Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the present invention relates to stable pharmaceutical formulations comprising atorvastatin magnesium as the active agent.
• Atorvastatin ([R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5- (l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid) belongs to a well known group of drugs, statins, which are useful for the treatment of hypercholesterolemia or hyperlipidemia.
• a commercial pharmaceutical formulation of atorvastatin calcium is produced and sold by Pfizer, under te trade name Lipitor.
• Statins block the hydroxyl-methylglutaryl-coenzyme A reductase (HMG-CoA), thereby specifically inhibiting cholesterol synthesis in the liver.
• cholesterol is a vital component of all cells, it also contributes to plaque formation in arteries, which plaques increase the risk for high blood pressure, heart attack and stroke.
• Statins stabilize the plaques, making them less prone to rupturing and subsequently forming blood cloths.
• EP 247,633 discloses the synthesis of atorvastatin and its use as hypocholesterolemic agent.
• EP 409,281 discloses the synthesis of the hemi calcium salt of atorvastatin.
• Atorvastatin exists in multiple amorphous and crystalline forms. Originally, atorvastatin was synthesized in the amorphous form and most of the clinical pharmacology studies were conducted on tablets with amorphous atorvastatin hemi calcium. However, amorphous atorvastatin calcium is reported to be hydroscopic and unstable when exposed to oxygen, and it has been proven difficult to develop a stable dosage form, which does not transform into different morphological forms, discolor or even degrade.
• EP 680,320 discloses a pharmaceutical composition containing atorvastatin hemi calcium stabilized with an excipient which is a basic inorganic salt of magnesium, calcium or lithium.
• WO 2006/117761 presents crystalline and amorphous form of magnesium atorvastatin.
• X-ray diffraction (XRD) data is provided with characteristic peaks listed. Examples are provided, describing how to produce these crystal forms and also how to produce therefrom amorphous form of atorvastatin magnesium. No data for pharmaceutical formulations is provided or indications of stability.
• WO 03/068191 focuses on certain specified particle size of atorvastatin material and gives examples (see Example 4 and 5) of atorvastatin magnesium of unspecified crystal form.
• the material is non-milled, having a particle size with d go of approximately 237 ⁇ m and a d 50 of approximately 98 ⁇ m.
• the material is formulated in Opadry coated tablets comprising sodium carbonate, microcrystalline cellulose, lactose and croscarmellose sodium as main inert ingredients. These tablets are shown to have similar stability as calcium atorvastatin tablets.
• the present invention provides novel alternative pharmaceutical compositions comprising the magnesium salt of atorvastatin, i.e. hemi magnesium of atorvastatin, herein referred to as atorvastatin magnesium or atorvastatin Mg.
• atorvastatin magnesium i.e. hemi magnesium of atorvastatin
• atorvastatin Mg i.e. hemi magnesium of atorvastatin
• Pharmaceutical formulations with atorvastatin magnesium have not hitherto been indicated as being any more stable or having other advantages as compared to formulations of the more known calcium atorvastatin.
• the present inventor has tested various polymorphic forms of atorvastatin Mg and developed therefrom novel pharmaceutical formulations. These formulations are found to be very stable, and surprisingly substantially much more stable than corresponding formulations with atorvastatin hemi calcium.
• Figure 1 X-ray diffraction spectrum of atorvastatin magnesium, form B2.
• Figure 2 X-ray diffraction spectrum of atorvastatin magnesium, form B4.
• Figure 3 Stability data for pharmaceutical formulations of the invention.
• Atorvastatin Mg can be suitably prepared by conversion from another salt of atorvastatin or the closed ring lactone (Formula II), as further described in the accompanying Examples.
• the free acid or the lactone preferably the lactone
• the free acid of the compound can be prepared by hydrolysis of the lactone form of formula II or by passing the salt through a cationic exchange resin (H + resin) and evaporating the water.
• the atorvastatin Mg material in the formulation of the invention may be completely crystalline or partially crystalline, e.g. where at least 10% by weight of the material is crystalline and more preferably at least 20% of the material, more preferably at least 25%, such as at least 30 or 40% and yet more preferably at least 50% is crystalline, such as at least 60% or 75% of the material such as at least 90% of the material.
• the crystallised atorvastatin magnesium is generally of a single polymorphic form but may also comprise a mixture of two or more different polymorphs, such as, e.g., a mixture of the two polymorphs further described hereid referred to as polymorphs B2 and B4, optionally further comprising one or more further polymorphs, or a combination of either form B2 or B4 together with one or more different polymorphs of atorvastatin Mg.
• Various crystal forms of atorvastatin Mg are suitable in the formulations of the present invention. Crystalline forms of atorvastatin Mg which have been analysed are shown to exhibit characteristic X-ray diffraction (XRD) peaks and spectra.
• the formulation comprises crystalline atorvastatin Mg exhibiting one or more X-ray diffraction spectral peak selected from the values listed in Table 1 and Table 2.
• the formulation comprises crystalline atorvastatin Mg exhibiting one or more X-ray diffraction spectral peak at about 3.22, 7.61, 15.57, 18.65, 19.95, 19.95, 21.74, 22.78 and 24.00 degrees 2-theta.
• the formulations comprise crystalline atorvastatin Mg exhibiting X-ray diffraction spectral peaks at about 2.93, 8.86, 9.88, 16.44, 18.79, 20.17 and 21.65 degrees 2- theta.
• Amorphous atorvastatin Mg can also be obtained and formulations thereof are as well encompassed by the invention, as are formulations with partially crystallised atorvastatin Mg, i.e. various mixtures of crystalline and amorphous material.
• the formulations of the present invention are administered in order to deliver to the patient doses in the range from 0.5 to 500 mg per day, roughly corresponding to about 0.007 to 7.1 mg/kg of body weight for an average adult person with a body weight of 70 kg.
• the formulation of the invention comprise suitable excipients such as, but not limited to, diluents such as mannitol microcrystalline cellulose, hydrous lactose, corn starch, sucrose, silicic anhydride, or polysaccharides of the types well known in the art; binders such as methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, or starch; disintegrants such as crosspovidone, carboxymethylcellulose calcium, croscarmellose sodium, or starch; surfactants such as Tween 80 or polyoxyethylene-polyoxypropylene copolymer, and lubricants such as magnesium stearate, calcium stearate and stearic acid.
• suitable excipients such as, but not limited to, diluents such as mannitol microcrystalline cellulose, hydrous lactose, corn starch, sucrose, silicic
• antioxidants can also be incorporated in the formulations in order to reduce or prevent oxidation of the drug compound, they may be suitably selected from one or more of butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium metabisulfate, malic acid, citric acid and ascorbic acid.
• BHA butylated hydroxyanisole
• BHT butylated hydroxytoluene
• sodium metabisulfate malic acid
• citric acid citric acid
• ascorbic acid sodium metabisulfate
• a stabilising alkali stabilising agent additive for example, but not limited to, one or more of the compounds sodium carbonate, sodium bicarbonate, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate disodium hydrogen orthophosphate, sodium silicate, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide and magnesium silicate.
• Sodium carbonate is particularly preferred.
• One embodiment of the invention relates to a formulation comprising a crystallised form of atorvastatin Mg, sodium or calcium carbonate as a stabilising alkali metal additive, and preferably mannitol and microcrystalline cellulose as diluent, and other additives.
• a formulation comprising a crystallised form of atorvastatin Mg, sodium or calcium carbonate as a stabilising alkali metal additive, and preferably mannitol and microcrystalline cellulose as diluent, and other additives.
• the most preferred embodiment of the present invention relates to a formulation comprising a crystallised form of atorvastatin Mg, sodium or calcium carbonate as a stabilising alkali metal additive, and preferably mannitol and microcrystalline cellulose as diluent, and other additives.
• a formulation comprising a crystallised form of atorvastatin Mg, sodium or calcium carbonate as a stabilising alkali metal additive, and preferably mannitol and microcrystalline cellulose as diluent, and other additives.
• Another aspect of the invention provides a process for preparing stable pharmaceutical formulations of atorvastatin magnesium. It has been found that wet granulation techniques using preferably an aqueous solution, e.g. water, as a granulating liquid provides homogeneous formulations that can be formed into very stable tablets. The process is suitably employed using fully or partially crystallised material as described herein, and any of the pharmaceutical excipients described above. The wet granulation is typically performed using standard blending equipment well known to the skilled person in the pharmaceutical industry with water as the granulation medium, organic solvents such as ethanol can alse be applied and mixtures there of.
• aqueous solution e.g. water
• Atorvastatin Mg and all tablet core excipients apart from Magnesium stearate are premixed in a intensive high shear mixer. After this the blend is mixed in the high shear mixer while water is added gradually until suitable granules have formed. These granules are then typically wet sieved before being transferred to a drying apparatus.
• the drying apparatus is suitably a typical fluid bed dryer well known in the industry, other forms of drying, for example, one-pot processing, can also be applied.
• Example 2 The following table depicts the stability of atorvastatin, using various forms, formulated as described in Example 2. The samples were kept at 40 0 C, 75% relative humidity, in closed Duma bottles. Impurities as measured by HPLC.

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