KR100814218B1 - Stable compositions of atorvastatin prepared with wet granulation - Google Patents

Abstract

The present invention comprises less than about 3% of atorvastatin lactones based on the ratio of the lactone peak area to the total drug-related peak cumulative area, and less than about 5% by weight of alkaline earth metal salt additives with disintegrants providing atorvastatin Wet granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof, wherein said wet granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof, together with one or more other active drugs, preparation of said composition Methods, kits containing such compositions, and methods of treating hypercholesterolemia and / or hyperlipidemia, osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease using therapeutically effective amounts of pharmaceutical compositions It is about.

Atorvastatin, wet granulation, unit dosage form, alkaline earth metal salt additive, disintegrant, volatile base, drying temperature

Description

STABLE COMPOSITIONS OF ATORVASTATIN PREPARED WITH WET GRANULATION

Cross-Reference to the Related Application

This application claims priority to US Provisional Application No. 60 / 478,119, filed June 12, 2003.

The present invention relates to pharmaceutical compositions comprising atorvastatin and pharmaceutically acceptable salts thereof, methods of making the same, kits containing such compositions, and hypercholesterolemia and / or hyperlipidemia, osteoporosis, benign prostate using such compositions A method of treating an individual suffering from hypertrophy (BPH) and Alzheimer's disease.

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an initial rate-limiting step in the cholesterol biosynthetic pathway. This step is facilitated by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from promoting this conversion. Thus, statins are collectively potent lipid lowering agents.

The atorvastatin calcium described in US Pat. No. 5,273,995, incorporated herein by reference, has the chemical name [R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydride Roxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptano acid calcium salt (2: 1) trihydrate and Lipitor having the formula It is currently marketed as Li (Lipitor, registered trademark).

Atorvastatin and its pharmaceutically acceptable salts are selective and competitive inhibitors of HMG-CoA reductase. As such, atorvastatin calcium is a potent lipid-lowering compound and therefore useful as a hyperlipidemic and / or hypercholesterolemic agent and for the treatment of osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease.

Numerous patents have been issued describing atorvastatin, preparations of atorvastatin and methods of making atorvastatin and key intermediates for the preparation. These include US Pat. 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, which are incorporated herein by reference.

Atorvastatin can exist in crystalline, liquid crystalline, non-crystalline and amorphous forms.

Crystalline forms of atorvastatin calcium are described in US Pat. Nos. 5,969,156 and 6,121,461, which are incorporated herein by reference. Additional crystalline forms of atorvastatin are described in US Pat. No. 6,605,729, which is incorporated herein by reference.

In addition, many published international patent applications describe crystalline forms of atorvastatin and methods for preparing amorphous atorvastatin. These include WO 00/71116; WO 01/28999; WO 01/36384; WO 01/42209; WO 02/41834; WO 02/43667; WO 02/43732; WO 02/051804; WO 02/057228; WO 02/057229; WO 02/057274; WO 02/059087; WO 02/083637; WO 02/083638; WO 03/011826; WO 03/050085; WO 03/070702; And WO 04/022053.

Amorphousities of many drugs have been shown to show different dissolution properties compared to crystalline forms and in some cases different bioavailability patterns (Konno, T., Chem. Pharm. Bull. , 1990; 38 : 2003-2007) . For some therapeutic indications, one bioavailability pattern may be more desirable than another.

Depending on the change in dissolution rate, it may be advantageous to prepare the atorvastatin preparation in crystalline or amorphous form. For example, potential uses of some of the atorvastatin (eg, Takemoto, M .; Node, K .; Nakagami, H .; Liao, Y .; Grimm, M .; Takemoto, Y .; Kitakaze, M For the acute treatment of patients with stroke, as described in Liao, JK, Journal of Clinical Investigation , 2001; 108 (10): 1429-1437). Can be.

Methods of preparing solid formulations of atorvastatin are described in US Pat. Nos. 5,686,104 and 6,126,971. In the methods described in these patents, atorvastatin is combined with stabilizing additives and excipients, such as alkaline earth metal salts, and wet granulated using a combination of water and surfactant (Tween ™ 80). Since alkaline earth metal salt additives can affect atorvastatin bioavailability, there remains a need to provide atorvastatin in wet granulated compositions that are substantially free of alkaline earth metal salt additives. Likewise, it may be desirable to minimize the use of alkalizer additives in the composition of atorvastatin to avoid potential bioavailability issues and to avoid interactions when the drug is used in combination dosage forms with other drugs.

At the same time, co-owned U.S. patent application, agent case number PC25684, describes a unit dosage form comprising atorvastatin or a pharmaceutically acceptable salt thereof prepared without a granulation step, and agent case number PC25686 describes atorvastatin or its pharmaceutical Dry granulated pharmaceutical compositions are described that include acceptable salts.

In preparing and storing dosage forms of atorvastatin, it is important to provide the active drug in pure form. Moreover, it may be desirable to obtain such high purity and stability using as simple a formulation as possible. There is a need to provide simple formulations of unit dosage forms of atorvastatin with low levels of impurities and methods for their preparation. There is also a need to provide atorvastatin formulations suitable for unit dosage forms in which minimal alkalinizing agent is added to provide adequate drug purity, stability, and desired dissolution rate and bioavailability.

One preferred unit dosage form for atorvastatin is a tablet. In the case of active drugs in tablets that must be rapidly absorbed once swallowed, it is generally important to allow the tablets to disintegrate rapidly upon exposure to fluid in the gastrointestinal tract. At the same time, it is important that the tablets are hard enough so that they do not break or cut during manufacture, handling or storage. These apparently contradictory needs can be met by the addition of disintegrants to the composition. A number of disintegrants for compositions of atorvastatin comprising calcium carboxymethylcellulose, starch and croscarmellose sodium are disclosed in the prior art (see US Pat. Nos. 5686014 and 6126971). When atorvastatin is used with minimal levels of alkaline additives or alkaline earth metal salt additives, the inventors have surprisingly found in standard wet granulation methods that only certain disintegrants provide tablets of atorvastatin with an acceptable purity. This is particularly unexpected because the disintegrants (crosscarmellose sodium) used in commercial formulations have been found to be unacceptable in wet granulation of amorphous atorvastatin with minimal addition of alkaline or alkaline earth metal salt additives. Moreover, this stability remains unexpected even when atorvastatin is amorphous. In addition to improving the formulation, the inventors have developed a wet granulation method that can incorporate a disintegrant into a formulation that provides atorvastatin with high purity, even in the case of a disintegrant which provides inferior stability by standard methods.

The inventors further found that the purity of the drug can be improved by adding volatile base to the granulation solvent when using wet granulation of atorvastatin (particularly amorphous atorvastatin). These volatile bases provide improved purity of the drug in the dosage form, but they are not present in the final dosage form and thus do not affect bioavailability.

Accordingly, it is an object of the present invention to provide a stable dosage form of atorvastatin with good disintegration rate and bioavailability. It is a further object of the present invention to provide a stable and pure composition of atorvastatin with a minimum level of alkaline earth metal salt additive or other added alkalizing agent in the composition.

Summary of the Invention

Accordingly, a first aspect of the invention provides a pharmaceutical composition comprising (a) atorvastatin or a pharmaceutically acceptable salt thereof; And (b) a disintegrant or a combination of disintegrants, containing up to about 3% of atorvastatin lactone based on the ratio of the lactone peak area to total drug-related peak cumulative area using HPLC, A wet granulated pharmaceutical composition of atorvastatin having less than about 5% by weight alkaline earth metal salt additive.

A second aspect of the present invention provides a pharmaceutical composition comprising (a) atorvastatin or a pharmaceutically acceptable salt thereof in combination with at least one active drug; And (b) a disintegrant or a combination of disintegrants, containing about 3% or less of atorvastatin lactone based on the ratio of the lactone peak area to the total drug-related peak cumulative area using HPLC; A wet granulated pharmaceutical composition of atorvastatin having an alkaline earth metal salt additive of less than%.

A third aspect of the present invention provides a method for preparing a atorvastatin or a pharmaceutically acceptable salt thereof, which comprises sodium starch glycolate, starch, sodium alginate, powdered cellulose, hydroxypropylcellulose, magnesium aluminum silicate or polyacrylic potassium or a combination thereof. , And optionally in combination with other excipients; (b) adding sufficient water, isopropanol, ethanol or mixtures thereof under shear to the atorvastatin blend from step (a) to produce granules; (c) optionally milling or sieving the wet granules; (d) drying the granules; (e) optionally milling, grinding or sieving the granules; (f) optionally mixing with other excipients; And (g) optionally forming the composition in unit dosage form.

A fourth aspect of the present invention provides a method for preparing a pharmaceutical composition comprising (a) combining atorvastatin or a pharmaceutically acceptable salt thereof with a diluent having less than 2% by weight of a disintegrant; (b) adding sufficient water, isopropanol, ethanol or mixtures thereof under shear to the atorvastatin blend from step (a) to produce granules; (c) optionally milling, milling or sieving the wet granules; (d) drying the granules; (e) optionally milling, milling or sieving the granules; (f) mixing with a disintegrant and optionally other excipients; And (g) optionally forming the composition in unit dosage form.

A fifth aspect of the present invention provides a method of preparing a pharmaceutical composition comprising (a) combining atorvastatin or a pharmaceutically acceptable salt thereof, and at least one excipient; (b) adding a solution of sufficient amount of volatile base dissolved in water, isopropanol, ethanol or mixtures thereof under shear to produce granules; (c) optionally milling, milling or sieving the wet granules; (d) drying the granules; (e) optionally milling, milling or sieving the granules; (f) optionally mixing with other excipients as needed to produce a final composition; And (g) optionally forming the composition in unit dosage form.

A sixth aspect of the present invention provides a method for preparing a atorvastatin or a pharmaceutically acceptable salt thereof in combination with at least one active drug, including sodium starch glycolate, starch, sodium alginate, powdered cellulose, hydroxypropylcellulose, magnesium aluminum silicate. Or combining with polyacrylic potassium or a combination thereof, and optionally other excipients; (b) adding sufficient water, isopropanol, ethanol or mixtures thereof under shear to the atorvastatin blend from step (a) to produce granules; (c) optionally milling or sieving the wet granules; (d) drying the granules; (e) optionally milling, milling or sieving the granules; (f) optionally mixing with other excipients; And (g) optionally forming the composition in unit dosage form.

A seventh aspect of the present invention provides a method of preparing a pharmaceutical composition comprising (a) combining atorvastatin or a pharmaceutically acceptable salt thereof in combination with at least one active drug with a diluent having a disintegrant of less than 2% by weight; (b) adding sufficient water, isopropanol, ethanol or mixtures thereof under shear to the atorvastatin blend from step (a) to produce granules; (c) optionally milling, milling or sieving the wet granules; (d) drying the granules; (e) optionally milling, milling or sieving the granules; (f) admixing with a disintegrant, and optionally other excipients; And (g) optionally forming the composition in unit dosage form.

An eighth aspect of the present invention provides a method comprising the steps of: (a) combining atorvastatin or a pharmaceutically acceptable salt thereof with one or more active drugs and one or more excipients; (b) adding a solution of sufficient amount of volatile base dissolved in water, isopropanol, ethanol or mixtures thereof under shear to produce granules; (c) optionally milling, milling or sieving the wet granules; (d) drying the granules; (e) optionally milling, milling or sieving the granules; (f) optionally mixing with other excipients as needed to produce a final composition; And (g) optionally forming the composition in unit dosage form.

A ninth aspect of the invention comprises a therapeutically effective amount of a tablet or capsule prepared from a wet granulated composition of atorvastatin prepared in unit dosage form from the composition, and a container for containing the dosage form. Kits for achieving a therapeutic effect.

A tenth aspect of the invention is a method of using the pharmaceutical composition to treat an individual suffering from hypercholesterolemia and / or hyperlipidemia, osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease.

Detailed description of the invention

Atorvastatin can be readily prepared as described in US Pat. Nos. 4,681,893, 5,273,995 and 5,969,156, which are incorporated herein by reference. Hemicalcium salts of atorvastatin are currently sold under Lipitor®.

Atorvastatin exists in many morphological forms, from highly crystalline forms to forms with varying degrees of disorder. Some of these disordered forms still have some structure, as indicated by the powder x-ray diffraction pattern. For the purposes of the present invention, all forms of atorvastatin are beneficial according to the invention and are included within the scope of the invention. Less ordered forms of atorvastatin, in particular amorphous or markedly amorphous forms, are particularly advantageous according to the invention. Such forms can be prepared from crystalline materials, for example, using the methods described in US Pat. No. 6,087,511, which is incorporated herein by reference. Alternatively, the amorphous atorvastatin material may be prepared according to the method described in co-owned US patent application attorney no. PC25825. For the practice of the present invention, non-crystalline and crystalline atorvastatin can be prepared by any method known in the art. A non-limiting list of patents and published patent applications describing atorvastatin in preferred forms of the present invention is as follows: US Patent No. 5,969,156; US Patent No. 6,121,461; US Patent No. 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 of these patents and applications are incorporated herein by reference.

Atorvastatin can be used in the form in which it is prepared, or can be applied to methods of changing the physical properties of a particle. For example, the material can be milled using any method known in the art. Non-limiting examples of such methods include mechanical grinding and jet grinding. The particles produced directly from the process of forming the non-crystalline atorvastatin or after the grinding operation preferably give an average particle diameter in the range of 1-200 μm, more preferably 5 to 150 μm.

Pharmaceutically acceptable base addition salts of atorvastatin are formed using metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (see, eg, Berge, SM et. al., “Pharmaceutical Salts”, J. Pharm. Sci. , 1977; 66 : 1).

Base addition salts of atorvastatin are prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to produce a salt. The free acid form can be regenerated by contacting the salt form with an acid and separating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but in other ways the salts correspond to their respective free acids for the purposes of the present invention.

In addition, atorvastatin may be present in unsolvated as well as solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, are intended to be included within the scope of the present invention.

The most significant benefit according to the invention is at least a somewhat disordered form of atorvastatin or a mixture of crystalline and disordered forms of atorvastatin. Somewhat disordered means that the line width (peak width at half the peak height) of any peak, measured using powder x-ray diffraction (PXRD), has a 2 theta value greater than about 2 °. Means that. Particularly advantageous amorphous or markedly amorphous forms of atorvastatin according to the invention are characterized by having very broad and uncharacteristic peaks. It should be noted that the combination of the crystalline and at least somewhat disordered form of atorvastatin will exhibit both sharp (ie less than 2 ° for 2 theta) and broad (ie greater than 2 °) peaks, Combinations are also beneficial in accordance with the present invention.

Atorvastatin has been shown to be an effective drug even at relatively low doses. Indeed, by keeping the dose low for a given patient, side effects can be minimized while still maintaining the efficacy of the drug. Thus, atorvastatin is preferably provided in a form that can provide a low dose to the patient. For the purposes of the present invention, the dose provided by the final dosage form of atorvastatin is preferably from 0.5 to 120 mgA (wherein mgA means milligrams of active drug based on the free acid), more preferably Preferably 5 to 80 mgA.

For convenience and ease of patient compliance, most drugs are delivered in unit dosage form. In the case of solid drug components, these unit dosage forms are generally in the form of tablets and capsules. In the present invention, the dosage form is preferably in the form of a capsule or tablet; Most preferably in the form of a tablet. Preparation of these forms involves the necessary steps of filling the mold or capsule with the powder. The unit dosage form has an equivalent effect within the allowable margin (relative standard deviation of less than 6% meets Stage I of the USP Directive and less than 7.8% meets Stage II). In order to have it, there should be no significant separation of formulation components. For this reason, it may be desirable to granulate atorvastatin, especially when drugs are used at low doses. Wet granulation combines the drug with excipients, thereby minimizing any separation tendency.

The present invention describes wet granulation methods and formulations that provide atorvastatin in pure and stable form. The term “impurity” refers to all drug-based substances formed in the preparation of unit dosage forms and substances in drug components present from the synthesis and purification processes. The term "degradant" refers to all drug-based materials produced after the preparation of a unit dosage form (during the shelf life of the dosage form). Analysis of impurities and degradation products is performed using reverse phase high performance liquid chromatography (HPLC) techniques on extracted samples as is known in the art. The calculation of the amount of impurities and degradation products is expressed as the percent of the cumulative area of all peaks other than the drug peak divided by the percent of the cumulative area of all peaks, or, where possible, based on the coefficient of response to the accumulation of peaks from a sample of certified material. Is expressed.

The combination of diluents, binders, disintegrants, lubricants, and other additives known in the art in the preparation of atorvastatin by wet granulation provides the necessary properties for unit dosage forms as is known in the art. For example, when preparing tablets, the formulation provides adequate tablet hardness upon compression while providing rapid disintegration in vivo. While there is a wide range of tolerances for formulating atorvastatin to meet these conditions, generally such tablet formulations are about 1-40% by weight with bulk containing diluents and / or other ingredients. (w: w) drug, about 1-15% disintegrant, about 0-10% binder and about 0.5-2% lubricant. Preferred binders include carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, dextrin, gelatin, guar gum, hydroxypropyl methylcellulose, maltodextrin, methylcellulose, polyethylene oxide, polymethacrylate and sodium alginate ; Particularly preferred binder is hydroxypropylcellulose. Preferred lubricants are magnesium stearate. Preferred diluents are calcium phosphate, calcium sulfate, cellulose acetate, dextrate, dextrin, dextrose, fructose, kaolin, lactitol, lactose, maltitol, maltodextrin, maltose, microcrystalline cellulose, polymethacrylate, powder Cellulose cellulose, silicified microcrystalline cellulose, sodium chloride, sorbitol, sucrose and talc.

In practicing the present invention, the level of alkaline earth metal salt additive in the composition is preferably about 0-5% (w: w); More preferably about 0-3%; Most preferably about 0-2%. Also, preferably, the level of other alkalizer additives in the composition is about 0-5% (w: w); More preferably about 0-3%; Most preferably about 0-2%. In addition, the amine polymer and the amide polymer are less than about 0-5% (w: w) of the formulation; More preferably about 0-3%; Most preferably about 0-2%. Examples of such polymers are described in international patent application WO 01 / 76566A1.

Alkalizing agents are additives or excipients which have the property of increasing the pH of the preparation when said preparation is added to water. Examples of alkalizing agents include inorganic and organic bases (buffers). Examples of inorganic alkalizing agents include sodium or potassium citrate, carbonates, bicarbonates, phosphates, sulfates, benzoates and ascorbates, and calcium carbonates and magnesium carbonates. The latter two examples also represent alkaline earth metal salts. Examples of organic alkalizing agents include amines. Specific examples of amines include N-methylglucamine, guanine and arginine.

In preparing the atorvastatin composition by wet granulation, any method known in the art for wet granulation can be used for the purposes of the present invention. An important factor in these methods is to put the powder blend under shear while adding the granulation solution to the atorvastatin composition. Shear acts to break the initial clump, thus providing more uniform granulation. Non-limiting examples of shearing methods include high shear wet granulation, fluidized bed granulation, extrusion granulation and low shear wet granulation (eg, blenders including stirrers, mixers, and bin blenders). Included. The amount of wet granulation solvent added is determined based on appropriate wetting to bind most of the fine particles. The addition of the wet granulation solvent can be carried out using any technique known in the art. For example, the liquid can be added by one or several rapid additions, sprayed onto a stirred powder bed, pumped directly onto the powder, or introduced into the fluidizing gas. The mixing time with the liquid is generally optimized so that most of the fine particles are combined into granules, but the granules themselves do not overcure.

Once the granules are formed, it is sometimes advantageous to grind, mill or sift the material while it is wet (softened) as is known in the art. The wet composition is preferably dried prior to use in the formation of unit dosage forms. This drying can be carried out using any method known in the art. Non-limiting examples of these methods include air drying, fluid bed drying, microwave drying, oven drying, radio frequency drying, vacuum oven drying, and convection oven drying. We have found that drying temperatures are important in controlling to provide low levels of atorvastatin impurities. Preferably, the drying temperature does not exceed about 60 ° C; More preferably, the temperature does not exceed about 50 ° C; Most preferably the temperature does not exceed about 40 ° C. Once the granules are dried, it is sometimes desirable to reduce particle size by grinding, milling or sieving as is known in the art. After this point the lubricant is generally added, followed by a short (about 1-10 minutes) mixing period, which is generally performed in a low shear blender such as a tumbling blender. Examples of such tumbling blenders include bin-blenders, V-blenders and Turbula ™ blenders. Preferred lubricants are magnesium stearate. Once the blend is prepared, unit dosage forms are made by methods known in the art. Preferred unit dosage forms include tablets or capsules. Tablets are prepared by filling an atorvastatin-containing composition into a mold and then pressing with a matching punch. Capsules are prepared by filling a molded capsule shell and then sealing. This operation is preferably carried out using a rotary tablet press or a commercial capsule-filler. Non-limiting examples of commercial rotary tablet presses include Niro Pharma Systems, Columbia, MD, Kilian and Company, Horsham, PA, Korsch, Berline, Germany, and Elizabeth. Produced by Hatta International (Elizabet-Hata International, North Huntingdon, PA). Non-limiting examples of commercial capsule filling devices include those made by Capsugel (Morris Plains, NJ) and CapPlus Technologies (PPlusenix, AZ). The tablets thus prepared may then be coated with a film designed to provide ease of swallowing, the exclusive or identifiable appearance and / or protection of the dosage form. The final unit dosage form is then packaged using methods known in the art. In the case of the invention, the package is preferably in the form of a foil-foil cold form blister, a plastic blister or a sealed bottle containing a desiccant. Optionally, the package may contain active oxygen absorbers such as those described in EP1243524A2 or EP1241110A1, which is incorporated herein by reference.

Atorvastatin undergoes two major degradation pathways, lactonization and oxidation. Lactones are formed by forming six-membered rings by internal condensation of alcohols and carboxylic acids (loss of water). This is the main degradation product of atorvastatin, which appears during wet granulation and tablet formation, especially in the absence of alkaline earth metal salts. The inventors have found that the level of lactone in tablets prepared by wet granulation using less than 5% (w: w) alkaline earth metal salt additives can be significantly reduced by combining excipient selection with wet granulation methods. Found out.

When atorvastatin is prepared in the form of tablets, disintegrants are preferred to provide rapid disintegration of the tablets in the gastrointestinal tract, thereby making the drug readily available for absorption. Many disintegrants for use with atorvastatin are disclosed in the prior art. For example, the following list of disintegrants is described in International Patent Publication WO 03 / 011283A1 with alkalizers and secondary active pharmaceutical ingredients: calcium carboxymethylcellulose, sodium carboxymethylcellulose, silica, croscarmellose sodium, Crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, potassium chlorine, cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch. In many patents, the examples focus on the use of croscarmellose sodium (see, eg, US Pat. Nos. 5686014, 6126971, 6531507B1, and published European Patent Application EP1336405A1). This disintegrant is also used in commercially available Lipitor®. Most of these disintegrants provide adequate disintegration properties, but in wet granulation of atorvastatin with an alkalizing agent additive of less than 5% (w: w), we unexpectedly find that only a few of the available disintegrants are suitable It was determined to provide drug purity. Indeed, the disintegrants (crosscarmellose sodium) used in most examples have been found to unexpectedly provide inferior drug purity.

Preferred disintegrants provide atorvastatin formulations having levels of atorvastatin lactone of less than about 3% (based on the area percent of lactone peak compared to all drug-related peaks by HPLC accumulation) after wet granulation and drying; More preferred disintegrants provide lactone levels of less than about 1%; Even more preferred disintegrants provide lactone levels of less than about 0.5%.

Disintegrants suitable for the present invention also provide a disintegration time of the tablets prepared in the present invention, preferably less than 30 minutes, even more preferably less than 15 minutes, even more preferably less than 8 minutes. Disintegration time is measured using a pH 6.8 phosphate buffer by a commercial disintegration measuring device.

Preferred disintegrants for compositions useful for wet granulation of atorvastatin with an alkalizing agent additive or alkaline earth metal salt of less than about 5% by weight include starch, sodium starch glycolate, sodium alginate, powdered cellulose, hydroxypropylcellulose, magnesium aluminum Silicates and polyacrylic potassium. Particularly preferred starches include corn starch and pregelatinized starch. These disintegrants are preferably used in the composition of atorvastatin at levels of about 1 to about 10% (w: w), more preferably about 3 to about 8% (w: w) of the total formulation.

Preferred wet granulation solvents have the property of inducing adhesion between particles without significant dissolution of atorvastatin, which can cause a change in the morphological form of the drug. In addition, such solvents are preferably volatile and of low toxicity so that no traces remaining are harmful. Thus, preferred granulation solvents for atorvastatin are water and alcohols. Particularly preferred alcohols are ethanol and isopropanol. In most cases, a combination of solvents may be advantageous. Preferably such blends contain ethanol or isopropanol with water. It may also be advantageous to add ingredients to the granulation solvent as is known in the art. For example, binders, wetting agents, and stabilizers can be incorporated as part of the granulation solvent and are included within the scope of the present invention.

We have found that the specific additive wetting agent Tween ™ 80 (polysorbate 80) to the granulation solvent is detrimental to the stability of atorvastatin. This is surprising because this additive is commonly used in most prior art formulations of atorvastatin (see, eg, US Pat. Nos. 5,686,104 and 6,126,971). Thus, the level of tween 80 used in the wet granulated composition of atorvastatin is preferably less than 0.5% (w: w), more preferably less than 0.2%, even more preferably less than 0.1%.

A preferred method for producing wet granulation of atorvastatin using less than about 5% by weight of alkalizer additive or alkaline earth metal salt with a preferred disintegrant comprises the following steps:

(a) Atorvastatin is blended with some or all of the preferred disintegrants and optionally the remaining excipients required for the final composition. These other excipients may include diluents, binders, and other materials necessary for the processing, flow, stability, or formation of unit dosage forms;

(b) Add the granulation solvent while keeping the material from step (a) under shear. Preferred granulation solvents include water, ethanol, isopropanol, and combinations thereof. Other components can be added to the granulation solvent as known in the art. Examples of such additives are binders, wetting agents, stabilizers and buffers. The solvent can be applied by any technique known in the art. Preferred methods of applying the solvent while imparting shear include high shear granulation, low shear granulation, fluid bed granulation and extrusion granulation.

(c) Optionally, the material from step (b) can be ground, milled or sieved. This wet material is then dried using preferably air drying, fluid bed drying, oven drying or microwave drying. Drying is preferably performed such that the drying temperature does not exceed about 60 ° C., more preferably the temperature does not exceed about 50 ° C., and most preferably the temperature does not exceed about 40 ° C.

(d) Optionally, this material is then milled or sieved.

(e) Thereafter, the material is blended with additional excipients.

(f) The composition is optionally formed in unit dosage form, preferably in tablets or capsules.

The inventors also find that such excipients can be incorporated by changing the method for the addition of disintegrants even when using disintegrants that induce lactonation of the drug (in the absence of base) during wet granulation. Revealed. More specifically, the inventors have found that adding a disintegrant, ie extragranular, to the composition after the wet granulation step provides an unexpected improvement in drug stability. Preferred steps in this method include:

(a) Atorvastatin is blended with at least some of the excipients needed in the final composition without a significant amount of disintegrant. A significant amount of disintegrant is considered to be more than about 2% (w: w) of the formulation. Other excipients may include diluents, binders, and other materials necessary for the processing, flow, stability, or formation of unit dosage forms.

(b) Add the granulation solvent while keeping the material from step (a) under shear. Preferred granulation solvents include water, ethanol, isopropanol, and combinations thereof. Other components can be added to the granulation solvent as known in the art. Examples of such additives are binders, wetting agents, stabilizers and buffers. The liquid can be applied by any technique known in the art. Preferred methods of applying liquid while imparting shear include high shear granulation, low shear granulation, fluid bed granulation and extrusion granulation.

(c) Optionally, the material from step (b) can be ground, milled or sieved. This wetted material is then dried, preferably using air drying, fluid bed drying, oven drying or microwave drying, which drying is preferably such that the drying temperature does not exceed about 60 ° C., more preferably Most preferably so that the temperature does not exceed about 40 ° C.

(d) Optionally, this material is then milled, milled or sieved.

(e) Thereafter, the composition is blended with one or more disintegrants and, optionally, additional excipients comprising a lubricant.

(f) The final composition is optionally formed in unit dosage form, preferably in tablets or capsules.

We also found another way to improve drug purity for wet granulation of atorvastatin in the presence of disintegrants that exhibit poor drug purity. More specifically, the inventors have unexpectedly found that having a base present in the composition only during the wet granulation and drying process provides stabilization of atorvastatin against lactonation although there is no base in the final product. In particular, it has been found that volatile bases provide wet granulation of atorvastatin with a higher degree of purity than in the absence of other added bases. Examples of such preferred volatile bases include ammonium hydroxide, tetraalkylalmonium hydroxides, secondary and tertiary alkyl and aryl amines, diethanolamines and monoethanolamines. Particularly preferred volatile bases include ammonium hydroxide and tetrabutyl ammonium hydroxide. These bases are granulated solvents (preferably water, isopropanol, ethanol or their Combination). The inventors have found that the concentration of volatile base used in the granulated water is preferably in the range of about 0.001 to about 50% (w: w), more preferably about 0.1 to about 40% (w: w). It was. The amount of granulation solution of base added to the granulation is preferably between about 40 and about 100% (w: w) of the solid material.

The present invention provides a composition of atorvastatin which is particularly well suited for combination products with other drug components due to the greater atorvastatin stability provided by the disintegrants of the present invention. This is particularly the case when the second drug (with its bound disintegrant) destabilizes the atorvastatin. Non-limiting examples of drugs that may be beneficial in combination with the atorvastatin compositions and methods of the present invention include torcetrapib and amlodipine and their pharmaceutically acceptable salts.

The composition of atorvastatin according to the invention can be combined with at least one other active drug to form a unit dosage form. Preferred unit dosage forms include tablets and capsules. In a combination of atorvastatin composition with at least one other active drug to form a unit dosage form, the following non-limiting list describes the options for such unit dosage forms: (a) formed of tablets or capsules, Wet granulated as a blend with excipients (ie, extragranular addition of other drugs and excipients to wet granulated atorvastatin), or as granules (ie a combination of wet granulated atorvastatin with other drug granules) Blends of atorvastatin with other active drugs themselves (ie, extragranular addition of other drugs to wet granulated atorvastatin); (b) single wet granulation of atorvastatin with other drugs, formed into tablets or capsules; (c) Two layer tablets comprising wet granulated atorvastatin in one layer and other drugs and optional excipients in the other layer.

The present invention provides for the treatment of diseases and conditions such as hyperlipidemia and / or hypercholesterolemia, osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease, low levels of degradation products and / or impurities contained in therapeutic packages or kits. A method of treating with atorvastatin or a pharmaceutically acceptable salt thereof as described above, which may be administered in a unit dosage form having. The kit includes unit dosage forms and containers. In general, the kit includes instructions for the administration of the dosage form. The container may be in any conventional shape or form known in the art, for example a blister pack having a paper box, a glass or plastic bottle, or an individual dosage form pushed back according to a therapeutic schedule. Can be.

The following non-limiting examples illustrate the preferred method of the present inventors for preparing and using the pharmaceutical composition of the present invention.

Example 1

General method for the preparation of amorphous atorvastatin

Amorphous atorvastatin, an example of disordered atorvastatin as described above and used in the examples below, is preferred according to the method described in concurrently filed and co-owned U.S. patent application agent case number PC-25825 (US Pat. No. 5,273,995). Was prepared by dissolving in methanol to form a 5% (w: w) solution. This solution was sprayed in a Niro PSD-1 spray dryer at a rate of 170 grams / minute (g / minute) using nitrogen as the atomizing gas. The inlet temperature was 195 ° C and the outlet temperature was 60 ° C. After spray drying, the powder was tray-dried in an oven at 40 ° C. for 12 hours to give amorphous atorvastatin.

Example 2

Preparation of amorphous atorvastatin calcium tablets using wet granulation without disintegrant

Amorphous atorvastatin calcium (1.3 g), 39.0 g of microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 50.7 g of lactose hydrate (Foremost Farms USA, Rothschild, WI) and 2.0 g of hydroxypropyl cellulose (Klucel EXF ™, Hercules Incorporated, Aqualon Division, Wilmington, DE) were combined in a 500-mm jar and a Turbula Shaker Mixer, Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland) was used for 10 minutes of mixing. Subsequently, the formulation was prepared using a 0.9 L bowl, using a Pro-C-ept Mi-Mi-Pro high shear wet granulator (Pro-C-epT nv, B-9060 Zelzate, Granules). The formulations were dry-mixed for 2 minutes at an impeller speed of 400 rpm and a chopper speed of 1000 rpm per minute. Wet mixing was performed at an impeller speed of 600-rpm and chopper speed of 1000-rpm. Water was added in 10-30 g increments at a rate of 20-30 g / min for a total of 45 g using a standard 60-mm syringe. The material was wet-mixed for a total of 2.5 minutes. The granules were wet sieved through a # 10 mesh sieve manually to reach a more uniform granule size before drying. The granules were tray-dried overnight at 50 ° C. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) for 16 hours. The granules were then ground at 500 rpm using a Fitzpatrick L1A grinder (Fitzpatrick Co., Elmhurst, IL) with a 0.040 "Conidur rasping plate. The material was 400 mg of granules. Levels of atorvastatin lactone (added to 50 ml 1: 1 (v: v) 0.05 M ammonium citrate buffer (pH 7.4): acetonitrile and shaken for 20 minutes (lactone to total peak cumulative area using HPLC) The material was then filtered using a Gelman Acrodisc polytetrafluoroethylene membrane (0.45 μm pore size) and high pressure-liquid chromatography (HPLC). (Phenomenex, Ultremex C18 column, 5 μm pore size, 25.0 cm × 4.6 mm, HPLC Waters 2690D, Waters Corp., Milford, MA, 20 μl injection volume, flow rate of 1.5 mL / min; mobile phase 53:27:20 ( v: v: v) 0.05 M ammonium citrate (pH 4.0): Analysis was performed using cetonitrile: tetrahydrofuran; detected using a Waters 2487 detector at 244 nm.The results are reported in Table 1. Purification was reported in single-zone Manesti F-press (single-station Manesty). Manufactured by hand using F-press; Manesty Liverpool, United Kingdom. Produce tablets weighing 450 mg each using 13/32 "standard round concave (SRC) punches and molds. It was. The target tablet hardness was 12 kP and the range was 10-14 kP (tablet hardness was tested using a Schleuniger Tablet Hardness Tester, Dr. Schleuniger Pharmatron AG, Solothurn, Switzerland).

Example 3

Preparation of amorphous atorvastatin calcium using wet granulation with croscarmellose sodium

Amorphous atorvastatin calcium (1.3 g), 39.0 g of microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 50.7 g of lactose hydrate (Foremost Farms USA, Rothschild, WI), 3.0 g croscarmellose sodium (Ac-Di-Sol ™, FMC Biopolymer, Philadelphia, PA) and 2.0 g hydroxypropyl cellulose (Clucell EXF ^™ , Hercules Incorporated, Aqualon) Division, Wilmington, DE) was combined in a 500-mm jar and mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The formulation was then granulated using a 0.9 L bowl using a Procept My-My-Pro High Shear Wet Granulator (Pro-C-epT nv, B-9060 Zelzate, Belgium). The formulations were dry-mixed for 2 minutes at an impeller speed of 400 rpm and a chopper speed of 1000 rpm. Wet mixing was performed at an impeller speed of 600-rpm and chopper speed of 1000-rpm. Water was added in 10-30 g increments at a rate of 20-30 g / min for a total of 60 g using a standard 60-mm syringe. The material was wet-mixed for a total of 5.5 minutes. The granules were wet sieved through a # 10 mesh sieve manually to reach a more uniform granule size before drying. The granules were tray-dried overnight at 50 ° C. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) for 16 hours. The granules were then ground at 500 rpm using a Fitzpatrick L1A grinder with a 0.040 "Conidour rapping plate. The material was analyzed as described in Example 2 and the results are reported in Table 1 below.

Example 4

Preparation of Amorphous Atorvastatin Calcium Using Wet Granulation with Sodium Starch Glycolate

Amorphous atorvastatin calcium (1.3 g), 39.0 g of microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 50.7 g of lactose hydrate (Foremost Farms USA, Rothschild, WI), 3.0 g sodium starch glycolate (Explotab ™, Penwest Pharmaceuticals Co., Cedar Rapids, IA) and 2.0 g hydroxypropyl cellulose (Clucel EXF ^™ , Hercules Incorporated, Aqualon Division, Wilmington , DE) were combined in a 500-mm jar and mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The formulation was then granulated using a 0.9 L bowl using a Procept My-My-Pro High Shear Wet Granulator (Pro-C-epT nv, B-9060 Zelzate, Belgium). The formulations were dry-mixed for 2 minutes at an impeller speed of 400 rpm and a chopper speed of 1000 rpm. Wet mixing was performed at an impeller speed of 600-rpm and chopper speed of 1000-rpm. Water was added in 10-30 g increments at a rate of 20-30 g / min for a total of 55 g using a standard 60-mm syringe. The material was wet-mixed for a total of 5.5 minutes. The granules were wet sieved through a # 10 mesh sieve manually to reach a more uniform granule size before drying. The granules were tray-dried overnight at 50 ° C. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) for 16 hours. The granules were then ground at 500 rpm using a Fitzpatrick L1A grinder with a 0.040 "Conidour rapping plate. The material was analyzed as described in Example 2 and the results are reported in Table 1 below.

Example 5

Preparation of Amorphous Atorvastatin Calcium Using Wet Granulation Using Corn Starch

Amorphous atorvastatin calcium (1.3 g), 39.0 g of microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 50.7 g of lactose hydrate (Foremost Farms USA, Rothschild, WI), 3.0 g of corn starch-purity 21 (National Starch and Chemical Corp., Bridgewater, NJ) and 2.0 g of hydroxypropyl cellulose (Klucel EXF ^™ , Hercules Incorporated, Aqualon Division, Wilmington, DE) 에서 blended in jars and mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The formulation was then granulated using a 0.9 L bowl using a Procept My-My-Pro High Shear Wet Granulator (Pro-C-epT nv, B-9060 Zelzate, Belgium). The formulations were dry-mixed for 2 minutes at an impeller speed of 400 rpm and a chopper speed of 1000 rpm. Wet mixing was performed at an impeller speed of 600-rpm and chopper speed of 1000-rpm. Water was added in 10-30 g increments at a rate of 20-30 g / min for a total of 45 g using a standard 60-mm syringe. The material was wet-mixed for a total of 2.5 minutes. The granules were wet sieved through a # 8 mesh sieve manually to reach a more uniform granule size before drying. The granules were tray-dried overnight at 50 ° C. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) for 16 hours. The granules were then ground at 500 rpm using a Fitzpatrick L1A grinder with a 0.040 "Conidour rapping plate. The material was analyzed as described in Example 2 and the results are reported in Table 1 below.

Example 6

Preparation of Amorphous Atorvastatin Calcium Using Wet Granulation with Pregelatinized Starch

Amorphous atorvastatin calcium (1.3 g), 39.0 g of microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 50.7 g of lactose hydrate (Foremost Farms USA, Rothschild, WI), 3.0 g pregelatinized starch (Starch 1500, Colorcon, West Point, PA) and 2.0 g hydroxypropyl cellulose (Clucell EXF ^™ , Hercules Incorporated, Aqualon Division, Wilmington, DE) Formulated in a 500-mm jar and mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The formulation was then granulated using a 0.9 L bowl using a Procept My-My-Pro High Shear Wet Granulator (Pro-C-epT nv, B-9060 Zelzate, Belgium). The formulations were dry-mixed for 2 minutes at an impeller speed of 400 rpm and a chopper speed of 1000 rpm. Wet mixing was performed at an impeller speed of 600-rpm and chopper speed of 1000-rpm. Water was added in 10-30 g increments at a rate of 20-30 g / min for a total of 40 g using a standard 60-mm syringe. The material was wet-mixed for a total of 3 minutes. The granules were wet sieved through a # 8 mesh sieve manually to reach a more uniform granule size before drying. The granules were tray-dried overnight at 50 ° C. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) for 16 hours. The granules were then ground at 500 rpm using a Fitzpatrick L1A grinder with a 0.040 "Conidour rapping plate. The material was analyzed as described in Example 2 and the results are reported in Table 1 below.

Example 7

Preparation of amorphous atorvastatin using wet granulation with sodium alginate

Amorphous atorvastatin calcium (40.5 mg), 1.22 g of microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 1.58 g of lactose hydrate (Foremost Farms USA, Rothschild, WI), 93.9 mg sodium alginate (Protanal ™, FMC BioPolymer, Philadelphia, PA) and 62.4 mg hydroxypropyl cellulose (Klucel EXF ^™ , Hercules Incorporated, Aqualon Division, Wilmington, DE) -Built in jars and mix for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The mixture was then vented micro with 1/2 "blades on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370). -Granulated in a 30-mm jar using a bent micro-spatula impeller.Before use, the blade can sweep away the granulated material, and a portion of this material from above the top of the blade. Bent at an angle sufficient to allow flow The blade was bent at an angle of about 30 ° from vertical The amount of 1.0 to 0.5 ml increase while the granulation fluid was wet mixed for 2.5 minutes until a suitable granule was formed based on visual observation Pipette was added (total 1.5 ml added) Granules at 50 ° C. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) for 16 hours Ray-dried material were analyzed as described in Example 2, the results are reported in Table 1 below.

Example 8

Preparation of amorphous atorvastatin calcium using wet granulation with alginic acid

Amorphous atorvastatin calcium (40.5 mg), 1.22 g of microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 1.58 g of lactose hydrate (Foremost Farms USA, Rothschild, WI), 93.9 mg of alginic acid (Protacid ™, FMC BioPolymer, Philadelphia, PA) and 62.4 mg of hydroxypropyl cellulose (Klucel EXF ^™ , Hercules Incorporated, Aqualon Division, Wilmington, DE) 에서 blended in jars and mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The mixture was then 30-mm using a vented micro-spatula impeller with 1/2 "blades on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370). Granules in the bottle Before use, the blades were swept away from the granulated material and bent at an angle sufficient to allow a portion of this material to flow above the top of the blade. The granulation fluid was transferred to a pipette in an amount of 1.0 to 0.5 ml in increments of 1.0 to 0.5 ml with wet mixing for 2.5 minutes until a suitable granule was formed, based on visual observation.The granules were added for 16 hours. Tray-dried at 50 ° C. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA.) The material is as described in Example 2. Was analyzed, the results are reported in Table 1 below.

Example 9

Preparation of Amorphous Atorvastatin Calcium Using Wet Granulation Using Powdered Cellulose

Amorphous atorvastatin calcium (40.5 mg), 1.22 g of microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 1.58 g of lactose hydrate (Foremost Farms USA, Rothschild, WI), 93.9 mg powdered cellulose (Solka-Floc 40NF ™), International Fiber Corp., North Tonawanda, NY) and 62.4 mg hydroxypropyl cellulose (Clucell EXF ^™ , Hercules Incorporated, Aqualon) Division, Wilmington, DE) was combined in a 30-mm jar and mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The mixture was then 30-mm using a vented micro-spatula impeller with 1/2 "blades on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370). Granules in the bottle Before use, the blades were swept away from the granulated material and bent at an angle sufficient to allow a portion of this material to flow above the top of the blade. The granulation fluid was transferred to a pipette in an amount of 1.0 to 0.5 ml in increments of 1.0 to 0.5 ml with wet mixing for 2.5 minutes until a suitable granule was formed, based on visual observation.The granules were added for 16 hours. Tray-dried at 50 ° C. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA.) The material is as described in Example 2. , Results are analyzed Reported in Table 1.

Example 10

Preparation of Amorphous Atorvastatin Calcium Using Wet Granulation Using Hydroxypropylcellulose

Amorphous atorvastatin calcium (40.5 mg), 1.22 g of microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 1.58 g of lactose hydrate (Foremost Farms USA, Rothschild, WI), 93.9 mg hydroxypropyl cellulose (Low Substitution, Shin-Etsu Chemical Co., Tokyo, Japan) and 62.4 mg hydroxypropyl cellulose (Clucell EXF ^™ , Hercules Incorporated, Aqualon Division, Wilmington, DE) Was combined in a 30-mm jar and mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The mixture was then 30-mm using a vented micro-spatula impeller with 1/2 "blades on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370). Granules in the bottle Before use, the blades were swept away from the granulated material and bent at an angle sufficient to allow a portion of this material to flow above the top of the blade. The granulation fluid was transferred to a pipette in an amount of 1.0 to 0.5 ml in increments of 1.0 to 0.5 ml with wet mixing for 2.5 minutes until a suitable granule was formed, based on visual observation.The granules were added for 16 hours. Tray-dried at 50 ° C. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA.) The material is as described in Example 2. Was analyzed, the results are reported in Table 1 below.

Example 11

Preparation of Amorphous Atorvastatin Calcium Using Wet Granulation with Magnesium Aluminum Silicate

Amorphous atorvastatin calcium (40.5 mg), 1.22 g of microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 1.58 g of lactose hydrate (Foremost Farms USA, Rothschild, WI), 93.9 mg magnesium aluminum silicate (Veegum F ™, RT Vanderbilt Co., Norwalk, CT) and 62.4 mg hydroxypropyl cellulose (Klucel EXF ^™ , Hercules Incorporated, Aqualon Division, Wilmington, DE ) Was combined in a 30-mm jar and mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The mixture was then 30-mm using a vented micro-spatula impeller with 1/2 "blades on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370). Granules in the bottle Before use, the blades were swept away from the granulated material and bent at an angle sufficient to allow a portion of this material to flow above the top of the blade. The granulation fluid was transferred to a pipette in an amount of 1.0 to 0.5 ml in increments of 1.0 to 0.5 ml with wet mixing for 2.5 minutes until a suitable granule was formed, based on visual observation.The granules were added for 16 hours. Tray-dried at 50 ° C. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA.) The material is as described in Example 2. Was analyzed, the results are reported in Table 1 below.

Example 12

Preparation of Amorphous Atorvastatin Calcium Using Wet Granulation with Polacryline Potassium

Amorphous atorvastatin calcium (40.5 mg), 1.22 g of microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 1.58 g of lactose hydrate (Foremost Farms USA, Rothschild, WI), 93.9 mg of Polacryline Potassium (Amberlite IRP88 ™, Rohm and Haas Co., Philadelphia, PA) and 62.4 mg of hydroxypropyl cellulose (Klucel EXF ^™ , Hercules Incorporated, Aqualon Division, Wilmington , DE) were combined in a 30-mm jar and mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The mixture was then 30-mm using a vented micro-spatula impeller with 1/2 "blades on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370). Granules in the bottle Before use, the blades were swept away from the granulated material and bent at an angle sufficient to allow a portion of this material to flow above the top of the blade. The granulation fluid was transferred to the pipette in 1.0-0.5 ml increments (wet 1.5 ml total added) with wet mixing for 2.5 minutes, until a suitable granule was formed based on visual observation. Tray-dried at 50 ° C. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA) for a period of time The material was as described in Example 2. This was analyzed and the result is Reported in Table 1.

Effect on Substance Purity of Drugs Formed by Wet Granulation of Atorvastatin Using Intragranular Excipients Example number Disintegrant Atorvastatin lactone% (measured by HPLC) 2 Control (no disintegrant) 0.21 3 Croscarmellose sodium 5.47 4 Sodium starch glycolate 0.41 5 Corn starch 0.25 6 Pregelatinized starch 0.20 7 Sodium alginate 0.52 8 Alginic acid 15.71 9 Powdered cellulose 0.41 10 Hydroxypropyl cellulose 0.38 11 Magnesium aluminum silicate 0.12 12 Polacryline Potassium 0.29

Example 13

Wet granulation of atorvastatin and its tablets by a method of providing pure atorvastatin using various disintegrants

To a material prepared in Example 2 of 13.30 g in a 60-mm jar was added 0.858 g of one of the following disintegrants: (a) sodium starch glycolate; (b) croscarmellose sodium; (c) corn starch; Or (d) pregelatinized starch. The blend was mixed for 5 minutes using a Turbula shake mixer. To this blend was added 0.143 g of magnesium stearate (Mallinckrodt Inc., St. Louis, Mo.) in each case. The formulation was then blended for 3 minutes using a Turbula shake mixer. The material was analyzed for levels of lactone as described in Example 2 and the results are reported in Table 2 below. Tablets were made by hand using a single zone Manesty F-Press (Manesty Liverpool, United Kingdom). Tablets weighing 450 mg each were produced using a 13/32 "SRC punch and a mold. The target tablet hardness was 12 kP and the range was 10-14 kP (tablet hardness was Schroenier tablet hardness tester ( (Dr. Schleuniger Pharmatron AG, Solothurn, Switzerland)) The material was analyzed as described in Example 2 and the results are reported in Table 2 below.

Unexpected Beneficial Effects on Drug Purity in the Case of Wet Granulation of Atorvastatin Using Extragranular Disintegrants Example Disintegrant Atorvastatin lactone% (measured by HPLC) 2 Control, no disintegrant 0.21 13a Sodium starch glycolate 0.25 13b Croscarmellose sodium 0.24 13c Corn starch 0.24 13d Pregelatinized starch 0.24

Example 14

Control of Wet Granulation of Atorvastatin Without Volatile Base

Amorphous atorvastatin calcium (62.1 mg), 1772.1 mg microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), 1010.4 mg lactose hydrate (Foremost Farms USA, Rothschild, prepared as described in Example 1 WI), 62.1 mg of hydroxypropyl cellulose (Klucel EXF ^™ , Hercules Incorporated, Aqualon Division, Wilmington, DE), and 93.3 mg of croscarmellose sodium (liquid-di-sol ^™ , FMC Biopolymer, Philadelphia, PA) Was placed in a 30-mm vial. The combined dry ingredients were mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The mixture was then 30-mm using a vented micro-spatula impeller with 1/2 "blades on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370). Granules in the bottle Before use, the blades were swept away from the granulated material and bent at an angle sufficient to allow a portion of this material to flow above the top of the blade. The granulation fluid was transferred to a pipette in 0.5-1.0 ml increments (2.5 ml total was added), with wet mixing for 4 minutes, until a suitable granule was formed based on visual observation. Dried overnight in a forced hot tray dryer at 50 ° C. The material was transformed into 275 mg using granules instead of 400 mg. The level of lactone was analyzed as described in Example 2. The results are reported in Table 3 below.

Example 15

Wet Granulation of Amorphous Atorvastatin Using Volatile Bases

Amorphous atorvastatin calcium (62.1 mg), 1772.1 mg microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), 1010.4 mg lactose hydrate (Foremost Farms USA, Rothschild, prepared as described in Example 1 WI), 62.1 mg of hydroxypropyl cellulose (Klucel EXF ^™ , Hercules Incorporated, Aqualon Division, Wilmington, DE), and 93.3 mg of croscarmellose sodium (liquid-di-sol ^™ , FMC Biopolymer, Philadelphia, PA) Was placed in a 30-mm vial. The combined dry ingredients were mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). Thereafter, the mixture was granulated as described in the comparative example using a volatile base solution for the following test: (a) 2.5 ml of 30% ammonium hydroxide (JT Baker Co.), (b) 2.5 ML 3% ammonium hydroxide, (c) 2.5 mL 0.00012% ammonium hydroxide, (d) 2.0 mL 40% tetrabutylammonium hydroxide (Mallinckrodt Co.). The wet granules were dried overnight at 50 ° C. in a forced hot tray dryer for 16 hours. For each sample, the material was modified to use 150 mg granules and 30 ml extraction volume and analyzed for lactone levels as described in Example 2. The results are reported in Table 3 below.

Unexpected Beneficial Effects on Drug Purity in the Case of Wet Granulation of Atorvastatin with Added Volatile Base Example Volatile base Atorvastatin lactone% (measured by HPLC) 14 Control, no base 4.35 15a 30% Ammonium Hydroxide 0.47 15b 3% Ammonium Hydroxide 0.46 15c 0.00012% Ammonium Hydroxide 2.75 15d 40% Tetrabutylammonium Hydroxide Below quantitative limit (<0.1%)

Example 16

Wet Granulation of Amorphous Atorvastatin by Drying at Various Temperatures

Amorphous atorvastatin calcium (40.5 mg), 1218.8 mg microcrystalline cellulose (Avisel PH102 ^™ , FMC Biopolymer, Philadelphia, PA), prepared as described in Example 1, 1572.1 mg lactose hydrate (Foremost Farms USA, Rothschild, WI), 62.5 mg of hydroxypropyl cellulose (Clusel EXF ^™ , Hercules Incorporated, Aqualon Division, Wilmington, DE), and 93.8 mg sodium starch glycolate (Explotab ^™ , Penwest Pharmaceuticals Co., Cedar Rapids, IA) ) Was placed in a 30-mm glass jar. The combined dry ingredients were mixed for 10 minutes using a Turbula shake mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). Granulation liquids prepared in excess were prepared by combining and mixing 99 g of H ₂ O with 1 g of Polysorbate 80 (Twin 80 ™, Spectrum Chemicals & Lab Products, Gardena, Calif.) In a 125 ml flask. The powder mixture was then granulated as described in Example 1 using 2.5 ml of granulation liquid with wet mixing for 4 minutes. The wet granules were then divided into three approximately equal parts. Each portion was dried for 16 hours under the following conditions: (a) 30 ° C. vacuum oven, (b) 50 ° C. convection oven, and (c) 70 ° C. vacuum oven. For each sample, the material was prepared by adding 300 mg of material to 1: 2: 2 (v: v: v) 0.05 M ammonium acetate buffer (pH 7.4): acetonitrile: tetrahydrofuran and shaking for 20 minutes. The level of lactone (analyzed based on the ratio of lactone peak accumulation to total peak accumulation area using HPLC) was analyzed. This mixture was filtered using a disposable 0.45 μm polytetrafluoroethylene membrane (Whatman), HPLC (HP 1100, Zorbax SB-C8 5 μm particle size, 25.0 cm × 4.6 mm column, incubated to 35 ° C., injection volume 20 μl; flow rate 1.5 mL / min; 244 nm detection). Elution begins at 67:21:12 (v: v: v) and after 40 minutes, 0.05 M ammonium acetate buffer (pH 5.0): acetonitrile: tetrahydrofuran at 54: 34; 12 (v: v: v) A linear gradient was used which was replaced with (after 55 minutes 100% of the latter mixture). The results are reported in Table 4 below.

Unexpected beneficial effects on drug purity in case of wet granulation of atorvastatin when dried at low temperatures Example Drying condition Atorvastatin lactone% (measured by HPLC) 16a 30 ℃ vacuum oven 0.25 16b 50 ℃ Convection Oven 1.18 16c 70 ℃ vacuum oven 4.36

Claims (15)

(a) atorvastatin, or a pharmaceutically acceptable salt thereof, at least in a somewhat disordered form or a mixture of crystalline and disordered forms; And (b) disintegrants or combinations of disintegrants And atorvastatin with less than 5% by weight alkaline earth metal salt additive, comprising less than 3% atorvastatin lactone, based on the ratio of lactone peak area to total drug-related peak cumulative area using HPLC Wet granulated pharmaceutical composition. The wet granulated pharmaceutical composition of claim 1 comprising less than 0.5% by weight of Tween 80 (polysorbate 80). A unit dosage form prepared from the wet granulated pharmaceutical composition of claim 1. The unit dosage form of claim 3, which is a tablet or capsule. The wet granulated pharmaceutical composition of claim 1, wherein the disintegrant or combination of disintegrants is present in the range of 1 to 10% (weight: weight) of the composition. The method of claim 1, wherein the disintegrant or combination of disintegrants is sodium starch glycolate, starch, corn starch, starch gelatinized starch, sodium alginate, powdered cellulose, hydroxypropylcellulose, magnesium aluminum silicate and potassium polychlorinate. Wet granulated pharmaceutical composition selected from the group consisting of. delete (a) atorvastatin, or a pharmaceutically acceptable salt thereof, in at least somewhat disordered form or in a mixture of crystalline and disordered forms, containing sodium starch glycolate, starch, sodium alginate, powdered cellulose, hydroxypropylcellulose, magnesium Combining with aluminum silicate, polyacrylic potassium or a combination thereof, and optionally with other excipients; (b) adding water, isopropanol, ethanol or mixtures thereof under shear to the atorvastatin blend from step (a) to produce granules; (c) optionally milling or sieving the wet granules; (d) drying the granules; (e) optionally milling, milling or sieving the granules; (f) optionally mixing with other excipients; And (g) optionally forming the composition in unit dosage form Including, a method for producing a wet granulated composition of atorvastatin. (a) combining atorvastatin, or a pharmaceutically acceptable salt thereof, in at least somewhat disordered form or a mixture of crystalline and disordered form with one or more excipients, wherein the disintegrant is less than 2% by weight; (b) adding water, isopropanol, ethanol or mixtures thereof under shear to the atorvastatin blend from step (a) to produce granules; (c) optionally milling or sieving the wet granules; (d) drying the granules; (e) optionally milling, milling or sieving the granules; (f) mixing with the disintegrant and optionally other excipients; And (g) optionally forming the composition in unit dosage form Including, a method for producing a wet granulated composition of atorvastatin. (a) combining at least one excipient with atorvastatin, or a pharmaceutically acceptable salt thereof, in at least somewhat disordered form or a mixture of crystalline and disordered form; (b) adding volatile bases dissolved in water, isopropanol, ethanol or mixtures thereof under shear to produce granules; (c) optionally milling or sieving the wet granules; (d) drying the granules; (e) optionally milling, milling or sieving the granules; (f) optionally mixing with other excipients as needed to produce a final composition; And (g) optionally forming the composition in unit dosage form Including, a method for producing a wet granulated composition of atorvastatin. delete A medicament for treating hypercholesterolemia and / or hyperlipidemia, osteoporosis, benign prostatic hyperplasia and Alzheimer's disease, comprising a therapeutically effective amount of the pharmaceutical composition of claim 1. A kit for achieving a therapeutic effect in a mammal comprising a therapeutically effective amount of the pharmaceutical composition of claim 1 prepared in a unit dosage form from the composition of claim 1 and a container for containing the dosage form. delete delete