Note: Descriptions are shown in the official language in which they were submitted.
CA 02202520 1997-04-11
DESCRIPTION
Lyophilized Pharmaceutical Preparations Capable of Providing
Aqueous Drug Composition Having Property of Reversible
Thermosetting Gelation
Technical Field
The present invention relates to a lyophilized
pharmaceutical preparation which can provide an aqueous drug
composition-having-property of reversible-thermosetting gelation
when reconstituted with a-solvent for r-econstitution. The
aqueous drug composition having property of reversible
thermosetting gelation reconstituted from the lyophilized
pharmaceutical preparation is characterized in that the aqueous
drug composition is a fluid liquid at room'temparature or lower
and, when administered to eyes or body cavities or spteaded on
skin, gelation happens-at body temperature-of mammal, so as to
achieve-a- greater degree-of bioavailability of the
pharmacologically effective component and maintain the effect
20 of the,drugs for long period. -
Background Art
- The pharmaceutical preparation having property of
reversible thermosetting gelation which causes a sol-gel-
25 transition at the drug-administered-site exhibits various
advantages such as improvement in the drug delivery and-
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CA 02202520 1999-09-02
patient's compliance as compared with the conventional
pharmaceutical preparations.
Hitherto, there have been proposed several aqueous drug
compositions which are liquid at room temperature or lower and
form a semi-solid or gel at body temperature of mammal, as
aqueous drug compositions which effectively release a
pharmacologically effective component to mammal to be treated.
U.S. Patent No. 4,188,373 discloses an aqueous composition
having property of thermosetting gelation, which comprises
PLURONIC (trademark) and form gel by application of heat, and a
desired sol-gel transition temperature thereof is obtained by
controlling the concentration of PLURONIC. Moreover, U.S.
Patents Nos. 4,474,751, 4,474,752, 4,474,753 and 4,478,822
disclose drug delivery systems utilizing aqueous drug
compositions having property of thermosetting gelation.
The inventors of this invention already provided a drug
composition having property of reversible thermosetting gelation
for treating eyes, body cavities and skin which comprises an
effective amount of a drug used for pharmacological therapy or
diagnosis, methylcellulose, citric acid and polyethylene glycol
and Whose pH ranges from 3 to 10, wherein the composition is a
highly fluid liquid prior to administration or application and
undergoes gelation immediately after administration or
application thereof due to the temperature of the site to which
the composition is administered or spreaded (Canadian Patent
Application No. 2,153,234).
However, it is difficult to store the foregoing
aqueous
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CA 02202520 1997-04-11
composition over a long time period, since in case where an drug
unstable to water is applied to the composition, the drug
undergo decomposition, although the composition exhibits
satisfactory effects such as enhancement of the bioavailability
of the drug and the long acting drug efficacy.
Accordingly, an object of the present invention is to
provide anaqueous-drug composition having property of
reversible thermosetting gelation which can-be applied to drugs
unstable to water, as well.
'IO
Disclosure of Invention ~.
The present inventors have diligently conducted many
researches in order to develop an aqueous drug composition
which can be applied to drugs unstable to water as well and, as
a -result, have found out that a drug can be formed into a
pharmaceutical preparation by incorporating, into the drug,
appropriate amounts of-methylcellulose, citric acid and
polyethylene glycol and then lyophilizing the resulting mixture,
even if the drug is unstable to water and thus have completed
the present invention.
That is, the present invention provides a lyophilized
pharmaceutical preparation which is prepared by-lyophilizing an
aqueous composition having pYoperty of reversible thermosetting
gelation comprising an effective amount of a drug used for
pharmacological therapy or surgical operations,-0.2 to 2.1
(W/V)~ of methylcellulose (the content of methoxyl group is
_3_
CA 02202520 1997-04-11
within the range of 26 to 33$), 1.2 to 2.3 (W/V)B of citric acid
and 0.5 to 13 (W/V)8 of-polyethylene glycol (PEG) (wherein
(W/V)$ means weight/volume
One of the excellent advantageous features of the
lyophilized pharmaceutical preparation according to the present
invention is that it can stably storean unstable drug till the
drug is practically used-and that it can immediately
reconstitute an aqueous composition having property of
reversible thermosetting gelation by adding a proper amount of a
solvent forreconstitution when it is used for treatment. The
aqueous composition thus reconstituted is a highly fluid liquid -,
prior to the administration--or-application; causes gelation
immedia~ely after the administration or application-due to body -
temperature of the site to which the composition is
administered or-applied to thus ensure an increase in the
bioavailability of the effective component and a--long acting
drug efficacy. -
Any methylcellulose products can be used,alone or as a
mixture thereof as the methylcellulose (content of methoxyl
group: 26-33~) component used in the lyophilized pharmaceutical
preparation of -the present invention, so long as they have a
viscosity of 2~ aqueous solution within the-range of 13 to
- 12,000 millipascal--~ sec at 20 °C . The content of methoxyl
group is preferably within the range_of,from 26 to 33~ in view
of the solubility in water. Such methylcellulose-products are
sold by Shin-Etsu Chemical Co., Ltd. as METOLOSE TM SM 15, SM
_q_
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25, SM 100, SM 400, SM 1500, SM 4000, SM 8000 (each numerical
value represents the viscosity of 2g aqueous solution as
determined at 20 °C and expressed in terms of millipascal~
sec), and by Matsumoto Oil and Fat Pharmaceutical Industry Inc.
-as MARPOLOSET~" M, and by Dow chemical Co.--as-METOCEL7"~ A, and
all commodities can be easily available.
PEG's used in the lyophilized pharmaceutical preparation
of the present-invention are sold by Wako Junyaku Industry Inc.
as PEG-200, PEG-300, PEG-600, PEG-1000, PEG-1540, PEG-2,000,
PEG-4,000, PEG-6,000, PEG-20,000, PEG-50,000, PEG-500,000, PEG-
2,000,000 and PEG-4,000,000, and by NipponOil and Fats Co.,
Ltd. as MACROGOL-200, MACROGOL-300, MACROGOL-400, MACROGOL-600,
MACROGOL-1,500, MACROGOL-1,540, MACROGOL-4,000, MACROGOL-6,000
and MACROGOL-20,000.
The weight-average molecular weight of PEG used in the
present invention is preferably 1000 to 50,000. This is because
if the weight-average molecular weight-is less than,1000, the
resulting composition tends to be hard to form gel at a local
region, while if. it-is more than 50,000, the viscosity thereof
in the liquid state is too high. Two or more kinds of PEG can be -
mixed to adjust the weight-average molecular weight thereof so
as to fall within the above optimum range.
- The concentration of the methylcellulose used in the
present invention is within the range-of 0.2 to- 2..1 (W/V)$.
This is because if the concentration of methylcellulose is less
than 0.2 (W/V)~, the resulting composition becomes hard to form
CA 02202520 1997-04-11
gel at a local region and, while if it is more than 2.1 (W/V)~,
the composition shows unduly high viscosity in the sol state
which makes the dosage thereof incorrect.
The concentration of the citric acid is within the range
of 1.2 to 2.3 (W/V)$. This is because if the concentration of
citric acid is less than 1.2 (W/V)~, the resulting composition
becomes hard to-form gel at a local region, while the use
thereof in an amount of more than 2:3 (W/V)$ is not preferred in
view of the stimulus on the composition-administered site.
The concentration of PEG is within the range of 0.5 to 13
(W/V)~. This is because if the concentration of PEG is less than
0.5 (W/V)~, the resulting composition becomes hard to form gel
at a local region and hence loses practical value, while if the
concentration is more than 13 (W/V)$, the composition shows high
viscosity in the-sol state. -
The lyophilized pharmaceutical preparation of the present
invention may be used for treating diseases -of, for example,
eyes, skin and body cavities. Examples-of medicines which can
be incorporated into the lyophilized pharmaceutical preparation
of the present.invention and administered to eyes of mammal, are
as follows: antiviral agents such as adenosine arabinoside and
interferons; antifungal agents such as Amphotericin B and
- Nystatin; antibacterial substances. such as Sodium Carbenicillin,
Potassium Penicillin G, Sodium Cefazolin, Tetracycline
Hydrochloride, Polymyxin B, Vancomycin-Hydrochloride; Amikacin
Sulfate and Erythromycin Lactobionate; antiallergic agents such
CA 02202520 1999-11-09
as ASPIRIN;anti-inflammatory agents such as Indomethacin;
miotics such as Acetylcholine Chloride and Physostigmine
Salicylate; vitamins such as Cocarboxylase and Cobamamide;
antiglaucoma drugs such as Dipivefrine; anticataract drugs such
as Glutathione and Pirenoxine; carbonic anhydrase inhibitors
such as Acetazolamide; immunosuppressive agents such as
Methotrexate and Cyclophosphamide; amino acids such as
cysteine; adjuvants for surgery such as hyaluronidase and a
Chymotrypsin; and anti-proliferative agents for fibroblast such
1 p as Mitomycin C; .
Examples of medicines which can be incorporated into the
lyophilized pr~armaceutical preparation of the present invention
and applied to sites or skin of mammal, are as follows:
antifungal agents such as Nystatin; antibacterial substances
such as Tetracycline Hydrochloride, Polymyxin B, Amikacin
Sulfate and~Erythromycin Lactobionate; and anti-inflammatory
agents such as ASP IRIN and Indomethacin.
Examples of drugs which can be incorporated into the
lyophilized pharmaceutical preparation of the present invention
and administered to body cavities of mammal, that is, rectum,
urethra, nasal cavity, vagina, auditory meatus, oral cavity and
buccal pouch, are as follows: antiviral agents such as
interferons; antifungal agents such as Nystatin; antibacterial
substances such as Tetracycline Hydrochloride, Amikacin Sulfate
and Erythromycin; antipyretics such as Aspirin; analgesics such
as ASPIRIN and Indomethacin; anti-inflammatory agents such as
* Trademark
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Indomethacin; and antineoplastics such as Doxorubicin and
Asparaginase.
The content of the effective drug in the lyophilized
pharmaceutical preparation may vary depending on the kinds of
the drugs selected, but it- is generally-preferred that the
composition- reconstituted from the lyophilized preparation
contains the effective drug-in an amount ranging from about
0.001 to 5~ by weight based on the composition.
Examples of pH-adjusting agents-used in the present-
invention include acids such as hydrochloric acid, sulfuric
acid,-boric acid, phosphoric acid and acetic acid and bases such
as sodium hydroxide ; monoethanolamine, diethanolamine and
triethanolamine.
In the invention, water. is generally used as the solvent
fot reconstitution of the pharmaceutical preparation, but- it
may, if necessary; comprise pharmaceutically acceptable
additives such as buffering agents, preserva~ ives and
solubilizing agents. Examples of such preservatives may include
invert soaps such as benzalkonium chloride and chlorhexidine
2D - gluconate, parabens such as methylparaben, ethylparaben,
propylparaben and butylparaben, alcohols-such as chlorobutanol,
phenylethyl alcohol and benzyl alcohol and organic acids such as
dehydroacetic acid, sorbic acid 'and salts thereof. Moreover,
surfactants or chelating agents may, ifnecessary; be added to
the reconstitution solvent: Generally, these components may be
used within the range of about 0.001 to_2~ by weight,- and
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preferably within the range of about 0.002 to 1$ by weight.
Examples of such buffering agents include alkaline metal salts
of acids such as phosphoric acid, boric acid, acetic acid,
tartaric acid, lactic acid and carbonic acid, amino acids such
as glutamic acid,E -aminocaproic acid,.aspartic acid, glycine,
arginine and lysine, taurine and trisaminomethane. These
buffering agents may be added to the reconstitution solvent in
an amount required foz maintaining the pH of the solvent within
the range of 3 to 10. Examples of such solubilizing agents
include POZYSORBATE 80 and polyoxyethylene hydrogenated castor -
oil and they may-be used in an amount ranging from -0 to 5~ by
weight. -
According to the present invention, a desired lyophilized
pharmaceutical preparation can be obtained by preparing an
aqueous composition comprising an-effective amount of a drug;
0.2 to 2.1 (W/V)B of methylcellulose, 1.2 ~ 0 2..3 (W/V)~ of
citric acid, 0.5 to 13 (W/V)~ of polyethylene-glycol and a-pH
adjusting agent in an amount required for controlling the pH of
the composition to 3 to 10; and then lyophilizing the aqueous
composition by the method_currently used. The method for
preparing the lyophilized pharmaceutical-preparation of the
present invention is not restricted-to specific ones and, for
example, comprises dissolving a citrate and PEG in sterilized
and purified water, ad-justing the pH of the resulting solution
with a pH adjusting agent; adding, if necessary; a variety of
additives such as a buffering agent and a preservative, adding a
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solution of methylcellulose in sterilized and-purified water
and then ice-cooling the solution. Then a drug is added to the
solution, followed by again adjusting the pH thereof, filling
up the volume of the mixture with sterilized and-purified water
and dissolving the mixture while stirring it with ice-cooling.
Thereafter, the resulting solution-is divided intb equal volume
portions and dispensed into proper containers and then
lyophilized-in a freeze -dryer according to the usual_ method
which comprises, for instance, freezing the dispensed solution
at about -40°C. to about -6D °C and sublimating the ice under a
reduced pressure of not more than 0.3 mmHg to thus give a
lyophilized pharmaceutical preparation. In this respect, if the -
drug used is hardly soluble or insoluble in water, it is
lyophilized after--suspending it in water or solubilized therein
using,a solubilizing agent.-
In themethod for-preparing the lyophilized pharmaceutical
preparation of the present invention including the foregoing
lyophilization step, methylcellulose, citric acid and
polyethylene glycol_as main,components do not undergo any
substantial change (decomposition or deterioration) and
accordingly;-thelyophilized pharmaceutical preparation of the
present invention comprises methylcellulose in an amount
- ranging from about 1 to about 50~ by wei-ght, preferably 1.5 to
34~ by weight; citric acid or-a salt thereof in an amount
ranging from abouf 5 to about 60$-by weight, preferably 7.2 to
38~ by weight (expressed in terms of the reduced amount of
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CA 02202520 1997-04-11
citric acid); polyethylene glycol in an amount ranging from
about 3to about 88~ by weight, preferably 7.0 to 82~ by
weight; and a drug in an amount of about-0.004 to about 70~ by
weight (in a case where the aqueous composition prior to the
lyophilization comprises the drug in an amount ranging from
0.001 to 5$ by weight).
The composition reconstituted from the lyophilized
pharmaceutical preparation of the present invention must be in
a liquid state at-room temperature-or lower and must undergo
gellation at body temperature of mammal. Therefore, the gelling
temperature thereof preferably ranges from about 20°C to about
40°C . However, the reconstituted aqueous composition has a
gelling temperature ranging from about 20°C to about 40°C so
far as the concentrations of methylcellulose, citric acid and
Polyethylene glycol in the aqueous composition prior to the
lyophilization fall within the rangesdefined above,
respectively.
When using the lyophilized pharmaceutical preparation of
the present invention; it isdissolved in water or a solvent
for reconstitution in an amount approximately identical to that
of the water evaporated during the lyophilization to thus
reconstitute an aqueous drug composition having property of
reversible thermosetting gelation which is ready for practical
use. The method for reconstituting the preparation is not
-restricted to specific ones and comprises, for=instance, adding
sterilized and purified water or, if necessary, a solvent for
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CA 02202520 1999-09-02
reconstitution containing a variety of additives to the
preparation and then ice-cooling to dissolve the same.
Best Mode for Carrying Out the Invention
The following examples are provided to illustrate a
variety of embodiments of the present invention and are not
intended to limit the scope of the present invention. In Table 1
given below, there are listed the compositions of thelaqueous
drug compositions having property of reversible thermosetting
gelation used in the following Examples in which the
lyophilized pharmaceutical preparations of the present invention
are prepared and the gelling temperatures thereof, the
conditions for reconstitution of the preparations, the gelling
temperatures of the reconstituted compositions, or the like.
~5
Example 1
There were dissolved, in 50 ml of sterile purified water,
2.3g of citric acid and 2.Og of : MACROGOL 4000
(weight-average molecular weight: 3000; available from Nippon
Oil and Fats Co., Ltd.) and then the pH of the resulting
solution was adjusted to 7.0 with a 3N sodium hydroxide
solution. A solution of 0.7g of METOLOSE*SM 400 (available from
Shin-Etsu Chemical Co., Ltd.) and 0.7g of METOLOSE SM 15
(available from Shin-Etsu Chemical Co., Ltd.) in 25 ml of
sterile purified water was added to the solution and the
mixture was sufficiently stirred with ice-cooling. Then, the pH
* Trade-mark
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CA 02202520 1999-09-02
thereof was adjusted to 8.0 with a 3N sodium hydroxide solution,
0.04g of Mitomycin C was then added to the solution, the volume
of the solution was filled up to 100m1 with sterile purified
water and the components were dissolved by sufficiently stirring
with ice-cooling. The resulting solution was dispensed intc
vials (1 ml each), frozen at -50 °C in a freeze dryer and
lyophilized at a reduced pressure of 0.2 to 0.02 mmHg to give
an eye drop.
The foregoing eye drop was reconstituted by adding 1 ml of
sterile purified water thereto and ice-cooling to dissolve it
therein.
Example 2
In 50 ml of sterile purified water, there were dissolved
3.5g of trisodium citrate dehydrate and 2.Og of MACROGOL
4000. A solution of 0.7g of METOLOSE SM 400 and 0.7g of
METOLOSE SM 15 in 25 ml of sterile purified water was added to
the solution and the mixture was sufficiently stirred with ice-
cooling. Then,l.Og of Amphotericin B was added to the mixture,
the pH thereof was adjusted to 8.0 with a 1N hydrochloric acid
solution or a 1N sodium hydroxide solution, the volume of the
mixture was filled up to 100m1 with sterile purified water and
the components were dissolved by sufficiently stirring with
ice-cooling. The resulting solution was dispensed into vials (1
ml each), frozen at -50°C in a freeze dryer and lyophilized at
a reduced pressure of 0.2 to 0.02 mmHg to give an eye drop.
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CA 02202520 1997-04-11
The foregoing eye drop was reconstituted by adding 1 ml of
sterile purified water thereto and then ice-cooling.
Examples 3-5
By a method similar-to that described in Example 2,
solutions each having a composition shown in Table 1 were
prepared and then-lyophilized to give eye-drops. The eye drops
each was reconstituted by the method similar to that used in
Example 2. -
Example 6
By a method similar to that described in Example 2, a
solution having a composition-shown in Table 1 was prepared and
then lyophilized to give an eye drop. The eye-drop thus obtained
was reconstituted by adding 1 ml of sterile purified-water -
containing 0.17W/V~ of boric acid, 0.-11W/V$ of borax and 0.2W/V~
of polyoxyethylene hydrogenated castor oil 60 and then ice-
cooling.
20 Example 7 - _
By a method similar to that described in Example 2,
solutions each having a composition shown--in Table 1 were
- prepared and then lyophilized to give an-eye -drop. The eye-drop
thus obtained was reconstituted by the method similar to that
25 used in Example 2.- _
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Example B
By a method similar to that described in Example 2, a
solution having a composition shown in Table 1 was prepared and
then lyophilized to give an eye-drop. The eye-drop thus prepared
was- reconstituted by adding 1- ml of sterile purified water
containing 0.005W/V~ of benzalkonium chloride and ice-cooling to
dissolve it therein.
Example 9-
BY a method similar to that described-in Example 2, a
solution having a composition shown in Table 1 was prepared and
then lyophilized to give an eye drop. The-eye-drop thus prepared
was reconstituted by adding 1 ml of sterile purified water-
containing O.D26W/V~ of methylparaben and 0.014W/V~ of
ProPYlparaben and ice-cooling to dissolve it in the water-.
Examples 10-16
By a method similar to-that described-in Example 2,
solutions each having a composition shown in_Table 1 were
prepared and then lyophilized to give eye-drops. The-eye drops
each was reconstituted by a method similaz to that used in
Example 2.
Example 17-20
By a method similar to,that described in Example 1,
solutions each having a composition shown in Table 1 were
_l5_
CA 02202520 1997-04-11
prepared and then lyophilized to give eye drops. The eye drops
each was reconstituted by a method similar to that used in
Example 1.
Examples 21 -.
By a method similar to that described in Example 2, a
solution having a composition-shown in Table 1 was prepared and
then lyophilized to give an agent for--dermal use. The agent was
reconstituted by a method similar to that used in Example 2.
Examples 22- -
By a method similar to that describe-d in Example 2, a
solution having a composition.shown in Table 1 was prepared and
then lyophilized-to give an agent for body cavitical use. The
~5 agent was reconstituted by a method similar o that used in
Example 2.
..~_L: , _ ~..
Samples of the lyophilized pharmaceutical preparations
20 prepared-_in Examples 1, 3, 4, 6, 8, 9, 21 and 22 and the
corresponding aqueous compositions prior to the lyophilization
as comparative samples each was stored at 40 °C for one month.
- Then the amounts of each drug present -in the corresponding
1-yophilized phazmaceutical preparation and the aqueous
25 composition were determined by the high performance liquid
chromatography (HPLC) technique-immediately after the
-16-
CA 02202520 1999-09-02
preparation thereof and after the completion of the storage
test to determine the rate of residual drug. The results are
summarized in the following Table 2. The results clearly
indicate that the lyophilized pharmaceutical preparations were
substantially improved in the stability of the drugs
incorporated therein as compared with that of the drugs present
in the compositions prior to the lyophilization.
The quantitative analysis of each drug by the HPLC
technique was performed under the following conditions. Column:
CHEMCOSORB*(5-ODS; available from Chemco Company) of 4 mm
(inner diameter) X 150 mm (length), mobile phase: a mixed
liquid comprising 1/300M phosphate buffer (pH 7.0)/methanol =
8/3, flow rate: 0.9 ml/min, detection: UV 254 nm, and the amount
of the sample injected: 20 a 1 for the quantitative analysis of
Mitomycin C; column: ~-BONDAPAK* C18 (available from Waters
Company) of 3.9 mm (inner diameter)X 300 mm (length), mobile
phase: a mixed liquid comprising 0.005M acetate buffer (pH 4.5)
/methanol = 4/1, flow rate: 1.0 ml/min, detection: UV 220 nm,
and the amount of the sample injected: 10 a 1 for the
quantitative analysis of Sodium Carbenicillin; column: a -
BONDAPAK C18 (available from Waters Company) of 3.9 mm (inner
diameter)X 300 mm (length), mobile phase: a mixed liquid
comprising 0.007M phosphoric acid/methanol = 7/3, flow rate:
1.3 ml/min, detection: UV 254 nm, and the amount of the sample
injected: 10 a 1 for the quantitative analysis of Cefazolin
Sosium; column:LICHROSPHER* 100RP-18 (available from E. Merck
* Trade-mark
- 1 7 -
CA 02202520 1999-09-02
Company) of 4 mm (inner diameter)X 250 mm (length), mobile
phase: a mixed liquid comprising methanol/1$ acetic acid = 3/1,
flow rate: 1.0 ml/min, detection: UV 265 nm, and the amount of
the sample injected: 10 a 1 for the quantitative analysis of
Indometacin; column: ASAHIPACK*GS-320 (available from Asahi
Chemical Industry Co., Ltd.) of 7.6 mm (inner diameter)X 500
mm (length), mobile phase: 0.04M EDTA~3Na (pH 8.0), flow rate:
1.0 ml/min, detection: post-labeling with o-phthalaldehyde
(excitation. wavelength 350 nm, fluorescent wavelength 420 nm),
and the amount of the sample injected: 5,~ 1 for the quantitative
analysis of Glutathion; column:LICHROSORB* RP-18 (available
from E. Merck Company) of 4 mm (inner diameter)X 150 mm
(length), mobile phase: a mixture of a solution of 1.39g of
tetra-n-butyl ammonium chloride and 4.5g of disodium hydrogen
phosphate in 1000m1 of water (pH was controlled to 6.5 with
phosphoric acid)/acetonitrile/tetrahydrofuran = 70/20/3, flow
rate: 1.0 ml/min, detection: UV 230 nm, and the amount of the
sample injected: 10 ,~ 1 for the quantitative analysis of
Pirenoxine; LICHROSORB Rp-g (available from E. Merck Company)
of 4.6 mm (inner diameter) X 250 mm (length), mobile phase: a
mixture of O.1M ammonium oxalate/dimethylformamide/0.2M ammonium
phosphate = 68/27/5 (pH was controlled to 7.6 to 7.7 with 3N
phosphoric acid or 3N ammonium hydroxide), flow rate: 2.0
ml/min, detection: UV 280 nm, and the amount of the sample
injected: 10 a 1 for the quantitative analysis of Tetracycline
hydrochloride; and LICHROSORB RP-8 (available from E. Merck
* Trade-mark
- 1 8 -
CA 02202520 1999-11-09
Company) of 4.6 mm (inner diameter) X 250 mm (length), mobile
phase: a mixed liquid of methanol/water/acetic acid = 43/36/1,
flow rate: 1.6 ml/min, detection: UV 285 nm, and the amount of
the sample injected: l0u 1 for the quantitative analysis of
ASPIRIDI.
Effects of the Invention
According to the present invention, an aqueous drug
composition having property of reversible thermosetting gelation
comprising a drug unstable to Water is lyophilized to prevent
any decomposition of the drug unstable to water and to thus
provide a lyophilized pharmaceutical preparation stable over a
long time period. Aqueous drug compositions having property of
reversible thermosetting gelation for use in treatments of
eyes, body cavities and skin can easily and quickly be
reconstituted from the lyophilized pharmaceutical preparation
through addition of an appropriate amount of a solvent for
reconstitution. The reconstituted aqueous composition is a
highly fluid liquid prior to the administration or application,
causes gelat:ion immediately after the administration or
application to thus ensure an increase in the bioavailability
of the effective component and a long acting drug efficacy.
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CA 02202520 1997-04-11
Table 1
Ex. No. Composition Prior Lyophilization W/VB Gelling Temp.~~
to
1- Mitomycin 0.04 32C
METOLOSE SM400 0,7
METOLOSE SM15 p,7
Citric Acid - - 2.3 --
PEG 4000 2.0
3N NaOH - to pH 8. 0
water ad. lODml
2 Amphotericin B- 1.0 34C
METOLOSE SM400 0
METOLOSE SM15 p
Citric Acid 3Na2H,0 3,5
PEG 4000 2.0
1N HC1 or 1N NaOH - to pH 8 . D-
water ad. 100m1 -
3 Sodium Carbenicillin1.0 34C
METOLOSE SM400 0
METOLOSE SM15 D
Citric Acid 3Na2H,0 3,5
PEG 4000 2,p
1N HC1 or 1N NaOH to pH 8.0
water -- ad. 100m1
4 Sodium Cefazolin 0.5 34C
METOLOSE SM400 0,
- METOLOSE SM15 0,~ -
Citric -Acid 3Na 3=5
2H, 0
PEG 4000 2,0
1N HC1 or 1N NaOH to pH 6.5
water -- ad. 100m1
_ 2 0 -
CA 02202520 1997-04-11
Table 1 (continued)
Ex. No. Composition Prior to Lyophilization -W/V9- Gelling Temp.'s
Nystatin (4400 U/mg) 0.1 34C
METOLOSE SM400 0.7
METOLOSE SM15 0.7
Citxic Acid 3Na 2H, O - 3. 5
PEG 4000 2.0
1N HC1 or 1N NaOH to pH 8.0
water _ . ad. 100m1
6 Indometacin 0~5 32C
METOLOSE SM400 0.7
METOLOSE SM15 0.7
Citric Acid 3Na2H,0 3.5
PEG 4000 2.0
1N HC1 or 1N NaOH to pH 8.0
water ad. 100m1
7 Acefylcholine Chloride 1.0 36C
METOLOSE SM400 -- 0.7
METOLOSE SM15 0.7
Citric Acid-3Na2H,0 3:5
PEG 4000 2.0
1N HC1 or 1N NaOH tb pH 6.0
water ad. 100m1
8 Glutathion 2.0- 36C -
METOLOSE SM400 0.7
METOLOSE SM15 0.7
Citric Acid 3Na2H,0 3.5
PEG 4000 2.0
1N HC1 or 1N NaOH to pH 7.0
water _ _ _._ - 100m1
ad.
CA 02202520 1997-04-11
Table 1 (cont.)
Ex. No. Composition Prior to Lyophilization W/V~ Gelling Temp.'s
9 Pirenoxine 0.005 34C
METOLOSE SM400 D.7
METOLOSE SM15 0.7
Citric Acid 3Na2H,0 3.5 -
PEG 4000 - - 2.D
1N HC1 orlN NaOH to pH 6.5
Water ad. 100m1
Cyclophosphamide 1:0 36C
METOLOSE SM400 0.7
METOLOSE SM15 0.7
Citric Acid 3Na2H,0 3.5
PEG 4000 2.0
1N HC1 or-1N NaOH to pH 6.0 -
water ad. - 100m1
11 Dipivef=ine - - 0.05 36C
METOLOSE SM400 - - 0.7
METOLOSE SM15 0.7 -
Citric Acid 3Na2H,0 3.5
PEG 4000 2.0
1N HC1 or 1N NaOH to pH 5.0
water . ad. 100m1
12 Mitomycin C 0.004- 32C
METOLOSE SM15 2.1
Citriclicid 3Na 2H, 0 _ 3. 5
PEG 20000 1.0
1N HC1 or 1N NaOH to pH 7.4
water - ad. 100m1
-22-
CA 02202520 1997-04-11
Table 1 (cont.)
Ex. No. Composition Prior to Lyophilization W/V9 - Gelling Temp.~~
13 Mitomycin C 0.004 36C
METOLOSE SM8000 0.2
Citric Acid 3Na2H,O 3.5
PEG 6000 _ 10
1N HC1 or 1N NaOH to pH 8.5
water _ ad. 100m1
14 Mitomycin C 0.004 36C
METOLOSE SM400 0.5
Citric Acid 3Na2H,0 3:5
PEG 1000 9.0
1N HC1 or 1N NaOH to pH 7.0
water. _ ad. 100m1
15 Mitomycin C 0.004 36C
METOLOSE SM8000 0.4
Citric Acid 3Na2H,0 2.9
PEG-4000 13
1N HCl or 1N NaOH to pH 8.0
water- ad. 100m1
16 Mitomy~in C 0.004 22C
METOLOSE-SM1500 - 2.1 -
Citric Acid 3Na2H,0 _- 1.8
PEG 4000 13-
1N HC1 or- 1N NaOH to pH-8.0
water -- ad. 100m1
-23-
CA 02202520 1997-04-11
Table 1 (cont.)
Ex. No. Composition Prior to Lyophilization W/V$ Gelling Temp.s~
17 Mitomycin C 0.004 36C
METOLOSE SM15 -- 2.1
Citric Acid 2.3
PEG 50000 0.5
Monoethanolamine to pA
6.2
water ad. 100m1
18 Mitomycin C. 0.004 34C
METOLOSE SM15 2.1
Citric Acid 1.2
PEG 4000 - 6.0
Triethanolamine to pes
5.0
water ad. 100m1
19 Mitomycin C 0.004 36C
METOLOSE SM400 0.5-
Citric Acid 2.3
PEG 4000 6.0
Diethanolamine to pH
6.0
water _ __ . ad. 100m1
20 Mitomycin C 0:004 36C
METOLOSE SM400 0.5
Citric Acid 2.3
PEG 4000 6.0
1N KOH to pH7.5
water_ - ad. 100m1
_ 2 q _
CA 02202520 1999-11-09
Table 1 (cont.)
Ex. No. Composition Prior to Lyophilization
W/V% Gelling Temp.l~
21 Tetracycline hydrochloride 0.5 36C
MET'OLOSE SM 4 0 0 0 , 7
METOLOSE SM15 0.7
Citric Acid 3Na 2H, 0 3 . 5
PEG. 4000 6.0
1N HCl or 1N NaOH to pH 3.0
water ad. 100m1
22 ASF~IRIN 1.0 36C
METOLOSE SM400 0,7
METOLOSE SM15 ~ 0.7
Citric Acid 3Na 2H, 0 3 .5
PEG 4000 2.0
1N HC1 or 1N NaOH to pH 6.0
water ad. 100m1
1): The gelling temperature prior lyophilization.
to the
-2 5-
CA 02202520 1997-04-11
Table
1 (continued)
Ex. 8mount Injec-wt. Solvent for Amount Gelling
(g)
ted Prior of Lyo- of the Temp. of
to
Lyophiliza- philized Recon. Reconstitu-
No. tion (ml) ProductReconstitution Liq.(ml)ted prod.
1 1.0 0.0655 water -- 1.0 32C
2 1.0 0.0747 water - 1.0 34C
3 1.0 0.0748 water 1.0 34C
4 1.0 0.0700 water 1.0 34C
1.0 0:0660 water - 1.0 34C
6 I.0 0.0699 Aq. soln. containing 32C
0.17 1.0
boric acid, 0.11 borax,
D.2~ polyoxyethylene
-
hydrogenated castor 60
oil
7 1.0 0.0754 water _ 1.0 36C
8 1.0 0.0847 0.005 aq. soln. of 1.0 36C
ben-
zalkonium chloride -
9 1.0 0.0648 aq, soln. containing 1.0 34C
0.026 of me~hylparaben,
0.014 of propylparaben
1.0 0-:0752water 1.0 36C
11 1.0 0.0658 water 1.0 36C
12 1.0 0.0618 water . 1.0 32C
13 1.0 0.1333 - - water -. 0.9 36C
14 1.0 0.1265 water 0.9 36C
1.0 0.1597 water 0.9 36C
16 1:0 0.1678 water 0.9 22C
17 1.0 0.0711 water-. - 1.0 36C
-
18 - 1.0 0.1219 -- water _ .. ._ 1.0 34C
~
- 19 1.0 0.1263 water - 1.0 36C
1.0 0.1017 wader .. 1.0 36C
21 1. 0 0 .1109water 1. 0 3 6C
22 1.0 0.0765 water 1.D 36C
-26-
CA 02202520 1997-04-11
Table 2
Ex. Rate ($) of-Residual Drug in Rate ($) of Residual Drug in
Lyophilized Product After Composition Prior to
Storing at 40 °C for 1 Month Lyophilization at
No. 40°C for 1 Month
1 77.8 19.3
3 82.4 1.8
4 94.2 1.9
6 89.0 15.2
g 96.6 0.0
9 -- 94.5 -- 4.6
218.2 0.0
22 - =.90.4-0,D
_2q_
