HK1088231A - Pharmaceutical compositions comprising atorvastatin manufactured without granulation - Google Patents

Description

Pharmaceutical compositions comprising atorvastatin prepared without granulation

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. provisional patent application No. 60/477,918, filed on 12/6/2003.

Technical Field

The present invention relates to pharmaceutical compositions comprising atorvastatin and pharmaceutically acceptable salts thereof, and processes for preparing such compositions, kits comprising such compositions, and methods of using such compositions to treat patients with hypercholesterolemia and/or hyperlipidemia and osteoporosis, Benign Prostatic Hyperplasia (BPH), and alzheimer's disease.

Background

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by HMG-CoA reductase. Statins may inhibit HMG-CoA reductase from catalyzing this conversion reaction. Thus, statins are, in general, highly effective lipid lowering agents.

Atorvastatin calcium disclosed in U.S. Pat. No. 5,273,995, which is incorporated herein by reference, is currently identified as Lipitor^*Is sold under the trade name of [ R- (R, R) ]]-2- (4-fluorophenyl) -beta, delta-dihydroxy-5- (1-methylethyl) -3-phenyl-4- [ (phenylamino) carbonyl]The trihydrate of calcium (2: 1) salt of (E) -1H-pyrrole-1-heptanoic acid, having the formula

Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase. Thus, atorvastatin calcium is a highly potent lipid lowering compound and is therefore very useful as a hypolipidemic and/or hypocholesterolemic agent, which is also useful in the treatment of osteoporosis, Benign Prostatic Hyperplasia (BPH), and alzheimer's disease.

Numerous patents have disclosed atorvastatin, atorvastatin formulations, and processes for preparing atorvastatin as well as key intermediates. These patents include: U.S. Pat. Nos. 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 and amorphous forms.

Crystalline forms of atorvastatin are disclosed in U.S. Pat. Nos. 5,969,156 and 6,121,461, both of which are incorporated herein by reference. Other crystal formation of atorvastatin is disclosed in U.S. Pat. No. 6,605,729, which is incorporated herein by reference.

In addition, a number of published international patent applications disclose the formation of crystalline forms of atorvastatin, as well as processes for preparing amorphous atorvastatin. These patents include: WO 00/71116, WO01/28999, WO 01/36384, WO 01/42209, WO 02/41834, WO 02/43667, WO 02/43732, WO02/051804, WO 02/057228, WO 02/057229, WO02/057274, WO 02/059087, WO 02/083637, WO 02/083638, WO03/011826, WO 03/050085, WO 03/070702 and WO 04/022053.

Amorphous forms of many drugs are disclosed to exhibit different dissolution characteristics than their crystalline forms, and in some cases even different patterns of bioavailability (Konno, T., ChemPharm Bull, 1990; 38: 2003-2007). For certain therapeutic indications, one mode of bioavailability may be preferred over another.

The change in dissolution rate facilitates the production of crystalline or amorphous atorvastatin formulations. For example, for some potential uses of atorvastatin (e.g., Takemoto, M.; Node, K.; Nakagami, H.; Liao, Y.; Grimm, M.; Takemoto, Y.; Kitakaze, M.; Liao, J.K., Journal of Clinical Investigation, 2001; 108 (10): 1429-.

The preparation of solid formulations of atorvastatin is described in U.S. Pat. nos. 5,686,104 and 6,126,971. In the procedure described therein, atorvastatin is mixed with stabilizers such as alkaline earth metal salts and excipients and subjected to wet granulation. Another U.S. patent application filed concurrently by the applicant as a co-holder (attorney docket No. PC25685, Current letters, Inc.) discloses a wet granulated pharmaceutical composition of atorvastatin and less than about 5% by weight of an alkaline earth metal salt additive. Although wet granulation is widely used in the pharmaceutical industry, it is desirable to avoid the use of wet granulation as much as possible, if possible, because this increases the number of manufacturing steps and reduces overall production efficiency. In general, wet granulation is intended to improve many of the properties of the drug in combination with excipients. In addition, another U.S. patent application filed concurrently by the present applicant as a co-holder (attorney docket No. PC25686, serial No. ____) discloses dry granulated pharmaceutical compositions comprising atorvastatin.

Because atorvastatin is a very active drug, pharmaceutical formulations are generally very dilute in order to provide a dosage form of suitable size for preparation and administration to a patient. When the drug is used in a diluted form, there is a risk of separation of the drug from the excipients during the manufacturing process of the drug to form its final dosage form, which may result in some dosage forms being either too potent or too potent. Unit dose pharmacodynamic control is primarily used to prevent an individual patient from taking an incorrect, less than therapeutically effective amount of a drug or dose that causes side effects. Granulation is one method to prevent segregation. There is no prior art that would predict that an excipient would reduce segregation sufficiently in its mixture with the drug to be administered that the excipient could be used in the preparation of a unit dosage form without a granulation step. Thus, there is a need to identify whether a combination of atorvastatin and excipients is suitable for use in the preparation of unit dosage forms that do not undergo a granulation step and wherein separation of drug and excipients is minimal. In the present invention, we have found that it is possible to unexpectedly identify, with a simple test procedure, excipients suitable for use in the preparation of atorvastatin unit dosage forms without a granulation step.

Among the excipients needed to provide a beneficial atorvastatin formulation, a large number or combination of excipients can be used to dilute the drug, thereby resulting in a convenient dosage for the preparation and manufacture of unit dosage forms. Such materials are known in the pharmaceutical art as diluents. Diluents are described, for example, in "Handbook of Pharmaceutical Excipients, 3rd Edition" (A.H.Kibbe, Edition; Pharmaceutical Press, London; 2000). Since these materials constitute a large portion of atorvastatin formulations, there is a need to identify diluents that can maintain good dose uniformity in the preparation of unit dosage forms under commercial manufacturing conditions.

International patent applications WO 00/35425 and WO01/76566a1 disclose dosage forms forming unit dosage forms of atorvastatin in a broad discussion of methods for stabilizing statins. However, these disclosures do not describe the uniformity of the delivered drug dose, nor the suitability of the dosage form for a commercially available process. In fact, the disclosed dosage forms contain excipients effective within a range of particle sizes, many of which do not allow for the tight weight (light weight) and pharmacodynamic control required for commercial production.

Furthermore, in the preparation and storage of atorvastatin unit dosage forms, it is important to provide pure active drug. Furthermore, it is particularly desirable to be able to achieve such high purity and high stability in formulations which are as simple as possible. U.S. Pat. Nos. 5,686,104 and 6,126,971 disclose a method of increasing the stability of atorvastatin formulations using alkaline earth metal salt additives in the wet granulation step. There remains a need to provide simple formulations and processes for preparing atorvastatin unit dosage forms having low levels of impurities and providing sufficient stability to achieve a commercially viable dosage form shelf life. In addition, alkaline earth metal salt additives and other alkaline substance additives in compositions and dosage forms can affect the solubility of the drug and potentially the pharmacokinetics of the drug in vivo. It is therefore also desirable to provide atorvastatin formulations suitable for preparation of unit dosage forms that provide adequate pharmaceutical purity, stability and desired dissolution rate and bioavailability by using a minimum amount of materials.

In general, it is an object of the present invention to provide atorvastatin unit dosage forms which exhibit acceptable pharmacodynamic variability between unit dosage forms using formulations and methods which provide stable dosage forms of atorvastatin with high speed manufacturing equipment. It is another object of the present invention to provide the consistency and stability of amorphous or amorphous atorvastatin.

Summary of The Invention

Accordingly, a first aspect of the present invention resides in a unit dosage form comprising atorvastatin or a pharmaceutically acceptable salt thereof, prepared without a granulation step, wherein the measured atorvastatin potency in said dosage form shows a Relative Standard Deviation (RSD) of atorvastatin activity per unit dosage form of not more than about 7.8% when said unit dosage form is prepared at a speed per machine above 10,000 unit dosage forms per hour per single unit dosage form.

A second aspect of the present invention is a unit dosage form comprising atorvastatin or a pharmaceutically acceptable salt thereof, in combination with at least one active agent, prepared without a granulation step, wherein the measured atorvastatin potency in said dosage form exhibits a Relative Standard Deviation (RSD) of atorvastatin activity per unit dosage form of no more than about 7.8% when said unit dosage form is prepared at a speed per machine higher than 10,000 unit dosage forms per hour per single unit dosage form.

In a third aspect, the present invention is a process for preparing a tablet or capsule of atorvastatin or a pharmaceutically acceptable salt thereof comprising the steps of:

(a) preparing an atorvastatin composition by mixing atorvastatin or a pharmaceutically acceptable salt thereof and one or more excipients suitable for use without a granulation step in a mixer; and

(b) filled into tablet dies or capsules and then compacted or sealed such that when the tablets or capsules are prepared on a tablet or capsule press at a speed of greater than 10,000 tablets or capsules per hour per machine, the measured atorvastatin potency exhibits a Relative Standard Deviation (RSD) of atorvastatin activity per tablet or capsule of no more than about 7.8%.

In a fourth aspect, the present invention resides in a process for preparing a tablet or capsule of atorvastatin or a pharmaceutically acceptable salt thereof, in combination with at least one active agent, comprising the steps of:

(a) preparing an atorvastatin composition by mixing atorvastatin or a pharmaceutically acceptable salt thereof and at least one active drug and one or more excipients suitable for use without a granulation step in a mixer; and

(b) filled into tablet dies or capsules and then compacted or sealed such that when the tablets or capsules are prepared on a tablet or capsule press at a speed of greater than 10,000 tablets or capsules per hour per machine, the measured atorvastatin potency exhibits a Relative Standard Deviation (RSD) of atorvastatin activity per tablet or capsule of no more than about 7.8%.

A fifth aspect of the invention is a commercially available therapeutic package or kit comprising a container and a therapeutically effective amount of a unit dosage form of atorvastatin or a pharmaceutically acceptable salt thereof prepared without granulation.

A sixth aspect of the present invention is a method of treating patients suffering from hypercholesterolemia and/or hyperlipidemia, osteoporosis, Benign Prostatic Hyperplasia (BPH), and Alzheimer's disease using the aforementioned pharmaceutical unit dosage forms.

Drawings

The invention is further illustrated by the following non-limiting examples, which are briefly described below with reference to FIG. 1.

FIG. 1 shows a schematic view of a

Figure 1 shows the correlation between the relative percent standard deviation (% RSD) of potency and the number of segregation numbers (segregation numbers) of mixtures of atorvastatin, magnesium stearate and various diluents for unit dosage forms prepared using these mixtures.

Detailed Description

Atorvastatin is readily prepared by the methods described in U.S. Pat. Nos. 5,273,995 and 5,969,156, which are incorporated herein by reference. The hemicalcium salt of atorvastatin is currently under the trade name Lipitor^*Is sold in the form of (1).

Atorvastatin exists in many different forms, ranging from highly crystalline to more or less disordered forms. Some of the disordered forms still retain some of the structure as shown by powder x-ray diffraction. All forms of atorvastatin can benefit from and are included within the scope of the present invention for the purposes of this invention. Partially or completely disordered forms of atorvastatin are particularly beneficial to the present invention. Amorphous or mostly amorphous in partially or fully disordered forms of atorvastatin benefits from the present invention. This form can be prepared, for example, by the use of crystalline atorvastatin using the methods disclosed in U.S. patent 6,087,511, which is incorporated herein by reference. Alternatively, the amorphous material may be prepared according to the method described in another U.S. application by the applicant as a co-holder, attorney docket No. PC-25825 (serial No.). For the practice of the present invention, amorphous and crystalline atorvastatin can be prepared by any of the methods known in the art. Preferred forms of atorvastatin are described in U.S. Pat. nos. 5,969,156, 6,121,461 and 6,605,729; and international patent publications WO 01/36384, WO 02/41834, WO 02/43732, WO02/051804, WO 02/057229, WO 3/011826, WO 03/050085, WO 03/070702 and WO 04/022053, which are incorporated herein by reference.

Atorvastatin can be directly applied to the invention in the prepared form, and can also be utilized after the physical properties of the particles are changed by other methods. For example, the material may be milled by any method known in the art. Such methods include, but are not limited to, mechanical milling and jet milling. The particle size of the particles, whether obtained directly after the step of forming amorphous atorvastatin or after comminution, is preferably in the range of 1 to 100 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 the like. Examples of suitable amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (see, e.g., Berge, S.M. et al, "Pharmaceutical Salts", J.pharm.Sci., 1977; 66: 1).

The base addition salts of atorvastatin are prepared by conventional methods by contacting the free acid form with sufficient of the desired base. In addition, atorvastatin can exist in insoluble and soluble forms, including hydrated forms. The scope of the present invention includes such salts of atorvastatin and dissolved forms thereof.

Atorvastatin forms that are at least somewhat disordered or a mixture of crystalline and disordered forms can most significantly benefit from the present invention. "slightly disordered" means that the line width of any peak (peak width at half peak height) measured using powder X-ray diffraction (PXRD) has a2 θ value greater than about 2 °. Atorvastatin, in amorphous or mostly amorphous form, particularly benefiting from the present invention is characterized by having very broad, uncharacterized peaks. It is noted that the combination of crystalline and at least somewhat disordered forms of atorvastatin will exhibit both sharp peaks (i.e., 2 θ values less than 2 °) and broad peaks (i.e., greater than 2 °), and such combinations of forms will also benefit from the present invention.

It was found that even relatively low doses of atorvastatin were effective. In practice, side effects are often minimized by controlling the dose administered to the patient at a lower level while ensuring that the efficacy is maintained. It is therefore desirable to provide a form of atorvastatin that can be administered to a patient at low doses. For the purposes of the present invention, atorvastatin final dosage forms provide a dose of preferably 0.5 to 120mgA (where mgA refers to milligrams of active drug based on free acid); more preferably 5 to 80 mgA.

Most drugs are delivered in unit dosage form for convenience and ease of administration to the patient. For solid drugs, these unit dosage forms are typically tablets, capsules, sachets (sachets), chewable tablets, and fast-dissolving dosage forms. In the present invention, the dosage form is preferably a capsule or tablet; most preferably tablets. The preparation of these dosage forms described above involves a necessary step, namely the filling of some type of powder, either by volume or by weight. For example, in the preparation of tablets and capsules, powders are filled by volume into molds or capsules, respectively. In order for the unit dosage forms to have the same potency (i.e. drug content per unit dosage form) within the allowable range (relative standard deviation RSD, less than 6% for grade I, less than 7.8% for grade II, USP, guidelines), there must not be any significant separation of active drug from excipients. This is particularly evident in highly diluted dosage forms. The invention discloses a composition without granulation, which comprises fixed weight of active atorvastatin and excipient and has reproducible drug effect. In addition, this control of the drug effect is throughout the entire product manufacturing process. The composition provides atorvastatin with a change in potency (mgA per gram of mixture) RSD of less than 7.8%; more preferably less than 6.0%. In addition, the present compositions have good powder flow properties such that weight control between unit dosage forms prepared using the compositions is maintained. Preferably, the composition provides a weight-controlled RSD of the unit dosage form within 6%; more preferably within 5%; most preferably within 4%. The weight control and the drug effect control are combined, so that the RSD of the actual drug effect of the atorvastatin in each unit dosage form in the unit dosage form provided by the preparation is preferably less than 7.8 percent; more preferably less than 6.0%. The above criteria are not granulated but are achieved by a more efficient manufacturing process which reduces the number of unit operations compared to processes involving granulation. In the process of preparing atorvastatin unit dosage forms using a non-granulation step, the above unit dosage forms can be produced without using the compositions of the present invention which are not suitable for commercial production processes. For example, the individual components may be weighed and added directly to the capsules. Therefore, the present invention is preferably used in connection with high speed production equipment. More specifically, when used at a rate greater than 10,000 unit dosage forms per hour; more preferably at a rate of greater than 25,000 unit dosage forms per hour; it is further preferred that the dosage unit be produced at a rate greater than 50,000 unit dosage forms per hour of the single unit dosage form manufacturing device, that the preferred formulation be such that the efficacy of the unit dosage form is controlled to be less than 7.8% RSD (more preferably less than 6.0% RSD). Preferred unit dose production devices or machines include rotary tablet presses and commercial capsule fillers. Examples of commercial rotary tablet presses include, but are not limited to, the machines manufactured by Niro Pharma Systems (Columbia, MD), Kilianand Company (Horsham, PA), Korsch (Berline, Germany), and Elizabet-Hata International (North Huntingdon, PA). Examples of commercially available capsule fillers include, but are not limited to, devices manufactured by Capsugel (Morris Plains, NJ) and CapPlus Technologies (Phoenix, AZ).

In determining the difference in activity between the unit dosage forms, it is necessary to measure the efficacy of atorvastatin unit dosage forms. One extraction method for independently known drug level criteria is best suited for measuring such drug effects. The pharmacodynamic analysis preferably employs reverse phase High Performance Liquid Chromatography (HPLC) techniques, such as those known in the art in connection with standards. For the purposes of the present invention, the measurement of RSD is preferably performed by sampling during the formation of the unit dosage form. More specifically, the unit dosage forms may be sampled at different points in time (beginning, middle, and end of process) during the manufacturing process. In measuring RSD, at least three unit dosage forms per fraction should be measured. An alternative method of measuring the potency of a sampled drug includes ultraviolet-visible absorption spectroscopy. In this technique, the corresponding absorption rate of atorvastatin is used to quantify the concentration of atorvastatin in the sample (note that excipients should not affect the absorption rate), as is well known in the art.

Methods and formulations for providing atorvastatin in a pure and stable form are disclosed. The term "impurities" refers to some of the drug substance that occurs during the synthetic process and purification process, as well as any drug matrix material formed during the process of making the unit dosage form. The term "degradant" refers to any drug matrix material produced after the unit dosage form manufacturing process. The withdrawn samples were analyzed for impurities and degradants by reverse phase HPLC using known techniques. The calculation of the amount of impurity and degradent is expressed as the percent integrated area of the peak of the degradent or impurity divided by the percent integrated area of all drug related peaks.

In atorvastatin formulations prepared by non-granulation methods, the use of a combination of diluents, binders, disintegrants, flavoring agents and lubricants, as is known in the art, may provide some of the properties desired in a unit dosage form. For example, when tablets are prepared, the combination provides sufficient hardness upon compression of the tablet and rapid disintegration in vivo. While a wide range of variations are possible in formulating atorvastatin formulations to meet these conditions, typically the composition comprises about 1-40% weight to weight (w: w) drug, about 5-10% disintegrant, about 0-10% binder and about 0.5-2% lubricant, with the balance being diluents of the present invention. Preferred disintegrants include carboxymethyl cellulose, hydroxypropyl cellulose (low substituted), microcrystalline cellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, cross-linked polyvinylpyrrolidone, magnesium aluminum silicate, methylcellulose, polacrilin potassium, polyvinylpyrrolidone, sodium alginate, sodium starch glycolate, and starch. Preferred binders include acacia, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, dextrin, gelatin, guar gum, hydroxypropylmethylcellulose, magnesium aluminum silicate, maltodextrin, methylcellulose, polyethylene oxide, polymethacrylates, polyvinylpyrrolidone, sodium alginate, starch, and zein. Preferred lubricants include calcium stearate, palmitoyl stearyl glyceride, magnesium oxide, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, and magnesium stearate.

To provide atorvastatin formulations in a form suitable for unit dose formulations that are not granulated, the drug and excipients are typically mixed in powder form. The mixing process may be carried out using mixing techniques well known to those skilled in the art. The mixing process preferably uses a high shear mixer, a V-blender (or other double shell mixer), a bin mixer or a Turbula^TMA mixing oscillator. Blending is usually first performed, in which case no lubricant is added for sufficient time to ensure uniform mixing. At this point, the lubricant should generally be added after a short period of further mixing (about 1-10 minutes). Once blended, the unit dosage form is prepared by procedures well known in the art. The unit dosage forms are preferably prepared on a rotary tablet press or capsule filling machine. The resulting dosage form may then be optionally coated for ease of swallowing, to show ownership, or to have an identifiable appearance and/or to protect the dosage form. The final dosage form is then packaged by techniques well known in the art. In the present invention, the packaging preferably uses foil-foil cold-processed blisters (foil-foil form blisters), plastic blisters or sealed bottles containing a desiccant. Optionally, the package may further comprise an active oxygen absorbing material as described in EP1243524a2 and EP1241110a1 (incorporated herein by reference).

Atorvastatin unit dosage forms prepared without granulation with preferred excipients have low levels of drug related impurities and degradants. Surprisingly, such low levels of impurities and degradants occur even without the addition of a basic substance or alkaline earth metal salt. Even more surprisingly, when atorvastatin is used which contains at least partially disordered forms, such low levels of impurities and degradants remain. In particular, when higher drug degradation occurred in the atorvastatin unit dosage form control prepared by wet granulation, the unit dosage form prepared without granulation still had better stability. Atorvastatin unit dosage forms prepared without granulation preferably contain no more than 2% in total of drug related impurities and/or degradants based on the area percentage of impurities and/or degradants relative to the integrated area of all drug related peaks as measured by HPLC; more preferably less than 1% impurities and/or degradants; still more preferably less than 0.7%. Furthermore, atorvastatin unit dosage forms prepared without granulation preferably have a stability such that the unit dosage forms can be stored at 40 ℃ and 75% Relative Humidity (RH) for four weeks comprising no more than about 2% total drug related impurities and/or degradants based on the area percentage of impurities and/or degradants relative to the integrated area of all drug related peaks as measured by HPLC; more preferably less than 1% impurities and/or degradants; still more preferably less than 0.7%.

Atorvastatin is degraded via two main pathways: lactonization and oxidation. Lactones are obtained by internal condensation (dehydration) of alcohol groups and carboxylic acids to form a six-membered ring. As described in U.S. patent nos. 5,686,104 and 6,126,971, this is the major degradation product of amorphous atorvastatin found in wet granules and tablets, especially without the addition of alkaline earth metal additives. We have surprisingly found that by using the excipients of the invention together with a process for preparing a unit dosage form without a granulation step, the level of lactone in the unit dosage form can be significantly reduced both initially and on storage under accelerated ageing conditions of warming and moistening. Unit dosage forms of atorvastatin prepared without granulation are thus prepared which preferably contain atorvastatin lactone levels of less than 2% (based on the ratio of the integral of the lactone peaks relative to the integral area of all drug related peaks as measured by HPLC) during the preparation and after storage for 4 weeks at 40 ℃/75% RH (where RH represents relative humidity); more preferably, less than 1%.

In order to minimize bioavailability problems and potential interactions with other drugs in the combined dosage form, the alkaline earth metal salt content of the formulation is preferably about 0-5% (w: w) in the practice of the present invention; more preferably about 0-2%; most preferably about 0-1%. The content of other alkaline substances in the preparation is preferably about 0-5% (w: w); more preferably about 0-3%; most preferably about 0-2%. The polyamide or polyamine is preferably present in the formulation in an amount of less than about 0-5% (w: w); more preferably about 0-3%; most preferably about 0-2%. Examples of such polymers are described in International patent publication WO01/76566A 1.

The alkalizing agent is an additive or excipient that raises the pH of the formulation when water is added to the formulation. Examples of the alkalinizing agent include organic bases and inorganic bases (buffers). Examples of inorganic alkalizing agents include sodium or potassium citrate, carbonates, bicarbonates, phosphates, sulfates, benzoates and ascorbic acid, and calcium and magnesium carbonates. The latter two also represent alkaline earth metal salts. Examples of organic alkalizing agents include amines. Specific examples of the amine include N-methylglucamine, guanine, and arginine.

One of the common mechanisms of particle separation is the "sifting" process. Sieving refers to the process by which small particles move through a matrix of larger particles, or vice versa. If the difference in particle size is large enough, this form of separation occurs (a 30% difference in size may be accompanied by sieving) and the materials do not adhere to each other and there is a mechanism for inter-particle movement. In forming a dosage form, interparticle movement can occur when powders are mixed or flowed. The use of atorvastatin and excipients of similar particle size potentially prevents the separation of the two materials when making a unit dosage form; however, it can be problematic for some reasons. As described below, the mean particle size of the excipient is preferably about 80-360 μm in order to provide sufficient flowability of the powder. In contrast, the average particle size of atorvastatin is preferably 1 to 100. mu.m. Such dimensions are preferred for ease of manufacture, reproducibility of drug dissolution (bioavailability), and improved pharmacodynamic variability of dosage forms prepared with these particles, due to statistical analysis of the number of particles in a unit dosage form. The general difference in particle size between atorvastatin and the primary excipient has led to problems with sieving atorvastatin in the presence of excipients suitable for use without granulation.

The second method of separation is fluidization. Fluidization is due to the tendency of smaller particles to remain empty longer than larger particles during processes involving the transfer or mixing of a high proportion of powder. The segregation due to fluidization is especially problematic in particles having a size of less than 100 μm, as is exhibited by atorvastatin.

The separation of smaller drug particles from larger excipient particles is minimized if sufficient adsorptive forces are generated between the drug particles and some of the excipient particles. This adsorptive force must be large enough to overcome the shear forces experienced by the powder. We have found that by using a simple test procedure on a binary mixture of drug and single excipient (containing a constant low level of magnesium stearate lubricant), excipients with sufficient adsorption to the drug can be identified to prevent segregation during unit dosage form manufacture (e.g. tablet manufacture).

In this procedure, a mixture of atorvastatin, magnesium stearate (1 wt%) and the excipients tested was first mixed in a V-blender or Turbula^TMBlending was performed in a mixing shaker. The relative weights of drug and excipient are the same as their relative weights in the final desired composition. The mixture was then subjected to a fluidized separation test by the method described in ASTM D6941-03. Such as model 6274.01-1 fluidization tester (available from Jenike)&Johanson inc. (commercially available from Westford, MA) can be used for this test. The mixture is added to the device. The gas flows through the powder bed of the device, separating the material vertically in the cylinder. The instrument can be sampled from different heights of the cylinder. Analysis of the efficacy of samples taken from the top, middle and bottom of the cylinder using HPLC or UV/visible absorption analysis provides an indication of whether the drug is adsorbed to a particular excipient. Can be used forThe number of separations is defined as the top of the fluidized bed (P)_{Top part}) And a bottom (P)_{Bottom part}) The difference in the pharmacological effects of (A) divided by the apical part (P)_{Top part}) Middle part (P)_{Middle part}) And a bottom (P)_{Bottom part}) Mean value of drug effect of the samples. Can be represented by the following formula:

separation number ═ P_{Top part}-P_{Bottom part}]/[(P_{Top part}+P_{Middle part}+P_{Bottom part})/3]

As shown in fig. 1, we have determined an empirical correlation between the pharmacodynamic variability (RSD) and the number of splits in a unit dosage form (tablet) during high speed production. Based on this, when the separation number of the excipient and the atorvastatin is less than 0.7; more preferably less than 0.6; even more preferably less than 0.5, it is expected that the resulting unit dosage form will have acceptable uniformity in the manufacturing process.

In addition, the individual excipients can be characterized by atorvastatin in a binary test. In this case, the concentration of standard atorvastatin is 1 wt% (98 wt% excipient and 1 wt% magnesium stearate). As described above, the number of separations can be calculated by the fluidization separation test as the ratio of the difference between the drug effects of the top and bottom samples to the total average potency of the drug effects of the top, middle and bottom samples. The final suitability of the excipients for use in admixture with atorvastatin depends on the average of the respective numbers of separate excipients weighted. For example, a weight ratio of 60: 40 for the two materials, with respective separation numbers (to a particular form of atorvastatin) of 0.3 and 0.6, respectively, gives a weighted average separation index of 0.60 × 0.3+0.40 × 0.6 ═ 0.42. Preferred compositions exhibit a weighted average number of separations based on binary values of atorvastatin of less than 0.7; more preferably less than 0.6; even more preferably less than 0.5.

Preferred excipients are diluents, preferably containing greater than or equal to 50% by weight of excipients in the atorvastatin-containing composition. Preferred diluents for use in unit dosage forms of atorvastatin prepared without granulation provide a weighted average split number of less than 0.7; more preferably less than 0.6; even more preferably less than 0.5. Potential diluents can be identified by methods such as those described in Handbook of Pharmaceutical Excipients, 3rd Edition (A.H.Kibbe, Edition; Pharmaceutical Press, London; 2000). Including the following non-limiting examples: calcium phosphate, calcium sulfate, carboxymethylcellulose calcium, cellulose acetate, dextrates, dextrin, glucose, fructose, palmitoyl stearoyl glyceride, hydrogenated vegetable oil, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, polymethacrylates, pregelatinized starch, silicified microcrystalline cellulose, sodium chloride, sorbitol, starch, sucrose, and talc.

In excipient testing, it is important that the particular form and particle size of atorvastatin used be that which is desired in the final dosage form. It has been found that the process by which atorvastatin is produced affects the number of discrete unit dosage forms produced and the corresponding content uniformity. For example, the values obtained for amorphous atorvastatin prepared by spray drying are different from those obtained for amorphous atorvastatin prepared by precipitation.

For diluents to be used in the commercial production of atorvastatin unit dosage forms, the flowability of the diluent must be sufficiently large to ensure weight control. As noted, we have found that the mean particle size of more than about 50% by weight of the diluent used in the manufacture of atorvastatin unit dosage forms is preferably between about 80 and 360 μm; more preferably between 90 and 280 μm; it is still further preferred that more than 70% of the diluent used in the manufacture of atorvastatin unit dosage forms have an average particle size of between about 80 to 360 μm. The average particle size can be measured with a laser diffraction particle sizer, such as an instrument manufactured by Sympatec GmbH (Goslar, Germany). For the purpose of the present invention, the average particle size may be considered that 50% of the particles have a particle diameter smaller than the number. Or the particle size can be assessed by sieve analysis. In this case, the size of the sieve pores which can retain half the weight of the material (half the material passing through the sieve pores) corresponds to the average particle size. The preferred average particle size of the diluent is based on sieve analysis, i.e., 50% by weight passes through a 200 (ASTM) (75 μm, respectively) to 45 (355 μm, respectively) sieve opening; more preferably from No. 170 (90 μm) to No. 50 (300 μm).

The tendency of the diluent to separate from the atorvastatin and the particle size of the diluent together define a range of diluents that are preferred for atorvastatin formulations. As noted, preferred excipients for atorvastatin formulations prepared without granulation include large particle size lactose monohydrate (e.g., Fast Flo 316)^TMCommercially available from Foremost Farms, Baraboo, Wis, having an average particle size of 101 μm), large particle size anhydrous lactose (e.g., the grade of lactose available from Quest International (Sheffield Products), Hoffman Etates, IL, having an average particle size of 136 μm), large particle size microcrystalline cellulose (e.g., Avicel PH200^TMCommercially available from FMC Biopolymers, philidelphia, PA, with an average particle size of 180 μm) and sodium chloride (e.g. particle-grade sodium chloride, commercially available from mallinkrodt Baker, inc., phillips burg, NJ, with an average particle size of 355 μm). Excipients which are commonly used in pharmaceutical formulations but are not preferred for use in the present invention include microcrystalline cellulose of small particle size (e.g. AvicelPH 105)^TMWith an average particle size of 20 μm, and Avicel PH 103, 113 and 301 with an average particle size of 50 μm each, and lactose of small particle size (e.g. the following grades with an average particle size of less than 75 μm: pharmatose^TM125M, 150M, 200M, 350M, 450M, available from DMVInterationary, Vegnel, The Netherlands; impalpable^TM#312 and #313, available from Foremost Ingredients Group, Rothschild, Wis; and monohydrate 80M, amorphous (impalpable) monohydrate, and anhydrous amorphous forms are available from Quest International, shefffield Products, Hoffman Estates, IL).

The present invention provides atorvastatin compositions which are well suited for use in combination with other pharmaceutical substances because of the lower tendency of atorvastatin to separate from the diluents of the present invention. Non-limiting examples of compositions and methods that benefit from combination with the inventive atorvastatin compositions include torcetrapib and amlodipine and pharmaceutically acceptable salts thereof.

The atorvastatin compositions of the present invention can be combined with at least one other active agent to prepare a unit dosage form. Preferred unit dosage forms include tablets and capsules. In combining the atorvastatin composition with at least one other active ingredient to prepare a unit dosage form, the following non-limiting examples describe such unit dosage forms: (a) a mixture of atorvastatin, excipients and other active agents, in unit dosage form; (b) granules of atorvastatin, excipients and other drugs and optionally mixtures comprising excipients, formulated in unit dosage form; and (c) a bilayer tablet comprising atorvastatin and excipients in one layer and other drug and optional excipients in the other layer.

The present invention relates to the use of the above-described atorvastatin or pharmaceutically acceptable salts thereof for the treatment of diseases and conditions such as hyperlipidemia and/or hypercholesterolemia, osteoporosis, Benign Prostatic Hyperplasia (BPH) and alzheimer's disease in a patient, which atorvastatin or pharmaceutically acceptable salts thereof is administered in unit dosage forms having low levels of degradation products and/or impurities in therapeutic packages and kits. The kit includes a unit dosage form and a container. Typically, the kit will include instructions for administration of the unit dosage form. The container may be of any conventional shape or form known in the art, such as a carton, glass or plastic bottle, or blister, in which individual dosage forms may be pressed out of the back side thereof according to a treatment regimen.

The following non-limiting examples are intended to illustrate the methods preferred by the inventors for making and using the pharmaceutical compositions of the present invention.

Example 1

General Process for the preparation of spray-dried amorphous atorvastatin

As an example of the unordered atorvastatin described in the detailed description of the invention, spray dried amorphous atorvastatin used in some of the examples below can be prepared by the methods described in the co-pending U.S. application Ser. No. PC-25825, attorney docket No. _________________________________________________________. Atorvastatin calcium (U.S. Pat. No. 5,273,995) was first dissolved in methanol to make a 5% (w: w) solution. The solution was sprayed into a NiropSD-1 spray dryer at a rate of 170 grams per minute (g/min), using nitrogen as the atomizing gas. The temperature of the air inlet was 195 ℃ and the temperature of the air outlet was 60 ℃. After spray drying, the resulting powder was dried in an oven with trays at 40 ℃ for 12 hours to produce amorphous atorvastatin.

Example 2

General Process for the preparation of precipitated amorphous atorvastatin

As an example of the non-simultaneously ordered atorvastatin described in the detailed description of the invention, precipitated amorphous atorvastatin used in some of the examples below can be prepared by the method described in U.S. application Ser. No. PC-32139, serial No., filed as a common holder. First 1.80kg of atorvastatin calcium (U.S. Pat. No. 5,273,995) was dissolved in 18L of Tetrahydrofuran (THF) and stirred in a jacketed glass reactor with a stir bar above. The THF solution was added continuously to the mixture of heptane (55L) and 2-propanol (1.125L) in the jacketed reactor over a period of 2 hours while the upper stir bar was stirring and maintaining the temperature at 15-25 ℃. The resulting slurry was stirred for an additional 1 hour and slowly cooled to 0-5 ℃ over 1 hour. The precipitate was isolated by vacuum filtration on a horizontal plate filter covered with polyethylene film and then dried under vacuum (20-30 inches pressure) at 50-60 deg.C to yield 1.6kg of amorphous atorvastatin.

Example 3

Preparation of amorphous atorvastatin tablets using wet granulation

The following were added to a 950-cc amber bottle: 2.59g of spray dried amorphous atorvastatin (prepared as described in example 1), 78.00g of microcrystalline cellulose (Avicel)^TMPH102 from FMCBiopolymer, Philadelphia, Pa.), 101.41g lactose (aqueous, available from Foremost farm USA, Rothschild, Wis.), 6.00g croscarmellose sodium (available from Ac-Di-Sol)^TMFMC Biopolymer, Philadelphia, Pa.) and 4.000g hydroxypropyl cellulose (Klucel)^TMEXF, available from hercules incorporated, Aqualon Division, Wilmington, DE). These materials were used Turbula in bottles^TMA Mixer (Turbula Shaker Mixer, available from Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland) was mixed for 10 minutes (min.) and poured out and the cake was removed by sieving with a 30 mesh sieve. Then the material was returned to the jar and Turbula was used^TMMix for an additional 10 minutes. The mixed material in the vial was added to a Pro-Cept Mi-Mi Pro high shear wet granulator (Pro-Cept n.v., B-9060 Zelzate, Belgium) using a 1.7L graduated cylinder. The material was dry stirred for 2 minutes at 1000 revolutions per minute (rpm) in a chopper (chopper) at a speed of 400rpm of the stirrer, and then the stirrer speed was increased to 600rpm while maintaining the chopper speed. At this time, 90ml of water was added in three portions (60ml, 15ml) at a rate of 30ml/min over a total time of 5.5 minutes, and wet stirring was performed. The material was decanted and sieved by hand through a #10 mesh sieve. The sieved material was placed on a polyethylene lined tray on a Gruenberg^TMDried in a hot air Oven (available from Gruenberg Oven Co., Williamsport, Pa.) at 50 ℃ for 16 hours. The dried material was milled using a Fitzpatrick L1A mill (available from The Fitzpatrick Co., Elmhurst, IL) with a 0.040 "Conidur rasping screen at 500 rpm. To 175.0g of the mixture was added 5.469g of Ac-Di-Sol^TMAnd the obtained mixture is treated with Turbula^TMThe mixer mixes in a bottle (950-cc amber bottle) for 5 minutes. Magnesium stearate (available from Mallinckrodt inc., st. louis, MO) 1.822g was then added followed by Turbula^TMThe mixer mixes for 3 minutes to complete the formulation. Tablets (. about.250) were prepared using an F-Press (available from Manesty F-Press, Liverpool, United Kingdom) with a standard circular concave Surface (SRC) of 13/32 "at a target weight of 450mg (+/-3%) and a target hardness of 12kP (in the range of 10-14 kP). Placing a total of 12 tablets into a 30-cc High Density Polyethylene (HDPE) bottle, sealing with heat-induced seal (HIS), and sealingThe mouth material was heat induced to seal the material (commercially available from Enercon Industries corp., Menomonee, WI). The samples were stored at 40 ℃ and 75% Relative Humidity (RH) for 4 weeks. One tablet was added to 50ml of 1: 1 (v: v)0.05M ammonium citrate buffer (pH 7.4): after 20 minutes of shaking in acetonitrile, the level of atorvastatin lactone in the sample was measured. The resulting material was filtered through a Gelma Crodis Teflon film (0.45 μ M pore size) and analyzed by High Performance Liquid Chromatography (HPLC) (Phenomenex, Ultremex C18 column, 25.0 cm. times.4.6 mm, HPLC HP1100 series, available from Agilent Corp., Wilmington, DE, injection at 20 μ L flow rate of 1.5mL/min, mobile phase 53: 27: 20 (v: v)0.05M ammonium citrate (pH4.0) acetonitrile: tetrahydrofuran; detection at 244 nm). The lactone level was 25.4% (based on the ratio of the lactone peak to all peak areas).

Example 4

Amorphous atorvastatin tablets by direct compression

The following were added to a 950-cc amber bottle: 2.59g of spray dried amorphous atorvastatin (prepared as described in example 1), 78.00g of microcrystalline cellulose (Avicel PH 102)^TM(ii) a Commercially available from FMC corp., philiadelphia, PA), 101.41g of aqueous lactose (REG 310; commercially available from Foremost farm USA, Rothschild, Wis.), 4.00g hydroxypropyl cellulose (Klucel)^TMEXF; available from Aqualon Division, Wilmington, DE) and 12.00g croscarmellose sodium (Ac-Di-Sol)^TM(ii) a Purchased from FMC corp., philiadelphia, PA). Turbula for mixture containing the above components^TMMixing was performed for 10 minutes on a mixing shaker (available from Glen Mills, Clifton, NJ). The resulting mixture was passed through a stainless steel sieve (#30 mesh) to remove lumps, followed by mixing for an additional 10 minutes. Finally, 2.00g magnesium stearate (available from Mallinckrodt co., st.louis, MO) was added to an amber glass bottle and Turbula was used^TMMixing was continued for 3 minutes. Tablets were made by a one-step Manesty F-Press (Manesty, Liverpool, United Kingdom). Each sheet 4 was made with an 13/32' Standard Round Concave (SRC) punch and die50mg tablet. The mean Hardness of the tablets was 11kP, in the range of 9-14kP (Hardness of tablets can be measured with Schleuniger Tablet Hardness Tester, Dr. Schleuniger Pharmatron AG, Solothurn, Switzerland). The average weight of the tablets was 451.2mg and RSD was 1.3%. The tablets were packaged and tested for stability as described in example 3 (4 weeks; 40 ℃/75% RH). The lactone content under this condition was 0.12% (based on the ratio of the lactone peak to the total peak area of all peaks).

Comparing examples 3 and 4, it was unexpectedly found that atorvastatin unit dosage forms prepared by direct compression had higher purity than wet granulation.

Example 5

Preparation and isolation analysis of spray-dried atorvastatin and diluent mixtures

Spray dried amorphous atorvastatin (prepared as described in example 1) was used in each of the following mixtures. The number of separations for these binary mixtures of atorvastatin was measured using a fluidization separation tester (model 6274.01-1; commercially available from Jenike & Johanson, Westford, Mass.). The fluidizing chamber was filled with about 75-cc of the mixture to be tested. The set test parameters were: air pressure, 25 psi; hold time, 120 seconds; impact time, 30 seconds. The gas flow arrangement for fluidizing each mixture is related to the formulation of that mixture and will be described below. Portions (top, middle and bottom) of the three fluidization columns were each split (model RR-5 RotaryMicro Riffler, available from Quantachrome Instruments, Boynton Beach, FL) to obtain representative samples for analysis. The results of each case are shown in Table 1. Presented in table 1 are the observed effects expressed as a percentage of the desired effect (% target).

(a) 1959.0g of lump (20 mesh) removed anhydrous calcium dihydrogen phosphate (A-tab) was added to a 4-quart V-type mixer (available from Patterson-Kelly Corp., EastStroudsburg, Pa.)^TMCommercially available from Rhodia Corp., Etoil Part-Dieu, France). At itOn top 21.1g atorvastatin (from example 1) was placed and coated on the dilution bed with a doctor blade. The mixture was mixed for 15 minutes. 20.0g of magnesium stearate (available from Mallinckrodt Corp., Hazelwood, Mo.) was added to the mixer and mixed for an additional 5 minutes. The separation analysis was performed with the gas flows set to 10 and 15 (low and high, respectively). 2.2g of the mixture were weighed and 250ml of 1: 1 (v: v)0.05M ammonium citrate buffer (pH7.4) were added: acetonitrile and shaking for 20 minutes, the potency values at the top, middle and bottom were measured, respectively. The material was then filtered through a Gelman Acrodisc Teflon film (0.45 μ M pore size) and analyzed by High Performance Liquid Chromatography (HPLC) (Phenomenex, Ultremex C18 column, 25.0 cm. times.4.6 mm, HPLC HP1100 series, injection at 20 μ L flow rate of 1.5mL/min, mobile phase 53: 27: 20 (v: v)0.05M ammonium citrate (pH4.0), acetonitrile: tetrahydrofuran; detection at 244 nm).

(b) 1959.0g of lump (20 mesh) removed anhydrous lactose (direct flaking grade, Quest International (Sheffield Products), Hoffman Estates, IL) was added to a 4-quart V-type mixer (available from Patterson-Kelly corp., eaststrousburg, PA). On top of this 21.1g atorvastatin (from example 1) was placed and coated on the dilution bed with a spatula. The mixture was mixed for 15 minutes. 19.9g of magnesium stearate (available from Mallinckrodt Corp., Hazelwood, Mo.) was added to the mixer and mixed for an additional 5 minutes. The separation analysis was performed with the gas flows set to 10 and 15 (low and high, respectively). 2.0g of the sample was weighed, and the top, middle and bottom potency values were measured in the same manner as in example 5 a.

(c) 1077.4g of lactose monohydrate (REG 310) was added to a 4-quart V-type mixer (available from Patterson-Kelly Corp., EastStroudsburg, Pa.)^TMCommercially available from Foremost Farms, Baraboo, Wis.). On top of this 11.6g atorvastatin (from example 1) was placed and coated on the dilution bed with a spatula. The mixture was mixed for 15 minutes. 11.0g of magnesium stearate (available from Mallinckrodt Corp., Hazelwood, Mo.) was added to the mixer and mixed for an additional 5 minutes. The separation analysis was performed with the gas flows set to 15 and 20 (low and high, respectively). Weigh the top sample 1.4g, middle andthe bottom sample (2.0 g, extracted into 100ml of extraction solvent) was subjected to the same measurement of the top, middle and bottom potency values as in example 5 a.

(d) 1077.1g of spray dried lactose monohydrate (Fast Flo 316) was added to a 4-quart V-type mixer (available from Patterson-Kelly Corp., EastStroudsburg, Pa.)^TMCommercially available from Foremost Farms, Baraboo, Wis.). On top of this 11.6g atorvastatin (from example 1) was placed and coated on the dilution bed with a spatula. The mixture was mixed for 15 minutes. 11.0g of magnesium stearate (available from Mallinckrodt Corp., Hazelwood, Mo.) was added to the mixer and mixed for an additional 5 minutes. The separation analysis was performed with the gas flows set to 20 and 30 (low and high, respectively). Samples 2.0g and 100ml extraction volumes were weighed and potency values were measured in the same way as in example 5 a.

(e) 881.5g of microcrystalline cellulose (Avicel PH 200) was added to a 4-quart V-type mixer (available from Patterson-Kelly Corp, EastStroudsburg, Pa.)^TMCommercially available from FMC Biopolymers, philiadelphia, PA). On top of this 9.6g atorvastatin (from example 1) was placed and coated on the dilution bed with a spatula. The mixture was mixed for 15 minutes. 9.0g of magnesium stearate (available from Mallinckrodt Corp., Hazelwood, Mo.) was weighed into the mixer and mixed for an additional 5 minutes. The separation analysis was performed with the gas flows set to 4 and 10 (low and high, respectively). Samples 1.3g and 100ml extraction volumes were weighed and the top, middle and bottom potency values were measured in the same way as in example 5 a.

(f) 1959.0g of direct flaking grade sucrose (DI-PAC) with lumps removed (30 mesh screen) was added to a 4-quart V-type mixer (available from Patterson-Kelly Corp., EastStroudsburg, Pa.)^TMCommercially available from Domino Foods, inc., Domino specialty ingredients, Baltimore, MD). On top of this 21.1g atorvastatin (from example 1) was placed and coated on the dilution bed with a spatula. The mixture was mixed for 15 minutes. 20.0g of magnesium stearate (available from Mallinckrodt Corp., Hazelwood, Mo.) was added to the mixer and mixed for an additional 5 minutes. Airflow was set to 18 and 25 (for low and high respectively)) Separation analysis was performed. 2.3g of the sample was weighed, and the top, middle and bottom potency values were measured in the same manner as in example 5 a.

(g) 1467.0g of lump (14 mesh) removed sodium chloride (granulation grade, available from Mallinckrodt Baker, Inc., Phillipsburg, N.J.) was added to a 2-quart V-type mixer (available from Patterson-Kelly Corp., EastStroudsburg, Pa.). On top of this 15.8g atorvastatin (from example 1) was placed and coated on the dilution bed with a spatula. The mixture was mixed for 15 minutes. 14.9g of magnesium stearate (available from Mallinckrodt Corp., Hazelwood, Mo.) was added to the mixer and mixed for an additional 5 minutes. The separation analysis was performed with gas flows set to 50 and 80 (low and high, respectively). Samples 4.5g and 500ml extraction volumes were weighed and the top, middle and bottom potency values were measured in the same way as in example 5 a.

(h) In a 950-cc amber glass bottle were added in order: 97.97g of spray dried lactose monohydrate (available from Foremost farm USA, Rothschild, Wis.), 2.12g of spray dried amorphous atorvastatin (from example 1), and 97.94g of spray dried lactose monohydrate. Mixing the above components with Turbula^TMThe mixer (available from Willy a. bachofen AG Maschinenfabrak, Basel, Switzerland) was shaken and mixed for 10 minutes. The resulting mixture was passed through a #30 mesh stainless steel U.S. standard sieve to remove lumps. Then using Turbula^TMThe mixture was mixed for 10 minutes. Finally, 1.99g of plant-derived magnesium stearate (available from Mallinckrodt, St. Louis, Mo.) was added and Turbula was used^TMMix for 3 minutes. The separation analysis was performed with the gas flows set to 4 and 11 (low and high, respectively). 2.3g of the sample was weighed, 250ml of 1: 1 (v: v) deionized water: acetonitrile was added, and after 30 minutes of shaking, the efficacy values of the top, middle and bottom were measured. This material was filtered through a Gelman Acrodisc Teflon film (0.45 μm pore size) and analyzed with a UV-Vis spectrophotometer (model 8453, available from Agilent Corp., Wilmington, DE, 0.1cm cell length, analysis at 244 nm).

(i) In a 950-cc amber glass bottle were added in order:97.94g of monocalcium phosphate dihydrate (Emcompress)^TMJRS Pharma LP, Chicago Heights, IL), 2.08g atorvastatin (from example 1), and 97.94g monocalcium phosphate dihydrate (Emcompress)^TM). Mixing the above components with Turbula^TMThe mixer was shaken and mixed for 10 minutes. The resulting mixture was passed through a #30 mesh stainless steel U.S. standard sieve to remove lumps. Then, Turbula was used^TMThe mixture was mixed for 10 minutes. Finally, 2.00g of magnesium stearate from plant sources is added and Turbula is used^TMMix for 3 minutes. The separation analysis was performed with the gas flows set to 8 and 15 (low and high, respectively). Sample 3.0g was weighed and the top, middle and bottom potency values were measured as in example 5 h.

(j) In a 950-cc amber glass bottle were added in order: 97.94g microcrystalline cellulose (Avicel PH 102)^TMCommercially available from FMC BioPolymers, Newark, DE), 2.08g atorvastatin (from example 1), and 97.94g microcrystalline cellulose (Avicel PH 102)^TM). Mixing the above components with Turbula^TMThe mixer was shaken and mixed for 10 minutes. The resulting mixture was passed through a #30 mesh stainless steel U.S. standard sieve to remove lumps. Then, Turbula was used^TMThe mixture was mixed for 10 minutes. Finally, 2.00g of magnesium stearate from plant sources is added and Turbula is used^TMMix for 3 minutes. The separation analysis was performed with the gas flows set to 6 and 15 (low and high, respectively). Samples 1.3g and 100ml extraction volume were weighed and the top, middle and bottom drug effects were measured as in example 5 h.

(k) In a 950-cc amber glass bottle were added in order: 97.96g of particulate mannitol (Mannogem 2080)^TMCommercially available from SPI Polyols, New Castle, DE), 2.12g atorvastatin (from example 1), and 97.94g particulate mannitol (Mannogem 2080)^TM). Mixing the above components with Turbula^TMThe mixer was shaken and mixed for 10 minutes. The resulting mixture was passed through a #30 mesh stainless steel U.S. standard sieve to remove lumps. Then, Turbula was used^TMThe mixture was mixed for 10 minutes. Finally, 2.00g of magnesium stearate from plant sources is added and Turbula is used^TMMix for 3 minutes. Will be provided withThe gas flow was set at 14 and 30 (low and high, respectively) for separate analysis. Sample 2.0g and 200ml extraction volume were weighed and the top, middle and bottom potency values were measured as in example 5 h.

(l) In a 950-cc amber glass bottle were added in order: 97.94g mannitol powder (available from EMD Chemicals, Gibbstown, N.J.), 2.12g atorvastatin (from example 1), and 97.90g mannitol powder. Mixing the above components with Turbula^TMThe mixer was shaken and mixed for 10 minutes. The resulting mixture was passed through a #30 mesh stainless steel U.S. standard sieve to remove lumps. Then, Turbula was used^TMThe mixture was mixed for 10 minutes. Finally, 2.00g of magnesium stearate from plant sources is added and Turbula is used^TMMix for 3 minutes. The separation analysis was performed with the gas flows set to 4 and 9 (low and high, respectively). Sample 2.0g and 200ml extraction volume were weighed and the top, middle and bottom potency values were measured as in example 5 h.

(m) in a 950-cc amber glass bottle, add in order: 97.94g of spray-dried mannitol (available from SPI Polyols, New Castle, DE), 2.12g of atorvastatin (from example 1), and 97.92g of spray-dried mannitol. Mixing the above components with Turbula^TMThe mixer was shaken and mixed for 10 minutes. The resulting mixture was passed through a #30 mesh stainless steel U.S. standard sieve to remove lumps. Then, Turbula was used^TMThe mixture was mixed for 10 minutes. Finally, 2.00g of magnesium stearate from plant sources is added and Turbula is used^TMMix for 3 minutes. The separation analysis was performed with the gas flows set to 6 and 12 (low and high, respectively). Samples 1.5g and 100ml extraction volumes were weighed and the top, middle and bottom potency values were measured as in example 5 h.

(n) adding in order in a 950-cc amber glass bottle: 97.94g of granulated Xylitol (available from Xylitol C Granular, Danisco, Thomson, IL), 2.12g of atorvastatin (from example 1), and 97.94g of granulated Xylitol. Mixing the above components with Turbula^TMThe mixer was shaken and mixed for 10 minutes. The resulting mixture was passed through a #30 mesh stainless steel U.S. Standard Sieve to remove lumps. Then, Turbula was used^TMThe mixture was mixed for 10 minutes. Finally, 2.00g of magnesium stearate from plant sources is added and Turbula is used^TMMix for 3 minutes. The gas flow was set to 15 and 29 (low and high, respectively) for separation analysis. Sample 3.0g was weighed and the top, middle and bottom potency values were measured as in example 5 h.

TABLE 1 fluidization test results for binary mixtures of spray-dried atorvastatin and diluent

Examples	Top sample,% target	Middle sample,% target	Bottom sample,% target	Number of separations
					5a5b5c5d5e5f5g5h5i5j5k5l5m5n	151.9110.8108.898.1104.8122.2108.1100.9137.493.9105.796.085.993.0	87.986.797.897.787.664.489.998.048.790.365.498.383.949.0	44.076.296.895.180.943.180.481.655.888.744.589.883.839.5	1.140.380.120.030.261.030.300.211.010.060.850.070.020.88

Example 6

Preparation and isolation analysis of a mixture of precipitated atorvastatin and diluent

The formulation containing precipitated atorvastatin (prepared as in example 2) was mixed with a diluent, and magnesium stearate (available from Mallinckrodt co., st. louis, MO) as follows: in a 950-cc amber glass bottle were added in order: 97.9g of the diluent listed below, 2.15g of precipitated amorphous atorvastatin (from example 2) and 97.9g of diluent. Mixing the above components with Turbula^TMThe mixer was shaken and mixed for 10 minutes. The resulting mixture was passed through a #30 mesh stainless steel U.S. standard sieve to remove lumps. Then, Turbula was used^TMThe mixture was mixed for 10 minutes. Finally, 1.99g of magnesium stearate (Mallinckrodt, St. Louis, Mo.) from a plant source was added and Turbula was used^TMMix for 3 minutes. The resulting mixture was subjected to separation analysis as in example 5h, with respect to the low and high fluidization gas flow settings and sample weight and extraction volume as will be explained below (when different from example 5 h). The results are shown in Table 2.

(a) The diluent is anhydrous, unmilled monocalcium phosphate (A-Tab)^TMAvailable from Rhodia, Chicago Heights, IL). Accordingly, the fluidizing gas flow is set at 5 and 11 (for low and high, respectively).

(b) The diluent was spray dried lactose monohydrate (available from Foremost farm USA, Rothschikd, Wis.). Accordingly, the fluidizing gas flow settings were 4 and 11 (for low and high, respectively).

(c) The diluent is compressible sucrose (available from d.c. & t.s.white Di-Pac, Tate & Lyle, Brooklyn, NY). Accordingly, the fluidization gas flow settings were 8 and 18 (for low and high, respectively).

(d) The diluent was microcrystalline cellulose (Avicel PH-200, available from FMC BioPolymer, Co. Cork, Ireland). Accordingly, the fluidization gas flow settings were 4 and 9 (for low and high, respectively). The sample analyzed was 1.3g and the extraction volume was 100 mL.

(e) The diluent was modified lactose monohydrate (Fast Flo316, available from foremos Farms USA, Rothschild, WI). Accordingly, the fluidization gas flow settings were 6 and 11 (low and high, respectively). The sample analyzed was 2.0g and the extraction volume was 200 mL.

(f) The diluent was mannitol in granular form (Mannogem2080, available from SPI Polyols, New Castle, DE). Accordingly, the fluidization gas flow settings were 20 and 35 (for low and high, respectively). The sample analyzed was 2.0g and the extraction volume was 200 mL.

TABLE 2 fluidization test results for binary mixtures of precipitated atorvastatin and diluent

Examples	Top sample,% target	Middle sample,% target	Bottom sample,% target	Index of separation
					6a6b6c6d6e6f	99.0102.886.6109.6100.1109.6	96.8102.378.889.797.362.2	89.584.070.379.3104.457.9	0.100.200.210.33-0.040.68

Examples 5 and 6 show that a series of diluents provide a series of discrete numbers different from the drug form in an unforeseeable manner.

Example 7

Preparation and homogeneity testing of atorvastatin/diluent tablets

Tablets were prepared from 5a-5g of each formulation using a Killian T100 rotary tablet press (available from Kilian & Co., Bristol, Pa.) with fine adjustments to the batch size of 5e (11.6g atorvastatin, 1075.0g microcrystalline cellulose and 11.0g magnesium stearate). Tablets were prepared using a four tool part setup with 1/4 "Standard Round Concave (SRC) flat tool. The weight of each tablet is approximately 100 mg. The tablet press was run at 37rpm (die speed 30 rpm). This corresponds to a speed of approximately 20000 tablets per hour. The tablets were sampled (at least three samples per spot) at the beginning, middle and end of the run (1 kg samples run in each case). The analysis of the tablets was carried out according to the following method: for sample (a), 7.5ml of 0.05M ammonium acetate was added to one tablet and shaken for 8 minutes, followed by 12.5ml of acetonitrile and shaken for 12 minutes; for (b), one tablet was added to 20ml of 1: 1 (v: v)0.05M ammonium acetate buffer (pH 7.4): in acetonitrile and shaking for 25 minutes; for (f), one tablet was added to 20ml of 1: 1 (v: v)0.05M ammonium acetate buffer (pH 7.4): oscillating in acetonitrile for 20 minutes; for (c), (d) and (e), one tablet was added to 10ml of 1: 1 (v: v)0.05M ammonium citrate buffer (pH 7.4): in acetonitrile and shaken for 20 min. In each case, the resulting solution was filtered through a Gelman Crodis polytetrafluoroethylene membrane (0.45 μ M pore size) and analyzed by high performance liquid chromatography HPLC (Phenomenex, Ultremex C18 column, 25.0 cm. times.4.6 mm, HPLC HP1100 series, injection rate of 20 μ l flow rate of 1.5 mL/min; mobile phase 53: 27: 20 (v: v)0.05M ammonium citrate (pH4.0) acetonitrile: tetrahydrofuran; detection at 244 nm). The results are shown in Table 3.

TABLE 3 drug efficacy uniformity of tablets prepared with atorvastatin without granulation step

Examples	Sources of mixtures (examples)	Initial run,% target	Mid run,% target	End of run,% target	Overall,% RSD
						7a	5a	109.5±8.4	94.9±2.4	96.4±3.5	8.6
7b	5b	92.7±2.2	101.0±1.2	93.9±0.8	4.3
						7c	5c	93.1±0.3	94.6±2.0	95.8±1.5	1.8
7d	5d	89.2±1.6	92.0±2.2	94.1±0.7	2.8
						7e	5e (different batch sizes)	83.6±1.3	92.5±0.5	97.1±1.2	5.7
7f	5f	108.1±4.6	89.7±5.4	81.2±0.6	13.3

As shown in figure 1, combining the data from example 5 (number of separations) and example 7 (tablet pharmacodynamic variability) shows a significant correlation. The above-described correlations with atorvastatin allow the determination of an appropriate split number as a means of selecting an appropriate diluent for preparing atorvastatin dosage forms without a granulation step.

Claims (15)

1. A unit dosage form comprising atorvastatin or a pharmaceutically acceptable salt thereof, prepared without a granulation step, wherein the atorvastatin potency measured in said dosage form shows a relative standard deviation of atorvastatin activity per unit dosage form of no more than about 7.8% when said unit dosage form is prepared at a speed greater than 10,000 unit dosage forms per hour per single unit dosage form per machine.

2. The unit dosage form of claim 1, further comprising an excipient or combination of excipients.

3. The unit dosage form of claim 1 wherein said atorvastatin or pharmaceutically acceptable salt thereof is a form of atorvastatin that is at least somewhat disordered or a mixture of crystalline and disordered forms of atorvastatin.

4. The unit dosage form of claim 2, wherein the excipient or combination of excipients comprises less than about 5% by weight of the alkalizing agent additive.

5. The atorvastatin unit dosage form according to claims 1-4, wherein said unit dosage form comprises no more than about 2% total drug related impurities and/or degradants based on the area percentage of impurities and/or degradants relative to the integrated area of all drug related peaks as measured by HPLC.

6. The unit dosage form of claim 2 wherein the excipient or composition of excipients comprises greater than about 50% by weight of a diluent or combination of diluents.

7. The unit dosage form of claim 6 wherein the diluent is lactose monohydrate, anhydrous lactose, microcrystalline cellulose, or sodium chloride.

8. The unit dosage form of claim 6 wherein the unit dosage form is a tablet or capsule and contains at least one active agent in addition to atorvastatin.

9. A process for preparing a tablet or capsule of atorvastatin or a pharmaceutically acceptable salt thereof comprising the steps of:

(a) preparing an atorvastatin composition by mixing atorvastatin or a pharmaceutically acceptable salt thereof and one or more excipients suitable for use without a granulation step in a mixer; and

(b) filled into tablet dies or capsules and then compacted or sealed such that when the tablets or capsules are prepared on a tablet or capsule press at a speed of greater than 10,000 tablets or capsules per hour per machine, the measured atorvastatin potency shows a relative standard deviation of atorvastatin activity per tablet or capsule of no more than about 7.8%.

10. The method according to claim 9, wherein the one or more excipients comprise greater than about 50% by weight of a diluent or combination of diluents.

11. The method according to claim 9 or 10 wherein said atorvastatin or pharmaceutically acceptable salt thereof is a form of atorvastatin that is at least somewhat disordered or a mixture of crystalline and disordered forms of atorvastatin.

12. The method according to claim 9, wherein the one or more excipients comprise less than about 5% by weight of an alkalizing agent additive.

13. A process for preparing a tablet or capsule containing atorvastatin and at least one other active agent wherein the composition prepared according to the process of claim 9 is combined with at least one other active agent and optionally additional excipients.

14. A method of treating hypercholesterolemia and/or hyperlipidemia, osteoporosis, benign prostatic hyperplasia, and alzheimer's disease comprising administering a therapeutically effective amount of an atorvastatin unit dosage form prepared without a granulation step.

15. A kit for obtaining a therapeutic effect in a mammal comprising a therapeutically effective dose of atorvastatin tablets or capsules prepared without a granulation step and a container for containing said unit dosage forms.