U.S. patent application number 10/655263 was filed with the patent office on 2004-04-15 for stable pharmaceutical formulation comprising a hmg-coa reductase inhibitor.
Invention is credited to Kerc, Janez.
Application Number | 20040072894 10/655263 |
Document ID | / |
Family ID | 20432372 |
Filed Date | 2004-04-15 |
United States Patent
Application |
20040072894 |
Kind Code |
A1 |
Kerc, Janez |
April 15, 2004 |
Stable pharmaceutical formulation comprising a HMG-CoA reductase
inhibitor
Abstract
Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin,
and derivatives and analogs thereof are known as HMG-CoA reductase
inhibitors and are used as antihypercholesterolemic agents. The
majority of them are produced by fermentation using microorganisms
of different species identified as species belonging to
Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or
Penicillium genus, and some are obtained by treating the
fermentation products using the methods of chemical synthesis or
they are the products of total chemical synthesis. The
aforementioned active substances may be destabilised by the
environmental factors, their degradation may also be accelerated by
interactions with other pharmaceutical ingredients, such as
fillers, binders, lubricants, glidants and disintegrating agents,
therefore the pharmaceutical ingredients and the process for
preparation of the pharmaceutical formulation should be
meticulously chosen to avoid the aforementioned undesired
interactions and reactions. The present invention relates to a
stable solid pharmaceutical formulation for the treatment of
hypercholesterolemia and hyperlipidemia. More precisely, the
present invention relates to the new stable solid pharmaceutical
formulation containing as an active ingredient a HMG-CoA reductase
inhibitor, such as atorvastatin, pravastatin, fluvastatin and
cerivastatin or pharmaceutically acceptable salts thereof.
Inventors: |
Kerc, Janez; (Ljubljana,
SI) |
Correspondence
Address: |
BROMBERG & SUNSTEIN LLP
125 SUMMER STREET
BOSTON
MA
02110-1618
US
|
Family ID: |
20432372 |
Appl. No.: |
10/655263 |
Filed: |
September 4, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10655263 |
Sep 4, 2003 |
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09600436 |
Oct 16, 2000 |
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6680341 |
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09600436 |
Oct 16, 2000 |
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PCT/IB99/01749 |
Oct 29, 1999 |
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Current U.S.
Class: |
514/423 ;
514/460; 514/548 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 3/06 20180101; A61K 9/2013 20130101; A61K 9/2009 20130101;
A61P 9/12 20180101; A61P 9/00 20180101 |
Class at
Publication: |
514/423 ;
514/460; 514/548 |
International
Class: |
A61K 031/401; A61K
031/366; A61K 031/225 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 16, 1998 |
SI |
P-9800309 |
Claims
1. A stable solid pharmaceutical formulation containing as an
active substance a HMG-CoA reductase inhibitor, characterized in
that an active substance is contained which is capable of providing
a pH in the range from 7 to 11.
2. A stable solid pharmaceutical formulation as defined in claim 1,
characterized in that an active substance is contained which is
capable of providing a pH in the range from 8 to 10.
3. A stable solid pharmaceutical formulation as defined in claim 1
or 2, wherein the active substance is a HMG-CoA reductase inhibitor
in the form of a salt.
4. A stable solid pharmaceutical formulation as defined in any one
of claims 1 to 3, wherein the active substance, which had been
incorporated into the formulation, contained a buffering agent.
5. A stable solid pharmaceutical formulation as defined in claim 4,
wherein the active substance, which had been incorporated into the
formulation, contained the buffering agent in an amount of less
than 1%.
6. A stable solid pharmaceutical formulation as defined in any one
of claims 1 to 5, wherein the active substance is selected from the
group consisting of pravastatin, atorvastatin, fluvastatin,
cerivastatin and a pharmaceutically acceptable salt thereof.
7. A stable solid pharmaceutical formulation as defined in claim 6,
wherein the active substance is a sodium salt of pravastatin
(pravastatin Na) or a calcium salt of atorvastatin (atorvastatin
Ca).
8. A stable solid pharmaceutical formulation as defined in claim 1,
which further comprises at least one constituent selected from the
group consisting of a filler, a binder, a disintegrating agent, a
glidant, a buffering agent; optionally further comprising at least
one constituent selected among colouring agents, lakes, aromas,
adsorbents, film formers and plasticizers.
9. A stable solid pharmaceutical formulation containing as an
active substance a HMG-CoA reductase inhibitor, characterized in
that the pharmaceutical formulation is capable of providing a pH
below 9.
10. A stable solid pharmaceutical formulation according to claim 9,
characterized in that the pharmaceutical formulation is capable of
providing a pH in the range from 6 to 9.
11. A stable solid pharmaceutical formulation according to claim 9,
characterized in that the pharmaceutical formulation is capable of
providing a pH in the range from 7 to 8.5.
12. A stable solid pharmaceutical formulation according to claim 9,
characterized in that an active substance being capable of
providing a pH in the range from 7 to 11 is incorporated into said
solid pharmaceutical formulation.
13. A stable solid pharmaceutical formulation according to claim 9,
characterized in that an active substance being capable of
providing a pH in the range from 8 to 10 is incorporated into said
solid pharmaceutical formulation.
14. A stable solid pharmaceutical formulation as defined in claim
12 or 13, wherein the active substance is a HMG-CoA reductase
inhibitor in the form of a salt.
15. A stable solid pharmaceutical formulation according to any one
of claims 12 to 14, wherein the incorporated active substance
contains a buffering agent.
16. A stable solid pharmaceutical formulation according to claim
15, wherein the buffering agent is contained in an amount of less
than 1%.
17. A stable solid pharmaceutical formulation according to claim
15, wherein additional amounts of a buffering agent are
incorporated into said formulation.
18. A stable solid pharmaceutical formulation according to any one
of claims 9 to 17, wherein the active substance is selected from
the group consisting of pravastatin, atorvastatin, fluvastatin,
cerivastatin and a pharmaceutically acceptable salt thereof.
19. A stable solid pharmaceutical formulation as defined in claim
18, wherein the active substance is a sodium salt of pravastatin
(pravastatin Na) or a calcium salt of atorvastatin (atorvastatin
Ca).
20. A stable solid pharmaceutical formulation as defined in claim
9, which further comprises at least one constituent selected from
the group consisting of a filler, a binder, a disintegrating agent,
a glidant, a buffering agent; optionally further comprising at
least one constituent selected among colouring agents, lakes,
aromas, adsorbents, film formers and plasticizers.
21. A process for the preparation of a stable solid pharmaceutical
formulation according to any of the aforementioned claims, wherein
the mixture of the active substance, filler, binder, buffering
agent, disintegrating agent and optionally surfactant and other
commonly used ingredients for solid pharmaceutical formulations are
homogenised in suitable mixers, glidants and/or lubricants are
added, the mixture is then re-homogenised and the resulting mixture
is compressed into tablets or filled into capsules; optionally the
tablets may be film-coated.
22. A process for the preparation of a stable solid pharmaceutical
formulation according to any of the claims 1 to 20, wherein the
mixture of the active substance, filler, binder, buffering agent,
disintegrating agent and optionally surfactant and other commonly
used ingredients for solid pharmaceutical formulations are
homogenised in suitable mixers, granulated with a suitable solvent;
the resulting granulation is dried in suitable dryers; to the dried
granulations, glidants and/or lubricants are added and optionally
other ingredients for solid pharmaceutical formulations and the
resulting mixture is re-homogenised and compressed into tablets or
filled into capsules; optionally the tablets may be
film-coated.
23. A stabilized pharmaceutically active substance consisting only
of a mixture of a HMG-CoA reductase inhibitor and a buffering
agent.
24. A stabilized pharmaceutically active substance according to
claim 23, wherein the buffering agent is present in the mixture in
an amount of less than 1 wt.--% based on the total weight of the
pharmaceutically active substance.
25. A stabilized pharmaceutically active substance according to
claim 23 or 24, wherein the HMG-CoA reductase inhibitor is in the
form of a salt.
26. A stabilized pharmaceutically active substance according to
claim 23 or 24, wherein the buffering agent imparts a pH in the
range from 7 to 11 to the pharmaceutically active substance.
27. A stabilized pharmaceutically active substance according to any
one of claims 23 to 26, wherein the HMG-CoA reductase inhibitor is
selected from the group consisting of pravastatin, atorvastatin,
fluvastatin, cerivastatin and a pharmaceutically acceptable salt
thereof.
28. A stabilized pharmaceutically active substance according to
claim 27, wherein the HMG-CoA reductase inhibitor is a sodium salt
of pravastatin (pravastatin Na) or a calcium salt of atorvastatin
(atorvastatin Ca).
29. A method for the stabilization of a HMG-CoA reductase inhibitor
as an active substance in a solid pharmaceutical formulation,
wherein an active substance being capable of providing a pH in the
range from 7 to 11 is incorporated into a pharmaceutical
formulation which is capable of providing a pH below 9.
30. The method according to claim 29, wherein the pharmaceutical
formulation is capable of providing a pH in the range from 6 to
9.
31. The method according to claim 29, wherein the pharmaceutical
formulation is capable of providing a pH in the range from 7 to
8.5.
32. The method according to claim 29, wherein the active substance
is a HMG-CoA reductase inhibitor in the form of a salt.
33. The method according to claim 29, wherein the incorporated
active substance contains a buffering agent in order to provide a
pH for said active substance in the range from 7 to 11.
34. The method according to claim 33, wherein the incorporated
active substance contains less than 1% of a buffering agent.
35. The method according to claim 33 or 34, wherein additional
amounts of a buffering agent are incorporated into the
pharmaceutical formulation in order to provide a pH for said
pharmaceutical formulation of below 9.
36. The method according to any one of claims 29 to 35, wherein the
active substance is selected from the group consisting of
pravastatin, atorvastatin, fluvastatin, cerivastatin and a
pharmaceutically acceptable salt thereof.
37. The method according to claim 36, wherein the active substance
is a sodium salt of pravastatin (pravastatin Na) or a calcium salt
of atorvastatin (atorvastatin Ca).
38. The method according to claim 29, wherein said stable solid
pharmaceutical formulation further comprises at least one
constituent selected from the group consisting of a filler, a
binder, a disintegrating agent, a glidant, a buffering agent;
optionally further comprising at least one constituent selected
among colouring agents, lakes, aromas, adsorbents, film formers and
plasticizers.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a new stable solid
pharmaceutical formulation which is particularly suitable for the
treatment of hypercholesterolemia and hyperlipidemia. More
precisely, the present invention relates to the new stable solid
pharmaceutical formulation containing as an active substance a
HMG-CoA reductase inhibitor, such as atorvastatin, pravastatin,
fluvastatin and cerivastatin, or pharmaceutically active salts
thereof.
BACKGROUND OF THE INVENTION
[0002] Lovastatin, pravastatin, simvastatin, mevastatin,
atorvastatin, fluvastatin and cerivastatin, derivatives and analogs
thereof are known as HMG-CoA reductase inhibitors and are used as
antihypercholesterolemic agents. The majority of them are produced
by fermentation using microorganisms of different species
identified as species belonging to Aspergillus, Monascus, Nocardia,
Amycolatopsis, Mucor or Penicillium genus. Some are obtained by
treating the fermentation products using the methods of chemical
synthesis like simvastatin or they are the products of total
chemical synthesis like fluvastatin, atorvastatin and
cerivastatin.
[0003] The purity of the active substance is an important factor
for manufacturing a safe and effective pharmaceutical formulation.
Maximum possible purity of the product is of particular importance
if the pharmaceutical product must be taken on a longer term basis
in the treatment or prevention of high cholesterol levels in blood.
Accumulation of impurities from drugs of a lower level of purity
may cause a variety of side effects during treatment. Besides
impurities, that cannot be completely eliminated in the process of
preparation of the active substance, degradation products occurring
by subjecting the final pharmaceutical formulation to various
environmental factors such as temperature, moisture, low pH and
light, may also impose a problem. HMG-CoA reductase inhibitors
occurring in the form of salts in the final pharmaceutical
formulation, such as atorvastatin, pravastatin, fluvastatin and
cerivastatin, are particularly sensitive to an acidic environment
in which hydroxy acids are degraded into a lactone.
[0004] Apart from the fact that the aforementioned active substance
may be destabilised by the environmental factors, their degradation
may also be accelerated by interactions with other pharmaceutical
ingredients, such as fillers, binders, lubricants, glidants and
disintegrating agents. Therefore, the pharmaceutical ingredients
and the process for preparation of the pharmaceutical formulation
should be meticulously chosen to avoid the aforementioned undesired
interactions and reactions.
[0005] The stability of the active substance in an acidic
environment is one of the major problems in the case of statins in
the form of salts. One of possible solutions of the aforementioned
problem is described in EP 0 336 298, disclosing a stable
pharmaceutical formulation for pravastatin. The essence of the
formulation is to maintain an alkaline environment so that the
aqueous dispersion of the pharmaceutical formulation reaches a pH
above 9, preferably about 10. In addition to the active substance
pravastatin, the composition of the invention includes a basifying
agent, such as magnesium oxide which imparts a pH to an aqueous
dispersion of the aforementioned formulation above 9. In view of
the stability of the active substance such a formulation is
effective. However, the local alkaline environment occurring at the
site of dissolution of the pharmaceutical formulation may have a
negative impact on the gastric mucosa with its normally acidic
environment. This negative impact may be particularly evident for
patients with a damaged gastric mucous membrane where the mucosa
per se is not able to create a sufficient acidic environment inside
the stomach for normal digestive functioning. It is particularly
important in chronic therapies as in the case of prophylaxis or
treatment with HMG-CoA reductase inhibitors.
SUMMARY OF THE INVENTION
[0006] It is an object of the present invention to provide a
pharmaceutical formulation containing as an active substance a
HMG-CoA reductase inhibitor which exerts an excellent stability
while avoiding the afore mentioned disadvantages. It is a
particular object to provide a stabilized active substance as such
where the HMG-CoA reductase inhibitor is precautionary protected
from being degraded.
[0007] It is a further object to provide a process for the
preparation of a stable pharmaceutical formulation which exerts an
excellent stability while avoiding the afore mentioned
disadvantages.
[0008] These and further objects are accomplished by the present
invention.
[0009] According to the present invention, there is provided a
stable solid pharmaceutical formulation containing as an active
substance a HMG-CoA reductase inhibitor, wherein an active
substance is contained which is capable of providing a pH in the
range from 7 to 11. Within the meaning of the present invention,
the term "active substance" denotes a HMG-CoA reductase inhibitor
alone or a mixture thereof with a small amount of a buffering
agent. Therefore, the present invention also makes available a
stabilized pharmaceutically active substance as such, which active
substance consists of a HMG-CoA reductase inhibitor and a low
amount of a buffering agent.
[0010] According to the present invention, there is further
provided a stable solid pharmaceutical formulation containing as an
active substance a HMG-CoA reductase inhibitor, wherein the
pharmaceutical formulation is capable of providing a pH below
9.
[0011] In addition, according to the present invention, there is
provided suitable processes for the preparation of the above
specified stable solid pharmaceutical formulation.
[0012] According to the present invention, there is further
provided a method for the stabilization of a HMG-CoA reductase
inhibitor as an active substance in a solid pharmaceutical
formulation, wherein an HMG-CoA reductase inhibitor being capable
of providing a pH in the range from 7 to 11 is incorporated into a
pharmaceutical formulation which is capable of providing a pH below
9.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1a is a diagram which shows the growth of weight of a
sample of pravastatin in crystal form and a sample of lyophilised
pravastatin when exposed to air moisture. FIG. 1b shows the
corresponding difference in the starting weight and the weight in
time.
[0014] FIG. 2 is a diagram which shows the occurrence of
pravastatin in lactone form when pravastatin was dissolved in
different buffers with the pH in a range between 7 and 11
(F=phosphate, C=citrate, B=borate).
[0015] FIG. 3 is a diagram which shows the formation of different
degradation products (impurities) when pravastatin was dissolved in
different buffers with the pH in a range between 7 and 11
(F=phosphate, C=citrate, B=borate).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] In the inventor's investigations, it was found that there
are three major reasons for instability problems in case of a
pharmaceutical formulation containing an active substance and in
case of a bulk active substance.
[0017] First, the active substance as such is very hygroscopic and
it is impossible to remove all water from it. This is illustrated
by the following experiment: 111.07 mg of pravastatin in crystal
form (prava izh) and 109.8 mg of lyophilized pravastatin (prava
lio) were exposed to air moisture. Their weights were measured in
different time intervals. The growth of weight of both samples and
the difference in the starting weight and the weight in time are
illustrated in FIGS. 1a and 1b.
[0018] Another observation was that carbon dioxide from the air can
irreversibly bind to the active substance and can cause a drop of
pH. This is illustrated by the following experiment: 5 g of
pravastatin sodium were dissolved in 30 ml of methanol, the pH was
adjusted to 10 with 3% aqueous solution of NaOH. 400 ml of
ethylacetate were added and the crystals of pravastatin sodium were
formed. Crystals were filtered and dried and then put into three
different atmospheres: normal air, nitrogen atmosphere and carbon
dioxide atmosphere. In normal air and in the nitrogen atmosphere
the pH remained the same during a period of 24 hours (normal air:
9.2, nitrogen: 9.5), but in the carbon dioxide atmosphere the pH
dropped in the first two minutes from 9.2 to 6.9. After 12 minutes
the pH was 6.6 and after 1 hour the pH was 6.5. After that, the pH
remained constant. The third observation is that a sufficient
stabilization of the active substance is already obtained at a pH
of at least 7.0, but a beneficially high stability is effected at a
pH of at least 8.0. We have noticed that at a pH below 8 the
formation of lactone has occured and also the amount of other
impurities has increased. The presence of humidity in the air and a
carbon dioxide-rich atmosphere makes the negative effect of a low
pH even stronger. This is illustrated by the following experiment:
Pravastatin was dissolved in different buffers with the pH in a
range between 7 and 11 (F=phosphate, C=citrate, B=borate). The
occurrence of pravastatin in lactone form and the formation of
different degradation products (impurities) was measured after 1,
5, 13 and 28 days. The results are shown in FIGS. 2 and 3.
[0019] In the present invention, we have surprisingly found that a
sufficient stability of the active substance, which is a HMG-CoA
reductase inhibitor preferably in the form of salt, can be also
obtained by using a pharmaceutical formulation which does not
create a marked alkaline environment in an aqueous dispersion.
[0020] Further, we have found that for the stability and
digestibility of a pharmaceutical formulation both the pH generated
by the formulation in an aqueous medium (usually being a
dispersion) and the pH of the active substance (HMG-CoA reductase
inhibitor) are of great importance.
[0021] Another surprising finding was that a sufficient stability
of a HMG-CoA reductase inhibitor in the form of a salt in bulk can
be obtained by the addition of small amounts of a buffering agent
to the pure HMG-CoA reductase inhibitor in the form of salt. Such
an addition of small amounts of buffering agents avoids the
negative effect of water already present in the bulk substance and
of moisture from the air, to avoid the negative effect of low pH
caused by other ingredients which will be co-admixed to the
pharmaceutical formulation, and to avoid the possible lowering of
the pH caused by carbon dioxide.
[0022] The active substance and the pharmaceutical formulation
according to the present invention were designed to avoid the
negative effect of the water present in the bulk substance and in
the pharmaceutical formulation, to avoid the negative effect of low
pH which can be caused by other ingredients of the pharmaceutical
formulation and to avoid possible lowering of the pH caused by
carbon dioxide.
[0023] The most acceptable stability of the active substance in the
formulations is obtained with an active substance which is capable
of providing a pH in the range from 7 to 11. The pH value is the
one which is obtained when the pH of an aqueous medium containing
said active substance would be measured. In the stable
pharmaceutical formulation according to the present invention, the
basic pH of the active substance has a minimal influence on the pH
of the formulation which is lower than 9. By creating locally an
environment around the active substance which affords the best
stability for the active substance, the potential of negative
impact of other ingredients of the composition of the
pharmaceutical formulation is reduced, and possible reactions among
the active substance and the rest of the ingredients of the
composition of the pharmaceutical formulation are also less
favoured. Accordingly, the active substance is maintained in a
stable form when an active substance which is capable of providing
a pH in an aqueous medium in the range from 7 to 11 is added to the
pharmaceutical formulation.
[0024] The active substance being added to the formulation of the
present invention generally is a HMG-CoA reductase inhibitor in the
form of a salt. The pH of the active substance may be adjusted
within the above specified range in the course of preparing the
salt of the HMG-CoA reductase inhibitor from the acid form and an
alkaline substance. As an example, the preparation of pravastatin
sodium from pravastatin acid and sodium hydroxide may be mentioned.
For a preferred adjustment of the pH of the active substance to be
incorporated into the formulation within the above specified range
of 7 to 11, the active substance is further mixed with an
appropriate buffering agent. Accordingly, the active substance may
contain small amounts of a buffering agent, preferably less than
1%, more preferably 0.1 to 0.5%, most preferably approximately
0.3%, based on the weight of the active substance added to the
formulation. A suitable buffering agent for this purpose is
carbonate buffer or phosphate buffer, such as sodium carbonate of
sodium phosphate. For example, an amount 0.3% of sodium carbonate
in pravastatin results in a pH of pravastatin between 9 and 10.
Thus, it is possible to mix pravastatin with other ingredients of
the pharmaceutical formulation without fear that a degradation can
be caused by the contact of pravastatin with acidic ingredients as
a microenvironment of pravastatin is still basic due to the
addition of small amounts of a buffering agent. This addition of
small amounts of a buffering agent is also important for an easier
handling of the pravastatin bulk without special requirements for a
carbon dioxide free atmosphere. Preferably, the acidifying effect
of carbon dioxide on the final formulation is neutralised by
further addition of an appropriate buffering agent to adjust the pH
of the formulation in the above specified range, preferably by
addition of 20%, more preferably of 10% per weight based on the
total weight of the tablet. Any buffering agent capable of
adjusting the pH of the total formulation in the desired range is
suitable, including sodium or potassium citrate, sodium phosphate,
dibasic sodium phosphate, calcium carbonate, hydrogen phosphate,
phosphate, sulphate, sodium or magnesium carbonate, sodium
ascorbinate, benzoate, sodium or potassium hydrogen carbonate,
lauryl sulphate, or mixtures of such buffering agents. Citrate
buffer, carbonate buffer and phosphate or hydrogen phosphate buffer
may be mentioned as specific examples.
[0025] Preferably, an active substance contained in the
pharmaceutical formulation according to the present invention is
capable of providing a pH in the range from 8 to 10.
[0026] Furthermore, the active substance may be selected from the
group consisting of pravastatin, atorvastatin, fluvastatin,
cerivastatin and a pharmaceutically acceptable salt thereof.
Preferably, the active substance is a sodium salt of pravastatin
(pravastatin Na) or a calcium salt of atorvastatin (atorvastatin
Ca).
[0027] As mentioned above, it is a further significant aspect of
the present invention that the pharmaceutical formulation is
capable of providing a pH below 9, preferably below 8.5. The lower
limit of the pH generated by the pharmaceutical formulation
suitably is 6, preferably 7.
[0028] By following the concepts of the present invention, the
solid pharmaceutical formulation is stable such that the HMG-CoA
reductase inhibitor as the active substance does not tend to be
decomposed and essentially retains its activity. Thereby, it is
ensured that the active substance in the pharmaceutical formulation
according to the present invention shows a sufficient stability
while, at the same time, avoiding the negative impact of a high
local alkaline environment at the site of dissolution of the
pharmaceutical formulation on the gastric mucosa which would occur
if the pH of an aqueous dispersion of the pharmaceutical
formulation is 9 or more and which results in anormal digestive
functioning.
[0029] The pharmaceutical formulation of this invention may
include, in addition to the HMG-CoA reductase inhibitor which is
sensitive to a low pH environment, one or more fillers, such as
microcrystalline cellulose, lactose, sugars, starches, modified
starch, mannitol, sorbitol and other polyols, dextrin, dextran and
maltodextrin, calcium carbonate, calcium phosphate and/or hydrogen
phosphate, sulphate, one or more binders, such as lactose,
starches, modified starch, dextrin, dextran and maltodextrin,
microcrystalline cellulose, sugars, polyethylene glycols,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
ethylcellulose, hydroxyethyl cellulose, methylcellulose,
carboxymethyl cellulose, gelatin, acacia gum, tragacanth,
polyvinylpyrrolidone, magnesium aluminium silicate, one or more
disintegrating agents such as croscarmellose sodium, cross-linked
polyvinylpyrrolidone, cross-linked carboxymethyl starch, starches
and microcrystalline cellulose, magnesium aluminium silicate,
polyacrylin potassium, one or more different glidants such as
magnesium stearate, calcium stearate, zinc stearate, calcium
behenate, sodium stearyl fumarate, talc, magnesium trisilicate,
stearic acid, palmitic acid, carnauba wax, silicon dioxide, one or
more buffering agents such as sodium or potassium citrate, sodium
phosphate, dibasic sodium phosphate, calcium carbonate, hydrogen
phosphate, phosphate, sulphate, sodium or magnesium carbonate,
sodium ascorbinate, benzoate, sodium or potassium hydrogen
carbonate, lauryl sulphate, or mixtures of such buffering
agents.
[0030] If required any, the formulation may also include
surfactants and other conventional components for solid,
pharmaceutical formulations such as colouring agents, lakes, aromas
and adsorbents. As surfactants the following may be used: ionic
surfactants, such as sodium lauryl sulphate or non-ionic
surfactants such as different poloxamers (polyoxyethylene and
polyoxypropylene copolymers), natural or synthesized lecithins,
esters of sorbitan and fatty acids (such as Span.RTM., manufactured
by Atlas Chemie), esters of polyoxyethylenesorbitan and fatty acids
(such as Tween.RTM., manufactured by Atlas Chemie),
polyoxyethylated hydrogenated castor oil (such as Cremophor.RTM.,
manufactured by BASF), polyoxyethylene stearates (such as
Brij.RTM., manufactured by Atlas Chemie), dimethylpolysiloxane or
any combination of the above mentioned surfactants.
[0031] If the solid pharmaceutical formulation is in the form of
coated tablets, the coating may be prepared from at least one
film-former such as hydroxypropyl methylcellulose, hydroxypropyl
cellulose, at least from one plasticizer such as polyethylene
glycols, dibutyl sebacate, triethyl citrate, and other
pharmaceutical auxiliary substances conventional for film coatings,
such as pigments, fillers and others.
[0032] The solid pharmaceutical formulations according to the
present invention may be prepared as described below:
[0033] The mixture of the active substance, filler, binder,
buffering agent, disintegrating agent and if required a surfactant
and other conventional ingredients for solid pharmaceutical
formulations is homogenised employing suitable mixers. Glidants
and/or lubricants are added and the mixture is re-homogenised. The
resulting mixture is compressed into tablets or filled into
capsules. If needed, tablets can be film-coated.
[0034] The mixture of the active substance, filler, binder,
buffering agent, disintegrating agent and if required a surfactant
and other conventional ingredients for solid pharmaceutical
formulations is homogenised employing suitable mixers, granulated
with a suitable solvent such as water, ethanol, methanol, isopropyl
alcohol, n-butyl alcohol, acetone, diethyl ether, ethyl acetate,
isopropyl acetate, methyl acetate, dichloromethane and methanol,
and mixtures of these solvents such as ethanol and acetone,
methanol and acetone, dichloromethane and methanol, and the
mixtures thereof. The resulting granulation is dried in suitable
dryers such as standard plate dryers, fluid bed dryers, vacuum and
microwave dryers. To the dried granulation, glidants and/or
lubricants and if required other conventional ingredients for solid
pharmaceutical formulations are added. The resulting mixture is
rehomogenised and compressed into tablets or filled into capsules.
Optionally, tablets are film-coated.
[0035] Moreover, according to the present invention the HMG-CoA
reductase inhibitor as an active substance in a solid
pharmaceutical formulation can be effectively stabilized by
incorporating a HMG-CoA reductase inhibitor, which is capable of
providing a pH in the range from 7 to 11, into a pharmaceutical
formulation which is capable of providing a pH below 9. The pH
generated by the pharmaceutical formulation may be adjusted by the
incorporation of appropriate agents such as buffering agents and
the like.
[0036] The present invention is illustrated but by no means limited
by the following examples.
EXAMPLES
Example 1
[0037] The pharmaceutical formulation with the active ingredient
pravastatin sodium in the form of tablets was prepared as follows:
the hereinunder listed ingredients were homogenised and the
resulting mixture was then compressed into tablets each containing
5, 10, 20 or 40 mg of pravastatin sodium.
[0038] The pH of the aqueous dispersion of this formulation is
8.3.
1 Ingredients % by weight Pravastatin sodium (pH 8.2) 5% Lactose
37.5% Microcrystalline cellulose 38% Sodium citrate 10% Magnesium
aluminium silicate 2% Polyacrylin potassium 3% Talc 3% Silicon
dioxide 0.5% Magnesium stearate 1%
Example 2
[0039] The pharmaceutical formulation with the active ingredient
pravastatin sodium in the form of tablets was prepared as follows:
the hereinunder listed ingredients were homogenised and the
resulting mixture was then compressed into tablets each containing
5, 10, 20, 40 or 80 mg of pravastatin sodium. The pH of the aqueous
dispersion of this formulation is 8.0.
2 Ingredients % by weight Pravastatin sodium (pH 8.5) 10% Lactose
32% Microcrystalline cellulose 37% Sodium citrate 10%
Croscarmellose sodium 2% Sodium lauryl sulphate 0.5% Polyacrylin
potassium 3% Talc 3% Silicon dioxide 0.5% Calcium stearate 2%
Example 3
[0040] The pharmaceutical formulation with the active ingredient
pravastatin sodium in the form of tablets was prepared as follows:
the first six hereinunder listed ingredients were homogenised,
granulated with water, dried, the remainder of the below listed
ingredients were added and homogenised and the resulting mixture
was then compressed into tablets each containing 5, 10, 20 or 40 mg
of pravastatin sodium.
[0041] The pH of the aqueous dispersion of this formulation is
8.2.
3 Ingredients % by weight Pravastatin sodium (pH 9) 5% Lactose 20%
Microcrystalline cellulose 20% Hydroxypropyl cellulose 1.5% Sodium
citrate 10% Magnesium aluminium silicate 2% Polyacrylin potassium
3% Microcrystalline cellulose 35% Talc 3% Magnesium stearate
0.5%
Example 4
[0042] The pharmaceutical formulation with the active ingredient
pravastatin sodium in the form of tablets was prepared as follows
(ingredients are listed in the following table): the mixture of the
active substance, filler, buffering agent, disintegrant and
surfactant is homogenised employing suitable mixers. Glidants and
lubricants are added and the mixture is re-homogenised. The
resulting mixture is compressed into tablets. The pH of the aqueous
dispersion of this formulation is 8.5.
4 Ingredient % by weight function pravastatin sodium* 8.3 active
substance lactose 58.3 filler microcrystalline 14.4 filler
cellulose Na.sub.2HPO.sub.4 10 buffering agent Na lauryl sulphate
0.4 absorption accelerator, surfactant cross-linked 4 disintegrant
carboxymethylcellulose colloidal silicon 0.5 glidant dioxide talc 3
glidant, lubricant magnesium stearate 1 lubricant *pravastatin
contains 0.3% of Na.sub.2CO.sub.3, so that the pH of the active
substance is between 9 and 10. The percentage in the above
mentioned formulation is calculated for the tablets containing 40
mg of pravastatin. The amount of pravastatin can be 80, 40, 20, 10
or 5 mg.
Example 5
[0043] The pharmaceutical formulation with the active ingredient
pravastatin sodium in the form of tablets was prepared as in
Example 4. The resulting mixture is compressed into tablets. The pH
of the aqueous dispersion of this formulation is 8.3.
5 Ingredient % by weight function pravastatin sodium* 8.3 active
substance lactose 58.3 filler microcrystalline 16.5 filler
cellulose Na.sub.2HPO.sub.4 (dried) 7.9 buffering agent sodium
lauryl sulphate 0.4 absorption accelerator, surfactant cross-linked
4 disintegrant carboxymethylcellulose colloidal silicon 0.5 glidant
dioxide talc 3 glidant, lubricant magnesium stearate 1 lubricant
*pravastatin contains 0.3% of Na.sub.2CO.sub.3, so that the pH of
the active substance is between 9 and 10. The amount of pravastatin
can be 80, 40, 20, 10 or 5 mg.
Example 6
[0044] The pharmaceutical formulation with the active ingredient
atorvastatin calcium in the form of tablets was prepared as in
Example 4. The resulting mixture is compressed into tablets.
6 Ingredient weight (mg) function Atorvastatin calcium 20.0 active
substance lactose 140.0 filler microcrystalline 34.8 filler
cellulose Na.sub.2HPO.sub.4 (dried) 24.0 buffering agent Na lauryl
sulphate 2.0 absorption accelerator, surfactant cross-linked 9.6
disintegrant carboxymethylcellulose colloidal silicon 1.2 glidant
dioxide talc 7.2 glidant, lubricant magnesium stearate 1.2
lubricant
[0045] In case of higher or lower dosages of atorvastatin calcium
(80, 40, 10 or 5 mg), proportional higher or smaller amounts of
other ingredients are used, or proportional bigger or smaller
tablets are prepared.
[0046] Tablets containing pravastatin or atorvastatin which were
formed according to Examples 1 to 6 were subjected to stability
studies and it was found that the tablets provide an excellent
stability; essentially no degradation products of pravastatin or
atorvastatin were observed.
* * * * *