Note: Descriptions are shown in the official language in which they were submitted.
A 02326603 2000-09-29
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A DRUG COMPOSITION CONTAINING SODIUM PRAVASTATIN
---
BACKGROUND OF THE INVENTION RECD Z 2 AUG ZOOO
Field of the Invention PCT
WIPO
The present invention relates to a drug composition containing sodium
ravastatin and more particularly, to the drug composition containing further
p . . .,_ _ ..~..L.a:..~,
as stabilizer for sodium
of sodium pravastatin which is unstable at
l0
Description of the Related Art
blyperlipidemia is a symptom characterized by high levels of lipids
(cholesterol, neutral lipid, phospholipid, free fatty acid, etc.) in the
plasma, and
is associated with a number of serious disorders, notably arteriosclerosis,
hypertension, ischemic heart disease, pancreatitis, etc.
To reduce the blood lipid levels, various drugs have been developed so
far. As expressed in the following formula, sodium pravastatin among these
drugs is known to be useful in the treatment of hyperlipidemia, since it
serves
to inhibit the activity of hydroxylmethyl glutaryl CoA reductase, which
results
in suppressing the synthesis of cholesterol. Sodium pravastatin generates its
lactones and several isomers at high humidity and temperature.
,.OH
Na00C~'
O HO
Ii ~ H
~C
3HC
CH3 ~ j ,C
HO
For formulating a drug composition containing sodium pravastatin as
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CA 02326603 2000-09-29 PC-1-~ ~ /
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active ingredient, the conventional method has adopted its manufacturing
process using some commonly available excipients such as lactose, silicon
dioxide, cross camellose sodium, micro crystalline cellulose and polyvinyl
pyrrolidone.
For example, the general drug composition contains sodium
pravastatin, lactose, micro crystalline cellulose, polyvinyl pyrrolidone,
cross
camellose sodium and magnesium stearate (VIDA , p. ,
VIDAL, pp.1750-1751(1997), VASTEN 20mg; ROTE LISTE 58 038(199b~
PRAVASTIN 5mg/l0mg/20mg). However, the drug composition consisting of
the above excipient is rapidly degraded at high humidity and temperature.
SUMMARY OF THE INVENTION
To overcome the shortcoming that the conventional method has faced
with, the inventors have completed this invention with a notion that ~i-
cyclodextrin may encloses molecules with a low-molecular weight which may
block any substances at the surrounding environment.
Accordingly, it is an object of this invention to provide a drug
composition comprising sodium pravastatin, excipient, binder, lubricants,
disintegrant and [3-cyclodextrin, whereby enhancing the stability of sodium
pravastatin which is unstable at high humidity and temperature.
Description of the Drawings
Fig. 1a is a graph which shows the stability of drug composition
prepared according to example 1 and comparative example 1 at 40 C .
Fig. 1b is a graph which shows the stability of drug composition
prepared according to example 1 and comparative example 1 at 50 °C .
Fig. 1c is a graph which shows the stability of drug composition
prepared according to example 1 and comparative example 1 at 60 C .
AMEND~C~ SHCET
CA 02326603 2000-09-29
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Fig. 1d is a graph which shows the stability of drug composition
prepared according to example 1 and comparative example 1 at 70 C .
Fig. 2a is a graph which shows the stability of drug composition
prepared according to example 2 and comparative example 2 at 40 C .
Fig. 2b is a graph which shows the stability of drug composition
prepared according to example 2and c
Fig. 2c is a graph which shows the stability of drug com
prepared according to example 2 and comparative example 2 at 60 C .
Fig. 2d is a graph which shows the stability of drug composition
prepared according to example 2 and comparative example 2 at 70 C .
Fig. 3a is a graph which shows the stability of drug composition
prepared according to example 3 and comparative example 3 at 40 C .
Fig. 3b is a graph which shows the stability of drug composition
prepared according to example 3 and comparative example 3 at 50 C .
Fig. 3c is a graph which shows the stability of drug composition
prepared according to example 3 and comparative example 3 at 60 °C .
Fig. 3d is a graph which shows the stability of drug composition
prepared according to example 3 and comparative example 3 at 70 C .
Fig. 4a is a graph which shows the stability of drug composition
prepared according to example 4 and comparative example 4 at 40 C .
Fig. 4b is a graph which shows the stability of drug composition
prepared according to example 4 and comparative example 4 at 50 C .
Fig. 4c is a graph which shows the stability of drug composition
prepared according to example 4 and comparative example 4 at 60 C .
Fig. 4d is a graph which shows the stability of drug composition
prepared according to example 4 and comparative example 4 at 70 C .
Fig. 5a is a graph which shows the stability of drug composition
A~iEPJOLO SHEET
CA 02326603 2000-09-29
PCT/ h:~ a
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prepared according to example 5 and comparative example 5 at 40 C .
Fig. 5b is a graph which shows the stability of drug composition
prepared according to example 5 and comparative example 5 at 50 C .
Fig. 5c is a graph which shows the stability of drug composition
prepared according to example 5 and comparative example 5 at 60 ~ .
Fig. 5d is a graph which shows the stability of drug composition
prepared according to example 5 and comparative exa~mp a 5 at . -
Fig. 6a is a graph which shows the stability o rug composition
prepared according to example 1 and comparative example 1 under accelerated
condition (40 C/75% R.H.).
Fig. 6b is a graph which shows the stability of drug composition
prepared according to example 2 and comparative example 2 under accelerated
condition (40 C/75% R.H.).
Fig. 6c is a graph which shows the stability of drug composition
prepared according to example 3 and comparative example 3 under accelerated
condition (40 C / 75 % R.H.).
Fig. 6d is a graph which shows the stability of drug composition
prepared according to example 4 and comparative example 4 under accelerated
condition (40 C/75% R.H.).
Fig. 6e is a graph which shows the stability of drug composition
prepared according to example 5 and comparative example 5 under accelerated
condition (40 C / 75 % R.H.).
Fig. 7a is a graph which shows the stability of drug composition
prepared in example 1 and A tablet" at 40 C .
Fig. 7b is a graph which shows the stability of drug composition
prepared in example 1 and A tablet" at 50 C .
Fig. 7c is a graph which shows the stability of drug composition
prepared in example 1 and A tablet's at 60 C .
AfVIEPd0E0 SHEET
' CA 02326603 2000-09-29
PCTf
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Fig. 7d is a graph which shows the stability of drug composition
prepared in example 1 and A tablet" at 70 C .
Detailed Description of the Invention
5 This invention is characterized by a drug composition comprising
sodium pravastatin as active ingredient and ~3-cyclodextrin as stabilizer as
well
as excipient, binder, disintegrant and lubricant. -
This invention is explained in detail as set forth:
This invention pertains to the drug composition containing sodium
pravastatin as active ingredient which has better stability in the mechanism
that ~3-cyclodextrin encloses some molecules with a low-molecular weight to
block any substances at the surrounding environment, thus preventing the
rapid degradation of the drug composition at high temperature and humidity.
The drug composition of this invention comprises the following
ingredients: sodium pravastatin as active ingredient; ~3-cyclodextrin as
stabilizer; excipient such as lactose, starch and micro crystalline cellulose;
I
binder such as hydroxypropyl cellulose, micro Gfystalline cellulose, ,~
hydroxypropyl methyl cellulose and dextrin; disin~tegrant such as low-
substituted hydoxypropyl cellulose and cross camellose sodium; and lubricant
such as magnesium stearate, talc and stearic acid.
The amount of sodium pravastatin as active ingredient, is
advantageously in the range of 2 to 50wt% in proportion to the total drug
composition, preferably in the range of 2 to 30wt%, at such levels, the drug
composition serves to inhibit the activity of hydroxylmethyl glutaryl CoA
reductase which results in suppressing the synthesis of cholesterol. If the
amount of sodium pravastatin is less than 2wt%, a drug compliance is reduced
due to increased weight of tablet; however, in case of exceeding 50wt%, a dose
adjustment of each patient becomes difficult.
AI~I~i~OLC~ SHEE'i'
- CA 02326603 2000-09-29 , ,
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Since the sodium pravastatin is apt to form its lactones and several
kinds of isomers at high humidity and temperature, ~i-cyclodextrin is added to
the drug composition of this invention as a stabilizer so as to prevent such
structural transformations. Unlike the conventional method using the common
excipients which leads to the rapid degradation of a drug composition, the
addition of ~i-cyclodextrin as a stabilizer according to this invention
contributes to production of a drug composition with etter sta i ity at ig --
humidity and temperature.
According to this invention, the amount of j3-cyclodextrin is
to advantageously in the range of 50 to 5,000 weight parts in proportion to
100
weight parts of sodium pravastatin, preferably in the range of 100 to 3,000
weight parts. If the amount of ~i-cyclodextrin is less than 50 weight parts,
insufficiently stabilized sodium pravastatin, is degraded at high humidity and
temperature; in case of exceeding 5,000 weight parts, the formulation becomes
difficult.
In addition to sodium pravastatin as active ingredient and
cyclodextrin as stabilizer, the drug composition of this invention contains
some
additives such as excipient, binder, disintegrant and lubricant.
The excipient of this invention is at least one selected from the group
consisting of corn starch, potato starch, wheat starch, lactose, white sugar,
glucose, fructose, D-mannitol, precipitated calcium carbonate, micro
crystalline
cellulose, dextrin and methyl cellulose; it is preferred that the amount of
excipient is in the range of 5-90wt% to the total drug composition.
The binder of this invention is at least one selected from the group
consisting of gelatin, methyl cellulose, micro crystalline cellulose, hydroxy
cellulose, hydroxymethyl cellulose, glycerin, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, dextrin and polyvinyl alcohol; it is preferred
that the amount of binder is in the range of 2.5-35wt% to the total drug
AM~~;DED SHEET
CA 02326603 2000-09-29 /"°tr~ 1 ~ ~~~:~ :~o
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composition.
The disintegrant of this invention is at least one selected from the
group consisting of hydroxypropyl methyl cellulose, hydroxypropyl starch,
polyvinyl pyrrolidone, ethyl cellulose and low-substituted hydoxypropyl
cellulose; it is preferred that the amount of disintegrant is in the range of
0.5-
l0wt% to the total drug composition.
The lubricant of this invention is at Ieast one se ec a rom a grou
consisting of stearic acid, magnesium stearate, to c, iqui para m an ig
anhydrous silic acid; it is preferred that the amount of lubricant is in the
range
of 0.25-5wt% to the total drug composition. Also, some edible dye may be
added to the drug composition depending on the objective of this invention.
The drug composition comprising the aforementioned ingredients is
prepared as follows:
First, sodium pravastadn and j3-cyclodextrin are ground in an
appropriate container for tens of minutes, followed by the addition of one or
more excipients. Then, for the purpose of use, the mixture is under wet
granulation in the presence of a solution containing one or more binders and
solvent (water, isopropanol, dichloromethane, etc.) and dried. As an
alternative
procedure, one or more lubricants and/ or binders are added to the mixture of
sodium pravastatin and j3-cyclodextrin and under drying granulation using a
rolling compactor.
After the procedure is completed, the drug composition of this
invention is prepared with the addition of one or more disintegrants,
lubricants
or binders, if deemed necessary.
As such, the drug composition of this invention prepared as mentioned
above, comprising sodium pravastatin as an active ingredient and
cyclodextrin as stabilizer is mixed with some pharmaceutically acceptable
carriers to formulate a variety of dosage forms (e.g., tablet, capsule,
powder,
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CA 02326603 2000-09-29
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s
granule and pill) in the pharmaceutical field.
The examples of the carriers according to this invention include some
pharmaceutically applicable carrier such as binder, lubricant, disintegrant,
excipient, stabilizer and conspergative agent.
Further, to prevent the degradation of the drug composition by gastric
acid during oral administration, the concurrent use of an antacid and enteric
coated tablet and granule are recommen a . t is recommen~e~a a rug
composition of this invention be orally administered as a esira a route
Compendium of Data Sheets, VIDAL, ROTE LISTE, Physicians' Desk
Reference).
According to this invention, a dose of the active ingredient varies
depending on its absorption rate, inactivation rate and excretion rate, and
other
variations such as age, sex and conditions of patients, severity of disease,
etc.
The regimen of the drug composition is recommended as follows: a) the usual
dose of the drug composition for adult is 10-40mg per day before bedtime
(ABPI Compendium of Data Sheets, pp.1780-1782(1995-1996), LIPOSTAT
TABLETS); b) the usual dose for adult is 10-40mg and in the case of the
elderly
patients, the usual dose is given at the dose of less than 20mg with initial
dose
of 10-20mg once daily (Physicians' Desk Reference, pp.732-735(1995),
PRAVACHOL); c) further, another initial dose is l0mg once per day with a
maximum dose of 40mg in the evening (VIDAL, p.568(1997), ELISOR; pp.1750-
1751(1997) VASTEN); and d) while the initial dose is 5-l0mg once daily with a
maximum dose of 40mg (ROTE LISTE, 58 038(1996), PRAVASIN
5mg/ l0mg/ 20mg).
Based on the cited references, therefore, it is preferred that the drug
composition of this invention is administered at a dose of 5-40mg once daily
in
the evening or before bedtime.
A~~Et~IQED SHOE'!'
CA 02326603 2000-09-29
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As described above, some physical strength is given to the drug
composition comprising sodium pravastatin as active ingredient and
cyclodextrin as stabilizer, so formulated, for enclosing the active
ingredient. As
a result, the drug composition containing j3-cyclodextrin shows excellent
stability at high temperature and humidity (Fig. 1a-7d).
When the drug composition of this invention is compared with
comparative examples and A tablet without -cyc o extrm as~own in~~ig. --
1a-5d and Fig. 7a-7d, it is evident that the drug composition o t s invention
has much better stability on the temperature than that of the conventional
drug
composition. Also, for stability on humidity, the same results were revealed
in
Fig. 6a-6e. Furthermore, the process for preparing the drug composition of
this
invention may utilize the existing machine such as a rolling compactor in mass-
production, thereby improving the aspects of economics such as the additional
cost for production:
The following specific examples are intended to be illustrative of the
invention and should not be construed as limiting the scope of the invention
as
defined by appended claims.
Example 1
Sodium pravastatin 5mg
~3 -cyclodextrin 120.09mg
Hydroxypropyl cellulose 5mg
Low-substituted hydroxypropyl cellulose 13.5mg
Lactose 48.51mg
Magnesium stearate 0.9mg
A mixture of sodium pravastatin and ~i -cyclodextrin was ground in a
reactor for 20 min. With the addition of lactose, the mixture was well mixed
and kneaded with an aqueous solution of a binder (hydroxypropyl cellulose
AM~P~O~L~ SWEET
CA 02326603 2000-09-29
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solution). The wet mass was dried in an oven at 30-40 C and sized with a
sieve of No. 20. With the addition of low-substituted hydroxypropyl cellulose
and magnesium stearate, the mixture was well mixed for its tableting process.
5 Example 2
Sodium pravastatin 5mg
_ _.. ___ _ _ ____.
~i -cyclodextrin . mg --
Hydroxypropyl cellulose mg
Low-substituted hydroxypropyl cellulose 13.5mg
10 Lactose 30.Omg
Corn starch 18.51mg
Magnesium stearate 0.9mg
A mixture of sodium pravastatin and j3 -cyclodextrin was ground in a
reactor for 20 mins. With the addition of lactose and corn starch, the mixture
was well mixed and kneaded with an aqueous solution of a binder
(hydroxypropyl cellulose solution). The wet mass was dried in an oven at 30-
40 C and sized with a sieve of No. 20. With the addition of low-substituted
hydroxypropyl cellulose and magnesium stearate, the mixture was well mixed
for its tableting process.
Example 3
Ssodium pravastatin 5mg
~i -cyclodextrin 127.09mg
Light anhydrous silicic acid 1.75mg
Low-substituted hydroxypropyl cellulose lO.Omg
Lactose 30.Omg
Magnesium stearate l.6mg
A mixture of sodium pravastatin and ~i -cyclodextrin was ground in a
1 ~ A.t~~ND~D SHEET
CA 02326603 2000-09-29
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reactor for 20 mires. With the addition of lactose, light anhydrous silicic
acid
and magnesium stearate (0.8mg), the mixture was well mixed and subjected to
rolling compactor, finally preparing dried granules. With the addition of low-
substituted hydroxypropyl cellulose and magnesium stearate (0.8mg), the
mixture was well mixed for its tableting process.
_ -Example 4 -_. _ _ __ _____ _ _ _. _.
Sodium pravastatin mg
~i -cyclodextrin 127.09mg
Low-substituted hydroxypropyl cellulose lO.Omg
Lactose 20.07mg
Corn starch 28.Omg
Dextrin 7.8mg
Red-dye # 3 0.12mg
Blue-dye #1 aluminium lake 0.12mg
Magnesium stearate l.6mg
A mixture of sodium pravastatin and ~3 -cyclodextrin was ground in a
reactor for 20 mires. With the addition of lactose and corn starch (l4.Omg),
the
mixture was well mixed and kneaded with an aqueous solution of a binder
(dextrin) containing dyes (red-dye # 3 and blue-dye #1 aluminium lake),
followed by drying in oven at 30-40 C . With the addition of remaining corn
starch (l4.Omg), low-substituted hydroxypropyl cellulose and magnesium
stearate, the mixture was well mixed for its tableting process.
Example 5
Sodium pravastatin 5mg
~i -cyclodextrin 127.09mg
Lactose 30.31mg
AMENDED SHEET
CA 02326603 2000-09-29
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Potato starch 30.Omg
Polyvinyl alcohol 7.8mg
Magnesium stearate l.6mg
A mixture of sodium pravastatin and ~3 -cyclodextrin was ground in a
reactor for 20 rains. With the addition of lactose and potato starch, the
mixture
was well mixed and kneaded with an aqueous solution of a-binder (polyvinyl
alcohol), followed by drying in oven at 30-40 C . Wit t a a ition o
magnesium stearate, the mixture was well mixed for its tableting process.
Comparative example 1
Sodium pravastatin 5mg
Hydroxypropyl cellulose 127.09mg
Low-substituted hydroxypropyl cellulose lO.Omg
Lactose 175.6mg
Magnesium stearate 0.9mg
A mixture of sodium pravastatin and lactose was well mixed and
kneaded with an aqueous solution of a binder (hydroxypropyl cellulose),
followed by drying in oven at 30-40 C . Then, the dried preparation was sized
with a sieve of No. 20. With the addition of low-substituted hydroxypropyl
cellulose and magnesium stearate, the mixture was well mixed for its tableting
process.
Comparative example 2
Sodium pravastatin 5mg
Hydroxypropyl cellulose 5mg
Low-substituted hydroxypropyl cellulose 13.5mg
Lactose 157.09mg
AMENDED SHEET
CA 02326603 2000-09-29
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Cornstarch 18.51mg
Magnesium stearate 0.9mg
A mixture of sodium pravastatin, lactose and corn starch was well
mixed and kneaded with an aqueous solution of a binder (hydroxypropyl
cellulose), followed by drying in oven at 30-40 C . Then, the dried
preparation
was sized with a sieve of No. 20. With the additior<- of low-substituted
hydroxypropyl cellulose and magnesium stearate, t a crux re was we mix
for its tableting process.
Comparative example 3
Sodium pravastatin 5mg
Light anhydrous silicic acid 1.75mg
Low-substituted hydroxypropyl cellulose lO.Omg
Lactose 181.65mg
Magnesium stearate l.6mg
With the addition of sodium pravastatin, light anhydrous silicic acid
and magnesium stearate (0.8mg), the mixture was well mixed and subjected to
rolling compactor, finally preparing dried granules. With the addition of low-
substituted hydroxypropyl cellulose and magnesium stearate (0.8mg), the
mixture was well mixed for its tableting process.
Comparative example 4
Sodium pravastatin 5mg
Low-substituted hydroxypropyl cellulose lO.Omg
Lactose 120.27mg
Corn starch 55.09mg
Dextrin 7.8mg
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CA 02326603 2000-09-29
14
Red-dye#3 0.12mg
Blue-dye #1 aluminium lake 0.12mg
Magnesium stearate l.6mg
With the addition of sodium pravastatin, lactose and corn starch (half
of the content), the mixture was well mixed and kneaded with an aqueous
solution of a binder (dextrin) containing dyes (red-dye -# 3--and-blue-dye #1
aluminium lake), followed by drying in oven at 30-4 " . Wit t a a Won o
remaining corn starch, low-substituted hydroxypropyl cellulose and
magnesium stearate, the mixture was well mixed for its tableting process.
Comparative example 5
Sodium pravastatin 5mg
Lactose 130.31mg
Potato starch 57.09mg
Polyvinyl alcohol 5.7mg
Magnesium stearate l.9mg
With the addition of sodium pravastatin, lactose and potato starch, the
mixture was well mixed and kneaded with an aqueous solution of a binder
(polyvinyl alcohol), followed by drying in oven at 30-40 C . With the addition
of
magnesium stearate, the mixture was well mixed for its tableting process.
Test 1
In order to confirm the effect of this invention, final preparations were
tested under rigorous temperature condition (40, 50, 60 and 70 C ) with regard
to an alteration of content and degraded products by using the following
machine, and the results are shown in Table 1a-1e and Fig.1a-5d:
1) High performance liquid chromatography (HPLC): Waters 510
~~ y ~i :fir ~s-~;~~
CA 02326603 2000-09-29
g-y .:
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Detector: ultraviolet absorption spectrophotometer (238nm)
Column: Cosmosil Cis
Mobile phase: methanol ~ H20 ~ TEA ~ acetic acid glacial
(500:500:1:1)
Flow rate: l.5ml/min
Infection amount: 5 ~ - _ _ _ _
2) Autosampler: Waters 717
3) Integrator: Waters 740
4) Detector: Waters 486
5) Oven
SY-IN.G (SUN YOUNG Co., Korea), if treated at 40 C
VO-C-2 (Space Science Co., Korea), if treated at 50 C and 60 C
NDO-600-ND (EYELA Co., Korea), if treated at 70 C
6) Life tester : JEIO TECH. Co. Ltd., TH-10
Table 1a
After After After After
Category Initial 7 15 23 29
days days days days
40 100 99.8 99.3 98.9 98.0
~
Exam.1
50 100 97.9 97.8 96.4 95.6
C
(remaining,
60 100 99.5 97.8 91.3 90.0
C
%)*
70 100 97.4 89.8 84.1 80.1
C
Comp. 40 100 99.1 97.9 95.4 93.1
C
Exam.1 50 100 93.7 92.0 91.9 89.0
C
(remaining,60 100 93.3 92.3 86.5 83.2
C
%)* 70 100 91.5 78.8 67.5 64.8
C
* The remaining amount of sodium pravastatin in the tablet
CA 02326603 2000-09-29
PCTi ~'
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16
Table 1b
After After After After
Category Initial 7 15 23 29
days days days days
40 C 100 99.7 99.0 98.7 98.6
Exam. 2
50 C 100 98.9 97.5 96.0 95.3
(remaining,
60 C 100 98.8 97.3 92.0 89.9
%)*
70 C 100 97.0 88.5 83.9 79.2
Comp. 40 C 100 99.0 97.5 95.2 94.0
Exam. 2 50 ~ 100 92.8 91.5 91.0 89.2
(remaining,60 C 100 91.2 90.6 88.5 82.5
%)* 70 C 100 90.9 80.3 72.0 63.9
* The remaining amount of sodium pravastatin in the tablet
Table 1c
After After After After
Category Initial 7 15 23 29
days days days days
40 C 100 99.9 99.5 99.0 98.6
Exam. 3
50 C 100 98.2 97.8 97.0 96.0
(remaining,
60 C 100 98.2 97.0 93.5 90.2
%)*
70 ~ 100 96.2 89.6 82.0 75.3
Comp. 40 C 100 99.2 98.1 96.7 95.5
Exam. 3 50 C 100 93.5 92.9 92.1 90.8
(remaining,60 C 100 91.3 90.2 89.3 80.5
%)* 70C 100 89.6 79.6 70.3 65.0
* The remaining amount of sodium pravastatin in the tablet
CA 02326603 2000-09-29
m
Table 1d
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After After After After
Category Initial 7 15 23 29
days days days days
40 C 100 99.2 98.8 96.5 96.0
Exam. 4
50 C 100 98.6 97.7 95.8 95.2
(remaining,
60 C 100 98.0 96.8 92.6 88.8
%)*
70 C 100 96.0 88.2 80.2 79.6
Comp. 40 C 100 99.0 98.0 95.0 94.5
Exam. 4 50 C 100 92.3 91.5 90.2 89.6
(remaining,60 C 100 90.6 89.9 86.0 80.0
%)* 70 ~ 100 88.5 80.3 68.8 60.2
* The remaining amount of sodium pravastatin in the tablet
Table 1e
After After After After
Category Initial 7 15 23 29
days days days days
40 C 100 99.7 99.0 99.0 98.5
Exam. 5
50 C 100 98.9 97.0 97.2 95.2
(remaining,
60 C 100 98.5 97.5 93.3 89.9
%)*
70 C 100 96.5 88.8 83.2 80.2
Comp. 40 C 100 99.0 98.0 96.8 94.5
Exam. 5 50 ~ 100 94.0 93.2 92.8 90.0
(remaining,60 C 100 93.0 92.6 89.2 80.0
%)* 70 C 100 90.5 80.9 75.5 70.0
* The remaining amount of sodium pravastatin in the tablet
~~~~~!~'~ ~ SHEET
CA 02326603 2000-09-29
,g ~ 5. ~~;~L'~ ~~~9
Test 2
In order to confirm the effect of this invention, final preparations were
tested under accelerated condition (40 C/75%R.H.) with regard to an alteration
of content and decomposed products, and the results are shown in Table 2 and
Fig.6a-6e:
Table 2
After After ter
1 2
Cate gory Initial
month months months
Exam.l 100 97.5 93.1 90.0
Exam.2 100 97.8 92.9 90.3
Exam.3 100 98.0 92.5 89.1
Exam.4 100 95.0 90.1 87.1
Exam.5 100 96.6 93.5 89.0
Com.
100 92.0 89.5 84.4
Exam.1
Remaining
Com.
( % ) 100 92.5 88.5 83.1
Exam. 2
Com.
100 93.1 88.0 82.3
Exam. 3
Com.
100 94.0 86.9 80.0
Exam. 4
Com.
100 91.3 89.3 83.0
Exam. 5
* The remaining amount of sodium pravastatin in the tablet
Test 3
In order to confirm the effect of this invention, final preparation
fTli~~ti~~~'t ei1 V~~~.~.
' CA 02326603 2000-09-29
' ~~:~A ~~ k~ ~,~~ ~ Q E
t a, M ~: t,w .".,.
25.
~r~ ~ ~~~m~ i~99
19
(prepared in example 1) and A tablet ~ (commercial product, Korea) were
tested under rigorous temperature condition (40, 50, 60 and 70 C ) with regard
to an alteration of content of an active ingredient and decomposed products,
and the results are shown in Table 3 and Fig. 7a-7d:
Table 3
After After After After
7 15 23 29
r Initial
days days ays ays
40 100 99.8 99.3 98.9 98.0
C
Exam.1
50 100 97.9 97.8 96.4 95.6
~
(remaining,
60 100 99.5 97.8 91.3 90.0
C
o~o)*
70 100 97.4 89.8 84.1 80.1
C
40 100 99.4 99.0 98.6 97.5
C
A Tablet
50 100 98.0 96.9 93.6 90.1
~
(remaining,
60 100 98.5 95.1 89.2 87.5
C
oho )*
70 100 89.1 84.3 76.8 65.9
C
* The remaining amount of sodium pravastatin in the tablet
As discussed above, the pharmaceutical composition of this invention,
comprising sodium pravastatin as active ingredient and j3 -cyclodextrin as
stabilizer, has excellent stability at high humidity and temperature so that
it
prohibits the sodium pravastatin from decomposing rapidly, and may employ
the existing machine in mass production, thereby improving the aspects of
economics such as the additional cost for production. '
