WO2008078341A2

WO2008078341A2 - Stable pharmaceutical formulations of atorvastatin magnesium salt

Info

Publication number: WO2008078341A2
Application number: PCT/IS2007/000024
Authority: WO
Inventors: Fjalar Johannsson
Original assignee: Actavis Group Hf.
Priority date: 2006-12-27
Filing date: 2007-12-21
Publication date: 2008-07-03
Also published as: EP2124899A2; WO2008078341A3; IS8587A

Abstract

Stable pharmaceutical formulations are provided comprising atorvastatin magnesium as active ingredient. The atorvastatin magnesium is preferably in crystallised form, fully crystallised or partially crystallised. The crystallised material may comprise one or more polymorphic forms, which have characterised powder X-ray diffraction spectra.

Description

Stable pharmaceutical formulations of atorvastatin magnesium salt

FIELD OF THE INVENTION

The present invention relates to stable pharmaceutical formulations comprising atorvastatin magnesium as the active agent.

TECHNICAL BACKGROUND AND PRIOR ART

Atorvastatin ([R-(R*,R*)]-2-(4-fluorophenyl)-β,δ -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. Although 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.

Several attempts have been made to prevent degradation of atorvastatin. For example 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.

Practical atorvastatin formulations must also be bio-available and importantly pharmaceutically active.

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 μm and a d₅₀ of approximately 98 μm. 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.

As atorvastatin has proved to be an extremely useful and commercially valuable drug, alternative formulations with increased stability and/or other pharmaceutical advantages will be highly appreciated.

SUMMARY OF THE INVENTION

Accordingly, 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. 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.

DESCRI PTION OF FIGURES

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.

DETAILED DESCRIPTION

The chemical formula of atorvastatin magnesium is depicted as Formula I:

Formula I

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. Generally, the free acid or the lactone, preferably the lactone, is dissolved in aqueous or aqueous alcohol solvent or other suitable solvents with an appropriate base of magnesium (Mg⁺²) and isolating the magnesium salt by evaporating the solution, or by reacting the free acid or lactone directly, or can be obtained by concentration of the solution. 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.

Formula II

General synthetic processes for producing the above materials from which to make atorvastatin Mg are described in the prior art, e.g., US patent 4,681,893 and EP 409 281.

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.

In one embodiment of the invention, 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.

In one embodiment of the invention, 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.

In another embodiment, 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.

At least two crystalline forms have been formulated in accordance with the invention and found to provide formulations with superior stability, having the advantages discussed herein. The XRD spectra of these forms, referred to as B2 and B4 are shown in Figures 1 and 2.

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.

In certain embodiments, 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. It is also found useful to include in certain embodiments 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. One particular example is illustrated in Example 2 below.

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. One particular example is illustrated in Example 2 below.

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. Typically the 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.

EXAMPLES

Example 1: Characterisation of atorvastatin magnesium polymorphs

Two polymorphs of atorvastatin Mg were analysed by powder X-ray diffraction analysis. The dry powder samples were placed in a PMMA sample holder and analysed using a Bruker AXS diffractometer (type D8 Focus) using Ni-filtered Cu k-alfa emission with a wavelength of 1.54 A, intensity of 40 mA and 40 kV. Background substraction or noise filtering is not applied. The spectrum of sample 1 is shown in Figure 1, showing clear characterising peaks, this form of the material is referred to as B2 and by defined by the peaks shown in the spectrum. Table 1 lists the peak data.

Table 1

Angle d value Intensity Intensity %

2-Theta ° Angstrom Count %

3,22 27,4166 1102 55,2

4,92 17,9520 858 43,0

6,23 14,1667 923 46,3

6,86 12,8720 965 48,4

7,61 11,6079 1482 74,3

9,31 9,4943 1294 64,8

10,37 8,5220 1129 56,6

11,35 7,7873 1135 56,9

11,57 7,6407 1146 57,4

12,53 7,0581 1055 52,9

13,36 6,6233 929 46,5

15,57 5,6863 1395 69,9

17,50 5,0649 1788 89,6

18,65 4,7548 1995 100,0

19,48 4,5539 1774 88,9

19,95 4,4467 1932 96,8

21,74 4,0839 1545 77,4

22,78 3,9010 1202 60,3

24,00 3,7045 1314 65,9

25,29 3,519 1012 50,7

27,80 3,2062 874 43,8

28,51 3,1284 868 43,5

The spectrum of sample 2 is shown in Figure 2, and is different from the spectrum of Figure 1. This form of material is referred to as B4 and can be defined by the peaks shown in the spectrum. Table 2 lists the peak data.

Table 2

Angle d value Intensity ReI. Intensity

2-Theta ° Angstrom Count %

2,93 30,1367 2891 100,0

5,87 15,0381 682 23,6

8,86 9,9709 1820 62,9

9,88 8,9447 1855 64,2 10,72 8,2496 986 34,1

11,84 7,4672 1146 39,7

12,37 7,1506 1054 36,5

14,79 5,9841 663 22,9

16,44 5,3861 2837 98,1

17,86 4,9630 1138 39,3

18,78 4,7200 1272 44,0

20,17 4,3991 1363 47,2

21,65 4,1016 2034 70,4

23,28 3,8182 1141 39,5

24,02 3,7022 1182 40,9

24,64 3,6101 881 30,5

26,91 3,3106 720 24,9

27,86 3,2000 546 18,9

Example 2: Formulation of atorvastatin Mq

The following ingredients were mixed in the following order using wet granulation, with water as granulating medium:

Ingredients mg amount in 10 mα tablet

Magnesium stearate 1,92

Povidone 2,4 Sodium carbonate anhydr. 6,6

Polyplasdone XL. 12

Cellulose microcrystalline 18

Mannitol 60, Ph Eur 68,38

Atorvastatin magnesium trihydrate 10,7 TOTAL 120 mg

Example 3: Stability of atorvastatin Mq formulations

The following table depicts the stability of atorvastatin, using various forms, formulated as described in Example 2. The samples were kept at 40⁰C, 75% relative humidity, in closed Duma bottles. Impurities as measured by HPLC.

Form used Age in months: 0

B2 - (Less crystalline) Total impurities (%): 0,35 0,73 1,18 2,24 B4 - (More crystalline) Total impurities (%): 0,92 0,95 Amorphous Ca atorvast. Total impurities (%): 1,48 1,91 3,21 The results illustrate the surprisingly good stability of the tested formulations, which are substantially more stable than the comparative formulation with amorphous Ca atorvastatin.

Much more impurities (degradation products) are formed in the calcium atorvastatin tablets, with 270% more impurities in the calcium atorvastatin tablets after 3 months storage in than in the B2 magnesium atorvastatin tablets. Even if substracting out the higher initial impurities in the calcium salt material, the impurities formed are still more than 100% higher than in the magnesium atorvastatin tablets. This illustrates the superior stability of tablets formed accordign to the present invention in comparison to tablets with calcium atorvastatin.

Claims

1. A pharmaceutical composition comprising a magnesium salt of atorvastatin and one or more suitable pharmaceutical excipient, wherein said magnesium salt of atorvastatin is at least partially crystalline, the crystalline portion of said magnesium salt characterized by one or more X-ray powder diffraction spectral peak selected from 3.22, 4.92, 6.23, 6.86, 7.61, 9.31, 10.37, 11.35, 11.57, 12.53, 13.36, 15.57, 17.50, 18.65, 19.48, 19.95, 21.74, 22.78, 24.00, 25.29, 27.80, 28.51, 2.93, 5.87, 8.86, 9.88, 10.72, 11.84, 12.37, 14.79, 16.44, 17.87, 18.78, 20.17, 21.65, 23.28, 24.02, 24.64, 26.91 and 27.86 degrees 2-theta.

2. The pharmaceutical composition of claim 1 wherein at least 50 wt% of said magnesium salt of atorvastatin is crystalline.

3. The pharmaceutical composition of claim 1 or2 wherein the crystalline portion of said magnesium salt is characterized by two or more X-ray powder diffraction spectral peaks selected from values in claim 1.

4. The pharmaceutical composition of claim 1 or2 wherein the crystalline portion of said magnesium salt is characterized by four or more X-ray powder diffraction spectral peaks selected from values in claim 1.

5. The pharmaceutical composition of any of claims 1 to 3 wherein the crystalline portion of said magnesium salt of atorvastatin is characterised by X-ray diffraction spectral peaks at about 18.65 and about 19.95 degrees 2-theta.

6. The pharmaceutical composition of claim 5 wherein the crystalline portion of said magnesium salt of atorvastatin is further characterised by X-ray diffraction spectral peaks at about 7.61 and 15.57 degrees 2-theta.

7. The pharmaceutical composition of claim 6 wherein the crystalline portion of said magnesium salt of atorvastatin is further characterised by X-ray diffraction spectral peaks at about 2.93 and 16.44 degrees 2-theta.

8. The pharmaceutical composition of claim 7 wherein the crystalline portion of said magnesium salt of atorvastatin is further characterised by X-ray diffraction spectral peaks at about 8.86 and 9.88, degrees 2-theta.

9. The pharmaceutical composition of claim 8 wherein the crystalline portion of said magnesium salt of atorvastatin is further characterised by X-ray diffraction spectral peaks at about 20.17 and 21.65 degrees 2-theta.

10. The pharmaceutical composition of claim 2 wherein the crystalline portion of said magnesium salt of atorvastatin is characterised by X-ray diffraction spectrum substantially as depicted in Figure 1.

11. The pharmaceutical composition of claim 2 wherein the crystalline portion of said magnesium salt of atorvastatin is characterised by X-ray diffraction spectrum substantially as depicted in Figure 2.

12. The pharmaceutical composition of claim 1 wherein said magnesium salt of atorvastatin is at least partially amorphous.

13. The pharmaceutical composition of claim 12 wherein at least 50 wt% of said magnesium salt of atorvastatin is amorphous.

14. The pharmaceutical composition of any of claims 1-13 wherein said one or more suitable pharmaceutical excipient is/are selected from the group consisting of diluents, binders, disintegrants, and lubricants.

15. The pharmaceutical composition of any of claims 1-14 further comprising an alkalizing agent.

16. The pharmaceutical composition of any of claims 1-14 further comprising an alkali metal salt additive.

17. The pharmaceutical composition of claim 16 wherein said alkali metal salt additive comprises one or more of 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.

18. The pharmaceutical composition of claim 17 wherein said alkali metal salt additive comprises sodium carbonate.

19. The pharmaceutical composition claim 15 comprising a diluent selected from mannitol and microcrystalline cellulose.

20. The pharmaceutical composition of claim 15 comprising magnesium stearate as lubricant.

21. The pharmaceutical composition of any of claims 15-20 comprising in the range of 1-50 wt% atorvastatin Mg, in the range of 10-70 wt% mannitol 60, in the range of 5-50 wt% microcrystalline cellulose, and in the range of 1-20 wt% alkali metal salt additive selected from the group consisting of sodium carbonate and calcium carbonate.

22. The pharmaceutical composition of claim 21 further comprising in the range of 0.1-5 wt% magnesium stearate and in the range of 0.5-5 wt% polyvinylpyrrolidone.

23. The pharmaceutical formulation of claim 22 comprising in the range of 1-15 wt% atorvastatin Mg, in the range of 50-70 wt% mannitol 60, in the range of 10-20 wt% microcrystalline cellulose, in the range of 4-10 wt% sodium carbonate, in the range of 0.1- 5 wt%, in the range of 1-2 wt% magnesium stearate, in the range of 0.5-5 wt% polyvinylpyrrolidone and in the range of 2-20% crosspovidone.

24. A pharmaceutical composition comprising as an active ingredient a salt of atorvastatin which exhibits a powder X-ray crystal diffraction spectrum substantially as in Figure 1.

25. A pharmaceutical composition comprising as an active ingredient a salt of atorvastatin which exhibits a powder X-ray crystal diffraction spectrum substantially as in Figure 2.

26. A process for preparing a pharmaceutical preparation comprising atorvastatin magnesium comprising mixing with wet granulation atorvastatin magnesium, which is at least partially crystallised, with at least one pharmaceutically acceptable excipient, using an aqueous solution as granulating liquid.

27. The process of claim 26 wherein said atorvastatin magensium is as defined in any of claims 1-13.

28. The process of claim 26 comprising mixing into said formulation an alkalizing agent.

29. The process of claim 26 comprising mixing into said formulation an alkali metal salt additive.

30. The process of claim 26, wherein said alkali metal salt additive comprises one or more of 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.

31. The process of claim 30, wherein said alkali metal salt additive comprises sodium carbonate.

32. The process of claim 26, comprising mixing into said formulation a diluent selected from mannitol and microcrystalline cellulose.

33. The process of claim 26, comprising mixing into said formulation in the range of 1-50 wt% atorvastatin Mg, 10-70 wt% mannitol 60, 5-50 wt% microcrystalline cellulose, 1-20 wt% alkali metal salt additive selected from sodium carbonate or calcium carbonate.

34. The process of claim 26, comprising mixing into said formulation in the range of 1-50 wt% atorvastatin Mg, in the range of 10-70 wt% mannitol 60, in the range of 5-50 wt% microcrystalline cellulose, in the range of 1-20 wt% alkali metal salt additive selected from sodium carbonate or calcium carbonate.

35. The process of claim 34 further comprising mixing into said formulation in the range of 0.1- 5 wt% magnesium stearate and in the range of 0.5-5 wt% polyvinylpyrrolidone.

36. The process of claim 34 further comprising mixing into said formulation in the range of 1- 15 wt% atorvastatin Mg, in the range of 50-70 wt% mannitol 60, in the range of 10-20 wt% microcrystalline cellulose, in the range of 4-10 wt% sodium carbonate, in the range of 0.1-5 wt%, in the range of 1-2 wt% magnesium stearate, in the range of 0.5-5 wt% polyvinylpyrrolidone and in the range of 2-20% crosspovidone.

37. The process of claim 26 wherein said aqueous solution is water.