the 3.0g pregelatinized starch, Colorcon, West Point is PA) with 2.0g hydroxypropyl cellulose (Klucel EXF TM, HerculesIncorporated, Aqualon Division, Wilmington DE) is incorporated in the 500cc bottle, utilizes Turbula vibration mixer (Willy A.Bachofen AG Maschinenfabrik, Basel Switzerland) mixed 10 minutes.(Pro-C-epT n.v., B-9060Zelzate Belgium) use the cylinder of 0.9L will form the thing pelletize to utilize Pro-C-epT Mi Mi Pro high shear wet granulator then.Change per minutes (rpm) in impeller speed 400, under the cutting knife speed 1000rpm, with preparation dry mixed 2 minutes.Moistening mixing is carried out under 600rpm impeller speed and 1000rpm cutting knife speed.Utilize standard 60cc syringe to add the water that amounts to 40g by 20-30g/min with the 10-30g increment.Make the moistening hash total of raw material 3 minutes.With hands that granule is moistening by the #8 mesh sieve, to reach more homogeneous granules size, dry then.The dried machine of forced heated air (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) in, granule is reached 16 hours 50 ℃ of following pallet dried overnight.Utilize Fitzpatrick L1A to mill then and use 0.040 " Conidur filing board, the rotating speed 500rpm granule of milling.As analysis raw material as described in the embodiment 2, the result is reported in the table 1.
Embodiment 7
Use the wet granulation preparation to contain the amorphous atorvastatin calcium of sodium alginate
Will be as amorphous atorvastatin calcium (40.5mg), 1.22g microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 1.58g lactose hydrous (Foremost Farms USA, Rothschild, WI), 93.9mg sodium alginate (Protanal TM, FMCBioPolymer, Philadelphia is PA) with 62.4mg hydroxypropyl cellulose (Klucel EXF TM, HerculesIncorporated, Aqualon Division, Wilmington DE) is incorporated in the 30cc bottle, and (Willy A.Bachofen AG Maschinenfabrik, Basel Switzerland) mixed 10 minutes to utilize Turbula vibration mixer.Utilizing then on the miniature drill press of speed change and have 1/2 " (Sonora is CA95370) with mixture pelletize in the 30cc bottle for Micro-Drill model 164C-7, Cameron Precision Engineering Co. for the crooked micro-spatula impeller of blade.Before use, to the angle that is enough to sweep to the granulation raw material, allow this feed stream of a part bending blade through vane tip.With bending blade to departing from vertical about 30 ° angle.Move the pelletize fluid with the suction of 1.0 to 0.5mL increments, moistening mixing 2.5 minutes is until form suitable granule (amount to and add 1.5mL) based on perusal.The dried machine of forced heated air (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) in, with granule 50 ℃ of following tray dried 16 hours.As analysis raw material as described in the embodiment 2, the result is reported in the table 1.
Embodiment 8
Use the wet granulation preparation to contain the amorphous atorvastatin calcium of alginic acid
Will be as amorphous atorvastatin calcium (40.5mg), 1.22g microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 1.58g lactose hydrous (Foremost Farms USA, Rothschild, WI), 93.9mg alginic acid (Protacid TM, FMCBioPolymer, Philadelphia is PA) with 62.4mg hydroxypropyl cellulose (Klucel EXF TM, HerculesIncorporated, Aqualon Division, Wilmington DE) is incorporated in the 30cc bottle, and (Willy A.Bachofen AG Maschinenfabrik, Basel Switzerland) mixed 10 minutes to utilize Turbula vibration mixer.Utilizing then on the miniature drill press of speed change and have 1/2 " (Sonora is CA95370) with mixture pelletize in the 30cc bottle for Micro-Drill model 164C-7, Cameron Precision Engineering Co. for the crooked micro-spatula impeller of blade.Before use, to the angle that is enough to sweep to the granulation raw material, allow this feed stream of a part bending blade through vane tip.With bending blade to departing from vertical about 30 ° angle.Move the pelletize fluid with the suction of 1.0 to 0.5mL increments, moistening mixing 2.5 minutes is until form suitable granule (amount to and add 1.5mL) based on perusal.The dried machine of forced heated air (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) in, with granule 50 ℃ of following tray dried 16 hours.As analysis raw material as described in the embodiment 2, the result is reported in the table 1.
Embodiment 9
Use the wet granulation preparation to contain the amorphous atorvastatin calcium of Powderd cellulose
Will be as amorphous atorvastatin calcium (40.5mg), 1.22g microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 1.58g lactose hydrous (Foremost Farms USA, Rothschild, WI), 93.9mg Powderd cellulose (Solka-Floc40NF TM, International Fiber Corp., North Tonawanda is NY) with 62.4mg hydroxypropyl cellulose (Klucel EXF TM, Hercules Incorporated, Aqualon Division, Wilmington DE) is incorporated in the 30cc bottle, and (Willy A.Bachofen AGMaschinenfabrik, Basel Switzerland) mixed 10 minutes to utilize Turbula vibration mixer.Utilizing then on the miniature drill press of speed change and have 1/2 " (Sonora is CA95370) with mixture pelletize in the 30cc bottle for Micro-Drill model 164C-7, CameronPrecision Engineering Co. for the crooked micro-spatula impeller of blade.Before use, to the angle that is enough to sweep to the granulation raw material, allow this feed stream of a part bending blade through vane tip.With bending blade to departing from vertical about 30 ° angle.Move the pelletize fluid with the suction of 1.0 to 0.5mL increments, moistening mixing 2.5 minutes is until form suitable granule (amount to and add 1.5mL) based on perusal.The dried machine of forced heated air (Gruenberg Forced Hot Air Oven, Gruenberg OvenCo., Williamsport, PA) in, with granule 50 ℃ of following tray dried 16 hours.As analysis raw material as described in the embodiment 2, the result is reported in the table 1.
Embodiment 10
Use the wet granulation preparation to contain the amorphous atorvastatin calcium of hydroxypropyl cellulose
Will be as amorphous atorvastatin calcium (40.5mg), 1.22g microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TMFMC Biopolymer, Philadelphia, PA), 1.58g lactose hydrous (Foremost Farms USA, Rothschild, WI), 93.9mg hydroxypropyl cellulose (low level, the Shin-Etsu Chemical Co. of replacing, Tokyo is Japan) with 62.4mg hydroxypropyl cellulose (Klucel EXF TM, Hercules Incorporated, Aqualon Division, Wilmington DE) is incorporated in the 30cc bottle, utilizes Turbula vibration mixer (Willy A.Bachofen AG Maschinenfabrik, Basel Switzerland) mixed 10 minutes.Utilizing then on the miniature drill press of speed change and have 1/2 " (Sonora is CA95370) with mixture pelletize in the 30cc bottle for Micro-Drill model 164C-7, Cameron Precision EngineeringCo. for the crooked micro-spatula impeller of blade.Before use, to the angle that is enough to sweep to the granulation raw material, allow this feed stream of a part bending blade through vane tip.With bending blade to departing from vertical about 30 ° angle.Move the pelletize fluid with the suction of 1.0 to 0.5mL increments, moistening mixing 2.5 minutes is until form suitable granule (amount to and add 1.5mL) based on perusal.The dried machine of forced heated air (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) in, with granule 50 ℃ of following tray dried 16 hours.As analysis raw material as described in the embodiment 2, the result is reported in the table 1.
Embodiment 11
Use the wet granulation preparation to contain the amorphous atorvastatin calcium of Magnesiumaluminumsilicate
Will be as amorphous atorvastatin calcium (40.5mg), 1.22g microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 1.58g lactose hydrous (Foremost Farms USA, Rothschild, WI), 93.9mg Magnesiumaluminumsilicate (Veegum F TM, R.T.Vanderbilt Co., Norwalk is CT) with 62.4mg hydroxypropyl cellulose (Klucel EXF TM, HerculesIncorporated, Aqualon Division, Wilmington DE) is incorporated in the 30cc bottle, and (Willy A.Bachofen AG Maschinenfabrik, Basel Switzerland) mixed 10 minutes to utilize Turbula vibration mixer.Utilizing then on the miniature drill press of speed change and have 1/2 " (Sonora is CA95370) with mixture pelletize in the 30cc bottle for Micro-Drill model 164C-7, Cameron Precision Engineering Co. for the crooked micro-spatula impeller of blade.Before use, to the angle that is enough to sweep to the granulation raw material, allow this feed stream of a part bending blade through vane tip.With bending blade to departing from vertical about 30 ° angle.Move the pelletize fluid with the suction of 1.0 to 0.5mL increments, moistening mixing 2.5 minutes is until form suitable granule (amount to and add 1.5mL) based on perusal.The dried machine of forced heated air (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) in, with granule 50 ℃ of following tray dried 16 hours.As analysis raw material as described in the embodiment 2, the result is reported in the table 1.
Embodiment 12
Use the wet granulation preparation to contain the amorphous atorvastatin calcium of bohr Acree woods potassium
Will be as amorphous atorvastatin calcium (40.5mg), 1.22g microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 1.58g lactose hydrous (Foremost Farms USA, Rothschild, WI), 93.9mg bohr Acree woods potassium (AmberliteIRP88 TM, Rohm and Haas Co., Philadelphia is PA) with 62.4mg hydroxypropyl cellulose (Klucel EXF TM, Hercules Incorporated, Aqualon Division, Wilmington DE) is incorporated in the 30cc bottle, and (WillyA.Bachofen AGMaschinenfabrik, Basel Switzerland) mixed 10 minutes to utilize Turbula vibration mixer.Utilizing then on the miniature drill press of speed change and have 1/2 " (Sonora is CA95370) with mixture pelletize in the 30cc bottle for Micro-Drill model 164C-7, CameronPrecision Engineering Co. for the crooked micro-spatula impeller of blade.Before use, to the angle that is enough to sweep to the granulation raw material, allow this feed stream of a part bending blade through vane tip.With bending blade to departing from vertical about 30 ° angle.Move the pelletize fluid with the suction of 1.0 to 0.5mL increments, moistening mixing 2.5 minutes is until form suitable granule (amount to and add 1.5mL) based on perusal.The dried machine of forced heated air (Gruenberg Forced Hot Air Oven, Gruenberg OvenCo., Williamsport, PA) in, with granule 50 ℃ of following tray dried 16 hours.As analysis raw material as described in the embodiment 2, the result is reported in the table 1.
Table 1: by the influence of following raw material to pharmaceutical purity, described raw material is formed by the atorvastatin wet granulation with disintegrating agent in the granule
The embodiment sequence number Disintegrating agent Atorvastatin lactone % (measuring) according to HPLC
2 Contrast (not having disintegrating agent) 0.21
3 Cross-linking sodium carboxymethyl cellulose 5.47
4 Primojel 0.41
5 Corn starch 0.25
6 Pregelatinized starch 0.20
7 Sodium alginate 0.52
8 Alginic acid 15.71
9 Powderd cellulose 0.41
10 Hydroxypropyl cellulose 0.38
11 Magnesiumaluminumsilicate 0.12
12 Bohr Acree woods potassium 0.29
Embodiment 13
Utilization provides the method wet granulation of pure atorvastatin and some disintegrating agents to prepare atorvastatin and tablet thereof
In the 60cc bottle, add one of following disintegrating agent of 0.858g to 13.30g embodiment 2 prepared raw materials: (a) primojel; (b) cross-linking sodium carboxymethyl cellulose; (c) corn starch; Or (d) pregelatinized starch.Utilize Turbula vibration mixer that admixture was mixed 5 minutes.In each case, and adding 0.143g magnesium stearate in this admixture (Mallinckrodt Co., St.Louis, MO).Utilize Turbula vibration mixer with said preparation fusion 3 minutes then.As the lactone level of analysis raw material as described in the embodiment 2, the result is reported in the table 2.Tablet is made by handwork to utilize single station Manesty F-Press (Manesty, Liverpool, United Kingdom).Utilize 13/32 " SRC drift and punch die production tablet, every heavy 450mg.The target tablet hardness is 12kP, and its scope is 10-14kP (utilizing Schleuniger tablet hardness tester, Dr.Schleuniger Pharmatron AG, Solothurn, Switzerland test tablet hardness).As analysis raw material as described in the embodiment 2, the result is reported in the table 2.
Table 2: the outer disintegrating agent of granule is to the unexpected useful influence of atorvastatin wet granulation pharmaceutical purity
Embodiment Disintegrating agent Atorvastatin lactone % (measuring) according to HPLC
2 Contrast does not have disintegrating agent 0.21
13a Primojel 0.25
13b Cross-linking sodium carboxymethyl cellulose 0.24
13c Corn starch 0.24
13d Pregelatinized starch 0.24
Embodiment 14
There is not the contrast of the atorvastatin wet granulation of volatility alkali
Will be as amorphous atorvastatin calcium (62.1mg), 1772.1mg microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 1010.4mg lactose hydrous (Foremost Farms USA, Rothschild, WI), 62.1mg hydroxypropyl cellulose (KlucelEXF TM, Hercules Incorporated, Aqualon Division, Wilmington is DE) with 93.3mg cross-linking sodium carboxymethyl cellulose (Ac-Di-Sol TM, FMC Biopolymer, Philadelphia PA) is incorporated in the 30cc vial, and (Willy A.Bachofen AGMaschinenfabrik, Basel Switzerland) mix the dried ingredients that is merged 10 minutes to utilize Turbula vibration mixer.Utilizing then on the miniature drill press of speed change and have 1/2 " (Sonora is CA95370) with mixture pelletize in the 30cc bottle for Micro-Drillmodel 164C-7, Cameron Precision Engineering Co. for the crooked micro-spatula impeller of blade.Before use, to the angle that is enough to sweep to the granulation raw material, allow this feed stream of a part bending blade through vane tip.With bending blade to departing from vertical about 30 ° angle.Move the pelletize fluid with the suction of 0.5 to 1.0mL increment, moistening mixing 4 minutes is until form suitable granule (amount to and add 2.5mL) based on perusal.In the dried machine of forced heated air, granule is reached 16 hours 50 ℃ of following dried overnight.As the lactone level of analysis raw material as described in the embodiment 2, use the 275mg granule to replace 400mg.The result is reported in the table 3.
Embodiment 15
The wet granulation preparation contains the amorphous atorvastatin of volatility alkali
Will be as amorphous atorvastatin calcium (62.1mg), 1772.1mg microcrystalline Cellulose (the Avicel PH 102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 1010.4mg lactose hydrous (Foremost Farms USA, Rothschild, WI), 62.1mg hydroxypropyl cellulose (KlucelEXF TM, Hercules Incorporated, Aqualon Division, Wilmington is DE) with 93.3mg cross-linking sodium carboxymethyl cellulose (Ac-Di-Sol TM, FMC Biopolymer, Philadelphia PA) places the 30cc vial.(Willy A.Bachofen AG Maschinenfabrik, Basel Switzerland) mix the dried ingredients that is merged 10 minutes to utilize Turbula vibration mixer.Then as described in the above-mentioned contrast with mixture pelleting, use following volatility aqueous slkali to be used for test: (a) 2.5mL 30% ammonium hydroxide (J.T.Baker Co.), (b) 2.5mL 3% ammonium hydroxide, (c) 2.5mL 0.00012% ammonium hydroxide, (d) 2.0mL 40% TBAH (Mallinckrodt Co.).In the dried machine of forced heated air, granule is reached 16 hours 50 ℃ of following dried overnight.With regard to every duplicate samples,, use 150mg granule and 30mL extraction volume as the lactone level of analysis raw material as described in the embodiment 2.The result is reported in the table 3.
Table 3: add of the unexpected useful influence of the atorvastatin wet granulation of volatility alkali to pharmaceutical purity
Embodiment Volatility alkali Atorvastatin lactone % (measuring) according to HPLC
14 Contrast does not have alkali 4.35
15a 30% ammonium hydroxide 0.47
15b 3% ammonium hydroxide 0.46
15c 0.00012% ammonium hydroxide 2.75
15d 40% TBAH Be lower than and quantize limit (＜0.1%)
Embodiment 16
Wet granulation preparation exsiccant amorphous atorvastatin under different temperatures
Will be as amorphous atorvastatin calcium (40.5mg), 1218.8mg microcrystalline Cellulose (the Avicel PH102 of preparation as described in the embodiment 1 TM, FMC Biopolymer, Philadelphia, PA), the 1572.1mg lactose hydrous (Foremost Farms USA, Rothschild, WI), 62.5mg hydroxypropyl cellulose (KlucelEXF TM, Hercules Incorporated, Aqualon Division, Wilmington is DE) with 93.8mg primojel (Explotab TM, Penwest Pharmaceuticals Co., Cedar Rapids IA) places the 30cc vial.(Willy A.Bachofen AGMaschinenfabrik, Basel Switzerland) mix the dried ingredients that is merged 10 minutes to utilize Turbula vibration mixer.In the 125mL flask, merge 99g H 2O and 1g polyoxyethylene sorbitan monoleate (Tween 80 TM, Spectrum Chemicals﹠amp; Lab Products, Gardena CA), mixes, and makes excessive granulation liquid.Use the 2.5mL granulation liquid then, moistening mixing 4 minutes, as described in the embodiment 1 with the mixture of powders pelletize.Then wet granular is divided into three parts of parts that approximately equate.With each part under following condition dry 16 hours: (a) 30 ℃ of vacuum drying ovens, (b) 50 ℃ of convection oven and (c) 70 ℃ of vacuum drying ovens.With regard to each sample, the lactone level of following analysis raw material (based on the ratio that utilizes HPLC gained lactone peak integration with total peak integral area), (v: v: v) 0.05M ammonium acetate buffer (pH7.4): acetonitrile: oxolane added the 300mg raw material, vibrates 20 minutes to 1: 2: 2.This mixture is filtered with disposable 0.45 μ m poly tetrafluoroethylene (Whatman), analyze with HPLC that (HP 1100, Zorbax SB-C85 μ m particle diameter, 25.0cm * 4.6mm post, constant temperature to 35 ℃; Volume injected 20 μ L; Flow velocity 1.5mL/min; 244nm detects).Eluting adopts linear gradient, and (v: v: v) 0.05M ammonium acetate buffer (pH5.0): acetonitrile: oxolane began, (the v: v: v) (being 100% latter's mixture after 55 minutes) that transfers 54: 34: 12 to after 40 minutes by 67: 21: 12.The result is reported in the table 4.
Table 4: when dry at a lower temperature, the wet granulation of atorvastatin is to the unexpected useful influence of pharmaceutical purity
Embodiment Drying condition Atorvastatin lactone % (measuring) according to HPLC
16a 30 ℃ of vacuum drying ovens 0.25
16b 50 ℃ of convection oven 1.18
16c 70 ℃ of vacuum drying ovens 4.36

Claims (15)

1, the atorvastatin pharmaceutical composition of wet granulation, it contains the alkaline-earth metal salt additives that is less than about 5 weight %, and said composition comprises:
(a) atorvastatin or its officinal salt; With
(b) combination of disintegrating agent or disintegrating agent, the pharmaceutical composition of wherein said wet granulation contain based on the atorvastatin lactone that utilizes HPLC gained lactone peak area with the ratio of total medicine relevant peaks integral area no more than about 3%.
2, the wet granulation pharmaceutical composition of claim 1, wherein said compositions comprises the Tween 80 that is less than about 0.5 weight %.
3, the wet granulation pharmaceutical composition of claim 2, wherein said atorvastatin are some unordered or the crystallization of atorvastatin and the mixture of ordered form, perhaps its officinal salt at least.
4, by the unit dosage form of the wet granulation preparation of compositions of claim 1.
5, the unit dosage form of claim 4, wherein said unit dosage form are tablet or capsule.
6, the wet granulation pharmaceutical composition of claim 1, the combination of wherein said disintegrating agent or disintegrating agent account for about 1 to 10% (w: w) of described compositions.
7, according to the wet granulation pharmaceutical composition of claim 1, the combination of wherein said disintegrating agent or disintegrating agent is selected from primojel, starch, corn starch, pregelatinized starch, sodium alginate, Powderd cellulose, hydroxypropyl cellulose, Magnesiumaluminumsilicate and bohr Acree woods potassium.
8, according to the wet granulation pharmaceutical composition of claim 1, wherein said compositions also contains at least a active medicine except atorvastatin.
9, the method for the compositions of atorvastatin of preparation wet granulation, it comprises:
(a) merge atorvastatin or its officinal salt and primojel, starch, sodium alginate, Powderd cellulose, hydroxypropyl cellulose, Magnesiumaluminumsilicate or bohr Acree woods potassium or their combination, and other optional excipient;
(b) under shearing, in the atorvastatin admixture that obtains by step (a), add water, isopropyl alcohol, ethanol or their mixture of capacity, generate granule;
(c) randomly mill or sieve described wet granular;
(d) dry described granule;
(e) the described granule of randomly milling, grind or sieve;
(f) randomly sneak into other excipient; With
(g) randomly make resultant composition form unit dosage form.
10, the method for the compositions of atorvastatin of preparation wet granulation, it comprises:
(a) merge atorvastatin or its officinal salt and contain the diluent that is less than 2 weight % disintegrating agents;
(b) under shearing, in the atorvastatin admixture that obtains by step (a), add water, isopropyl alcohol, ethanol or their mixture of capacity, generate granule;
(c) randomly mill or sieve described wet granular;
(d) dry described granule;
(e) the described granule of randomly milling, grind or sieve;
(f) mix disintegrating agent and other optional excipient; With
(g) randomly make resultant composition form unit dosage form.
11, the method for the compositions of atorvastatin of preparation wet granulation, it comprises:
(a) merge atorvastatin or its officinal salt and one or more excipient;
(b) solution of volatility alkali in water, isopropyl alcohol or ethanol or their mixture of adding capacity under shearing generates granule;
(c) randomly mill or sieve described wet granular;
(d) dry described granule;
(e) the described granule of randomly milling, grind or sieve;
(f) randomly sneak into other excipient as required, make final compositions; With
(g) randomly make described compositions form unit dosage form.
12, preparation contains the method for unit dosage form of atorvastatin and at least a other active medicine, wherein will be according to the compositions and at least a other active medicine and other optional excipient merging of claim 9,10 or 11 method preparation.
13, the method for treatment hypercholesterolemia and/or hyperlipemia, osteoporosis, benign prostatic hyperplasia and Alzheimer, it comprises the pharmaceutical composition of the claim 1 for the treatment of effective dose.
14, in mammal, reach the test kit of therapeutic effect, the container that it comprises claim 1 pharmaceutical composition of the unit dosage form form of making for the treatment of effective dose and contains described dosage form.
15, the atorvastatin that contains according to the test kit of claim 14, it is some unordered or the crystallization of atorvastatin and the mixture of ordered form, perhaps its officinal salt at least.
CNB2004800163910A 2003-06-12 2004-06-01 Stable compositions of atorvastatin prepared with wet granulation Expired - Fee Related CN100434069C (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104069078A (en) * 2014-05-22 2014-10-01 安东 Atorvastatin calcium medicine composition and preparation method thereof

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI94339C (en) 1989-07-21 1995-08-25 Warner Lambert Co Process for the preparation of pharmaceutically acceptable [R- (R *, R *)] - 2- (4-fluorophenyl) -, - dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H- for the preparation of pyrrole-1-heptanoic acid and its pharmaceutically acceptable salts
GB0613925D0 (en) * 2006-07-13 2006-08-23 Unilever Plc Improvements relating to nanodispersions
AU2007355452B2 (en) * 2007-06-25 2011-12-15 Pharmathen S.A. Improved pharmaceutical formulation containing an HMG-CoA reductase inhibitor and method for the preparation thereof
CA2716671A1 (en) * 2008-02-27 2009-09-03 Thommen Medical Ag Implant and method for the manufacture thereof
WO2010033179A1 (en) * 2008-09-17 2010-03-25 Mylan Laboratories, Inc. Granulates, process for preparing them and pharmaceutical products containing them
HUP1000299A2 (en) 2010-06-08 2012-02-28 Nanoform Cardiovascular Therapeutics Ltd Nanostructured atorvastatin, its pharmaceutically acceptable salts and pharmaceutical compositions containing them and process for their preparation
IN2014CN04119A (en) 2011-11-15 2015-07-10 Reddys Lab Ltd Dr
EA202191301A1 (en) * 2014-07-25 2021-11-30 Новартис Аг COMPOSITION OF TABLETS 2-FLUORO-N-METHYL-4- [7- (QUINOLIN-6-YLMETHYL) IMIDAZO [1,2-b] [1,2,4] TRIAZIN-2-YL] BENZAMIDE
KR101658350B1 (en) * 2015-02-06 2016-09-30 경성대학교 산학협력단 Pharmaceutical Composition For Treating Hyperlipidaemia
EP3267977B1 (en) * 2015-03-12 2021-08-11 DuPont Nutrition USA, Inc. Solid dispersions
EP3437646A4 (en) 2016-03-31 2019-11-27 Intercept Pharmaceuticals, Inc. Oral preparation having exceptional elutability

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0680320B1 (en) * 1993-01-19 1999-04-14 Warner-Lambert Company Stable oral ci-981 formulation and process of preparing same
JPH06242003A (en) * 1993-02-12 1994-09-02 Nkk Corp Grain size measuring method for alumina in steel
JP3014040B2 (en) * 1996-10-30 2000-02-28 信久 川野 Dietary fiber bread and method for producing the same
IL152179A (en) * 2000-04-10 2009-06-15 Teva Pharma Stable pharmaceutical compositions containing 7-substituted-3,5- dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids
US6242003B1 (en) * 2000-04-13 2001-06-05 Novartis Ag Organic compounds
EP1226818A1 (en) * 2001-01-26 2002-07-31 Pfizer Products Inc. Pharmaceutical dosage forms with enhanced cohesive and compressibility properties
SI20848A (en) * 2001-03-14 2002-10-31 Lek, Tovarna Farmacevtskih In Kemijskih Izdelkov, D.D. Pharmaceutical formulation containing atorvastatin calcium

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104069078A (en) * 2014-05-22 2014-10-01 安东 Atorvastatin calcium medicine composition and preparation method thereof
CN104069078B (en) * 2014-05-22 2019-06-11 西藏九瑞健康股份有限公司 Atorvastatin calcium medicine compound and preparation method thereof

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