WO2004110406A1 - Pharmaceutical compositions of atorvastatin - Google Patents
Pharmaceutical compositions of atorvastatin Download PDFInfo
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- WO2004110406A1 WO2004110406A1 PCT/IB2004/001859 IB2004001859W WO2004110406A1 WO 2004110406 A1 WO2004110406 A1 WO 2004110406A1 IB 2004001859 W IB2004001859 W IB 2004001859W WO 2004110406 A1 WO2004110406 A1 WO 2004110406A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Definitions
- This invention relates to pharmaceutical compositions comprising atorvastatin and pharmaceutically acceptable salts thereof and a process for the preparation of the same, kits containing such compositions, as well as methods of using such compositions to treat subjects suffering from hypercholesterolemia and/or hyperlipidemia, as well as osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease.
- HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
- mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase.
- Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are collectively potent lipid lowering agents.
- Atorvastatin calcium disclosed in United States Patent No. 5,273,995 which is incorporated herein by reference, is currently sold as Lipitor ® having the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid calcium salt (2: 1) trihydrate and the formula
- Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase.
- atorvastatin calcium is a potent lipid-lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent, as well as in the treatment of osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease.
- Atorvastatin can exist in crystalline, liquid crystalline and non-crystalline and amorphous forms.
- Crystalline forms of atorvastatin calcium are disclosed in United States Patent Numbers 5,969,156 and 6,121,461, which are herein incorporated by reference. Further crystalline forms of atorvastatin are disclosed United States Patent 6,605,729 which is herein incorporated by reference.
- atorvastatin As well as processes for preparing amorphous atorvastatin. These include: WO 00/71116; WO 01/28999; WO 01/36384; WO 01/42209; WO 02/41834; WO 02/43667; WO 02/43732; WO 02/051804; WO 02/057228; WO 02/057229; WO 02/057274; WO 02/059087; WO 02/083637; WO
- atorvastatin e.g., acute treatment of patients having strokes as described in Takemoto, M.; Node, K.; Nakagami, H.; Liao, Y.; Grimm, M.; Takemoto, Y.; Kitakaze, M.; Liao, J.K., Journal of Clinical Investigation, 2001; 108(10): 1429-1437
- a rapid onset of activity may be highly beneficial in improving the efficacy of the drug.
- atorvastatin is combined with a stabilizing additive, such as, an alkaline earth metal salt and excipients and subjected to wet granulation using a combination of water and a surfactant (Tween 80).
- a stabilizing additive such as, an alkaline earth metal salt and excipients
- Tween 80 a surfactant
- atorvastatin is a highly potent drug
- formulations of the drug are generally quite dilute in order to provide dosage forms of adequate size for manufacturing and ease of handling by patients.
- Granulations are one method for preventing segregation. Although it is possible to select excipients such that unit dosage forms can be prepared without a granulation step, as disclosed in concurrently filed United States Patent Application, commonly owned, attorney case number PC25684, Serial Number , granulations can assure that drug and excipients are bound together such that segregation will not occur and the particle size of the granules will allow for good flow. Wet granulations represent one option for providing atorvastatin in a form unlikely to segregate and with good flow (see concurrently filed United States Patent Application, commonly owned, attorney case number PC25685, Serial Number ). Wet granulations, however, require the formulation to be exposed to water and/or solvents.
- a 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 preparing a dry- granulated pharmaceutical composition of atorvastatin comprising:
- a third aspect of the present invention is a dry-granulated pharmaceutical composition
- 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 preparing a dry- granulated pharmaceutical composition of atorvastatin comprising:
- a fifth aspect of the present 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 is a method of using a dry-granulated atoravastatin composition to treat subjects suffering from hypercholesterolemia and/or hyperlipidemia, osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease.
- Atorvastatin can readily be prepared as described in United States Patent
- Atorvastatin exists in a number of morphological forms ranging from highly crystalline forms to forms with varying degrees of disorder. Some of these disordered forms still possess some structure as indicated by powder x-ray diffraction patterns.
- all forms of atorvastatin benefit from the invention and are included within the scope of the invention.
- Partially or completely disordered forms of atorvastatin particularly benefit from the invention.
- Partially or completely disordered forms of atorvastatin that are amorphous or predominantly amorphous derive the greatest benefit from the present invention.
- Such forms can be prepared, for example, from crystalline atorvastatin using procedures disclosed in United States Patent Number 6,087,511, which is incorporated herein by reference.
- amorphous material can be prepared according to the processes disclosed in United States Patent Application, commonly owned, attorney's case number PC-25825 Serial Number .
- non-crystalline and crystalline atorvastatin can be prepared by any method known in the art. Preferred forms of atorvastatin are described in United States Patents 5,969,156, 6,121,461, and 6,605,729; and in International Patent Applications WO 01/36384, WO 02/41834; WO 02/43732; WO 02/051804, WO
- the atorvastatin can be used in the form in which it is prepared, or it can be subjected to a process which changes the physical nature of the particles.
- the material can be milled by any process known in the art.
- Non-exclusive examples of such processes include mechanical milling and jet milling.
- the particles produced either directly from the process of forming atorvastatin or after a milling operation preferably provide mean particle diameters in the range of 1-200 ⁇ m; more preferably between 5 and 150 ⁇ m.
- Pharmaceutically acceptable base addition salts of atorvastatin are formed with metals or amines, such as alkaline and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like.
- Suitable amines are N.N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, S.M., et al., "Pharmaceutical Salts", J. Pharm. ScL, 1977; 66: 1).
- the base addition salts of atorvastatin are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
- the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner.
- the free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
- atorvastatin can 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.
- atorvastatin that are at least somewhat disordered or a mixture of crystalline and disordered forms of atorvastatin benefit most significantly from the present invention.
- somewhat disordered it is meant that the line width (peak width at half the height of the peak) of any of the peaks measured using powder x-ray diffraction (PXRD) have 2 theta values greater than about 2°.
- Amorphous or predominantly amorphous forms of atorvastatin, which especially benefit from the present invention, are characterized by having very broad, featureless peaks.
- Atorvastatin has been found to be an effective drug even at relatively low doses. In fact, by keeping the dose low for a given patient, it is possible to minimize side-effects while still maintaining drug efficacy. It is therefore desirable to provide atorvastatin in a form capable of providing a low dose to the patient.
- the dose provided by the final dosage form of atorvastatin is preferably between 0.5 and 120 mgA (where mgA means milligrams of active drug based on the free acid); more preferably, between 5 and 80 mgA.
- these unit dosage forms are generally in the form of tablets, capsules, sachets, chewable tablets and fast dissolving dosage forms.
- the dosage form is preferably in the form of a capsule or tablet; most preferably in the form of a tablet.
- the preparation of these forms involves a necessary step of some type of powder filling, either by volume or weight. For example, in production of tablets and capsules, powder is volume filled into a die or capsule, respectively.
- the unit dosage forms In order for the unit dosage forms to have the same potency (i.e., amount of drug per unit dosage form) within allowable margins (relative standard deviation, RSD, of less than 6% to meet Stage I, and less than 7.8% to meet Stage II of the United States Pharmacopoeia, USP, guidelines), there must not be any significant segregation of the active drug from the excipients. This is especially significant for highly dilute forms.
- the present invention discloses compositions that provide reproducible potency for a fixed weight of active atorvastatin plus excipients. Moreover, this potency control is maintained through the process of producing unit dosage forms.
- compositions before being processed into unit dosage forms, provide atorvastatin with potency (mgA per gram of blend) variability of less than an RSD of 7.8%; more preferably, less than 6.0%.
- the present compositions provide for good powder flow such that weight control is maintained between unit dosage forms produced with such compositions (i.e., variability in the weights of unit dosage forms produced from such compositions is minimal).
- such compositions provide unit dosage forms with weight control within an RSD of 6%; more preferably, within 5%; even more preferably, within 4%. Combining the weight control and the potency control allows the present compositions to provide unit dosage forms with potencies of atorvastatin per unit dosage form having an RSD preferably less than 7.8%; more preferably less than 6.0%.
- Measurement of the potency of unit dosage forms of atorvastatin is necessary in determining the variability in activity between unit dosage forms.
- An extraction process against a standard with independently known drug levels best determines such potency.
- the potency analysis is best conducted using reverse phase high performance liquid chromatography (HPLC) techniques such as those known in the art relative to standards.
- HPLC reverse phase high performance liquid chromatography
- RSD measurements are best carried out using sampling during a process for forming the unit dosage form. More specifically, unit dosage forms can be sampled from a preparation process at various time points (beginning, middle and end of the run).
- At least three unit dosage forms should be measured from each section.
- An alternative analytical technique for determining the potency of a sample of drug involves the use of ultraviolet- visible absorption spectroscopy. In this technique, the absorbance corresponding to atorvastatin is used to quantify the concentration of atorvastatin in a sample (taking care that no excipient has interfering absorptions), as is known in the art.
- the present invention discloses processes and compositions that provide atorvastatin in a pure and stable form.
- impurities describes materials in the drug substance present from the synthesis and purification process and any drug-based materials formed in the preparation of the unit dosage form.
- degradationants refers to any drug-based materials generated after the preparation of the unit dosage form. Analysis of impurities and degradants is done using reverse phase HPLC techniques on extracted samples as is known in the art. Calculations of the amount of impurities and degradants is expressed as the integrated area percent of the degradant or impurity peak(s) divided by the integrated area percent of all drug-related peaks.
- mean particle sizes can be measured using a laser diffraction particle size instrument such as those made by Sympatec GmbH (Goslar, Germany).
- Mean particle sizes for the purpose of the present invention, can be considered the size for which 50% of the particles have diameters smaller than the indicated number.
- particle size can be assessed using sieve analysis. The percent of the total weight of material retained on sieves of particular sizes is used to measure the mean particle size.
- the mean particle size is the sieve size that allows about 50% of the weight of material to pass through (50% retained).
- diluents In the preparation of compositons of atorvastatin with a dry granulation, combinations of diluents, binders, disintegrants, flavorants and lubricants are used to provide the properties needed for the unit dosage form as is known in the art.
- the combination For example, for preparation of tablets, the combination provides for adequate tablet hardness upon compression while providing rapid disintegration in vivo.
- typically such formulations contain about 1-40% (w:w) drug, about 5-10% disintegrant, about 0-10% binder and about 0.5-2% lubricant, with the remaining percentage comprising the inventive diluents.
- Preferred disintegrants include carboxymethylcellulose, hydroxyproyl cellulose (low-substituted), macrocrystalline cellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium aluminum silicate, methylcellulose, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate and starches.
- Preferred binders include acacia, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, dextrin, gelatin, guar gum, hydroxypropyl methylcellulose, magnesium aluminum silicate, maltodextrin, methylcellulose, polyethylene oxide, polymethacrylates, povidone, sodium alginate, starches 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 magnesium stearate.
- atorvastatin In improving the flow of atorvastatin compositions and minimizing segregation from excipients, compaction of the drug with excipients can be carried out in a dry granulation process. With atorvastatin, however, we have found that due to the brittle nature of the drug, only certain excipients form acceptable dry granulations with the drug. Acceptable excipients can be defined in terms of those which when dry granulated (i.e., compacted and milled) in the presence of atorvastatin, provide for a significant reduction in the amount of fine drug particles, unbound to excipient, remaining in the blend. For the purpose of the present invention, fine drug particles (or "fines”) can be defined as particles that pass through a 200 mesh sieve.
- granulation factor (GF) 1 - [(percentage atorvastatin as fines in granulation)/(percentage of atorvastatin as fines in ungranulated blend)].
- a sifting device such as a Sonic SifterTM (Allen Bradley Sonic Sifter, Advantech Manufacturing, New Berlin, WI).
- the percentage atorvastatin as fines is determined by multiplying the weight of by the potency of the fines divided by the overall weight of drug in the blend.
- excipient or excipient combinations with atorvastatin that provide for minimal tendency to segregate during unit dosage form preparation can be characterized as having granulation factors preferably between 0.4 and 1.0; more preferably, between 0.5 and 1.0; and still more preferably between 0.6 and 1.0.
- the first step involves determining the true density of the blend, i.e., the density of the materials without air spaces between particles.
- the solid fraction of a dry granulation represents the ratio of the density of a compact (or ribbon) to the true density of the material from which the compact was made. Control of the solid fraction is achieved by controlling the compression forces during compaction. We have found that to achieve good binding of atorvastatin while still providing sufficient compressibility for subsequent tableting, granulations preferably have a solid fraction after granulation between about 0.55 and 0.85; more preferably between about 0.60 and 0.80.
- tensile strength of the compacts or ribbons is the tensile strength of the compacts or ribbons.
- the tensile strength of a compact (or ribbon) can be measured using appropriate equipment as is known in the art, such as, a CT5 tensile strength Tester (Engineering System (NOTTM), Nottingham, England).
- a CT5 tensile strength Tester Engineing System (NOTTM), Nottingham, England.
- rectangular compacts having dimensions of 10 X 22 X 2 mm are used for this measurement.
- a preferred tensile strength for ultimately producing acceptable granulations of atorvastatin is 0.5 to 7.0 megapascals (Mpa); more preferably, 0.8 to 6.0 MPa.
- Combinations of materials with atorvastatin that can achieve the preferred tensile strength within the range of preferred solid fractions are preferred.
- examples of such materials include lactose and microcrystalline cellulose.
- An example of a material unable to achieve the desired tensile strength is mannitol.
- Preferred excipients are diluents, which preferably comprise greater than or equal to 40 wt% of the total composition in the formulation with atorvastatin; more preferably, greater than 50 wt%; still more preferably, greater than 60 wt%.
- Preferred diluents when tested in binary blends with atorvastatin, provide granulation factors of preferably between 0.4 and 1.0; more preferably, between 0.5 and 1.0; and still more preferably between 0.6 and 1.0.
- Potential diluents are identified as such in "Handbook of Pharmaceutical Excipients, 3rd Edition" (A. H. Kibbe, Editor; Pharmaceutical Press, London; 2000).
- calcium phosphate calcium sulfate, carboxymethylcellulose calcium, cellulose, cellulose acetate, dextrates, dextrin, dextrose, fructose, glyceryl palmitostearate, 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.
- excipients appropriate for use in dry granulations with atorvastatin, it is important that the particular form and particle size of atorvastatin be used that is desired for the final dosage form. Similarly, the excipient or excipient combination used will have properties that depend on the particle size and method of preparation. Since compression of the excipients with atorvastatin in a dry granulation process is generally more facile with smaller particle-size excipients, preferred excipients are generally smaller than would be preferred without granulation. As such, preferably the excipients have mean particle sizes between 20 and 200 ⁇ m; more preferably, between 40 and 150 ⁇ m.
- particle size ranges correspond to 50 weight % of the blend passing through sieves having between a 635 mesh sieve (ASTM number) and a 70 mesh; more preferably, between a 325 mesh and a 100 mesh.
- the preferred size for a given excipient depends on the specific properties of the atorvastatin form used and must be determined experimentally in each case. More preferred excipients in combination with atorvastatin, therefore, are diluents that provide high values of granulation factors, can achieve a high tensile strength and have preferred mean particle sizes, preferably between 20 and 200 ⁇ m; more preferably, between 40 and 150 ⁇ m.
- Particularly preferred diluents include microcrystalline celluloses having a mean particles size of 20 to 40 ⁇ m (such as AvicelTM PH105, available from FMC Biopolymer, Philadelphia, PA), lactoses having a particle size range of 80 to 150 ⁇ m (such as the spray dried monohydrate material or Fast FloTM 316 available from Foremost Farms, Rothschild, WI; or the anhydrous, direct tableting grade, available from Quest International, Flavors & Food Ingredients CCL, Norwich, NY), xylitol (such as the C granular grade available from Danisco Sweeteners, Thomson, IL), mannitol (such as MannogemTM 2080 granular, available from SPI Polyols, New Castle, DE), sucrose (such as Di-PacTM, available from Tate & LyIe Co.
- microcrystalline celluloses having a mean particles size of 20 to 40 ⁇ m such as AvicelTM PH105, available from FMC Biopolymer, Philadelphia,
- the preferred diluents comprise greater than 50% (w:w) of the diluent content of the dry-granulated composition of atorvastatin; more preferably 60% (w:w); still more preferably 70% (w:w).
- Unit dosage forms of atorvastatin that are formed with a dry granulation step with preferred excipients show low levels of drug-related impurities and degradants. Surprisingly, this low level of impurities and degradants was found even in the absence of added alkalizing agents or alkaline earth metal salts. Even more surprisingly, this low level of impurities and degradants was maintained even when the atorvastatin used was an at least somewhat disordered form of the drug. In particular, it was found that while wet granulated control unit dosage forms of atorvastatin show high levels of drug degradation, unit dosage forms prepared with dry granulation have greater stability.
- unit dosage forms of atorvastatin prepared with dry granulation are preferred that contain not more than about 2% total drug related impurities and/or degradants based on the area percent of the impurities/degradants relative to the integrated area of all drag related peaks as determined by HPLC; more preferably, they contain less than 1%; still more preferably, less than 0.7%.
- unit dosage forms of atorvastatin prepared with dry granulation are preferred that provide stability such that upon storage at 40 0 C and 75% relative humidity (RH) for four weeks, the unit dosage forms contain not more than about 2% total drag related impurities and/or degradants based on the area percent of the impurities/degradants relative to the integrated area of all drag related peaks as determined by HPLC; more preferably, they contain less than 1%; still more preferably, less than 0.7%.
- Atorvastatin undergoes two major degradation pathways: lactonization and oxidation. The lactone is formed by internal condensation (loss of water) of the alcohol and carboxylic acid to form a six-membered ring.
- the level of atorvastatin lactone in unit dosage forms is less than 2% (based on the ratio of lactone peak integration compared to the total peak integrated areas using HPLC) after said unit dosage forms are produced and stored at 40°C/75% RH (where RH represents relative humidity) for four weeks; more preferably, less than 1%.
- the level of alkaline earth metal salts in the formulation is preferably about 0-5% (w:w); more preferably, about 0-3%; most preferably about 0-2%. It is also preferred that the level of other alkalizing agents in the formulation be about 0-5% (w:w); more preferably, about 0-3%; most preferably about 0-2%.
- Dry granulation of atorvastatin with excipients is preferably carried out by first blending the atorvastatin with at least some of the preferred excipients. Preferably, the excipients in this blend constitute between 50 and 95% (w:w) of the blend.
- Blending is typically carried out first without the addition of a lubricant for sufficient time to assure complete mixing. At that point, the lubricant is typically added followed by a short (about 1-10 minute) further mixing period.
- This blend is then compressed into slugs or ribbons using a tablet press (such as a single-station press or a rotary tablet press) or a roller compactor. In the former case, compacts (slugs) are produced using flat-faced die and punch combinations.
- the density of the compacts or ribbons is preferably chosen to provide compacts or ribbons having tensile strengths of about 0.5 to 7.0 MPa; more preferably, about 0.8 to 6.0 MPa.
- the compacts or ribbons are then preferably milled, ground or sieved.
- the particle size reduction is carried out in optimized processes designed to give good throughput while providing a suitable particle size distribution, as is known in the art.
- less than 30% (w:w) of the milled material will pass through a 200-mesh sieve and greater than 70% (w:w) will pass through a 60-mesh sieve.
- additives are preferably mixed using a high shear mixer, V-blender (or other twin-shell blender), bin blender or TurbulaTM mixer-shaker. Blending is typically carried out first without the addition of a lubricant for sufficient time to assure complete mixing. At that point, the lubricant is typically added followed by a short (about 1-10 minute) further mixing period. At this point, the granulated material can be used in the preparation of unit dosage forms.
- unit dosage forms include sachets, tablets, fast-dissolving dosage forms, chewable dosage forms and capsules.
- Preferred dosage forms include tablets and capsules.
- the packaging is preferably in the form of foil-foil cold form blisters, plastic blisters or sealed bottles containing desiccants.
- the packaging can contain active oxygen absorbing materials as is disclosed in EP1243524A2, which is incorporated herein by reference.
- unit dosage forms of atorvastatin with dry granulation it is possible to produce such unit dosage forms without the present formulations using processes unsuitable to commercial production. For example, even granulated material with a tendency to segregate could be weighed into a capsule directly.
- the present invention is preferably used in conjunction with high-speed production equipment. More specifically, preferred formulations provide dry granulations that allow potency control during unit dosage form production of less than 7.8% RSD (more preferably less than 6.0% RSD) when used with a single apparatus-unit dosage form production equipment at a rate of greater than 10,000 unit dosage forms per hour; more preferably, greater than 25,000 unit dosage forms per hour; most preferably, greater than 50,000 unit dosage forms per hour.
- Preferred single apparatus-unit dosage form production equipment or machines include single rotary tablet presses and a single commercial capsule filling machines.
- Non-exclusive examples of commercial rotary tablet presses include those produced by Niro Pharma Systems (Columbia, MD), Kilian and Company (Horsham, PA), Korsch (Berline, Germany) and Elizabet-Hata International (North Huntingdon, PA).
- Non-exclusive examples of commercial capsule filling equipment include those made by Capsugel (Morris Plains, NJ) and CapPlus Technologies (Phoenix, AZ).
- the present invention provides for compositions of atorvastatin which are particularly well suited for combination products with other drug substances because the granulation does not require a potentially solubilizing and/or otherwise destabilizing solvent and yet maintains the atorvastatin content uniformity. This is especially true when the second drug (with its associated excipients) can destabilize atorvastatin.
- Non- limiting examples of drugs which may benefit from combinations with the inventive atorvastatin compositions and processes include torcetrapib and amlodipine and pharmaceutically acceptable salts thereof.
- compositions of atorvastatin according to the present invention can be combined with a least one other active drug to form unit dosage forms.
- Preferred unit dosage forms include tablets and capsules. Ih the combination of the atorvastatin composition with at least one other active drug to form a unit dosage form, the following non-limiting list describes options for such unit dosage forms: (a) a blend of the atorvastatin granulation with the other active drug itself (i.e., extragranular addition of the other drug to the dry granulated composition of atorvastatin), as a blend with excipients (i.e., extragranular addition of the other drug plus excipients to the dry granulated composition of atorvastatin), or as a granulation (i.e., a mixture of a granulation of the other drug with the dry granulated composition of atorvastatin), formed into tablets or capsules; (b) a single dry granulation of atorvastatin with the other drug, formed into tablets of capsules;
- the present invention relates to the treatment of diseases and conditions in a subject, such as, hyperlipidemia and/or hypercholesterolemia, osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease with atorvastatin or a pharmaceutically acceptable salt thereof as described above that may be administered in a unit dosage form having low levels of degradation products and/or impurities contained in a therapeutic package or kit.
- the kit includes the unit dosage form and a container.
- the kit includes directions for administration of the unit dosage form.
- the container can be in any conventional shape or form as known in the art, for example, a paper box, a glass or plastic bottle, or a blister pack with individual dosage forms pressing out of the back according to a therapeutic schedule.
- Spray dried amorphous atorvastatin an example of disordered atorvastatin as previously described in the Detailed Description of the Invention, and used in the following examples was prepared according to concurrently filed U.S. Patent
- amorphous atorvastatin prepared as described in Example 1, 78.00 g of microcrystalline cellulose (AvicelTM PH102, FMC Biopolymer, Philadelphia, PA), 101.41 g of lactose (hydrous, Foremost Farms USA, Rothschild, WI), 6.00 g of croscarmellose sodium (Ac-Di-SolTM FMC Biopolymer, Philadelphia, PA), and 4.000 g of hydroxypropyl cellulose (KlucelTM EXF, Hercules Incorporated, Aqualon Division, Wilmington, DE).
- the materials were bottle blended for 10 minutes using a TurbulaTM mixer (Turbula Shaker Mixer, Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland) and then discharged and sieved through a 30 mesh screen to delump. The material was then put back into the bottle and TurbulaTM mixed an additional 10 minutes.
- the bottle-blended material was added to a Procept Mi-Mi-Pro high shear wet granulator (Pro-CepT n.v., B- 9060 Zelzate, Belgium) using a 1.7 L bowl.
- the materials were dry mixed for two minutes at a chopper speed of 1000 revolutions per minute (rpm) and an impeller speed of
- the dried material was then milled using a Fitzpatrick LlA mill (The Fitzpatrick Co., Elmhurst, IL) with a 0.040" Conidur rasping screen at 500 rpm.
- a Fitzpatrick LlA mill The Fitzpatrick Co., Elmhurst, IL
- a 0.040" Conidur rasping screen at 500 rpm.
- To 175.0 g of the blend was added 5.469 g of Ac-Di-SolTM and the mixture was bottle blended (950-cc amber bottle) using a TurbulaTM mixer for 5 minutes
- Magnesium stearate (Mallinckrodt Inc., St. Louis, MO) 1.822 g was then added and the mixture TurbulaTM blended an additional 3 min. to complete the formulation.
- Tablets were prepared using an F-press (Manesty F-Press, Liverpool, United Kingdom) with 13/32" standard round concave (SRC) tooling, with a target weight of 450 mg ( ⁇ 3%) and a target hardness of 12 kP (range 10-14kp).
- a total of 12 tablets were set up in 30-cc high density polyethylene (HDPE) bottles sealed using heat induction seal (HIS) closures, sealed using a heat induction sealer (Enercon Industries Corp., Menomonee, WI). Samples were stored for 4 weeks at 40 0 C and 75% relative humidity (RH).
- F-press Manesty F-Press, Liverpool, United Kingdom
- SRC standard round concave
- a total of 12 tablets were set up in 30-cc high density polyethylene (HDPE) bottles sealed using heat induction seal (HIS) closures, sealed using a heat induction sealer (Enercon Industries Corp., Menomonee, WI). Samples were stored for 4 weeks at 40 0 C and 75% relative humidity (
- amorphous atorvastatin calcium prepared as described in Example 1, 78.00 g microcrystalline cellulose (Avicel PH102TM; EMC Corp., Philadelphia, PA), 101.41 g lactose, hydrous (REG 310; Foremost Farms USA, Rothschild, WI), 4.00 g hydroxypropyl cellulose (Klucel EXF TM; Aqualon, Wilmington, DE), 6.00 g croscarmellose sodium (Ac-Di-SolTM; FMC Corp., Philadelphia, PA), and 1.00 g magnesium stearate (Mallinckrodt Co., St. Louis, MO).
- the combination of the above ingredients was mixed using a TurbulaTM blender (Glen Mills, Clifton, NJ) for 10 minutes
- the blend was then passed through a stainless steel sieve (#30 mesh) to delump, after which an additional 10 minutes of mixing was performed.
- the blend was then dry granulated by slugging with 1" flat-faced tooling using a single station Manesty F-Press (Manesty, Liverpool, UK) to 1.00 g compacts with a hardness of 3.5 kP (tablet hardness was tested using a Schleuniger Tablet Hardness Tester, Dr. Schleuniger Pharmatron AG, Solothurn, Switzerland).
- the compacts were milled using a Fitzpatrick LlA mill
- lactose (spray dried monohydrate, Foremost Farms, Rothschild, WI);
- lactose anhydrous, direct tableting grade, Quest International, Flavors & Food Ingredients CCL, Norwich, NY
- lactose Fest HoTM 316, Foremost Farms, Rothschild, WI
- microcrystalline cellulose (AvicelTM PH102, FMC Biopolymer,
- microcrystalline cellulose (AvicelTM PH105, FMC Biopolymer,
- microcrystalline cellulose (AvicelTM PHlOl, FMC Biopolymer,
- Table 1 Sample preparation conditions for HPLC analyses. Dilution involves taking the initial solution formed by combining the amount analyzed with the extraction volume, and diluting by the indicated amount with 1:1 (v:v) acetonitrilerwater.
- lactose (spray dried monohydrate, Foremost Farms, Rothschild, WI);
- lactose anhydrous, direct tableting grade, Quest International, Flavors & Food Ingredients CCL, Norwich, NY
- lactose (Fast FloTM 316, Foremost Farms, Rothschild, WI);
- microcrystalline cellulose (AvicelTM PH102, FMC Biopolymer,
- microcrystalline cellulose (AvicelTM PH105, FMC Biopolymer,
- microcrystalline cellulose (AvicelTM PHlOl, FMC Biopolymer,
- Table 2 Sample preparation conditions for HPLC analyses. Dilution involves taking the initial solution formed by combining the amount analyzed with the extraction volume, and diluting by the indicated amount with 1:1 (v:v) acetonitrile: water.
- true density was measured for each excipient and the atorvastatin at 25.1 0 C ⁇ 0.9° using a Micro-Ultrapycnometer 1000 (Quantachrome Corp., Boynton Beach, FL) with ultra high purity helium at 20 psig inlet pressure. All density measurements were performed using the large cell (cup volume 4.5 cm 3 ) with the instrument programmed to operate in multi-run mode (maximum runs 15, runs to average
- the thicknesses and weights were varied to achieve a range of densities and corresponding solid fractions (i.e., density of the compact divided by 1.48 g/cc), in this case, the thicknesses, weights and solid fractions were 1.90 mm, 500 mg, 0.80; 2.16 mm,
- compacts of the blend were prepared using 0.50" round, flat-faced tooling on an F-press with 351 mg per compact and a thickness of 2.0 mm. These compacts (10 g total) were milled using a Mini Comil 193 (Quadro Engineering Incorporated, Waterloo, Ontario, Canada) with 0.040" rasping screen, run at 900 rpm. Samples of material were analyzed as described in Example 4 with extraction volumes reported in Table 3, and analytical results reported in Table 4.
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 0.19, 0.25, 0.39, 1.03, 0.98, 0.40 and 1.92 MPa.
- the best-fit solid fraction for a 1.0 MPa tensile strength was found to be 0.84.
- Example 6a Based on this, compacts were prepared as described in Example 6a with 305 mg per compact and a thickness of 1.95 mm. In addition, compacts were prepared with a tensile strength of 3.30 MPa, using 320 mg/compact at 1.90 mm thick. Both compacts were milled 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 potency as described in
- Compacts were prepared from a blend prepared as described in Example 4c using an F- press with rectangular tooling of 10 X 22 mm.
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 0.76, 2.06, 2.15,
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 1.55, 1.05, 0.74, 0.35, 0.60 and 1.83 MPa.
- the best-fit solid fraction for a 1.0 MPa tensile strength was found to be 0.78. Based on this, compacts of the blend (302 mg/compact, 2.02 mm thick) were prepared and milled as described in Example 6a.
- the thicknesses, weights and solid fractions for compacts prepared 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 corresponding tensile strengths for the compacts were 0.68, 2.16, 2.52 and 1.80 MPa.
- the best-fit solid fraction for a 1.0 MPa tensile strength was found to be 0.75.
- compacts of the blend (286 mg/compact, 2.02 mm thick) were prepared and milled as described in Example 6a. Samples of material were analyzed as described in Example 4 with extraction volumes reported in Table 3 and the final results reported in Table 4.
- Compacts were prepared from a blend prepared as described in Example 4g using an F-press with rectangular tooling of 10 X 22 mm.
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 0.22, 3.36, 6.99, 0.64, 2.58 and
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 4.17, 7.99, 1.29, 2.62, 0.27 and 2.31 MPa.
- the best-fit solid fraction for a 1.0 MPa tensile strength was found to be 0.51.
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 0.98, 1.55, 2.32 and
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 0.62, 0.98, 1.19, 0.09, 1.31 and 0.71 MPa.
- the best-fit solid fraction for a 1.0 MPa tensile strength was found to be 0.86. Based on this, compacts of the blend (296 mg/compact, 1.92 mm thick) were prepared and milled as described in Example 6a.
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 0.63, 0.84, 2.13, 1.74, 2.91 and 2.72 MPa.
- the best-fit solid fraction for a 1.0 MPa tensile strength was found to be 0.76. Based on this, compacts were prepared as described in Example 6a with 269 mg per compact and a thickness of 2.00 mm.
- Compacts were prepared from a blend prepared as described in Example 5c using an F- press with rectangular tooling of 10 X 22 mm.
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 0.20, 0.74, 1.43, 2.07, 0.46, 2.31, and 1.98 MPa.
- Example 6a The best-fit solid fraction for a 1.0 MPa tensile strength was found to be 0.77. Based on this, compacts of the blend (298 mg/compact, 2.13 mm thick) were prepared and milled as described in Example 6a. Samples of material were analyzed as described in Example 4 with extraction volumes reported in Table 3 and the final results reported in Table 5. (n) The true density of a 40% (w:w) atorvastatin blend with lactose monohydrate was assumed to be a weighted average of the true densities of the lactose (1.49 g/cc) and atorvastatin prepared as described in Example 1; 1.24 g/cc, i.e., 1.39 g/cc.
- Compacts were prepared from a blend prepared as described in Example 5d using an F-press with rectangular tooling of 10 X 22 mm.
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 1.79, 1.34, 0.73, and 2.62 MPa.
- the best-fit solid fraction for a 1.0 MPa tensile strength was found to be 0.74. Based on this, compacts of the blend (265 mg/compact, 1.96 mm thick) were prepared and milled as described in Example 6a.
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 0.81, 1.58, 1.52, 2.80, and 0.37 MPa.
- the best-fit solid fraction for a 1.0 MPa tensile strength was found to be 0.72.
- compacts of the blend (278 mg/compact, 2.08 mm thick) were prepared and milled as described in Example 6a. Samples of material were analyzed as described in Example 4 with extraction volumes reported in Table 3 and the final results reported in Table 5.
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 0.09, 0.44, 0.43, 1.15 and 2.02 MPa.
- the best-fit solid fraction for a 1.0 MPa tensile strength was found to be 0.70. Based on this, compacts of the blend (262 mg/compact, 1.99 mm thick) were prepared and milled as described in Example 6a.
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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 corresponding tensile strengths for the compacts were 0.85, 0.66, 2.22, 0.76, 2.00, and 4.42 MPa.
- the best-fit solid fraction for a 1.0 MPa tensile strength was found to be 0.58.
- the thicknesses, weights and solid fractions for compacts prepared as described in Example 6a were 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,
- Table 3 Sample preparation conditions for HPLC analyses. Dilution involves taking the initial solution formed by combining the amount analyzed with the extraction volume, and diluting by the indicated amount with 1:1 (v:v) acetonitrile: water.
Abstract
Description
Claims
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EP04735617A EP1635788A1 (en) | 2003-06-12 | 2004-06-01 | Pharmaceutical compositions of atorvastatin |
JP2006516511A JP2006527259A (en) | 2003-06-12 | 2004-06-01 | Pharmaceutical composition of atorvastatin |
MXPA05012955A MXPA05012955A (en) | 2003-06-12 | 2004-06-01 | Pharmaceutical compositions of atorvastatin. |
KR1020057023718A KR100760112B1 (en) | 2003-06-12 | 2004-06-01 | Pharmaceutical compositions of atorvastatin |
CNA200480016386XA CN1805732A (en) | 2003-06-12 | 2004-06-01 | Pharmaceutical compositions of atorvastatin |
BRPI0411354-3A BRPI0411354A (en) | 2003-06-12 | 2004-06-01 | Atorvastatin pharmaceutical compositions, unit dosage form, methods for preparing a granular pharmaceutical composition and for preparing a unit dosage form, use of the pharmaceutical composition and kit thereof |
AU2004246867A AU2004246867A1 (en) | 2003-06-12 | 2004-06-01 | Pharmaceutical compositions of atorvastatin |
NO20060149A NO20060149L (en) | 2003-06-12 | 2006-01-10 | Pharmaceutical compounds of atorvastatin |
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- 2004-04-29 CA CA002465693A patent/CA2465693A1/en not_active Abandoned
- 2004-06-01 JP JP2006516511A patent/JP2006527259A/en active Pending
- 2004-06-01 MX MXPA05012955A patent/MXPA05012955A/en unknown
- 2004-06-01 KR KR1020057023718A patent/KR100760112B1/en not_active IP Right Cessation
- 2004-06-01 EP EP04735617A patent/EP1635788A1/en not_active Withdrawn
- 2004-06-01 CN CNA200480016386XA patent/CN1805732A/en active Pending
- 2004-06-01 RU RU2005136743/15A patent/RU2325903C2/en not_active IP Right Cessation
- 2004-06-01 WO PCT/IB2004/001859 patent/WO2004110406A1/en active Application Filing
- 2004-06-01 BR BRPI0411354-3A patent/BRPI0411354A/en not_active IP Right Cessation
- 2004-06-01 AU AU2004246867A patent/AU2004246867A1/en not_active Abandoned
- 2004-06-09 TW TW093116574A patent/TW200503689A/en unknown
- 2004-06-10 AR ARP040102009A patent/AR044660A1/en unknown
-
2005
- 2005-10-11 ZA ZA200508204A patent/ZA200508204B/en unknown
- 2005-12-07 CO CO05124314A patent/CO5640071A2/en unknown
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2006
- 2006-01-10 NO NO20060149A patent/NO20060149L/en not_active Application Discontinuation
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WO2002076376A2 (en) * | 2001-03-27 | 2002-10-03 | Ranbaxy Laboratories Limited | A stable pharmaceutical composition of pravastatin |
WO2003097039A1 (en) * | 2002-05-21 | 2003-11-27 | Bernard Charles Sherman | Stable dosage forms comprising atorvastatin calcium |
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Cited By (11)
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US20060106230A1 (en) * | 2004-10-18 | 2006-05-18 | Michael Pinchasov | Processes for preparing amorphous atorvastatin hemi-calcium |
WO2007034316A1 (en) * | 2005-09-21 | 2007-03-29 | Pfizer Products Inc. | Process for annealing amorphous atorvastatin |
WO2007111027A1 (en) * | 2006-03-29 | 2007-10-04 | Kowa Co., Ltd. | Triglyceride-lowering agent and hyperinsulinism-ameliorating agent |
US8124622B2 (en) | 2006-03-29 | 2012-02-28 | Kowa Co., Ltd. | Triglyceride-lowering agent and hyperinsulinism-ameliorating agent |
JP5330825B2 (en) * | 2006-03-29 | 2013-10-30 | 興和株式会社 | Triglyceride lowering agent and hyperinsulinemia improving agent |
US8604054B2 (en) | 2006-03-29 | 2013-12-10 | Kowa Co., Ltd. | Triglyceride-lowering agent and hyperinsulinism-ameliorating agent |
WO2011074961A1 (en) | 2009-12-18 | 2011-06-23 | Frieslandcampina Nederland Holding B.V. | Co-processed tablet excipient composition its preparation and use |
US10071059B2 (en) | 2009-12-18 | 2018-09-11 | Frieslandcampina Nederland Holding B.V. | Co-processed tablet excipient composition its preparation and use |
WO2011152803A1 (en) | 2010-06-03 | 2011-12-08 | Mahmut Bilgic | Water soluble formulation comprising a combination of amlodipine and a statin |
WO2023025672A1 (en) | 2021-08-25 | 2023-03-02 | Basf Se | Direct tableting auxiliary composition |
CN114674944A (en) * | 2022-03-04 | 2022-06-28 | 苏州东瑞制药有限公司 | Method for detecting related substances of amlodipine besylate and atorvastatin calcium compound preparation |
Also Published As
Publication number | Publication date |
---|---|
BRPI0411354A (en) | 2006-07-11 |
MXPA05012955A (en) | 2006-02-13 |
AU2004246867A1 (en) | 2004-12-23 |
ZA200508204B (en) | 2007-03-28 |
CN1805732A (en) | 2006-07-19 |
RU2325903C2 (en) | 2008-06-10 |
KR20060025167A (en) | 2006-03-20 |
KR100760112B1 (en) | 2007-09-18 |
CA2465693A1 (en) | 2004-12-12 |
RU2005136743A (en) | 2006-07-27 |
TW200503689A (en) | 2005-02-01 |
AR044660A1 (en) | 2005-09-21 |
NO20060149L (en) | 2006-03-06 |
JP2006527259A (en) | 2006-11-30 |
EP1635788A1 (en) | 2006-03-22 |
CO5640071A2 (en) | 2006-05-31 |
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