JP2006527259A - Pharmaceutical composition of atorvastatin - Google Patents

Abstract

The present invention relates to a dry granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof, or a dry granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof in combination with at least one other active drug. Product, method for producing the composition, kit containing such composition, and therapeutically effective amount of the pharmaceutical composition, hypercholesterolemia and / or hyperlipidemia, osteoporosis, benign prostatic hypertrophy (BPH) and methods of treating Alzheimer's disease are provided.

Description

This application claims priority from US Provisional Patent Application No. 60 / 477,917, filed Jun. 12, 2003.
The present invention relates to a pharmaceutical composition comprising atorvastatin and a pharmaceutically acceptable salt thereof, a method for producing the same, a kit including such a composition, and hypercholesterolemia and / or hyperlipidemia, osteoporosis, benign prostate It relates to methods of using such compositions to treat subjects suffering from hypertrophy (BPH) and Alzheimer's disease.

  Conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthesis pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are generally potent lipid lowering agents.

Atorvastatin calcium disclosed in US Pat. No. 5,273,995 (incorporated herein by reference) is currently sold as Lipitor® and has the chemical formula [ R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H -Pyrrole-1-heptanoic acid calcium salt (2: 1) trihydrate and having the following chemical formula:

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

  There are a number of patents disclosing atorvastatin, atorvastatin formulations, methods for preparing atorvastatin and important intermediates. These patents include: U.S. Pat. Nos. 4,681,893, 5,273,995, 5,003,080, 5,097,045, and 5,103,024. No. 5,124,482, No. 5,149,837, No. 5,155,251, No. 5,216,174, No. 5,245,047, No. 5,248,793, No. No. 5,280,126, No. 5,397,792, No. 5,342,952, No. 5,298,627, No. 5,446,054, No. 5,470,981, No. 5, 489,690, 5,489,691, 5,510,488, 5,686,104, 5,998,633, 6,087,511, 6,126, No. 971, No. 6,433,213 and No. 6,476,235. These are incorporated herein by reference.

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

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

  In addition to these, many international patent application publications disclose crystalline forms of atorvastatin and methods for producing amorphous forms of atorvastatin. These patent applications include: International Patent Publication Nos. 00/71116, 01/28999, 01/36384, 01/42209, 02/41834, 02/43667. No. 02/43732, No. 02/051804, No. 02/057228, No. 02/057229, No. 02/057274, No. 02/059087, No. 02/083637, No. 02/083638, No. 03/011826, 03/050085, 03/070702 and 04/022053.

  It has been disclosed that in many drugs the amorphous form exhibits a different solubility and in some cases a different bioavailability pattern compared to the crystalline form (Konno, T., Chem. Pharm. Bull., 1990, 38: 2003-2007). For certain therapeutic indications, one bioavailability pattern may be more advantageous than another.

  The change in dissolution rate is advantageous for producing formulations of atorvastatin in either crystalline or amorphous form. For example, some possible uses of atorvastatin (eg, Takemoto, M .; Node, K .; Nakagami, H .; Liao, Y .; Grimm, M .; Takemoto, Y .; Kitakaze, M .; For acute treatment of stroke as described in Liao, JK, Journal of Clinical Investigation, 2001; 108 (10): 1429-1437), rapid onset of activity can It seems very beneficial to improve.

  The production of solid formulations of atorvastatin is described in US Pat. Nos. 5,686,104 and 6,126,971. In the method described therein, atorvastatin is combined with stabilizers, eg, alkaline earth metal salts and excipients, in a wet granulation method using a combination of water and a surfactant (Tween 80). It is processed. Since alkaline earth metal salts can potentially affect the bioavailability of atorvastatin, there remains a need to provide atorvastatin in a formulation that minimizes the level of alkaline earth metal salts.

  In the manufacture and storage of atorvastatin unit dosage forms, it is important to provide the active agent in a pure form. Furthermore, it is desirable to achieve this high purity and stability with as simple a formulation as possible. There remains a need to provide simple formulations and manufacturing methods for unit dosage forms of atorvastatin that provide low levels of impurities and sufficient stability to allow the dosage form to be commercially valid. Has been.

Because atorvastatin is a very powerful drug, drug formulations are generally highly diluted to provide a suitably sized dosage form so that it is easy to manufacture and handle by the patient. When the drug is used in diluted form, the separation of drug and excipients that occurs while the drug is in the process prior to its final dosage form may cause some of the unit dosage form to There is a risk that it can lead to high titers. Controlling the unit dosage titer is essential to protect individual patients from inaccurate, sub-therapeutic effects, or formulation doses that produce side effects. Granulation is one way to prevent separation. U.S. patent application owned by the present applicant, agent case number PC25684, application number, filed concurrently It is possible to select excipients so that the unit dosage form can be produced without the granulation step as disclosed in the issue, but granulation does not cause separation, And it makes it possible to ensure the bond between the drug and the excipient so that the particle size of the granules allows a good flow. Wet granulation shows one option to form atorvastatin in a form with good flowability that does not separate (co-filed US patent application owned by the applicant, agent case number PC25685, application number Issue). However, wet granulation requires exposing the formulation to water and / or solvent. Such exposure increases the risk that the solid form of atorvastatin will change (eg, crystallize or polymorphic form will change) or chemically degrade. Since the amount and rate of addition of the liquid will depend on factors such as the volume and surface area of the wet granulation vessel and the exact particle size of the drugs and excipients used in the particular manufacturing process, Scaling up the grain process can be difficult (ie, variations in performance). Therefore, the object of the present invention is to minimize drug separation, the fluidity of the composition is acceptable for commercial dosage unit formation, the drug is not exposed to solvent, and is robust (scalable ) To provide a dry granule formulation of atorvastatin and a method for producing the same.

  In a dry granulation process, the drug and at least some excipients are generally compressed together to form a ribbon or blob. These compacted materials are ground to an appropriate size to prevent separation of the drug during unit dosage form manufacture and to ensure good flowability. The present inventors have found that the drug itself compresses to form a small lump, but that most of the material returns to a fine powder with poor fluidity by grinding. Therefore, there is a need to provide a composition suitable for dry granulation of atorvastatin that provides the proper fluidity of the drug so that the unit dosage form is manufactured with good weight control.

  It is an object of the present invention to provide a dosage form composition of atorvastatin having a good homogeneity of titer between doses, dissolution rate and bioavailability, and a method for producing the same. It is a further object of the present invention to provide a stable and pure composition of atorvastatin in crystalline or amorphous form with minimal addition of alkali metal salts.

  The first aspect of the present invention is a dry granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof.

A second aspect of the present invention is a method for producing a dry granulated pharmaceutical composition of atorvastatin, comprising:
(A) a combination of atorvastatin or a pharmaceutically acceptable salt thereof and one or more excipients suitable for use in the dry granulation step;
(B) mixing the mixture with a mixer;
(C) compressing the mixture;
(D) grinding, grinding or sieving the compressed material;
(E) optionally adding additional excipients and mixing the combination to form the composition;

  A third aspect of the present invention is a dry granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof in combination with at least one other active drug.

A fourth aspect of the present invention is a method for producing a dry granulated pharmaceutical composition of atorvastatin, comprising:
(A) combining atorvastatin or a pharmaceutically acceptable salt thereof in combination with at least one active drug and one or more excipients suitable for use in the dry granulation step;
(B) mixing the mixture with a mixer;
(C) compressing the mixture;
(D) grinding, grinding or sieving the compressed material;
(E) optionally adding additional excipients and mixing the combination to form the composition;

  A fifth aspect of the invention is a therapeutic package or kit suitable for commercial sale comprising a container and a therapeutically effective amount of dry granulated atorvastatin or a pharmaceutically acceptable salt thereof.

  A sixth aspect of the present invention provides a dry granulated atorvastatin composition for treating subjects suffering from hypercholesterolemia and / or hyperlipidemia, osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease. This is the method to use.

  Atorvastatin is disclosed in US Pat. Nos. 4,681,893, 5,273,995, and 5,969,156, which are incorporated herein by reference. Can be easily manufactured. The hemicalcium salt of atorvastatin is currently sold as Lipitor®.

Atorvastatin exists in many forms, ranging from highly crystallized forms to forms with varying degrees of disorder. Certain of these disordered forms have several structures shown by powder X-ray diffraction patterns. For the purposes of the present invention, all forms of atorvastatin enjoy the benefits of the present invention and are encompassed within the scope of the present invention. A partially or completely disordered form of atorvastatin particularly enjoys the benefits of the present invention. A partially or completely disordered form of atorvastatin, which is amorphous or mostly amorphous, derives the greatest benefit from the present invention. Such forms can be obtained from crystalline forms of atorvastatin using, for example, the means disclosed in US Pat. No. 6,087,511 (incorporated herein by reference). Can be manufactured. Instead, amorphous atorvastatin is co-filed with the applicant's US patent application, agent case number PC-25825, application number. Can be produced according to the method disclosed in the Japanese Patent No. For the practice of the present invention, amorphous and crystalline atorvastatin can be prepared by any method known in the art. Preferred forms of atorvastatin are US Pat. Nos. 5,969,156, 6,121,461 and 6,605,729, and International Patent Application Publication Nos. 01/36384, 02/41834, 02/43732, 02/051804, 02/057228, 02/057229, 03/011826, 03/050085, 03/070702, and 04/022053 , Which is incorporated herein by reference).

  Atorvastatin can be used in the form in which it is produced or can be treated to alter the physical properties of the particles. For example, the material can be ground by any method known in the art. Non-limiting examples of such methods include mechanical grinding and jet grinding. Either the particles produced directly from the step of forming atorvastatin or the particles produced after the grinding operation preferably provide an average particle size in the range of 1 to 200 μm, more preferably between 5 and 150 μm.

  Pharmaceutically acceptable base addition salts of atorvastatin are formed with 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 others. Examples of suitable amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (see, for example, 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, which is a common method for preparing salts. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in the usual manner. Free acid forms differ somewhat from their corresponding salt forms in certain physical properties, such as solubility in polar solvents, but in other respects salts are for purposes of the present invention. Is equivalent to each free acid. Atorvastatin can also exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are intended to be encompassed within the scope of the present invention.

  Forms of atorvastatin that are at least somewhat disordered forms of atorvastatin, or a mixture of crystalline and disordered forms, benefit most significantly from the present invention. The somewhat disordered form indicates that the line width of any peak (peak width at half the height of the peak) measured using powder X-ray diffraction (PXRD) is greater than about 2 ° (θ ) Means having a value. The amorphous or predominantly amorphous form of atorvastatin that has benefited particularly from the present invention is characterized by having a very broad, uncharacterized peak. The combination of the crystalline form of atorvastatin with at least some disordered form shows both a sharp peak (ie the value of 2θ is less than 2 °) and a broad peak (ie more than 2 °), such a form This combination benefits from the benefits of the present invention.

  Atorvastatin has been found to be an effective drug even at relatively low doses. In fact, by keeping the dose low in some patients, it is possible to minimize side effects while retaining the drug effect. It is therefore desirable to provide atorvastatin in a form that can provide a low dose to the patient. For the purposes of the present invention, the dosage provided by the final dosage form of atorvastatin is preferably 0.5 to 120 mgA (where mgA means milligrams of active drug based on free acid), More preferably, it is between 5 and 80 mgA.

Most drugs are supplied in unit dosage form to facilitate and facilitate patient compliance. For solid drug substances, these unit dosage forms are generally in the form of tablets, capsules, drug bags, chewable tablets and fast dissolving dosage forms. 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. The production of these forms involves certain necessary powder filling steps, either by volume or weight. For example, in the manufacture of tablets and capsules, the powder is filled into dies or capsules each at a constant volume. Unit dosage form is within acceptable range [relative standard deviation (RSD) of less than 6% to meet Stage I of the US Pharmacopoeia (USP) guidelines, less than 7.8% to meet Stage II] In order to have the same titer (ie the amount of drug per unit dosage form), there must be no significant separation of the active drug from the excipient. This is particularly important for highly diluted forms. The present invention discloses a composition that provides reproducible potency for a given weight of active atorvastatin plus excipients. Furthermore, this titer control is maintained throughout the process of manufacturing the unit dosage form. Such compositions provide atorvastatin having various titers (mgA per gram of blend) of less than 7.8% RSD, more preferably less than 6% before being processed into unit dosage forms. It should be noted that this composition maintains weight control between unit dosage forms produced from such compositions (ie, the variability in the weight of unit dosage forms produced from such compositions is very small). Good powder flowability. Preferably, such a composition provides a unit dosage form with a weight control within 6% RSD, more preferably within 5%, and even more preferably within 4%. Combining weight control and potency control, the composition preferably has a unit dosage form having an atorvastatin titer per unit dosage form having an RSD of preferably less than 7.8%, more preferably less than 6.0% Can be provided.

  Measurement of the unit dosage form of atorvastatin is necessary to measure the variation in activity between unit dosage forms. Extraction methods against standards with drug levels that are independently known determine the titer best. Titer analysis is best performed using reverse phase high performance liquid chromatography (HPLC) techniques known in the art, compared to standards. For the purposes of the present invention, RSD measurements are best performed by sampling between the steps of forming a unit dosage form. More specifically, unit dosage forms can be sampled from the manufacturing process at various time points (start of operation, intermediate and final). In determining the RSD value, at least three unit dosage forms must be measured from each part. Another analytical technique for determining drug sample titers involves the use of UV-visible spectrophotometry. In this technique, as is known in the art, absorption corresponding to atorvastatin is used to quantify the concentration of atorvastatin in the sample (care should be taken that the excipient does not interfere with absorption).

  The present invention discloses methods and compositions that provide atorvastatin in a pure and stable form. The term “impurity” refers to any substance in the drug that exists from the synthesis and purification process, and any substance derived from the drug that is formed in the manufacture of the unit dosage form. The term “degradation product” refers to any substance derived from a drug that occurs after the manufacture of a unit dosage form. The analysis of impurities and degradation products is performed on the extracted samples using reverse phase HPLC techniques as is known in the art. Calculation of the amount of impurities and degradation products is expressed as the integrated area percent of the degradation product or impurity peak divided by the integrated area percent of all drug-related peaks.

  The particle size of atorvastatin and excipients plays a prominent role in the effectiveness of the dry granulation process in preventing separation. As such, the average particle size can be measured using a laser diffraction particle size device such as a device manufactured by Sympatec GmbH (Goslar, Germany). For the purposes of the present invention, the average particle size can be considered as a size where 50% of the particles have a diameter smaller than the indicated value. Alternatively, the particle size can be assessed using sieve analysis. The total weight percent of material retained on a particular diameter sieve is used to measure the average particle size. The average particle size is the size of the sieve through which about 50% of the weight of the material can pass (retained 50%).

  In the preparation of atorvastatin compositions by dry granulation, the combination of excipients, binders, disintegrants, flavors and lubricants provides the necessary properties for unit dosage forms, as is known in the art. Used for. For example, to produce a tablet, the combination provides adequate hardness by compression and at the same time provides rapid disintegration in vivo. Although there is wide latitude in formulating atorvastatin that meets these conditions, such formulations generally comprise about 1-40% drug, about 5-10% disintegrant, about 0-10% binder and about 0.5-2% by weight lubricant, and the remaining percentage contains the original excipients. Preferred disintegrants include carboxymethylcellulose, hydroxypropylcellulose (low substitution), microcrystalline cellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, aluminum / magnesium silicate, methylcellulose, polacrilin potassium, povidone , Sodium alginate, sodium glycol starch and starch. Preferred binders include gum arabic, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, dextrin, gelatin, guar gum, hydroxypropylmethylcellulose, aluminum silicate magnesium / maltodextrin, methylcellulose, polyethylene oxide, polymethacrylate, povidone, sodium alginate , Starch and zein. Preferred lubricants include calcium stearate, glyceryl palmitostearate, magnesium oxide, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and stearin. Examples include magnesium acid.

To improve the fluidity of the atorvastatin composition and minimize separation from the excipient, the drug and excipient can be compacted in a dry granulation process. However, using atorvastatin, the inventors have found that due to the fragile nature of the drug, only certain excipients form acceptable dry granules with the drug. An acceptable excipient is a significant amount of fine drug particles that do not bind to the excipient and remain in the blend when dry granulated (ie, compressed and milled) in the presence of atorvastatin. It can be defined by the expression excipients that show a decrease. For the purposes of the present invention, fine drug particles (or “fines”) can be defined as particles that pass through a 200 mesh sieve. The inventors can also define the granulation factor as follows. Granulation factor (GF) = 1-[(percent atorvastatin as fines in granules) / (percent atorvastatin as fines in ungranulated blend)]. To determine the granulation factor for an excipient or combination of excipients, a blend of drugs is first prepared with the selected excipient. The blend is passed through a sieve using, for example, a sieving device such as Sonic Shifter ^™ (Allen Bradley Sonic Shifter, Advanced Tech Manufacturing, New Berlin, WI). The percentage of atorvastatin as a fine powder is determined by multiplying the weight of the fine powder by the fine powder titer and dividing by the total weight of the drug in the blend. The same analysis can be performed on the material granulated with atorvastatin. From these analyses, the overall ability of an excipient or combination of excipients to form a dosage form with a low tendency to separate can be determined. We believe that the atorvastatin and excipient or excipient combination that gives the least tendency for separation during unit dosage form production is preferably between 0.4 and 1.0, more preferably 0.5. It has been found to be characterized as having a granulation factor between ˜1.0 and even more preferably between 0.6 and 1.0.

  In determining the preferred excipients for dry granulation with atorvastatin, we have determined that compression of the blend under conditions that can be translated into commercial dry granulation is a true separation of the atorvastatin blend. I found it important to determine the trend. One of the important criteria to be considered when atorvastatin granulation is, especially if the granulation is subjected to an additional compression step that takes place during tablet formation, such as a blended blob or ribbon solid It is a ratio. The solids ratio is an indicator of the amount of compression remaining in the material. As such, the first step involves determining the true density of the blend, that is, the density of the material without air space between the particles. This density can be measured using techniques such as the helium specific gravity method or similar techniques, as is known in the art. It is also possible to estimate this value as a weighted average of the true density for each component. The solid fraction of dry granulation indicates the ratio of the specific gravity of the blob (or ribbon) to the true specific gravity of the material from which the blob was made. Control of the solid fraction is achieved by controlling the compression force during compression. In order to provide sufficient compressibility for tableting in the next step and to achieve good binding of atorvastatin, the inventors preferably have a granule between about 0.55 and 0.85. More preferably, it has been found to have a solid fraction after granulation of between about 0.60 and 0.80.

  Another criterion for achieving acceptable dry granulation of atorvastatin is the tensile strength of the blob or ribbon. The tensile strength of the blob (or ribbon) can be measured using any suitable device known in the art, such as a CT5 tensile strength tester (Engeneering System (NOTTM), Nottingham, England). Preferably a cuboid nodule with dimensions 10 × 22 × 2 mm is used for this measurement. The preferred tensile strength for the inventors to finally produce acceptable granules of atorvastatin is 0.5 to 7.0 megapascals (MPa), more preferably 0.8 to 6.0 MPa. I found out. A combination of atorvastatin and a substance that can achieve a preferred tensile strength within a preferred solids ratio is preferred. Examples of such materials include lactose and microcrystalline cellulose. An example of a material that cannot achieve the desired tensile strength is mannitol.

  By plotting solid fraction against tensile strength, it is possible to find a range of solid fractions that are suitable to give favorable tensile strength for a given blend of atorvastatin and excipient or excipient combination It is. The inventors have found that an interpolation method between measured values can be used assuming an exponential least squares method.

  A preferred excipient is a diluent, which is preferably included in the atorvastatin formulation at 40% or more, more preferably more than 50%, even more preferably more than 60% by weight of the total composition. Preferred diluents are preferably between 0.4 and 1.0, more preferably between 0.5 and 1.0, even more preferably between 0.6 and 1 when tested in a two-component blend with atorvastatin. Gives a granulation factor between 0.0. Potential excipients are identified as being in “Handbook of Pharmaceutical Excipients, 3rd Edition” (AH Kibbe, Editor, Pharmaceutical Press, London; 2002). These diluents include the following non-limiting examples: calcium phosphate, calcium sulfate, carboxymethylcellulose calcium, cellulose, cellulose acetate, dextran, dextrin, dextrose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin , Lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, polymethacrylate, alpha starch, silicified microcrystalline cellulose, sodium chloride, sorbitol, starch, sucrose and talc.

  To determine excipients suitable for use in dry granulation with atorvastatin, it is important that the particular form and particle size of atorvastatin used is desirable for the final dosage form. Similarly, the excipient or excipient combination used appears to have properties that depend on the particle size and method of manufacture. Because compression of atorvastatin and excipients in the dry granulation process is generally easier with smaller particle size excipients, preferred excipients are generally not granulated. Smaller than preferred. As such, preferably the excipient has an average particle size between 20 and 200 μm, more preferably between 40 and 150 μm. This particle size is in a range corresponding to 50% by weight of the blend passing through a sieve having between 635 mesh (ASTM number) to 70 mesh, more preferably between 325 mesh to 100 mesh. The preferred size for certain excipients depends on the particular nature of the form of atorvastatin used and must be determined experimentally in each case.

Therefore, more preferred excipients to be combined with atorvastatin are those with high granulation factor values, can achieve high tensile strength, and are preferred average particle sizes, preferably between 20-200 μm, more Preferably it is a diluent having between 40 and 150 μm. Particularly preferred diluents include microcrystalline cellulose having an average particle size of 20-40 μm [eg, Avicel ^™ PH105 available from FMC Biopolymer, Philadelphia, Pa.], Lactose having a particle size range of 80-150 μm [eg, Foremost Spray dried monohydrate available from Farms, Rothschild, WI, ie Fast Flo ^™ 316, or anhydrous direct compression grade available from Quest International, Flavors & Food Ingredients CCL, Norwich, NY], xylitol (Eg C granular grade available from Danisco Sweeteners, Thompson, IL), mannitol [eg SPI Polyo s, New Castle, Mannogem ^TM 2080 particulate form available from DE], sucrose [e.g., Tate & Lyle Co. Di-Pac ^™ available from American Sugar Inc., Brooklyn, NY], and anhydrous dibasic calcium phosphate [eg, A-Tab ^™ available from Rhodia, Chicago Heights, IL]. Preferably, these preferred diluents comprise a diluent content of 50% by weight, more preferably 60% by weight, and even more preferably more than 70% by weight of the dry granulated composition of atorvastatin.

  The unit dosage form of atorvastatin formed in a dry granulation step with preferred excipients exhibits low levels of drug-related impurities and degradation products. Surprisingly, this low level of impurities and degradation products is found even in the absence of added alkalizing agents or alkaline earth metal salts. Even more surprising, this low level of impurities and degradation products was maintained even when the atorvastatin used was at least a somewhat disordered drug. In particular, it has been found that the unit dosage form of atorvastatin produced by dry granulation has higher stability even when the control unit dosage form of atorvastatin wet granulation exhibits a high level of drug degradation. The unit dosage form of atorvastatin produced by dry granulation is preferably about 2% or less, based on the area percentage of impurities / degradants relative to the integrated area of all peaks associated with the drug as measured by HPLC Preferably contains less than 1%, more preferably less than 0.7% of all drug related impurities and / or degradation products. In addition, the unit dosage form of atorvastatin produced by dry granulation, when stored for 4 weeks at 40 ° C. and 75% relative humidity (RH), the unit dosage form shows all the peaks associated with the drug as measured by HPLC. Less than about 2%, more preferably less than 1%, even more preferably less than 0.7% of all impurities and / or degradation associated with the drug, based on the area percent of impurities / degradants relative to the integrated area It is preferable to provide such stability that the product is contained.

  Atorvastatin goes through two major degradation pathways: lactonization and oxidation. Lactones are formed by forming a 6-membered ring by intramolecular condensation (loss of water) of alcohol and carboxylic acid. This is the major amorphous atorvastatin described in US Pat. Nos. 6,126,971 and 5,686,104, especially during wet granulation and tablet formation, in the absence of alkaline earth metal salts. It is a serious decomposition product. The inventors unexpectedly found that the levels of lactone, both at the beginning and after storage under accelerated testing at elevated temperatures and humidity, were measured in units using this excipient and the dry granulation process. It has been found that it can be significantly reduced by the combination of dosage form production. Preferably, the level of atorvastatin lactone in the unit dosage form is 2% after the unit dosage form is produced and stored at 40 ° C./75% RH (where RH means relative humidity) for 4 weeks. Less than (based on the ratio of the integrated area of the lactone peak to the integrated area of all peaks using HPLC), more preferably less than 1%.

  In the practice of the present invention, the level of alkaline earth metal salt in the formulation is preferably in order to minimize bioavailability issues in the combination dosage form and possible interactions with other drugs. About 0 to 5% by weight, more preferably about 0 to 3%, and most preferably about 0 to 2%. The level of the other alkalizing agent in the preparation is preferably about 0 to 5% by weight, more preferably about 0 to 3% by weight, and most preferably about 0 to 2% by weight.

Dry granulation of excipients and atorvastatin is preferably performed by first blending atorvastatin with at least some preferred excipients. The excipient in this blend preferably comprises between 50 and 95% by weight of the blend. This blending process preferably uses a high shear mixer, V-blender (or other twin shell blender), bin blender or Turbula ^™ mixer shaker (available from Wily A. Bachlofen AG Machinenfabrik, Basel, Switzerland). Implemented using. The blending is generally first performed for a sufficient amount of time without the addition of a lubricant to ensure thorough mixing. At that point, lubricant is generally added, followed by a short (about 1-10 minutes) further mixing time. This blend is then compressed into slugs or ribbons using a tablet press (eg, a single station press or a rotary tablet press) or a roller compressor. In the former case, the blob (slag) is manufactured using a combination of planar dies and punches. In both cases, the density of the blob or ribbon preferably provides a lump or ribbon having a tensile strength of about 0.5 to 7.0 MPa, more preferably a tensile strength of about 0.8 to 6.0 MPa. Selected. The blob or ribbon is then preferably ground, ground or sieved. As is known in the art, particle size reduction is performed in an optimal process designed to provide good throughput and a suitable particle size distribution. Preferably less than 30% by weight of the crushed material passes through a 200 mesh sieve and more than 70% by weight of the crushed material passes through a 60 mesh sieve. Once the material is ground, other excipients can be added extragranular to give the final blend for unit dosage form manufacture. These additives are preferably mixed using a high shear mixer, V-blender (or other twin shell blender), bottle blender or Turbula ^™ mixer shaker. The blending is generally first performed for a sufficient amount of time without the addition of a lubricant to ensure thorough mixing. At that point, lubricant is generally added, followed by a short (about 1-10 minutes) further mixing time. At this point, the granulated material can be used in the production of unit dosage forms. Such unit dosage forms include sachets, tablets, quick dissolve dosage forms, chewable dosage forms and capsules. Preferable dosage forms include tablets and capsules. In the case of tablets, it may also be desirable to coat the dosage form with a film designed to facilitate swallowing, ownership or identification, and / or protection. The final dosage form is packaged using procedures known in the art. For the purposes of the present invention, the packaging is preferably in the form of foil-foil cold form blisters, plastic blisters or desiccant-containing sealed bottles. Optionally, the packaging can also contain an active oxygen absorber as disclosed in EP 1 243 524 A2 (incorporated herein by reference).

In the manufacture of unit dosage forms of atorvastatin in dry granulation, it is possible to produce unit dosage forms without using this formulation using a process unsuitable for commercial production. For example, even granulated materials that tend to separate may be metered directly into capsules. Therefore, the present invention is preferably used in combination with high speed manufacturing equipment. More specifically, preferred formulations exceed 10,000 unit dosage forms per hour, more preferably 25,000 unit dosage forms per hour, most preferably over 50,000 unit dosage forms per hour. When using single unit dosage form production equipment at speed, it is possible to control the RSD of titer during unit dosage form production to less than 7.8% (more preferably less than 6.0) Provide dry granulation. Preferred single device unit dosage form manufacturing machines or machines include a single rotary tablet press and a single commercial capsule filling machine. Non-limiting examples of commercial rotary tablet presses include Niro Pharma Systems (Columbia, MD), Kilian and Company (Horsham, PA), Korsch (Berline, Germany), and Elizabeth-Hata International (North). Product made. Non-limiting examples of commercial capsule filling machines include products from Capsugel (Morris Plains, NJ) and CapPlus Technologies (Phoenix, AZ).

  The present invention does not require a solvent in which the granulation method is potentially solubilized and / or otherwise destabilized, but retains the atorvastatin content uniformly, so that it is particularly suitable for combination products with other drug substances. A composition of atorvastatin that is well suited is provided. This is particularly true when the second drug (with associated excipients) can destabilize atorvastatin. Non-limiting examples of drugs that can benefit from the combination and process of the atorvastatin compositions of the present invention include torcetrapib and amlodipine and pharmaceutically acceptable salts thereof.

  The composition of atorvastatin according to the present 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 the combination of an atorvastatin composition and at least one other active drug that forms a unit dosage form, the following non-limiting list describes options for such unit dosage form: (a ) A blend of atorvastatin granules and the other active drug itself formed in a tablet or capsule (ie, adding other drugs extragranular to the dry granulated composition of atorvastatin) as a blend with excipients ( That is, other drugs and excipients are added extragranularly to the dry granulated composition of atorvastatin) or as granules (ie, a mixture of the other drug granules and the dry granulated composition of atorvastatin), b) Single dry granules of atorvastatin with other drugs formed in tablets or capsules, (c) Dry granulated atorvastatin in one layer, other drugs in other layers and necessary Correspondingly bilayer tablets containing excipients.

  The present invention uses atorvastatin or a pharmaceutically acceptable salt thereof as described above, which is contained in a therapeutic package or kit and can be administered as a unit dosage form with low levels of degradation products and / or impurities. Relates to the treatment of diseases and symptoms in subjects such as hypercholesterolemia and / or hyperlipidemia, osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease. The kit includes unit dosage forms and packaging containers. In general, the kit includes a unit dosage form. The packaging container may be any conventional mold or form known in the art, such as a paper box, a glass or plastic bottle, or a blister pack with individual dosage forms that are removed by pressing the back according to the treatment schedule. obtain.

  The following non-limiting examples illustrate our preferred methods for making and using the pharmaceutical compositions of the present invention.

General Method for Producing Spray-Dried Amorphous Atorvastatin As previously described in the Detailed Description of the Invention and used in the following examples, an example of a disordered form, spray-dried amorphous atorvastatin, was co-filed with the present application. US patent application published by applicant, agent case number PC-25825, application number First, atorvastatin calcium (US Pat. No. 5,273,995) was dissolved in methanol to prepare a 5 wt% solution. Using this solution as the atomizing gas, nitrogen is used.
Sprayed into a Niro PSD-1 spray dryer at a rate of 70 g / min. 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.

Preparation of amorphous atorvastatin tablets by wet granulation The following ingredients were added to a 950 cc amber bottle: 2.59 g of spray-dried amorphous atorvastatin prepared as described in Example 1, microcrystalline cellulose [Avicel ^TM PH102, FMC Biopolymer, Philadelphia, PA] 78.00 g, Lactose (hydrated, Forrest Farms USA, Rothschild, WI) 101.41 g, Croscarmellose sodium [Ac-Di-Sol ^TM , FMC Biopolymer, PA] 6.00 g, and hydroxypropyl cellulose ^{[Klucel TM EXF, Hercules Incorporated,} Aqualon Division, Wilmington, DE] .000g. The material was bottle blended for 10 minutes using a Turbula ^™ mixer (Turbula Shaker Mixer, Willy A. Bachofen AG Maskinfabrik, Basel, Switzerland) and sieved through a 30 mesh screen to break up the mass. The material was returned to the jar again and mixed with Turbula ^™ for an additional 10 minutes. The bottle blended material was added to a Procept Mi-Mi-Pro high shear wet granulator (Pro-CepT nb, B-9060 Zelzate, Belgium) using a 1.7 L bowl. The material was dry mixed at chopper speed: 1000 revolutions per minute (rpm), impeller speed: 400 rpm for 2 minutes, and then the impeller speed was increased to 600 rpm while maintaining the chopper speed. At this point, 90 L of water was added in three portions (60 mL, 15 mL, 15 mL) at a rate of 30 mL / min and wet mixed for a total of 5.5 minutes. Good granules with minimal fines were formed. The material was removed and passed through a wet sieve by handing a # 10 mesh sieve. The screened material was placed on a polyethylene lined tray and dried in a Gruenberg ^™ forced hot air oven (Gruenberg Oven Co., Williamsport, Pa.) At 50 ° C. for 16 hours. The dried material was ground at 500 rpm using a Fitzpatrick L1A mill with 0.040 "Conidur scraping screen (The Fitzpatrick Co., Elmhurst, Ill.). Add 5.469 g of Ac-Di-Sol ^{™ to} 175.0 g of blend. The mixture was bottle blended (950 cc amber bottle) for 5 minutes using a Turbula ^™ mixer, 1.822 g of magnesium stearate (Malllinkrod Inc., St. Louis, MO) was added and the mixture was added for an additional 3 minutes to the Turbula ^™ mixer. The tablets (˜250) were finished with a 13/32 ″ standard circular concave (SRC) finish using a F-press (Manesty F-Press, Liverpool, UK) and the target weight. It was manufactured at 450 mg (± 3%) and a target hardness of 12 kP (range 10-14 kp). A total of 12 tablets were placed in 30 cc high density polyethylene (HDPE) bottles sealed using a heat induction seal (HIS) closure and sealed using a heat induction sealer (Enercon Industries Corp., Menomonee, WI). Samples were stored at 40 ° C. and 75% relative humidity (RH) for 4 weeks. One sample was added to 50 mL of 0.05 M ammonium citrate buffer (pH 7.4): acetonitrile = 1: 1 (v / v) and shaken for 20 minutes to analyze for atorvastatin lactone levels. The material was then filtered using a Gelman Acrodisc polytetrafluoroethylene membrane (pore size: 0.45 μm) and high performance liquid chromatography (HPLC) {Phenomenex, Ultramex C18 column, 25.0 cm × 4.6 mm, HPLC HP1100 series, Agilent Corp. Wilmington, DE, injection volume 20 μl, flow rate 1.5 mL / min, mobile phase: 0.05 M ammonium citrate (pH 4.0): acetonitrile: tetrahydrofuran = 53: 27: 20 (v: v: v), detection: 244 nm}. The lactone level was 25.4% (based on the ratio of the lactone peak area to the total peak area of all peaks).

Preparation of amorphous atorvastatin calcium tablets using dry granulation The following ingredients were added to a 950 cc amber bottle: 2.59 g of amorphous atorvastatin calcium prepared as described in Example 1, microcrystalline cellulose [Avicel PH102 ^TM , FMC Corp. , Philadelphia, PA] 78.00 g, lactose (hydrous, REG 310; Foremost Farms USA, Rothschild, Wis.) 101.41 g, hydroxypropyl cellulose [Klucel EXF ^™ ; Aqualon, Wilmington, DE] 4.00 g, Cal. Sodium [Ac-Di-Sol ^™ , FMC Corp. , Philadelphia, PA] 6.00 g and magnesium stearate (Mallinckrodt Co., St. Louis, Mo.) 1.00 g. The combination of ingredients was mixed for 10 minutes using a Turbula ^™ blender (Glen Mills, Clifton, NJ). The blend was then broken through a stainless steel sieve (# 30 mesh) and then mixed for an additional 10 minutes. The blend was then dry granulated using a single station Manesty F-press (Manesty, Liverpool, UK) and 1 "flat finish slagging to a hardness of 3.5 kP (tablet hardness is Schleuniger Tablet Hardness Tester, Dr. 1.00 g of lumps (tested using Schleuniger Pharmatron AG, Solothurn, Switzerland). The lumps were fitted with a 0.040 "Conidur shaving plate Fitzpatrick L1A mill (Fitzpatrick Co., ILmh). And ground at 500 rpm. The collected pulverized product was returned to the glass bottle, 6.0 g of croscarmellose sodium was added thereto, and the contents were blended for 5 minutes. Finally, 1.00 g of magnesium stearate was added to the brown glass bottle and the contents were blended using Turbula for 3 minutes. Tablets were produced using a single station Manesty F-press. Tablets weighing 450 mg each were manufactured using 13/32 "standard circular concave (SRC) punches and dies. The average hardness of the tablets was 13 kilopascals (kP) and ranged from 12 to 14 kP. The average tablet weight was 447.9 mg and the RSD was 0.7% The tablets were packaged, stored and analyzed as described in Example 2, and the level of atorvastatin lactone was 0.17%. (Based on the area percentage of the lactone peak).

Amorphous Atorvastatin Calcium and Excipient Blend-Manufacture and Analysis of 5% Drugs In each of the 10 60cc bottles, 500 mg of amorphous atorvastatin prepared as described in Example 1 and one of the following excipients 9.4 g was added.
(A) Xylitol (C granule, Danisco Sweetners, Thomson, IL)
(B) Mannitol [Mannogem ^™ 2080 granules, SPI Polyols, New Castle, DE]
(C) Sucrose [compressible sucrose, White Di-Pac ^™ , Tate & Lyle Co. American Sugars Inc. , Brooklyn, NY]
(D) Lactose (spray-dried monohydrate, Foremost Farms, Rothschild, WI)
(E) Lactose (anhydride, direct compression grade, Quest International, Flavors & Food Ingredients, CCL, Norwich, NY)
(F) Lactose [Fast Flo ^™ 316, Foremost Farms, Rothschild, WI]
(G) Microcrystalline cellulose [Avicel ^™ PH102, FMC Biopolymer, Philadelphia, PA]
(H) Microcrystalline cellulose [Avicel ^™ PH105, FMC Biopolymer, Philadelphia, PA]
(I) Microcrystalline cellulose [Avicel ^™ PH101, FMC Biopolymer, Philadelphia, PA]
(J) Anhydrous dibasic calcium phosphate [A-Tab ^™ , Rhodia, Chicago Heights, IL].

Each mixture was blended for 15 minutes using a Turbula ^™ shaker mixer (WillyA. Bachofen AG Machinenfabrik, Basel, Switzerland). To each bottle, 100 mg of magnesium stearate (plant derived, Mallinckrodt Inc., St. Louis, MO) was added and the mixture was blended with Turbula for an additional 5 minutes. A stack of sieves (from top to bottom) was made with 5 spacers, 60 mesh sieve, 200 mesh sieve and pan on the bottom. A 6 "gravimetric paper was placed between the 4th and 5th. Each blend was placed separately on a 60 mesh sieve and the stack of sieves was placed on a Sonic Shifter ^™ (Allen Bradley Sonic Shifter, Advanced Tech. New Berlin, WI) The blend was sieved for 6 minutes with sieving and pulse amplitude 6. The weight of each sieving section was measured and deionized water: acetonitrile = 1: 1 (v / v). The sample was shaken and extracted for 30 minutes, and the material was filtered using a Gelman Acrodisc ^™ polytetrafluoroethylene membrane (pore size: 0.45 μm) and UV-visible spectrophotometry. (Model 8453, Agilent Corp., Wilmington, DE Were analyzed using. Using an external standard curve for quantification of atorvastatin content. The weight and extraction volumes for each sample in Table 1. The results are shown in Table 4.

Amorphous Atorvastatin Calcium and Excipient Blend—Production and Analysis of 40% Drug In each of the 10 60 cc bottles, 4.0 g of amorphous atorvastatin prepared as described in Example 1 and the following excipients: One item, 5.8 g, was added.
(A) Xylitol (C granule, Danisco Sweetners, Thomson, IL)
(B) Mannitol [Mannogem ^™ 2080 granules, SPI Polyols, New Castle, DE]
(C) Sucrose [compressible sucrose, White Di-Pac ^™ , Tate & Lyle Co. American Sugars Inc. , Brooklyn, NY]
(D) Lactose (spray-dried monohydrate, Foremost Farms, Rothschild, WI)
(E) Lactose (anhydride, direct compression grade, Quest International, Flavors & Food Ingredients, CCL, Norwich, NY)
(F) Lactose [Fast Flo ^™ 316, Foremost Farms, Rothschild, WI]
(G) Microcrystalline cellulose [Avicel ^™ PH102, FMC Biopolymer, Philadelphia, PA]
(H) Microcrystalline cellulose [Avicel ^™ PH105, FMC Biopolymer, Philadelphia, PA]
(I) Microcrystalline cellulose [Avicel ^™ PH101, FMC Biopolymer, Philadelphia, PA]
(J) Anhydrous dibasic calcium phosphate [A-Tab ^™ , Rhodia, Chicago Heights, IL].

Each mixture was blended for 15 minutes using a Turbula ^™ shaker mixer (WillyA. Bachofen AG Machinenfabrik, Basel, Switzerland). To each jar, 200 mg of magnesium stearate (plant derived, Mallinckrodt Inc., St. Louis, MO) was added and the mixture was blended with Turbula for an additional 5 minutes. Sieve and titer analysis was performed as described in Example 4. Table 2 shows the extraction volume, and Table 4 shows the analysis results.

Production and analysis of dry granules of amorphous atorvastatin calcium and excipient blend For the dry granulation process, the true density for each excipient and atorvastatin is 25.1 ° C ± 0.9 ° C. A Micro-Ultrapycnometer 1000 (Quantachrome Corp., Boynton Beach, FL) was used and measured with ultra high purity helium gas and an inlet pressure of 20 psig. All density measurements are programmed in the multi-run mode (max 15 runs, average 3 runs, deviation 0.1%, purge mode flow, purge time 15 minutes) and a large cell (cup volume) 4.5 cm ³ ). Reported values were from the average of one replicate or two replicates using a new sample in each experiment. The weight of the sample was at least 1 g (weight range: 1.1-2.7 g).

(A) The true density of the 5 wt% atorvastatin and xylitol blend is the true density of xylitol (1.49 g / cc) and the true density of atorvastatin produced as described in Example 1.24 g / Cc weighted average, ie 1.48 g / cc. Using a F-press, a 10 × 22 rectangular mold was used to make a blob from the blend produced as described in Example 4a. Thickness and weight were varied to obtain a range of densities and corresponding solids fractions (i.e., the density of the blob divided by 1.48 g / cc). In this case, the thickness, weight and solid fraction are 1.90 mm, 500 mg, 0.80; 2.16 mm, 597 mg, 0.84; 2.05 mm, 599 mg, 0.89; and 2.01 mm, 606 mg, 0.92. The deformation force corresponding to the blob was measured using a CT5 tensile strength tester (Engineering System (NOTTM), Nottingham, England) and found to be 0.034, 0.042, 0.152 and 0.163 kg. It was issued. These values are converted to tensile strength by dividing the deformation force by the square of the thickness (multiplied by 22.07 to give units of megapascals, MPa) and the following corresponding values: 0.21 0.20, 0.80 and 0.89 MPa were obtained. Since this sample failed to achieve the desired tensile strength of 1.0 MPa, the sample with the largest solid fraction of 0.92 was used for the production of the blob. Based on this, blend lumps were produced using a 0.50 "circular, flat mold using an F-press at 351 mg per blob and a thickness of 2.0 mm. A total amount of 10 g) was ground at 900 rpm using a Mini Comil 193 (Quadro Engineering Incorporated, Waterloo, Ontario, Canada) with a 0.040 "shaving screen. Samples of material were analyzed as described in Example 4. Table 3 shows the extraction volume, and Table 4 shows the analysis results.

(B) The true density of the 5 wt.% Atorvastatin and mannitol blend is the true density of mannitol (1.45 g / cc) and the true density of atorvastatin produced as described in Example 1. A weighted average of 24 g / cc, ie 1.44 g / cc, was estimated. Using a F-press, a lump was made from the blend produced as described in Example 4b using a 10 × 22 mm rectangular mold. The thickness, weight and solid fraction for the blob produced as described in Example 6a are 1.98 mm, 460 mg, 0.73; 1.77 mm, 422 mg, 0.75; 1.61 mm, 394 mg, 0.77; 1.43 mm, 386 mg, 0.84; 2.07 mm, 552 mg, 0.84; 2.14 mm, 532 mg, 0.78; and 2.13 mm, 596 mg, 0.88. The tensile strengths corresponding to the blob were 0.19, 0.25, 0.39, 1.03, 0.98, 0.40 and 1.92 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.84. Based on this, a blob was produced as described in Example 6a, with 305 mg per blob and a thickness of 1.95 mm. In addition, a nodule having a tensile strength of 3.30 MPa was produced using 320 mg per nodule and a thickness of 1.90 mm. Both small lumps were ground as described in Example 6a. Both samples of material were analyzed for particle size distribution by sieve analysis as described in Example 4. The latter sample was analyzed for titer as described in Example 4. The extraction volume is listed in Table 3 and the final result is listed in Table 4.

(C) The true density of the blend of 5 wt% atorvastatin and direct compression grade sucrose is atorvastatin manufactured as described in Example 1 with the true density of sucrose (1.52 g / cc) Was estimated to be a true density of 1.24 g / cc, a weighted average of 1.51 g / cc. Using a F-press, a lump was produced from the blend produced as described in Example 4c using a 10 × 22 mm rectangular mold. The thickness, weight and solid fraction for the blob produced as described in Example 6a are 1.56 mm, 397 mg, 0.76; 1.43 mm, 398 mg, 0.83; 2.10 mm, 604 mg, 0.86; 2.14 mm, 500 mg, 0.70; and 1.83 mm, 498 mg, 0.81. The tensile strengths corresponding to the blob were 0.76, 2.06, 2.15, 0.34 and 1.15 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.78. Based on this, a blend blob (311 mg / blob, 2.00 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3 and the final result is listed in Table 4.

(D) The true density of the blend of 5 wt% atorvastatin and lactose monohydrate is the true density of lactose (1.49 g / cc) and the true density of atorvastatin produced as described in Example 1. The density was estimated to be a weighted average of 1.24 g / cc, ie 1.48 g / cc. Using a F-press, a lump was made from the blend produced as described in Example 4d using a 10 × 22 mm rectangular mold. The thickness, weight, and solid fraction for the blob produced as described in Example 6a is 1.54 mm, 415 mg, 0.81; 1.72 mm, 456 mg, 0.81; 1.92 mm, 478 mg, 0.76; 1.76 mm, 395 mg, 0.68; 1.98 mm, 488 mg, 0.75; and 1.84 mm, 506 mg, 0.83. The tensile strengths corresponding to the blob were 1.55, 1.05, 0.74, 0.35, 0.60 and 1.83 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.78. Based on this, a blob of blend (302 mg / nob, 2.02 mm thickness) was produced and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3 and the final result is listed in Table 4.

(E) The true density of the blend of 5 wt% atorvastatin and lactose anhydride is the true density of lactose (1.50 g / cc) and the true density of atorvastatin produced as described in Example 1. A weighted average of 1.24 g / cc, or 1.49 g / cc, was estimated. Using a F-press, a lump was produced from the blend produced as described in Example 4e using a 10 × 22 mm rectangular mold. The thickness, weight, and solid fraction for the blob produced as described in Example 6a were 1.82 mm, 427 mg, 0.71; 1.66 mm, 440 mg, 0.80; 1.58 mm, 430 mg, 0.82; and 1.82 mm, 479 mg, 0.80. The tensile strengths corresponding to the blob were 0.68, 2.16, 2.52 and 1.80 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.75. Based on this, a blend blob (286 mg / blob, 2.02 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3 and the final result is listed in Table 4.

(F) The true density of the blend of 5 wt% atorvastatin and lactose Fast Flo ^™ is the true density of lactose (1.54 g / cc) and the true density of atorvastatin produced as described in Example 1. A weighted average of 1.24 g / cc, ie 1.53 g / cc, was estimated. Using a F-press, a lump was made from the blend produced as described in Example 4f using a 10 × 22 mm rectangular mold. The thickness, weight and solid fraction for the blob produced as described in Example 6a are 1.98 mm, 476 mg, 0.70; 1.80 mm, 440 mg, 0.72; 1.72 mm, 411 mg, 0.70; 1.80 mm, 342 mg, 0.55; and 1.73 mm, 475 mg, 0.80. The tensile strengths corresponding to the blob were 1.10, 1.27, 1.16, 0.13 and 2.61 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.70. Based on this, a blend blob (272 mg / blob, 2.01 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3 and the final result is listed in Table 4.

(G) The true density of the blend of 5 wt% atorvastatin and microcrystalline cellulose [Avicel ^™ PH102] was prepared as described in Example 1 with the true density of microcrystalline cellulose (1.58 g / cc). It was estimated that the true density of atorvastatin was 1.24 g / cc, a weighted average of 1.56 g / cc. Using a F-press, a lump was produced from the blend produced as described in Example 4g using a 10 × 22 mm rectangular mold. The thickness, weight and solid fraction for the blob produced as described in Example 6a is 2.56 mm, 417 mg, 0.47; 1.83 mm, 418 mg, 0.66; 1.60 mm, 420 mg, 0.76; 2.29 mm, 382 mg, 0.48; 1.70 mm, 383 mg, 0.65; and 1.91 mm, 347 mg, 0.52. The tensile strengths corresponding to the blob were 0.22, 3.36, 6.99, 0.64, 2.58 and 1.03 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.56. Based on this, a blend blob (226 mg / blob, 2.01 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3 and the final result is listed in Table 4.

(H) The true density of the blend of 5 wt% atorvastatin and microcrystalline cellulose [Avicel ^™ PH105] was prepared as described in Example 1 with the true density of microcrystalline cellulose (1.55 g / cc). It was estimated that the true density of atorvastatin was 1.24 g / cc, a weighted average of 1.53 g / cc. Using a F-press, a lump was produced from the blend produced as described in Example 4h using a 10 × 22 mm rectangular mold. The thickness, weight and solid fraction for the blob produced as described in Example 6a are 1.87 mm, 432 mg, 0.68; 1.55 mm, 387 mg, 0.73; 2.21 mm, 390 mg, 0.52; 1.63 mm, 329 mg, 0.59; 2.18 mm, 311 mg, 0.42; and 1.35 mm, 258 mg, 0.56. The tensile strengths corresponding to the blob were 4.17, 799, 1.29, 2.62, 0.27 and 2.31 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.51. Based on this, a blend blob (211 mg / blob, 2.03 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3 and the final result is listed in Table 4.

(I) The true density of the blend of 5 wt% atorvastatin and microcrystalline cellulose [Avicel ^™ PH101] was prepared as described in Example 1 with the true density of microcrystalline cellulose (1.56 g / cc). It was estimated that the true density of atorvastatin was 1.24 g / cc, a weighted average of 1.54 g / cc. Using a F-press, a 10 × 22 mm rectangular mold was used to produce a blob from the blend produced as described in Example 4i. The thickness, weight and solid fraction for the blob produced as described in Example 6a is 2.06 mm, 541 mg, 0.77; 2.09 mm, 506 mg, 0.71; 1.96 mm, 478 mg, 0.71; 2.20 mm, 432 mg, 0.57; and 1.84 mm, 450 mg, 0.72. The tensile strengths corresponding to the blob were 7.25, 4.96, 5.11, 1.79 and 5.11 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was estimated to be 0.50. Based on this, a blend blob (208 mg / blob, 2.06 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3 and the final result is listed in Table 4.

(J) The true density of the blend of 5 wt% atorvastatin and dicalcium phosphate anhydrous [A-Tab ^™ ] was prepared as described in Example 1 with the true density of calcium phosphate (2.78 g / cc). The estimated true density of atorvastatin was 1.24 g / cc, a weighted average of 2.70 g / cc. Using a F-press, a lump was produced from the blend produced as described in Example 4j, using a 10 × 22 mm rectangular mold. The thickness, weight and solid fraction for the blob produced as described in Example 6a are 2.22 mm, 706 mg, 0.53; 1.82 mm, 598 mg, 0.55; 2.29 mm, 796 mg, 0.58; and 2.05 mm, 598 mg, 0.49. The tensile strengths corresponding to the blob were 0.98, 1.55, 2.32 and 0.49 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.53. Based on this, a blend blob (357 mg / lump, thickness 1.94 mm) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3 and the final result is listed in Table 4.

(K) The true density of the 40 wt% atorvastatin and xylitol blend is the true density of xylitol (1.49 g / cc) and the true density of atorvastatin produced as described in Example 1. A weighted average of 24 g / cc, or 1.39 g / cc, was estimated. Using a F-press, a lump was produced from the blend produced as described in Example 5a using a 10 × 22 mm rectangular mold. The thickness, weight and solid fraction for the blob produced as described in Example 6a are 1.66 mm, 434 mg, 0.84; 2.03 mm, 535 mg, 0.85; 1.95 mm, 530 mg, 0.88; 2.00 mm, 431 mg, 0.69; 2.14 mm, 587 mg, 0.88; and 2.28 mm, 595 mg, 0.84. The tensile strengths corresponding to the blob were 0.62, 0.98, 1.19, 0.09, 1.31, and 0.71 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.86. Based on this, a blend blob (296 mg / blob, 1.92 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3, and the final results are listed in Table 5.

(L) The true density of the 40 wt.% Atorvastatin and mannitol blend is the true density of mannitol (1.45 g / cc) and the true density of atorvastatin produced as described in Example 1. A weighted average of 24 g / cc, ie 1.37 g / cc, was estimated. Using a F-press, a 10 × 22 mm rectangular mold was used to produce a blob from the blend produced as described in Example 5b. The thickness, weight and solid fraction for the blob produced as described in Example 6a are 1.97 mm, 426 mg, 0.71; 1.97 mm, 455 mg, 0.76; 1.79 mm, 460 mg, 0.84; 1.97 mm, 485 mg, 0.81; 1.90 mm, 519 mg, 0.90; and 1.93 mm, 516 mg, 0.88. The tensile strengths corresponding to the blob were 0.63, 0.84, 2.13, 1.74, 2.91 and 2.72 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.76. Based on this, a blob was produced as described in Example 6a, with 296 mg per blob and a thickness of 2.00 mm. In addition, a nodule having a tensile strength of 2.18 MPa was produced with a thickness of 300 mg and 1.98 mm per nodule. Both small lumps were ground as described in Example 6a. Both samples of material were analyzed for particle size distribution by sieve analysis as described in Example 4. The latter sample was analyzed for titer as described in Example 4. The extraction volume is listed in Table 3, and the final results are listed in Table 5.

(M) The true density of the blend of 40 wt% atorvastatin and direct compression grade sucrose was prepared as described in Example 1 with the true density of sucrose (1.52 g / cc). The true density of atorvastatin was estimated to be a weighted average of 1.24 g / cc, ie 1.41 g / cc. Using a F-press, a lump was produced from the blend produced as described in Example 5c using a 10 × 22 mm rectangular mold. The thickness, weight and solid fraction for the blob produced as described in Example 6a was 2.08 mm, 403 mg, 0.62; 2.00 mm, 466 mg, 0.74; 1.66 mm, 412 mg, 0.79; 1.73 mm, 467 mg, 0.86; 2.12 mm, 478 mg, 0.72; 1.82 mm, 481 mg, 0.84; and 1.83 mm, 478 mg, 0.83. The tensile strengths corresponding to the blob were 0.20, 0.74, 1.43, 2.07, 0.46, 2.31, and 1.98 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.77. Based on this, a blend blob (298 mg / blob, 2.13 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3, and the final results are listed in Table 5.

(N) The true density of the 40 wt% atorvastatin and lactose monohydrate blend is the true density of lactose (1.49 g / cc) and the true density of atorvastatin produced as described in Example 1. The density was estimated to be a weighted average of 1.24 g / cc, or 1.39 g / cc. Using a F-press, a lump was produced from the blend produced as described in Example 5d using a 10 × 22 mm rectangular mold. The thickness, weight and solid fraction for the blob produced as described in Example 6a is 2.09 mm, 541 mg, 0.83; 1.90 mm, 471 mg, 0.80; 1.54 mm, 331 mg, 0.69; and 2.18 mm, 594 mg, 0.88. The tensile strengths corresponding to the blob were 1.79, 1.34, 0.73 and 2.62 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.74. Based on this, a blend blob (265 mg / bump, 1.96 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3, and the final results are listed in Table 5.

(O) The true density of the 40 wt.% Atorvastatin and lactose anhydride blend is the true density of lactose (1.50 g / cc) and the true density of atorvastatin produced as described in Example 1. A weighted average of 1.24 g / cc, or 1.40 g / cc, was estimated. Using a F-press, a lump was made from the blend produced as described in Example 5e using a 10 × 22 mm rectangular mold. The thickness, weight, and solid fraction for the blob produced as described in Example 6a are 1.85 mm, 400 mg, 0.69; 1.97 mm, 467 mg, 0.76; 2.07 mm, 501 mg, 0.77; 2.01 mm, 527 mg, 0.84; and 2.00 mm, 398 mg, 0.64. The tensile strengths corresponding to the blob were 0.81, 1.58, 1.52, 2.80 and 0.37 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.72. Based on this, a blend blob (278 mg / blob, 2.08 mm thickness) was produced and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3, and the final results are listed in Table 5.

(P) The true density of the blend of 40 wt% atorvastatin and lactose [Fast Flo ^™ ] is the true density of lactose (1.54 g / cc) and the true density of atorvastatin produced as described in Example 1. The weighted average of 1.24 g / cc, ie 1.42 g / cc, was estimated. Using a F-press, a 10 × 22 mm rectangular mold was used to make a blob from the blend produced as described in Example 5f. The thickness, weight and solid fraction for the blob produced as described in Example 6a is 2.26 mm, 360 mg, 0.50; 1.97 mm, 375 mg, 0.60; 2.14 mm, 409 mg, 0.60; 1.92 mm, 437 mg, 0.72; and 2.17 mm, 530 mg, 0.77. The tensile strengths corresponding to the blob were 0.09, 0.44, 0.43, 1.15 and 2.02 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.70. Based on this, a blend blob (262 mg / blob, 1.99 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3, and the final results are listed in Table 5.

(Q) The true density of the blend of 40 wt% atorvastatin and microcrystalline cellulose [Avicel ^™ PH102] was prepared as described in Example 1 with the true density of microcrystalline cellulose (1.58 g / cc). It was estimated that the true density of atorvastatin was 1.24 g / cc, a weighted average of 1.44 g / cc. Using a F-press, a 10 × 22 mm rectangular mold was used to produce a blob from the blend produced as described in Example 5g. The thickness, weight and solid fraction for the blob produced as described in Example 6a are 1.90 mm, 343 mg, 0.56; 1.88 mm, 400 mg, 0.66; 2.10 mm, 441 mg, 0.65; and 2.30 mm, 366 mg, 0.49. The tensile strengths corresponding to the blob were 0.78, 2.28, 1.88 and 0.29 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.59. Based on this, a blend blob (223 mg / blob, 2.04 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3, and the final results are listed in Table 5.

(R) The true density of the blend of 40% by weight atorvastatin and microcrystalline cellulose [Avicel ^™ PH105] was prepared as described in Example 1 with the true density of microcrystalline cellulose (1.55 g / cc). It was estimated that the true density of atorvastatin was 1.24 g / cc, a weighted average of 1.43 g / cc. Using a F-press, a 10 × 22 mm rectangular mold was used to produce a blob from the blend produced as described in Example 5h. The thickness, weight and solid fraction for the blob produced as described in Example 6a are 1.91 mm, 335 mg, 0.55; 1.82 mm, 312 mg, 0.54; 1.90 mm, 399 mg, 0.66; 2.23 mm, 393 mg, 0.55; 2.10 mm, 445 mg, 0.67; and 1.82 mm, 433 mg, 0.75. The tensile strengths corresponding to the blob were 0.85, 0.66, 2.22, 0.76, 2.00 and 4.42 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.58. Based on this, a blend blob (228 mg / blob, 2.03 mm thick) was produced and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3, and the final results are listed in Table 5.

(S) The true density of the blend of 40% by weight atorvastatin and microcrystalline cellulose [Avicel ^™ PH101] was prepared as described in Example 1 with the true density of microcrystalline cellulose (1.56 g / cc). It was estimated that the true density of atorvastatin was 1.24 g / cc, a weighted average of 1.43 g / cc. Using a F-press, a lump was produced from the blend produced as described in Example 5i using a 10 × 22 mm rectangular mold. The thickness, weight, and solid fraction for the blob produced as described in Example 6a are 1.59 mm, 368 mg, 0.73; 2.24 mm, 397 mg, 0.56; 1.97 mm, 460 mg, 0.73; 1.81 mm, 363 mg, 0.63; 1.69 mm, 394 mg, 0.73 and 1.97 mm, 381 mg, 0.61. The tensile strengths corresponding to the blob were 3.66, 0.75, 3.90, 1.62, 3.72 and 1.50 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.58. Based on this, a blend blob (209 mg / blob, 2.00 mm thickness) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3, and the final results are listed in Table 5.

(T) The true density of the blend of 40 wt% atorvastatin and dicalcium phosphate anhydrous [A-Tab ^™ ] was prepared as described in Example 1 with the true density of calcium phosphate (2.78 g / cc). The estimated true density of atorvastatin was 1.24 g / cc, a weighted average of 2.16 g / cc. Using a F-press, a lump was produced from the blend produced as described in Example 5j using a 10 × 22 mm rectangular mold. The thickness, weight, and solid fraction for the blob produced as described in Example 6a are 1.92 mm, 525 mg, 0.57; 1.79 mm, 484 mg, 0.56; 1.87 mm, 485 mg, 0.54; 1.99 mm, 579 mg, 0.60; and 2.10 mm, 481 mg, 0.48. The tensile strengths corresponding to the blob were 1.56, 1.31, 1.13, 1.95 and 0.45 MPa. The most suitable solid fraction for a 1.0 MPa tensile strength was found to be 0.54. Based on this, a blend blob (294 mg / lump, thickness 1.97 mm) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4. The extraction volume is listed in Table 3, and the final results are listed in Table 5.

  Because atorvastatin is a very powerful drug, drug formulations are generally highly diluted to provide a suitably sized dosage form so that it is easy to manufacture and handle by the patient. When the drug is used in diluted form, the separation of drug and excipients that occurs while the drug is in the process prior to its final dosage form may cause some of the unit dosage form to There is a risk that it can lead to high titers. Controlling the unit dosage titer is essential to protect individual patients from inaccurate, sub-therapeutic effects, or formulation doses that produce side effects. Granulation is one way to prevent separation. As disclosed in co-filed U.S. patent application owned by the applicant, agent case number PC25684, application number 10 / 828,419, publication number US2005-0271717. It is possible to select the excipients so that they can be produced without steps, but granulation is such that no separation occurs and that the particle size of the granules allows a good flow. It makes it possible to ensure the bond between the drug and the excipient. Wet granulation shows one option to form atorvastatin in a form with good flowability that does not separate (co-filed US patent application owned by the applicant, agent case number PC25685, application number 10 / 828,079, publication number US 2004-0247673). However, wet granulation requires exposing the formulation to water and / or solvent. Such exposure increases the risk that the solid form of atorvastatin will change (eg, crystallize or polymorphic form will change) or chemically degrade. Since the amount and rate of addition of the liquid will depend on factors such as the volume and surface area of the wet granulation vessel and the exact particle size of the drugs and excipients used in the particular manufacturing process, Scaling up the grain process can be difficult (ie, variations in performance). Therefore, the object of the present invention is to minimize drug separation, the fluidity of the composition is acceptable for commercial dosage unit formation, the drug is not exposed to solvent, and is robust (scalable ) To provide a dry granule formulation of atorvastatin and a method for producing the same.

  It is an object of the present invention to provide a dosage form composition of atorvastatin having a good homogeneity of titer between doses, dissolution rate and bioavailability and a method for producing the same. It is a further object of the present invention to provide a stable and pure composition of atorvastatin in crystalline or amorphous form with minimal addition of alkali or alkaline earth metal salts.

  Atorvastatin exists in many forms, ranging from highly crystallized forms to forms with varying degrees of disorder. Certain of these disordered forms have several structures shown by powder X-ray diffraction patterns. For the purposes of the present invention, all forms of atorvastatin enjoy the benefits of the present invention and are encompassed within the scope of the present invention. A partially or completely disordered form of atorvastatin particularly enjoys the benefits of the present invention. A partially or completely disordered form of atorvastatin, which is amorphous or mostly amorphous, derives the greatest benefit from the present invention. Such forms can be obtained from crystalline forms of atorvastatin using, for example, the means disclosed in US Pat. No. 6,087,511 (incorporated herein by reference). Can be manufactured. Alternatively, amorphous atorvastatin is produced according to the method disclosed in co-filed US patent application owned by the applicant, agent case number PC-25825, application number 10 / 828,488. can do. For the practice of the present invention, amorphous and crystalline atorvastatin can be prepared by any method known in the art. Preferred forms of atorvastatin are US Pat. Nos. 5,969,156, 6,121,461 and 6,605,729, and International Patent Application Publication Nos. 01/36384, 02/41834, 02/43732, 02/051804, 02/057228, 02/057229, 03/011826, 03/050085, 03/070702, and 04/022053 , Which is incorporated herein by reference).

[0050]
General Method for Producing Spray-Dried Amorphous Atorvastatin As previously described in the Detailed Description of the Invention and used in the following examples, an example of a disordered form, spray-dried amorphous atorvastatin, was co-filed with the present application. First, atorvastatin calcium (US Pat. No. 5,273,995) is dissolved in methanol in accordance with the applicant's US Patent Application Publication No. PC-25825, Application No. 10 / 828,488, 5 wt. % Solution was prepared and manufactured. This solution was sprayed into a Niro PSD-1 spray dryer at a rate of 170 g / min 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.
[Example 2]

Claims (15)

  A dry granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof.   The pharmaceutical composition of claim 1, wherein the composition contains less than about 5% by weight of an alkaline earth metal salt additive.   The dry granulated composition after 4 weeks storage at 40 ° C. and 75% relative humidity contains less than about 2% total impurities and / or degradation products, based on the area percent of the HPLC peak associated with the drug. The pharmaceutical composition according to claim 1.   The pharmaceutical composition according to claim 1, wherein the composition is used in the form of a solid unit dosage form.   The pharmaceutical composition according to claim 4, wherein the unit dosage form is selected from the group consisting of tablets and capsules.   The pharmaceutical composition according to claim 1, wherein the atorvastatin contains at least some partially or completely disordered form of atorvastatin or a pharmaceutically acceptable salt thereof.   The unit dosage form after storage for 4 weeks at 40 ° C. and 75% relative humidity contains less than about 1% total impurities and / or degradation products, based on the area percent of the HPLC peak associated with the drug. Item 5. A pharmaceutical composition according to Item 4.   The pharmaceutical composition according to claim 1, wherein the composition comprises a diluent.   9. The pharmaceutical composition according to claim 8, wherein the diluent comprises microcrystalline cellulose, lactose, sucrose, xylitol or dicalcium phosphate in an amount greater than about 50% by weight.   5. A unit dosage form according to claim 4, wherein the dosage form contains at least one active drug in addition to atorvastatin.   11. A unit dosage form according to claim 10, wherein the active drug contained in addition to atorvastatin includes torcetrapib or amlodipine and pharmaceutically acceptable salts thereof. A method for producing a dry granulated pharmaceutical composition of atorvastatin comprising:
a. Atorvastatin or a pharmaceutically acceptable salt thereof and one or more excipients suitable for use in the dry granulation step;
b. Mix the mixture with a mixer;
c. Compressing the mixture;
d. Grinding, grinding or sieving the compressed material;
e. Optionally adding additional excipients and mixing the combination to form the composition;
A method involving that.   Atorvastatin and at least one other active drug, characterized in that the composition produced according to the method of claim 12 is combined with at least one other active drug and optionally additional excipients. A method for producing a unit dosage form.   A method of treating hypercholesterolemia and / or hyperlipidemia, osteoporosis, benign prostatic hypertrophy and Alzheimer's disease comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 1.   A kit for achieving a therapeutic effect in a mammal comprising a therapeutically effective amount of dry granulated atorvastatin or a pharmaceutically acceptable salt thereof in unit dosage form and a container for containing the dosage form.