Note: Descriptions are shown in the official language in which they were submitted.
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STABLE DOSAGE FORMS COMPRISING ATORVASTATIN CALCIUM
FIELD OF INVENTION
This invention relates to solid pharmaceutical compositions for oral
administration comprising atorvastatin calcium, and improvement of the
stability of such compositions.
BACKGROUND OF THE INVENTION
Atorvastatin is a synthetic lipid-lowering agent, and is disclosed and claimed
in U.S. patent 5273995.
Tablets comprising atorvastatin as the hemi-calcium salt (known as
atorvastatin calcium) are sold in the United States as elsewhere under the
tradename LipitorTM
Atorvastatin is a member of a class of compounds known as "statins". These
compounds are HMG-CoA reductase inhibitors, and are used as
antihypercholesterolemic agents.
Some of these compounds and, in particular, fluvastatin, pravastatin and
atorvastatin, have in their molecule a non-esterified hydroxy acid moiety, and
thus will form basic salts, such as sodium or calcium salts. When these
compounds are in the acid form, they are relatively unstable and are prone to
degradation into the corresponding lactones.
It is known from the prior art that stable compositions comprising such
compounds can be made either by using these compounds in the form of
basic salts, or alternatively, if the acid form is used, including in the
composition a basic excipient so as to keep the compound in a basic
environment.
TM _ Registered trademark.
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There are several such prior art publications that deal with stabilization of
statins having a non-esterified hydroxy acid moiety.
U.S. patent 5180589 deals specifically with pravastatin. The disclosure
explains that stability of pravastatin in a composition may be improved by
including a basifying agent to raise the pH of an aqueous dispersion of the
composition to at least 9 and preferably at least 9.5. Nine examples are given
along with data which confirms that, in each example, inclusion of magnesium
oxide as basifying agent inhibits conversion of the pravastatin to the
lactone.
The disclosure deals only with pravastatin in its acid form, and not with
basic
salts of pravastatin such as pravastatin sodium. Pravastatin sodium already
being basic, does not require inclusion of a basifying agent in the tablet to
improve stability, so long as the tablet contains no acidic excipient
(inactive
ingredient). This publication makes no mention of atorvastatin calcium.
Similarly, U.S, patent 5356896 relates to stabilization of solid compositions
of
fluvastatin against lactone formation by inclusion of a basifying agent so
that
an aqueous dispersion of the composition will have a pH of at least 8. The
disclosure and claims of this patent appear to confuse fluvastatin with its
basic
salts, and in particular appear to confuse fluvastatin with fluvastatin
sodium.
All of the examples in the disclosure show compositions which contain, as the
active drug, fluvastatin and not fluvastatin sodium, and the examples confirm
that compositions which comprise fluvastatin along with a basifying agent are
stable. However, all of the claims of this patent are limited to compositions
which comprise the drug in the form of a basic salt and not the acid form.
Moreover, when the active ingredient is fluvastatin sodium, and not
fluvastatin, compositions are stable without the inclusion of a basifying
agent,
so long as the compositions do not include an acidic excipient. A basifying
agent is thus not needed for stability in the case of fluvastatin sodium. It
thus
appears that the claims erroneously state the drug to be in the form of basic
salt, whereas the invention, if any, relates to the drug in the form of the
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hydroxy acid. Again, this publication makes no reference to atorvastatin
calcium.
WO 00/35425 discloses compositions comprising an active substance that is
a HMG-CoA reductase inhibitor, wherein that active substance is one which is
capable of providing a pH in the range of 7 to 11. The term "active substance"
is defined as meaning the HMG-CoA reductase inhibitor alone or a mixture
thereof with a small amount of a buffering agent. The essence of the
invention is that, by using an active substance which provides a pH in the
range of 7 to 11, it is possible to achieve improved stability even if the
final
composition in which it is contained exhibits pH below 9. In other words, by
creating an environment locally within each particle of the active substance
such that a dispersion of such particles in water would have a pH of 7 to 11,
it
is not necessary that the entire mass of the composition be highly basic.
WO 00/35425 has only six examples. The first five all comprise pravastatin
sodium as the active drug and the sixth comprises atorvastatin calcium along
with dibasic sodium phosphate as buffering agent. The concluding paragraph
of the disclosure states that the compositions of all six examples provide
excellent stability, with essentially no degradation of the pravastatin or
atorvastatin observed. However, as aforesaid, pravastatin sodium is a basic
salt and does not require further stabilization in the absence of an acid, so
that it is not surprising that the composition of examples 1 to 5 are stable.
Moreover, with respect to example 6, as will be explained hereafter, while
atorvastatin calcium is stable against conversion to the lactone in the
absence
of an acid, it is prone to other types of degradation, and in particular
oxidation,
even at pH of 7 to 11. It is thus more difficult to provide stable
compositions
for atorvastatin calcium than for pravastatin sodium or fluvastatin sodium. It
thus appears that the statement in WO 00/35425 that the composition of
example 6 is stable is likely erroneous. It may be that not all degradation
products were measured, but only the lactone.
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U.S. patent application 2002/0035142 discloses stabilized compositions
comprising a statin that is a hydroxy acid or salt thereof and a stabilizing
amount of an amido-group containing polymer or an amino-group containing
polymer. The compositions are said to provide stability against lactone
formation. However, where the active ingredient is atorvastatin calcium, such
compositions will not provide good stability against types of degradation
other
than lactone formation.
As aforesaid, atorvastatin calcium is disclosed in U.S. patent 5273995. The
processes of this patent produce atorvastatin calcium in amorphous form.
Because atorvastatin calcium is a basic salt of atorvastatin, like pravastatin
sodium and fluvastatin sodium, it is not unstable against formation of the
lactone unless mixed with other acidic compounds. However, it is more prone
than pravastatin sodium and fluvastatin sodium to other types of degradation,
including oxidation, even as the calcium salt.
U.S. patent No. 5969156 teaches new crystalline forms of atorvastatin
calcium which are designated as Form I, Form II, Form IV, and are said to be
more stable than the amorphous form. LipitorTM tablets comprise atorvastatin
sodium in crystalline Form I.
U.S. patent 6126971 relates specifically to stable solid dosage forms
comprising atorvastatin calcium. The disclosure confirms that this compound
is unstable in that it is susceptible to heat, moisture, low pH environment
and
light; and that in an acid environment, in particular, the hydroxy acid will
degrade to lactone. Since the calcium salt is basic and not acidic,
compositions comprising atorvastatin calcium do not require stabilizing
against formation of the lactone, so long as the composition does not
comprise an acidic excipient. However, as aforesaid, atorvastatin calcium is
still unstable to other types of degradation even in the absence of an acid.
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U.S. patent 6126971 teaches that compositions comprising atorvastatin
calcium, even in the absence of an acidic excipient, will exhibit improved
stability if the composition comprises at least one excipient that is also a
salt
5 of an alkaline earth metal such as calcium or magnesium. All of the examples
in this patent comprise atorvastatin calcium as the active ingredient, and
calcium carbonate as the stabilizer. The test data in the disclosure confirms
that tablets comprising calcium carbonate are more stable than tablets without
calcium carbonate.
U.S. patent 6126971 thus teaches that, when atorvastatin is in the form of the
calcium salt (calcium being an alkaline earth metal), and even in the absence
of an acidic ingredient, stability is improved by inclusion of an excipient
that is
another salt of an alkaline earth metal. This patent thus leads the reader to
conclude that, for atorvastatin calcium formulations, metal salts other than
those of alkaline earth metals are either ineffective as stabilizers or are
less
effective as stabilizers than alkaline earth metal salts.
The disclosure of U.S. patent 6126971, does not specify whether the
atorvastatin calcium being in the examples used is the amorphous form or
one of the crystalline forms disclosed in U.S. patent 5969156. However, as
LipitorTM tablets contain crystalline Form I, which is the most stable form,
it
appears that the atorvastatin calcium used in the examples is crystalline Form
I.
It has been found when the atorvastatin calcium is in amorphous form, the
compositions within the scope of U.S. patent 6126971 do not enable good
stability. Moreover, even LipitorTM tablets exhibit slow degradation of the
atorvastatin calcium content.
In view of this prior art, one objective of the present invention is to enable
solid compositions for oral administration comprising atorvastatin calcium
that
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are stable, even when the atorvastatin calcium is an amorphous form.
Another objective of the invention is to enable atorvastatin calcium tablets
that
are stable without comprising an excipient that is an alkaline earth metal
salt.
Another objective of the invention is to enable atorvastatin calcium tablets
that
are more stable than LipitorTM tablets.
DESCRIPTION OF THE INVENTION
As aforesaid, WO 00135425 teaches that atorvastatin sodium is best stabilized
by incorporating it into particles for which the pH of an aqueous dispersion
is
between 7 and 11; and U.S. patent 6126971 teaches that atorvastatin calcium
is best stabilized by including in the composition an excipient that is also
an
alkaline earth metal salt (as is atorvastatin calcium itself).
In light of this prior art, it has now been surprisingly found that
atorvastatin
calcium is best stabilized against degradation, including oxidation, by
incorporating a basic sodium or potassium compound along with the
atorvastatin calcium in the composition, or in particles within the
composition,
such that an aqueous dispersion of the composition or of the particles is
capable of providing a pH above 11.
Accordingly, compositions within the scope of the present invention will
comprise atorvastatin calcium and at least one sodium or potassium
compound, such that either:
i) an aqueous dispersion of the composition is capable of producing a pH
of above 11; or
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ii) the composition comprises particles which further comprise said
atorvastatin calcium and said sodium or potassium compound, and an
aqueous dispersion of said particles is capable of producing a pH of
above 11.
The sodium or potassium compound may be a hydroxide or a salt of a weak
acid. Suitable compounds will include sodium hydroxide, potassium
hydroxide, sodium carbonate, potassium carbonate, tribasic sodium
phosphate, and tribasic potassium phosphate. The sodium or potassium
compound may be either anhydrous or hydrated.
Especially preferred are tribasic sodium phosphate and tribasic potassium
phosphate. Most preferred is tribasic sodium phosphate.
The composition will preferably be tablets.
The composition will also preferably include one or more excipients other than
the sodium or potassium compound.
Such excipients may include, for example, any or all of:
i) A binder, such as microcrystalline cellulose.
ii) A disintegrant, such as starch, croscarmellose sodium, sodium starch
glycolate, or crospovidone.
iii) A lubricant, such as magnesium stearate.
iv) A glidant, such as colloidal silicon dioxide.
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When the composition is in the form of tablets, the tablets may be made by a
direct compression process, wherein the ingredients are mixed together in dry
form and the mixture is directly compressed into tablets.
If the powder mixture does not flow well enough for direct compression, then
the flow may be improved by either a wet granulation or a dry granulation
process.
In a wet granulation process, ingredients are made into a wet mass using
water or an organic solvent, in which a binder may optionally be dissolved,
and the wet mass is then dried and milled into free-flowing granules.
Alternatively, flow may be improved by a dry granulation process, also known
as compaction or slugging, in which a mixture of ingredients is first
compressed into compacted material, which is then milled into granules,
which are then recompressed into the final tablets.
The invention will be better understood from the following examples which are
meant to be illustrative and not limiting the scope of the invention.
EXAMPLES
Examples 1 to 4 were made as follows:
Example No.: 1 2 3 4
Atorvastatin Calcium
Amorphous 5.4 5.4 5.4 5.4
Sodium Carbonate
Monohydrate 124.6 0 0 0
Sodium Citrate
Dihydrate 0 124.6 0 0
Sodium Phosphate
Dibasic Anhydrous 0 0 124.6 0
Sodium Phosphate
Tribasic, Anhydrous 0 0 0 124.6
130. 130. 130. 130.
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For each of the four examples, the ingredients were mixed in the proportion
shown. The mixture was then compressed into slugs using a tablet press.
The slugs were then ground up into granules, which are particles comprising
atorvastatin calcium and the sodium compound. The granules were
recompressed into tablets at a weight of 130 mg each. Each tablet thus
contained about 5.4 mg of atorvastatin calcium, which is equivalent to about 5
mg of atorvastatin, allowing for a water content of about 4 percent.
Sample tablets of each of the four examples and also sample tablets of
LipitorTM were then stored at 60°C for two weeks. Samples of each,
along
with samples that had been kept at room temperature, were then tested for
degradation products by a High Performance Liquid Chromatographic (HPLC)
method. The amounts by which the total degradation products in the samples
stored at 60°C exceeded the total degradation products in the samples
stored
at room temperature were as follows:
Increase in Degradation
Example # Stabilizer Products at 60°C Levels
1 Sodium carbonate Monohydrate 1.16%
2 Sodium citrate Dihydrate 1.27%
3 Sodium phosphate dibasic Anhydrous 1.52%
4 Tribasic sodium phosphate Anhydrous 0
LipitorTM Calcium carbonate 0.18%
For the tablets of examples 1 and 4, the pH of an aqueous dispersion (and
also the pH of an aqueous dispersion of the granules from which they were
made) exceeds 11; whereas for examples 2 and 3 the pH is less than 11.
Examples 1 and 4 are thus examples of the present invention; examples 2
and 3 are not examples of the present invention, but are included for
comparison purposes.
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It can be seen that the stability of the tablets of examples 1 and 4 is
superior
to that of examples 2 and 3. Also, and very surprisingly, the stabilizing
effect
of tribasic sodium phosphate in example 4 is even better than that of sodium
5 carbonate, in example 1, despite the fact that the pH of the aqueous
dispersions for both exceed 11. Use of tribasic sodium phosphate in
compositions of the present invention thus enables stability even better than
that of LipitorTM.
10 As tribasic potassium phosphate is very similar to tribasic sodium
phosphate
in physico-chemical characteristics, it may be concluded that tribasic sodium
phosphate and tribasic potassium phosphate are both especially preferred as
stabilizers for atorvastatin calcium, in compositions of the present
invention.
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