U.S. patent application number 13/877037 was filed with the patent office on 2013-08-22 for meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide.
This patent application is currently assigned to Toyama Chemical Co., Ltd.. The applicant listed for this patent is Namika Nakamatsu, Takayoshi Nakashima, Keiko Takakura, Sakiko Takeshima. Invention is credited to Namika Nakamatsu, Takayoshi Nakashima, Keiko Takakura, Sakiko Takeshima.
Application Number | 20130217708 13/877037 |
Document ID | / |
Family ID | 45893135 |
Filed Date | 2013-08-22 |
United States Patent
Application |
20130217708 |
Kind Code |
A1 |
Takakura; Keiko ; et
al. |
August 22, 2013 |
MEGLUMINE SALT OF 6-FLUORO-3-HYDROXY-2-PYRAZINE CARBOXAMIDE
Abstract
A preparation replete with a meglumine salt of
6-fluoro-3-hydroxy-2-pyrazine carboxamide has superior solubility,
and is useful as a preparation for injection.
Inventors: |
Takakura; Keiko; (Toyama,
JP) ; Nakamatsu; Namika; (Toyama, JP) ;
Takeshima; Sakiko; (Toyama, JP) ; Nakashima;
Takayoshi; (Toyama, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Takakura; Keiko
Nakamatsu; Namika
Takeshima; Sakiko
Nakashima; Takayoshi |
Toyama
Toyama
Toyama
Toyama |
|
JP
JP
JP
JP |
|
|
Assignee: |
Toyama Chemical Co., Ltd.
Shinjuku-ku, TOKYO
JP
|
Family ID: |
45893135 |
Appl. No.: |
13/877037 |
Filed: |
September 29, 2011 |
PCT Filed: |
September 29, 2011 |
PCT NO: |
PCT/JP2011/072329 |
371 Date: |
May 9, 2013 |
Current U.S.
Class: |
514/255.06 ;
544/406 |
Current CPC
Class: |
A61K 47/18 20130101;
A61P 31/16 20180101; C07C 215/10 20130101; A61K 9/19 20130101; A61P
31/12 20180101; A61K 47/183 20130101; A61K 31/4965 20130101; A61P
31/00 20180101; C07D 241/24 20130101; A61K 47/22 20130101; A61K
9/0019 20130101; A61K 47/26 20130101; A61K 31/497 20130101; A61K
9/08 20130101 |
Class at
Publication: |
514/255.06 ;
544/406 |
International
Class: |
C07D 241/24 20060101
C07D241/24 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 30, 2010 |
JP |
2010-221620 |
Claims
1: A meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or
a hydrate thereof.
2: The meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
or the hydrate thereof of claim 1, in a crystal form.
3: The meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
or the hydrate thereof of claim 1, in an amorphous form.
4: An injectable preparation comprising the meglumine salt of
6-fluoro-3-hydroxy-2-pyrazinecarboxamide or the hydrate thereof of
claim 1.
5: The injectable preparation of claim 4, wherein the meglumine
salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or the hydrate
thereof is in a crystal form.
6: The injectable preparation of claim 4, wherein the meglumine
salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or the hydrate
thereof is in an amorphous form.
7: The injectable preparation of claim 4, further comprising an
amino acid and a saccharide, or an amino acid and a sugar
alcohol.
8: A lyophilized preparation comprising a meglumine salt of
6-fluoro-3-hydroxy-2-pyrazinecarboxamide.
9: The lyophilized preparation of claim 8, wherein the meglumine
salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is in a crystal
form.
10: The lyophilized preparation of claim 8, wherein the meglumine
salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is in an amorphous
form.
11: The lyophilized preparation of claim 8, further comprising an
amino acid and a saccharide, or an amino acid and a sugar
alcohol.
12: A process for producing a lyophilized preparation comprising a
crystal of a meglumine salt of
6-fluoro-3-hydroxy-2-pyrazinecarboxamide, the process comprising:
(1) cooling an aqueous solution comprising
6-fluoro-3-hydroxy-2-pyrazinecarboxamide and meglumine to produce a
frozen product; (2) increasing the temperature of the frozen
product; (3) cooling the frozen product again; and (4) carrying out
lyophilization.
13: The process according to claim 12, wherein in (2) the
temperature of the frozen product is increased to a temperature
within the range of -20 of -5.degree. C.
14: The meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
or the hydrate thereof of claim 1, which is the salt.
15: The meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
or the hydrate thereof of claim 1, which is the hydrate.
16: The meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
or the hydrate thereof of claim 2, which is the salt.
17: The meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
or the hydrate thereof of claim 2, which is the hydrate.
18: The meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
or the hydrate thereof of claim 3, which is the salt.
19: The meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
or the hydrate thereof of claim 3, which is the hydrate.
20: The injectable preparation of claim 5, further comprising an
amino acid and a saccharide, or an amino acid and a sugar alcohol.
Description
TECHNICAL FIELD
[0001] The present invention relates to a meglumine salt of
6-fluoro-3-hydroxy-2-pyrazinecarboxamide (hereinafter referred to
as "Compound A"), an injectable preparation containing the same and
a process thereof
BACKGROUND ART
[0002] These days, worldwide pandemic has been caused by H1N1
influenza virus and occurrence of pandemic by a further virulent
virus in the future is a concern.
[0003] At present, as therapeutic agents for influenza, e.g.,
Oseltamivir, Zanamivir, Peramivir, Laninamivir and Amantadine are
used. However, these therapeutic agents have, for example, the
following drawbacks. Oseltamivir cannot be administered to patients
having difficulty in oral administration. It is difficult to
administer Zanamivir to children and aged persons. It takes a long
time to administer Peramivir. Amantadine is ineffective against
Type B influenza virus and resistant viruses have emerged.
Laninamivir is an inhalation drug, which is not suitable to
patients with dementia and a severe disease and it is difficult to
administer it to children.
[0004] A further superior therapeutic agent for influenza has been
desired. Particularly, an injection that can be administered to
patients having difficulty in oral administration, children and
aged persons has been desired.
[0005] Meanwhile, many reports have been published on methods for
improving solubility of medicinal compounds in water. For example,
a method for improving the solubility in water by changing the
state of a water-insoluble medicinal compound into an amorphous
state is known. In general, an amorphous state of a compound
exhibits more superior solubility in water than a crystalline state
thereof (PATENT DOCUMENT 1).
[0006] Compound A or a salt thereof has a superior antiviral
activity and is useful as a therapeutic agent for viral infection
(PATENT DOCUMENT 2). However, Compound A has low solubility in
water and thus an injection of Compound A or a salt thereof has not
been known yet.
[0007] The present inventors prepared an aqueous solution of a
sodium salt of Compound A by using sodium hydroxide generally used
as a base, and then produced a lyophilized preparation in
accordance with a common method, for improving the water solubility
of Compound A. The sodium salt of Compound A obtained by this
process was an amorphous dry powder, thus quick dissolution thereof
in water was expected. However, contrary to the expectation, the
obtained lyophilized preparation was a lyophilized cake having poor
solubility and required a long time to dissolve. To describe more
specifically, when a solvent was added to the lyophilized
preparation, the lyophilized cake changed into a poorly soluble
mass substance that took a long time to dissolve. The amorphous
lyophilized preparation of a sodium salt of Compound A was a
preparation needing a long time to dissolve, and was difficult to
handle with significant loss of convenience in use.
[0008] Meanwhile, as a method for preparing a lyophilized
preparation, a process having an annealing step provided therein is
known. However, the effect of the annealing step on the solubility
of a lyophilized preparation differs depending on substances.
Therefore, studies have been made in a trial-and-error manner
(NON-PATENT DOCUMENT 1).
PRIOR ARTS REFERENCES
Patent Documents
[0009] PATENT DOCUMENT 1: JP 3413406 [0010] PATENT DOCUMENT 2:
International Publication No. WO 00/10569 pamphlet [0011]
NON-PATENT DOCUMENT 1: Development of medicinal drug, Vol. 11, page
393, 2000
DISCLOSURE OF THE INVENTION
Problem to be Solved by the Invention
[0012] There is a need for the development of an injectable
preparation of Compound A or a salt thereof with superior
solubility.
Means for Solving the Problems
[0013] The present inventors have intensively conducted studies
with the view to attaining the above desire. As a result, they have
found that [0014] (1) a meglumine salt of Compound A (hereinafter
referred to as "Salt A") can also be present in an amorphous or
crystalline state, [0015] (2) the solubility of Salt A in water is
high, [0016] (3) the dissolution rate of amorphous Salt A in water,
the dissolution rate of a crystal of Salt A in water, and the
dissolution rate of a milled crystal of Salt A in water are
significantly high, and [0017] (4) a preparation containing
amorphous Salt A, a crystal of Salt A and/or a milled crystal of
Salt A is superior in solubility.
[0018] More specifically, amorphous Salt A can be produced by
lyophilizing an aqueous solution of Salt A. Amorphous Salt A has
high solubility and significantly high dissolution rate in water.
Thus, a preparation containing amorphous Salt A is superior in
solubility and useful as an injectable preparation.
[0019] A crystal of Salt A can be produced by precipitating a
crystal from a solution of Salt A. The crystal has high solubility
and significantly high dissolution rate in water. Thus, a
preparation containing a crystal of Salt A is superior in
solubility and useful as an injectable preparation.
[0020] Furthermore, a milled crystal of Salt A has high solubility
and significantly high dissolution rate in water. Thus, a
preparation containing a milled crystal of Salt A is superior in
solubility and useful as an injectable preparation.
[0021] A powder filling method is known as a technique for filling
a vial, etc. with a powder. However, in a powder filling method, it
is difficult to accurately control the filler content and
contamination with minute foreign bodies occurs easily, when
compared to a method that divides a solution into small portions.
For these reasons, as a process for producing a solid injection, a
process by lyophilization is the most reliable process.
[0022] As a result of intensive studies, the present inventors have
found that a lyophilized preparation of a crystal of Salt A having
significantly high dissolution rate can be produced in a short
crystallization time by controlling the temperature
(crystallization temperature) range in a temperature-increasing
step after primary freezing in lyophilization. More specifically, a
crystal of Salt A can be produced by providing a step of increasing
temperature after the primary freezing of lyophilization. The
resultant crystal has high solubility in water and significantly
high dissolution rate, even though it is not milled. Therefore, the
preparation containing the crystal is superior in solubility and
useful as an injectable preparation.
[0023] As a result of intensive studies conducted repeatedly, the
present inventors have found that a further superior lyophilized
preparation can be produced by adding additives to an aqueous
solution of Salt A to be subjected to lyophilization. In such a
manner, the present invention has been accomplished.
[0024] Meanwhile, it is known that a crystalline state changes to
an amorphous state when water is removed from the crystal of a
hydrate (Yu L., Advanced Drug Delivery Reviews, Vol. 48, page 29,
2001).
[0025] However, the crystal of Salt A of the present invention does
not change to an amorphous state even if a dehydration operation is
applied during lyophilization. In addition, a lyophilized
preparation of Salt A of the present invention has more superior
solubility and much higher stability, compared to the amorphous
lyophilized preparation of a sodium salt of Compound A.
[0026] A superior lyophilized preparation of a crystal of Salt A
can be produced according to the process of the present invention.
The lyophilized preparation can be easily maintained in aseptic
conditions and from which insoluble foreign bodies can be easily
removed. Therefore, the lyophilized preparation is an injection
superior in usability.
[0027] More specifically, the present invention is as follows:
[0028] 1. Salt A or a hydrate thereof Salt A or a hydrate thereof
has high solubility in water and significantly high dissolution
rate. [0029] 2. A crystal of a Salt A or a hydrate thereof. The
crystal has high solubility in water and significantly high
dissolution rate. [0030] 3. Amorphous Salt A. The amorphous Salt A
has high solubility in water and significantly high dissolution
rate. [0031] 4. An injectable preparation containing Salt A or a
hydrate thereof. The injectable preparation is superior in
solubility. [0032] 5. An injectable preparation containing a
crystal of Salt A or a hydrate thereof. The injectable preparation
is superior in solubility. [0033] 6. An injectable preparation
containing an amorphous Salt A or a hydrate thereof. The injectable
preparation is superior in solubility. [0034] 7. The injectable
preparation according to 4 or 5 above, further containing an amino
acid and a saccharide, or an amino acid and a sugar alcohol. The
injectable preparation is superior in solubility. [0035] 8. A
lyophilized preparation containing Salt A. The lyophilized
preparation is superior in solubility. [0036] 9. A lyophilized
preparation containing a crystal of Salt A. The lyophilized
preparation is superior in solubility. [0037] 10. A lyophilized
preparation containing amorphous Salt A. The lyophilized
preparation is superior in solubility. [0038] 11. The lyophilized
preparation according to 8 or 9 above, further containing an amino
acid and a saccharide, or an amino acid and a sugar alcohol. The
lyophilized preparation is superior in solubility. [0039] 12. A
process for producing a lyophilized preparation containing a
crystal of Salt A, including the following steps: (1) cooling an
aqueous solution containing Compound A and meglumine to produce a
frozen product; (2) increasing the temperature of the frozen
product; (3) further cooling the frozen product; and (4) carrying
out lyophilization. The process can produce a lyophilized
preparation of a crystal of Salt A, which has significantly high
dissolution rate, in a short crystallization time. [0040] 13. The
process according to 12 above, wherein the achieving temperature of
the frozen product falls within the range of -20 of -5.degree. C.
in the step of increasing the temperature of the frozen product. By
setting the temperature of the frozen product so as to fall within
the range of -20 to -5.degree. C., a further superior lyophilized
preparation of a crystal of Salt A can be produced.
Advantages of the Invention
[0041] Salt A of the present invention is superior in solubility in
water and useful as a drug substance of an injectable
preparation.
[0042] Furthermore, a preparation containing Salt A of the present
invention is useful as an injectable preparation which is superior
in solubility and stability and even satisfactory in
appearance.
[0043] Moreover, the process for producing Salt A of the present
invention is useful as a process for producing a lyophilized
preparation of a crystal of Salt A which is superior in solubility
and stability and even satisfactory in appearance.
MODE FOR CARRYING OUT THE INVENTION
[0044] Hereinafter, the present invention will be described in
detail.
[0045] Compound A can be produced by a method described, for
example, in PATENT DOCUMENT 2. Compound A has a tautomer:
6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide. This tautomer is
included in the present invention.
[0046] Salt A of the present invention and an injectable
preparation containing Salt A can be produced, for example,
according to the following processes.
Process 1: Crystal of Salt A Monohydrate
[0047] A crystal of Salt A monohydrate can be produced by adding
Compound A and meglumine to water, heating the mixture to dissolve,
adding 2-propanol and collecting a precipitated crystal by
filtration.
[0048] The amount of water is satisfactorily 1 to 10 times (v/w),
and preferably 2 to 4 times (v/w) as large as that of Compound
A.
[0049] The amount of meglumine is satisfactorily 1.0 time (mole) or
above, and preferably 1.0 to 1.5 times (mole) as large as that of
Compound A.
[0050] The temperature of the reaction with meglumine is
satisfactorily 30 to 100.degree. C. and preferably 40 to 80.degree.
C.
[0051] The amount of 2-propanol is satisfactorily 5 to 50 times
(v/w), and preferably 10 to 15 times (v/w) as large as that of
Compound A.
[0052] An injectable preparation can be produced by filling a vial,
etc. with the crystal of Salt A monohydrate and/or the milled
crystal of Salt A monohydrate thus obtained.
Process 2: Crystal of Salt A anhydrate
[0053] A crystal of Salt A anhydrate can be produced by allowing a
crystal of Salt A monohydrate to stand still at -20 to 60.degree.
C. under reduced pressure.
[0054] The standstill time is satisfactorily 0.5 to 120 hours and
preferably 1 to 72 hours.
[0055] The degree of pressure reduction is not particularly
limited; however it is satisfactorily 100 Pa or below and
preferably 50 Pa or below.
[0056] Alternatively, a crystal of Salt A anhydrate can be produced
by allowing a crystal of Salt A monohydrate to stand still under
heating.
[0057] The heating temperature is satisfactorily 30.degree. C. or
above, preferably 50.degree. C. to 110.degree. C. and more
preferably 50.degree. C. to 90.degree. C.
[0058] An injectable preparation can be produced by filling a vial,
etc. with the crystal of Salt A anhydrate and/or the milled crystal
of Salt A anhydrate thus obtained.
[0059] Alternatively, an injectable preparation of a Salt A
anhydrate can be produced by grinding the crystal of Salt A
monohydrate and then drying it in the same manner as mentioned
above.
Process 3: Amorphous Salt A (Lyophilization)
[0060] Amorphous Salt A can be produced by lyophilizing an aqueous
solution of Compound A and meglumine.
[0061] The amount of water is satisfactorily 10 to 100 times (v/w),
and preferably 10 to 50 times (v/w) as large as that of Compound
A.
[0062] Meglumine is added such that the pH of the aqueous solution
becomes satisfactorily 4.0 to 10 and preferably 7.0 to 9.0.
[0063] Lyophilization may be performed, for example, by freezing an
aqueous solution of Compound A and meglumine at -40.degree. C. or
below and maintaining the temperature of the resultant product at a
collapse temperature or below.
Process 4: Crystal of Salt A (Lyophilization)
(1) First Step (Primary Freezing Step)
[0064] An aqueous solution of Compound A and meglumine can be
frozen to obtain an amorphous frozen product.
[0065] The amount of water is satisfactorily 10 to 100 times (v/w),
and preferably 10 to 50 times (v/w) as large as that of Compound
A.
[0066] Meglumine is added such that the pH of the aqueous solution
becomes 4.0 to 10 and preferably 7.0 to 9.0.
[0067] The temperature of the primary freezing step is
satisfactorily a collapse temperature or below. In the case of the
present invention, the temperature of -60 of -40.degree. C. is
preferable.
[0068] The period of time for the primary freezing step is
satisfactorily 1 to 10 hours and preferably 2 to 5 hours.
(2) Second Step (Annealing Step)
[0069] The temperature of the amorphous frozen product is increased
and the frozen product is maintained for a preset time (annealing)
to allow crystallization to proceed to obtain a crystalline frozen
product.
[0070] The temperature, at which thawing of the frozen product dose
not occur and crystallization proceeds to the extent that the
frozen product maintains a frozen state, may be satisfactory in the
annealing step; preferably -20 of -2.degree. C., more preferably
-20 of -5.degree. C., and further preferably -15 of -5.degree.
C.
[0071] The period of time for maintaining the annealing step is
satisfactorily 0.5 to 48 hours and preferably 1 to 24 hours.
(3) Third Step (Secondary Freezing Step)
[0072] Subsequently, the crystalline frozen product is cooled
again.
[0073] The temperature of the secondary freezing step is preferably
-60 of -30.degree. C.
[0074] The period of time for the secondary freezing step is
satisfactorily 1 to 10 hours and preferably 2 to 5 hours.
(4) Fourth Step (Lyophilization Step)
[0075] Subsequently, pressure reduction treatment can be performed
to produce a lyophilized preparation.
[0076] This step can be performed in accordance with a
lyophilization method usually used, for example, in two steps,
i.e., a primary drying step and a secondary drying step.
[0077] The primary drying step is carried out under reduced
pressure while product temperature is maintained at the eutectic
point or below; however, since the temperature drops as the
moisture sublimates from the frozen product, the preset temperature
of an apparatus may be the eutectic point or above.
[0078] The product temperature of the frozen product is
satisfactorily -40 of -3.degree. C. and preferably -30 of
-5.degree. C.
[0079] The preset temperature of an apparatus is satisfactorily -20
to 60.degree. C. and preferably -10 to 50.degree. C.
[0080] The degree of pressure reduction in the primary drying step
is not particularly limited; however it is satisfactorily 100 Pa or
below and preferably 50 Pa or below.
[0081] As the amount of sublimating moisture decreases, the rate of
temperature decrease becomes slower. As a result, the product
temperature increases and becomes almost equal to the preset
temperature. Usually, at this time point, the primary drying step
is determined to have completed.
[0082] Subsequently, the secondary drying step is carried out.
[0083] The secondary drying step is carried out at room temperature
or above and preferably 30 to 60.degree. C.
[0084] In the secondary drying step, the degree of pressure
reduction is preferably enhanced in order to accelerate removal of
water. The degree of pressure reduction is satisfactorily 0.5 to 10
Pa and preferably 1 to 5 Pa.
[0085] The secondary drying step may be satisfactorily carried out
up until the point where the product temperature becomes almost
equal to the preset temperature and a product temperature virtually
does not change.
[0086] The powder X-ray diffraction pattern of a crystal of Salt A
produced by the process was the same as the powder X-ray
diffraction pattern of a crystal of Salt A anhydrate produced in
process 2. More specifically, a lyophilized preparation of a
crystal of Salt A anhydrate can be produced by the use of the
process.
[0087] In the process for producing the lyophilized preparation of
the present invention, a sterilization treatment or the like may be
carried out in accordance with the procedure usually employed.
[0088] In the process of the present invention, since no organic
solvents are used, the lyophilized preparation has no residual
solvent.
[0089] The lyophilized preparation of the present invention is not
harmful to a human body.
[0090] Unless otherwise, powder X-ray diffraction measurement
conditions are as follows.
[0091] Powder X-ray diffraction measurement conditions:
[0092] X-rays to be used: CuK.alpha.
[0093] Applied voltage: 40 kV
[0094] Supplied current: 40 mA
[0095] Scanning axis: 2.theta.
[0096] Scanning range: 2.theta.=2 to 40.degree.
[0097] The characteristic peaks of powder X-ray diffraction
sometimes varies depending on measurement conditions. Generally,
2.theta. has a margin of error of .+-.0.2.degree.. Accordingly,
"the diffraction angle of X.degree. represented by 2.theta." refers
to "a diffraction angle of ((X-0.2) to (X+0.2)).degree. represented
by 2.theta.".
[0098] The Salt A of the present invention includes a crystal of a
monohydrate, a crystal of an anhydrate and amorphous anhydrate.
Furthermore, various shapes of crystals are included in the
crystal.
[0099] Additives can be added to the lyophilized preparation
containing Salt A of the present invention for improving solubility
and/or appearance.
[0100] The temperature range of the annealing step can be extended
by adding additives.
[0101] Examples of the additives include amino acids, saccharides,
sugar alcohols, salts, urea, ethyl urea, creatinine, nicotinic acid
amide and trometamol. These may be used alone or as a mixture of
two or more types. Examples of preferable additives include amino
acids, saccharides, sugar alcohols, salts, urea, creatinine,
nicotinic acid amide and trometamol.
[0102] Examples of the amino acids include glycine, L-alanine,
L-phenylalanine, L-leucine, L-isoleucine, taurine, DL-methionine,
L-threonine, L-glutamine, sodium L-glutamate, acetyltryptophan and
L-histidine. Glycine, L-alanine, taurine and L-histidine are more
preferable and glycine and L-alanine are further preferable.
[0103] Examples of the saccharides include trehalose, maltose,
glucose, lactose, purified white sugar, fructose, dextran and
cyclodextrin. Trehalose, maltose, glucose, lactose and purified
white sugar are more preferable and trehalose and purified white
sugar are further preferable.
[0104] Examples of the sugar alcohols include D-sorbitol, xylitol,
inositol and D-mannitol.
[0105] Examples of the salts include sodium acetate, sodium
lactate, sodium L-tartrate, sodium citrate, sodium salicylate,
sodium benzoate and sodium caprylate. Sodium acetate, sodium
lactate and sodium benzoate are more preferable.
[0106] Furthermore, a combination use of an amino acid and a
saccharide, or an amino acid and a sugar alcohol is preferable and
a combination use of an amino acid and a saccharide is more
preferable.
[0107] Preferable examples of the amino acids include glycine and
L-alanine.
[0108] Preferable examples of the saccharide include trehalose and
purified white sugar.
[0109] Preferable examples of the sugar alcohol include D-sorbitol,
xylitol and D-mannitol.
[0110] Furthermore, if necessary, conventional additives, such as
an osmo-regulator, a pH regulator, a buffer, a solubilizer, a
stabilizer, a surfactant, a soothing agent, and/or a preservative,
may be added to the preparation of the present invention.
[0111] Examples of the osmo-regulator include sodium chloride,
glycerin and propylene glycol.
[0112] Examples of the pH regulator and/or the buffer include acids
such as hydrochloric acid, phosphoric acid, sulfuric acid,
methanesulfonic acid, acetic acid, lactic acid, maleic acid, citric
acid, tartaric acid, ascorbic acid and benzoic acid; salts such as
sodium bicarbonate, sodium carbonate, sodium dihydrogenphosphate,
potassium dihydrogenphosphate, disodium hydrogenphosphate,
dipotassium hydrogenphosphate, trisodium phosphate, disodium
citrate and sodium sulfite; and bases such as sodium hydroxide,
trometamol, monoethanolamine, diethanolamine, triethanolamine,
L-arginine and L-lysine.
[0113] Examples of the solubilizer include Macrogol and purified
soybean lecithin.
[0114] Examples of the stabilizer include sodium hydrogen sulfite,
sodium pyrosulfite, potassium pyrosulfite, sodium pyrophosphate,
sodium thiosulfate, sodium metasulfobenzoate, sodium formaldehyde
sulfoxylate, ethylene diamine, edetate sodium, thioglycolic acid,
sodium gluconate, potassium L-glutamate, L-lysine-L-glutamate,
sodium chondroitin sulfate, albumin, L-aspartic acid, L-cysteine
and dibutylhydroxytoluene.
[0115] Examples of the surfactant include, sorbitan fatty acid
ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene
sorbitan monolaurate, polyoxyethylene polyoxypropylene glycol and
polysorbate.
[0116] Examples of the soothing agent include lidocaine, procaine,
meprylcaine and benzyl alcohol.
[0117] Examples of the preservative include cresol, phenol, methyl
paraoxybenzoate, ethyl paraoxybenzoate, benzalkonium chloride and
benzethonium chloride.
[0118] In an injectable preparation of the present invention, the
dose of an active ingredient is appropriately determined in
accordance with dosage form, age and gender of a patient,
conditions of a disease and other conditions; however, usually 0.1
to 100 mg/kg per adult per day may be administered.
[0119] In an injectable preparation of the present invention, the
content of Compound A is 10 to 6000 mg and preferably 100 to 2000
mg.
[0120] In an injectable preparation of the present invention, the
content of the additives to be added for improving solubility
and/or appearance is 0.1 to 115% (w/w) and preferably 5 to 65%
(w/w) relative to the content of Compound A.
EXAMPLES
[0121] Hereinafter, the present invention will be described by
showing Examples and Experimental Examples; however, the present
invention is not limited to these examples.
[0122] DMSO-d.sub.6 refers to heavy dimethylsulfoxide.
[0123] The water content was measured by the Karl Fischer
method.
Example 1
[0124] A suspension of Compound A (10.0 g) and meglumine (15.0 g)
in water (30 mL) was heated to 50.degree. C. for dissolution. After
2-propanol (120 mL) was added dropwise at 40.degree. C., the
mixture was cooled to 5.degree. C. and stirred at the same
temperature for one hour. A solid substance was collected by
filtration to obtain a light-yellow crystal of Salt A monohydrate
(21.3 g).
[0125] Water content: 5.2%
[0126] .sup.1H-NMR (400MHz, DMSO-d.sub.6) .delta. (ppm): 10.43 (1H,
brs), 7.93 (1H, d, J=9.0 Hz), 7.27 (1H, brs), 3.90-3.80 (1H, m),
3.70-3.55 (2H, m), 3.55-3.35 (3H, m), 3.05-2.85 (2H, m), 2.54 (3H,
s)
[0127] The result of powder X-ray diffraction of the crystal of
Salt A monohydrate is shown in FIG. 1 and Table 1.
TABLE-US-00001 TABLE 1 2.theta. d Relative intensity 10.8 8.20 15
12.4 7.13 35 16.2 5.46 15 16.5 5.38 49 18.7 4.75 100 18.9 4.69 75
19.5 4.56 30 20.7 4.29 24 21.7 4.10 27 22.0 4.03 16 23.2 3.83 18
23.6 3.76 67
Example 2
[0128] The crystal obtained in Example 1 was milled and passed
through No. 60 (250 .mu.m) sieve to obtain a powder remaining on
No. 282 (53 .mu.m) sieve. Each vial was filled with the powder
(1.41 g) to obtain an injectable preparation of a monohydrate
crystal.
Example 3-1
[0129] The crystal (1.35 g) obtained in Example 1 was allowed to
stand still at 40.degree. C. under vacuum (50 Pa or below) for 64
hours to obtain a crystal of an anhydrate.
[0130] Water content: 0.07%
[0131] In the powder X-ray diffraction pattern of the obtained
crystal, peaks were observed at 2.theta. (.degree.): 11.3, 13.0,
17.0, 19.7, 20.5, 22.0, 24.2, 26.4, 28.1.
Example 3-2
[0132] The crystal (86 mg) obtained in Example 1 was allowed to
stand still at 80 to 90.degree. C. for 5 minutes and thereafter at
90.degree. C. for 180 minutes to obtain a crystal of an
anhydrate.
[0133] The result of powder X-ray diffraction of the crystal of the
anhydrate is shown in FIG. 3 and Table 2.
[0134] The powder X-ray diffraction pattern coincided with that of
Example 3-1.
[0135] Powder X-ray diffraction measurement conditions:
[0136] X-rays to be used: CuK.alpha.1, CuK.alpha.2, CuK.beta.
[0137] Applied voltage: 45 kV
[0138] Supplied current: 40 mA
[0139] Scanning axis: 2.theta.
[0140] Scanning range: 2.theta.=2 to 40.degree.
[0141] Measurement temperature: 90.degree. C.
TABLE-US-00002 TABLE 2 2.theta. Relative intensity 10.2 12 11.3 19
13.0 64 15.9 14 17.0 44 18.7 27 19.7 100 20.5 37 22.0 30 24.2 53
26.4 42 28.1 40
Example 4
[0142] The injectable preparation obtained in Example 2 was allowed
to stand still at 40.degree. C. under vacuum (50 Pa or below) for
60 hours to obtain an injectable preparation of a crystal of the
anhydrate.
[0143] Water content: 0.17%
Example 5
[0144] To a suspension of Compound A (45.1 g) in Water for
Injection (500 mL) was added meglumine (55.9 g), and the mixture
was stirred to dissolve Compound A. After to the solution was added
Water for Injection to give a total volume of 600 mL, the mixture
was filtered through a 0.22-.mu.m membrane filter to obtain a
liquid preparation (pH 7.6). Each vial was filled with the liquid
preparation (8 mL), lyophilized and then closed airtight to obtain
a lyophilized preparation of an amorphous product.
[0145] Water content: 0.17%
[0146] The result of powder X-ray diffraction of the lyophilized
preparation is shown in FIG. 2.
[0147] Lyophilization method [0148] 1. Vials were cooled at the
shelf temperature of -60.degree. C. to freeze the content. [0149]
2. The temperature of the vials was increased to the shelf
temperature of -20.degree. C. under vacuum (50 Pa or below) and the
vials were maintained at the same pressure and the same temperature
for 64 hours. [0150] 3. The temperature of the vials was increased
to the shelf temperature of -10.degree. C. and the vials were
maintained at the same pressure and the same temperature for 7
hours. [0151] 4. The temperature of the vials was increased to the
shelf temperature of 0.degree. C. and the vials were maintained at
the same pressure and the same temperature for 11 hours. [0152] 5.
The temperature of the vials was increased to the shelf temperature
of 20.degree. C. and the vials were maintained at the same pressure
and the same temperature for 10 hours. [0153] 6. The temperature of
the vials was increased to the shelf temperature of 40.degree. C.
and the vials were maintained at the same pressure and the same
temperature for 17 hours.
Example 6
[0154] To a suspension of Compound A (72.0 g) in Water for
Injection (1000 mL) was added meglumine (90.7 g), and the mixture
was stirred to dissolve Compound A. To the obtained solution was
added Water for Injection to give a total volume of 1200 mL.
Thereafter, the mixture was filtered through a 0.22-.mu.m membrane
filter to obtain a liquid preparation (pH 8.0). Each vial was
filled with the liquid preparation (10 mL), lyophilized and then
closed airtight to obtain a lyophilized preparation of a
crystal.
[0155] Water content: 0.01%
[0156] In the powder X-ray diffraction pattern of the lyophilized
preparation, the same peaks as those of the crystal of Salt A
anhydrate observed in Example 3 were observed.
[0157] Lyophilization method [0158] 1. Vials were cooled at the
shelf temperature of -60.degree. C. to freeze the content. [0159]
2. The temperature of the vials was increased to the shelf
temperature of -5.degree. C. and the vials were maintained at the
same temperature for 25 hours. [0160] 3. The temperature of the
vials was cooled to the shelf temperature of -55.degree. C. or
below and the vials were maintained at the same temperature for 3
hours. [0161] 4. The temperature of the vials was increased to the
shelf temperature of 40.degree. C. under vacuum (50 Pa or below)
and the vials were maintained at the same pressure and the same
temperature for 60 hours.
Example 7
[0162] To a suspension of Compound A (132 g) in Water for Injection
(1900 mL) was added meglumine (166 g), and the mixture was stirred
to dissolve Compound A. To the obtained solution was added Water
for Injection to give a total volume of 2200 mL. Thereafter, the
mixture was filtered through a 0.22-.mu.m membrane filter to obtain
a liquid preparation (pH 8.0). Each vial was filled with the liquid
preparation (10 mL), lyophilized and then closed airtight to obtain
a lyophilized preparation of a crystal.
[0163] Water content: 0.01%
[0164] In the powder X-ray diffraction pattern of the lyophilized
preparation, the same peaks as those of the crystal of Salt A
anhydrate observed in Example 3 were observed.
[0165] Lyophilization method [0166] 1. Vials were cooled at the
shelf temperature of -60.degree. C. to freeze the content. [0167]
2. The temperature of the vials was increased to the shelf
temperature of -10.degree. C. and the vials were maintained at the
same temperature for 24 hours. [0168] 3. The temperature of the
vials was cooled to the shelf temperature of -55.degree. C. or
below and the vials were maintained at the same temperature for 2
hours. [0169] 4. The temperature of the vials was increased to the
shelf temperature of 40.degree. C. under vacuum (50 Pa or below)
and the vials were maintained at the same pressure and the same
temperature for 48 hours.
Example 8
[0170] To a suspension of Compound A (132 g) in Water for Injection
(1800 mL) was added meglumine (166 g), and the mixture was stirred
to dissolve Compound A. To the obtained solution was added Water
for Injection to give a total volume of 2200 mL. Thereafter, the
mixture was filtered through a 0.22-.mu.m membrane filter to obtain
a liquid preparation (pH 8.0). Each vial was filled with the liquid
preparation (10 mL), lyophilized and then closed airtight to obtain
a lyophilized preparation of a crystal.
[0171] Water content: 0.00%
[0172] In the powder X-ray diffraction pattern of the lyophilized
preparation, the same peaks as those of the crystal of Salt A
anhydrate observed in Example 3 were observed.
[0173] Lyophilization method [0174] 1. Vials were cooled at the
shelf temperature of -60.degree. C. to freeze the content. [0175]
2. The temperature of the vials was increased to the shelf
temperature of -15.degree. C. and the vials were maintained at the
same temperature for 24 hours. [0176] 3. The temperature of the
vials was cooled to the shelf temperature of -55.degree. C. or
below and the vials were maintained at the same temperature for 2
hours. [0177] 4. The temperature of the vials was increased to the
shelf temperature of 40.degree. C. under vacuum (50 Pa or below)
and the vials were maintained at the same pressure and the same
temperature for 46 hours.
Example 9
[0178] To a suspension of Compound A (54.0 g) in Water for
Injection (750 mL) was added meglumine (68.0 g), and the mixture
was stirred to dissolve Compound A. To the obtained solution was
added Water for Injection to give a total volume of 900 mL.
Thereafter, the mixture was filtered through a 0.22-.mu.m membrane
filter to obtain a liquid preparation (pH 8.0). Each vial was
filled with the liquid preparation (10 mL), lyophilized and then
closed airtight to obtain a lyophilized preparation of a
crystal
[0179] Water content: 0.02%
[0180] In the powder X-ray diffraction pattern of the lyophilized
preparation, the same peaks as those of the crystal of Salt A
anhydrate observed in Example 3 were observed.
[0181] Lyophilization method [0182] 1. Vials were cooled at the
shelf temperature of -60.degree. C. to freeze the content. [0183]
2. The temperature of the vials was increased to the shelf
temperature of -30.degree. C. and the vials were maintained at the
same temperature for 14 hours. [0184] 3. The temperature of the
vials was increased to the shelf temperature of -25.degree. C. and
the vials were maintained at the same temperature for 25 hours.
[0185] 4. The temperature of the vials was increased to the shelf
temperature of -20.degree. C. and the vials were maintained at the
same temperature for 25 hours. [0186] 5. The temperature of the
vials was cooled to the shelf temperature of -55.degree. C. or
below and the vials were maintained at the same temperature for 2
hours. [0187] 6. The temperature of the vials was increased to the
shelf temperature of 40.degree. C. under vacuum (50 Pa or below)
and the vials were maintained at the same pressure and the same
temperature for 50 hours.
Example 10
[0188] To a suspension of Compound A (73.2 g) in Water for
Injection (1000 mL) was added meglumine (91.9 g), and the mixture
was stirred to dissolve Compound A. To the obtained solution was
added Water for Injection to give a total volume of 1220 mL. To
this solution (200 mL) was added glycine (2.00 g), and it was
dissolved, then filtered through a 0.22-.mu.m membrane filter to
obtain a liquid preparation (pH 7.8). Each vial was filled with the
liquid preparation (10 mL), lyophilized and then closed airtight to
obtain a lyophilized preparation of a crystal.
[0189] Water content: 0.03%
[0190] In the powder X-ray diffraction pattern of the lyophilized
preparation, the same peaks as those of the crystal of Salt A
anhydrate observed in Example 3 were observed.
[0191] Lyophilization method: the same as in Example 7.
Example 11
[0192] To a suspension of Compound A (73.2 g) in Water for
Injection (1000 mL) was added meglumine (91.9 g), and the mixture
was stirred to dissolve Compound A. To the obtained solution was
added Water for Injection to give a total volume of 1220 mL. To the
solution (200 mL) was added L-alanine (2.00 g), and it was
dissolved. Thereafter, the mixture was filtered through a
0.22-.mu.m membrane filter to obtain a liquid preparation (pH 7.9).
Each vial was filled with the liquid preparation (10 mL),
lyophilized and then closed airtight to obtain a lyophilized
preparation of a crystal.
[0193] Water content: 0.03%
[0194] In the powder X-ray diffraction pattern of the lyophilized
preparation, the same peaks as those of the crystal of Salt A
anhydrate observed in Example 3 were observed.
[0195] Lyophilization method: the same as in Example 7.
Example 12
[0196] To the liquid preparation (35 mL) produced in the same
manner as in Example 7 was added L-histidine (0.35 g), and a
solution (pH 8.0) was obtained. Each vial was filled with the
solution (10 mL), lyophilized and then closed airtight to obtain a
lyophilized preparation of a crystal.
[0197] Lyophilization method: the same as in Example 7.
Example 13
[0198] To a suspension of Compound A (69.0 g) in Water for
Injection (760 mL) was added meglumine (85.8 g), and the mixture
was stirred to dissolve Compound A. To the obtained solution was
added Water for Injection to give a total volume of 920 mL. To the
solution (240 mL) was added taurine (1.20 g), and it was dissolved.
Thereafter, the mixture was filtered through a 0.22-.mu.m membrane
filter to obtain a liquid preparation (pH 7.6). Each vial was
filled with the liquid preparation (8 mL), lyophilized and then
closed airtight to obtain a lyophilized preparation of a
crystal.
[0199] Water content: 0.02%
[0200] Lyophilization method: the same as in Example 7.
Example 14
[0201] To the liquid preparation (100 mL) produced in the same
manner as in Example 7 was added trehalose (1.00 g), and a solution
(pH 8.0) was obtained. Each vial was filled with the solution (10
mL), lyophilized and then closed airtight to obtain a lyophilized
preparation of a crystal.
[0202] Water content: 0.05%
[0203] Lyophilization method: the same as in Example 7.
[0204] In the powder X-ray diffraction pattern of the lyophilized
preparation, the same peaks as those of the crystal of Salt A
anhydrate observed in Example 3 were observed.
Example 15
[0205] To the liquid preparation (160 mL) produced in the same
manner as in Example 7 was added trehalose (3.20 g), and a solution
(pH 8.0) was obtained. Each vial was filled with the solution (10
mL), lyophilized and then closed airtight to obtain a lyophilized
preparation of a crystal.
[0206] Lyophilization method: the same as in Example 7.
Example 16
[0207] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 was added D-maltose monohydrate (1.65 g),
and a solution (pH 8.1) was obtained. Each vial was filled with the
solution (10 mL), lyophilized and then closed airtight to obtain a
lyophilized preparation of a crystal.
[0208] Lyophilization method: the same as in Example 7.
Example 17
[0209] To a suspension of Compound A (73.2 g) in Water for
Injection (1000 mL) was added meglumine (91.9 g), and the mixture
was stirred to dissolve Compound A. To the obtained solution was
added Water for Injection to give a total volume of 1220 mL. To the
solution (200 mL) was added glucose (2.00 g), and it was dissolved.
Thereafter, the mixture was filtered through a 0.22-.mu.m membrane
filter to obtain a liquid preparation (pH 8.0). Each vial was
filled with the liquid preparation (10 mL), lyophilized and then
closed airtight to obtain a lyophilized preparation of a
crystal.
[0210] Water content: 0.04%
[0211] Lyophilization method: the same as Example 7.
Example 18
[0212] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 was added lactose (1.65 g), and a solution
(pH 8.0) was obtained. Each vial was filled with the solution (10
mL), lyophilized and then closed airtight to obtain a lyophilized
preparation of a crystal.
[0213] Lyophilization method: the same as Example 7.
Example 19
[0214] Each vial was filled with the liquid preparation (pH 8.1, 10
mL) produced in the same manner as in Example 7, and purified white
sugar (0.30 g)(manufactured by Ensuiko Sugar Refining Co., Ltd.)
was added and dissolved. After lyophilization, the vials were
closed airtight to obtain a lyophilized preparation of a
crystal.
[0215] Lyophilization method: the same as Example 7.
Example 20
[0216] To the liquid preparation (160 mL) produced in the same
manner as in Example 7 was added D-sorbitol (1.60 g), and a
solution (pH 8.0) was obtained. Each vial was filled with the
solution (10 mL), lyophilized and then closed airtight to obtain a
lyophilized preparation of a crystal.
[0217] Lyophilization method: the same as Example 7.
Example 21
[0218] To the liquid preparation (35 mL) produced in the same
manner as in Example 7 was added xylitol (0.35 g), and a solution
(pH 8.0) was obtained. Each vial was filled with the solution (10
mL), lyophilized and then closed airtight to obtain a lyophilized
preparation of a crystal.
[0219] Lyophilization method: the same as Example 7.
Example 22
[0220] To a suspension of Compound A (69.0 g) in Water for
Injection (760 mL) was added meglumine (85.8 g), and the mixture
was stirred to dissolve Compound A. To the obtained solution was
added Water for Injection to give a total volume of 920 mL.
Thereafter, the mixture was filtered through a 0.22-.mu.m membrane
filter to obtain a liquid preparation (pH 7.6). Each vial was
filled with the liquid preparation (8 mL) and inositol (0.10 g) was
added and dissolved. After lyophilization, the vials were closed
airtight to obtain a lyophilized preparation of a crystal.
[0221] Lyophilization method: the same as Example 7.
Example 23
[0222] To the liquid preparation (160 mL) produced in the same
manner as in Example 7 was added D-mannitol (1.60 g), and a
solution (pH 8.1) was obtained. Each vial was filled with the
solution (10 mL), lyophilized and then closed airtight to obtain a
lyophilized preparation of a crystal.
[0223] Lyophilization method: the same as Example 7.
Example 24
[0224] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 was added sodium acetate trihydrate (0.55
g), and a solution (pH 8.1) was obtained. Each vial was filled with
the solution (10 mL), lyophilized and then closed airtight to
obtain a lyophilized preparation of a crystal.
[0225] Lyophilization method: the same as Example 7.
Example 25
[0226] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 was added sodium lactate (50% solution, 1.11
g), and a solution (pH 8.1) was obtained. Each vial was filled with
the solution (10 mL), lyophilized and then closed airtight to
obtain a lyophilized preparation of a crystal.
[0227] Lyophilization method: the same as Example 7.
Example 26
[0228] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 was added sodium benzoate (0.55 g), and a
solution (pH 8.1) was obtained. Each vial was filled with the
solution (10 mL), lyophilized and then closed airtight to obtain a
lyophilized preparation of a crystal.
[0229] Lyophilization method: the same as Example 7.
Example 27
[0230] To the liquid preparation (35 mL) produced in the same
manner as in Example 7 was added creatinine (0.35 g), and a
solution (pH 8.0) was obtained. Each vial was filled with the
solution (10 mL), lyophilized and then closed airtight to obtain a
lyophilized preparation of a crystal.
[0231] Lyophilization method: the same as Example 7.
Example 28
[0232] To a suspension of Compound A (69.0 g) in Water for
Injection (760 mL) was added meglumine (85.8 g), and the mixture
was stirred to dissolve Compound A. To the obtained solution was
added Water for Injection to give a total volume of 920 mL. To the
solution (240 mL) was added urea (1.50 g), and it was dissolved,
then filtered through a 0.22-.mu.m membrane filter to obtain a
liquid preparation (pH 7.7). Each vial was filled with the liquid
preparation (8 mL), lyophilized and then closed airtight to obtain
a lyophilized preparation of a crystal.
[0233] Water content: 0.02%
[0234] Lyophilization method: the same as Example 7.
Example 29
[0235] To a suspension of Compound A (15.0 g) in Water for
Injection (160 mL) were added meglumine (18.6 g) and nicotinic acid
amide (1.25 g), and the mixture was stirred to dissolve Compound A.
To the obtained solution was added Water for Injection to give a
total volume of 200 mL. Thereafter the mixture was filtered through
a 0.22-.mu.m membrane filter to obtain a liquid preparation (pH
7.8). Each vial was filled with the liquid preparation (8 mL),
lyophilized and then closed airtight to obtain a lyophilized
preparation of a crystal.
[0236] Water content: 0.02%
[0237] Lyophilization method [0238] 1. Vials were cooled at the
shelf temperature of -60.degree. C. to freeze the content. [0239]
2. The temperature of the vials was increased to the shelf
temperature of -10.degree. C. and the vials were maintained at the
same temperature for 24 hours. [0240] 3. The temperature of the
vials was cooled to the shelf temperature of -55.degree. C. or
below and the vials were maintained at the same temperature for 2
hours. [0241] 4. The temperature of the vials was increased to the
shelf temperature of 10.degree. C. under vacuum (50 Pa or below)
and the vials were maintained at the same pressure and the same
temperature for 30 hours. [0242] 5. The temperature of the vials
was increased to the shelf temperature of 20.degree. C. and the
vials were maintained at the same pressure and the same temperature
for 2 hours. [0243] 6. The temperature of the vials was increased
to the shelf temperature of 40.degree. C. and the vials were
maintained at the same pressure and the same temperature for 10
hours.
Example 30
[0244] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 was added trometamol (0.55 g), and a
solution (pH 8.9) was obtained. Each vial was filled with the
solution (10 mL), lyophilized and then closed airtight to obtain a
lyophilized preparation of a crystal.
[0245] Lyophilization method: the same as Example 7.
Example 31
[0246] To the liquid preparation (210 mL) produced in the same
manner as in Example 7 were added glycine (2.10 g) and trehalose
(2.10 g), and a solution (pH 7.9) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0247] Lyophilization method: the same as Example 7.
Example 32
[0248] To the liquid preparation (210 mL) produced in the same
manner as in Example 7 were added L-alanine (2.10 g) and trehalose
(2.10 g), and a solution (pH 8.0) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0249] Lyophilization method: the same as Example 7.
[0250] Water content: 0.05%
[0251] In the powder X-ray diffraction pattern of the lyophilized
preparation, the same peaks as those of the crystal of Salt A
anhydrate observed in Example 3 were observed.
Example 33
[0252] Vials were filled with the liquid preparation (pH 8.1, 10
mL) produced in the same manner as in Example 7 and glycine (0.10
g) and purified white sugar (0.10 g, manufactured by Ensuiko Sugar
Refining Co., Ltd.) were added and dissolved. After lyophilization,
the vials were closed airtight to obtain a lyophilized preparation
of a crystal.
[0253] Lyophilization method: the same as Example 7.
Example 34
[0254] Vials were filled with the liquid preparation (pH 8.1, 10
mL) produced in the same manner as in Example 7 and L-alanine (0.10
g) and purified white sugar (0.10 g, manufactured by Ensuiko Sugar
Refining Co., Ltd.) were added and dissolved. After lyophilization,
the vials were closed airtight to obtain a lyophilized preparation
of a crystal.
[0255] Lyophilization method: the same as Example 7.
Example 35
[0256] To the liquid preparation (90 mL) produced in the same
manner as in Example 7 were added glycine (0.90 g) and D-sorbitol
(0.90 g), and a solution (pH 8.0) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0257] Lyophilization method: the same as Example 7.
Example 36
[0258] To the liquid preparation (210 mL) produced in the same
manner as in Example 7 were added L-alanine (2.10 g) and D-sorbitol
(2.10 g), and a solution (pH 8.0) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0259] Lyophilization method: the same as Example 7.
Example 37
[0260] To the liquid preparation (90 mL) produced in the same
manner as in Example 7 were added glycine (0.90 g) and xylitol
(0.90 g), and a solution (pH 7.9) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0261] Lyophilization method: the same as Example 7.
Example 38
[0262] To the liquid preparation (90 mL) produced in the same
manner as in Example 7 were added L-alanine (0.90 g) and xylitol
(0.90 g), and a solution (pH 8.0) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0263] Lyophilization method: the same as Example 7.
Example 39
[0264] To the liquid preparation (90 mL) produced in the same
manner as in Example 7 were added glycine (0.90 g) and D-mannitol
(0.90 g), and a solution (pH 7.9) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0265] Lyophilization method: the same as Example 7.
Example 40
[0266] To the liquid preparation (210 mL) produced in the same
manner as in Example 7 were added L-alanine (2.10 g) and D-mannitol
(2.10 g), and a solution (pH 8.0) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0267] Lyophilization method: the same as Example 7.
Example 41
[0268] To a suspension of Compound A (12.0 g) in Water for
Injection (180 mL) was added meglumine (14.9 g), and the mixture
was stirred to dissolve Compound A. To the obtained solution was
added Water for Injection to give a total volume of 200 mL.
Thereafter, the mixture was filtered through a 0.22-.mu.m membrane
filter to obtain a liquid preparation (pH 7.4). Each vial was
filled with the liquid preparation (10 mL), lyophilized and then
closed airtight to obtain a lyophilized preparation of a
crystal.
[0269] Water content: 0.03%
[0270] Lyophilization method: the same as Example 6.
Example 42
[0271] To a suspension of Compound A (12.0 g) in Water for
Injection (170 mL) was added meglumine (15.7 g), and the mixture
was stirred to dissolve Compound A. To the obtained solution was
added Water for Injection to give total volume of 200 mL.
Thereafter, the mixture was filtered through a 0.22-.mu.m membrane
filter to obtain a liquid preparation (pH 8.5). Each vial was
filled with the liquid preparation (10 mL), lyophilized and then
closed airtight to obtain a lyophilized preparation of a
crystal.
[0272] Water content: 0.02%
[0273] Lyophilization method: the same as Example 6.
Example 43
[0274] Production was performed in the same manner as in Example 41
to obtain a liquid preparation (pH 7.6). Each vial was filled with
the liquid preparation (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0275] Water content: 0.01%
[0276] Lyophilization method: the same as Example 7.
Example 44
[0277] Production was performed in the same manner as in Example 42
to obtain a liquid preparation (pH 8.5). Each vial was filled with
the liquid preparation (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0278] Water content: 0.00%
[0279] Lyophilization method: the same as Example 7.
Example 45
[0280] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added trehalose (1.10 g) and glycine
(1.10 g), and a solution (pH 7.7) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0281] Water content: 0.12%
[0282] Lyophilization method: the same as Example 6.
Example 46
[0283] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added trehalose (1.10 g) and glycine
(1.10 g), and a solution (pH 7.8) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0284] Water content: 0.03%
[0285] Lyophilization method: the same as Example 7.
Example 47
[0286] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added D-mannitol (0.28 g) and glycine
(0.28 g), and a solution (pH 7.9) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0287] Water content: 0.07%
[0288] Lyophilization method: the same as Example 6.
Example 48
[0289] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added D-mannitol (1.10 g) and glycine
(1.10 g), and a solution (pH 7.8) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0290] Water content: 0.04%
[0291] Lyophilization method: the same as Example 7.
Example 49
[0292] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added purified white sugar (1.10 g,
manufactured by Ensuiko Sugar Refining Co., Ltd.) and glycine (1.10
g), and a solution (pH 7.7) was obtained. Each vial was filled with
the solution (10 mL), lyophilized and then closed airtight to
obtain a lyophilized preparation of a crystal.
[0293] Water content: 0.14%
[0294] Lyophilization method: the same as Example 6.
Example 50
[0295] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added purified white sugar (1.10 g,
manufactured by Ensuiko Sugar Refining Co., Ltd.) and glycine (1.10
g), and a solution (pH 7.8) was obtained. Each vial was filled with
the solution (10 mL), lyophilized and then closed airtight to
obtain a lyophilized preparation of a crystal.
[0296] Water content: 0.02%
[0297] Lyophilization method: the same as Example 7.
Example 51
[0298] To the liquid preparation (55 mL) produced in the same
manner as in Example 41 were added trehalose (0.55 g) and L-alanine
(0.55 g), and a solution (pH 7.4) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0299] Water content: 0.03%
[0300] Lyophilization method: the same as Example 6.
Example 52
[0301] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added trehalose (0.28 g) and L-alanine
(0.28 g), and a solution (pH 7.9) was obtained.
[0302] Each vial was filled with the solution (10 mL), lyophilized
and then closed airtight to obtain a lyophilized preparation of a
crystal.
[0303] Water content: 0.04%
[0304] Lyophilization method: the same as Example 6.
Example 53
[0305] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added trehalose (0.55 g) and L-alanine
(0.55 g), and a solution (pH 7.9) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0306] Water content: 0.04%
[0307] Lyophilization method: the same as Example 6.
Example 54
[0308] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added trehalose (1.10 g) and L-alanine
(1.10 g), and a solution (pH 7.8) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0309] Water content: 0.04%
[0310] Lyophilization method: the same as Example 6.
Example 55
[0311] To the liquid preparation (55 mL) produced in the same
manner as in Example 42 were added trehalose (0.55 g) and L-alanine
(0.55 g), and a solution (pH 8.4) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0312] Water content: 0.03%
[0313] Lyophilization method: the same as Example 6.
Example 56
[0314] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added trehalose (0.28 g) and L-alanine
(0.28 g), and a solution (pH 8.0) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0315] Water content: 0.02%
[0316] Lyophilization method: the same as Example 7.
Example 57
[0317] To the liquid preparation (55 mL) produced in the same
manner as in Example 41 were added trehalose (0.55 g) and L-alanine
(0.55 g), and a solution (pH 7.5) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0318] Water content: 0.01%
[0319] Lyophilization method: the same as Example 7.
Example 58
[0320] To the liquid preparation (55 mL) produced in the same
manner as in Example 42 were added trehalose (0.55 g) and L-alanine
(0.55 g), and a solution (pH 8.4)was obtained. Each vial was filled
with the solution (10 mL), lyophilized and then closed airtight to
obtain a lyophilized preparation of a crystal.
[0321] Water content: 0.02%
[0322] Lyophilization method: the same as Example 7.
Example 59
[0323] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added trehalose (1.10 g) and L-alanine
(1.10 g), and a solution (pH 7.9) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0324] Water content: 0.02%
[0325] Lyophilization method: the same as Example 7.
Example 60
[0326] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added D-sorbitol (0.28 g) and L-alanine
(0.28 g), and a solution (pH 7.9) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0327] Water content: 0.03%
[0328] Lyophilization method: the same as Example 6.
Example 61
[0329] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added D-sorbitol (0.28 g) and L-alanine
(0.28 g), and a solution (pH 7.9) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0330] Water content: 0.04%
[0331] Lyophilization method: the same as Example 7.
Example 62
[0332] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added D-mannitol (1.10 g) and L-alanine
(1.10 g), and a solution (pH 7.8) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0333] Water content: 0.07%
[0334] Lyophilization method: the same as Example 6.
Example 63
[0335] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added D-mannitol (1.10 g) and L-alanine
(1.10 g), and a solution (pH 7.8) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0336] Water content: 0.04%
[0337] Lyophilization method: the same as Example 7.
Example 64
[0338] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added purified white sugar (0.28 g,
manufactured by Ensuiko Sugar Refining Co., Ltd.) and L-alanine
(0.28 g), and a solution (pH 7.9) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0339] Water content: 0.03%
[0340] Lyophilization method: the same as Example 6.
Example 65
[0341] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added purified white sugar (0.55 g,
manufactured by Ensuiko Sugar Refining Co., Ltd.) and L-alanine
(0.55 g), and a solution (pH 7.8) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0342] Water content: 0.02%
[0343] Lyophilization method: the same as Example 6.
Example 66
[0344] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added purified white sugar (1.10 g,
manufactured by Ensuiko Sugar Refining Co., Ltd.) and L-alanine
(1.10 g), and a solution (pH 7.8) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0345] Water content: 0.03%
[0346] Lyophilization method: the same as Example 6.
Example 67
[0347] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added purified white sugar (0.28 g,
manufactured by Ensuiko Sugar Refining Co., Ltd.) and L-alanine
(0.28 g), and a solution (pH 7.9) was obtained. Each vial was
filled with the solution (10 mL), lyophilized and then closed
airtight to obtain a lyophilized preparation of a crystal.
[0348] Water content: 0.02%
[0349] Lyophilization method: the same as Example 7.
Example 68
[0350] To the liquid preparation (55 mL) produced in the same
manner as in Example 7 were added purified white sugar (1.10 g,
manufactured by Ensuiko Sugar Refining Co., Ltd.) and L-alanine
(1.10 g), and a solution (pH 7.8)was obtained. Each vial was filled
with the solution (10 mL), lyophilized and then closed airtight to
obtain a lyophilized preparation of a crystal.
[0351] Water content: 0.02%
[0352] Lyophilization method: the same as Example 7.
Example 69
[0353] To a suspension of Compound A (36.0 g) in Water for
Injection (400 mL) was added meglumine (46.2 g), and the mixture
was stirred to dissolve Compound A. To the obtained solution was
added Water for Injection to give a total volume of 480 mL.
Thereafter, the mixture was filtered through a 0.22-.mu.m membrane
filter to obtain a liquid preparation (pH 8.6). Each vial was
filled with the liquid preparation (8 mL), lyophilized and then
closed airtight to obtain a lyophilized preparation of a
crystal.
[0354] Water content: 0.02%
[0355] Lyophilization method: the same as Example 6.
Comparative Example 1
[0356] To a suspension of Compound A (13.8 g) in Water for
Injection (50 mL) was added 1 mol/L aqueous sodium hydroxide
solution, and the mixture was stirred to dissolve
[0357] Compound A. Thereafter, 1 mol/L aqueous sodium hydroxide
solution was further added to adjust the pH to 8.5. To the solution
was added Water for Injection to give a total volume of 161 mL.
Thereafter, the mixture was filtered through a 0.22-.mu.m membrane
filter to obtain a liquid preparation (pH 8.4). Each vial was
filled with the liquid preparation (7 mL), lyophilized and then
closed airtight to obtain a lyophilized preparation of an amorphous
product.
[0358] Water content: 2.2%
[0359] Lyophilization method [0360] 1. Vials were cooled at the
shelf temperature of -60.degree. C. to freeze the content. [0361]
2. The temperature of the vials was increased to the shelf
temperature of -10.degree. C. under vacuum (50 Pa or below) and the
vials were maintained at the same pressure and the same temperature
for 37 hours. [0362] 3. The temperature of the vials was increased
to the shelf temperature of 0.degree. C. and the vials were
maintained at the same pressure and the same temperature for 9
hours. [0363] 4. The temperature of the vials was increased to the
shelf temperature of 10.degree. C. and the vials were maintained at
the same pressure and the same temperature for 4 hours. [0364] 5.
The temperature of the vials was increased to the shelf temperature
of 20.degree. C. and the vials were maintained at the same pressure
and the same temperature for 4 hours. [0365] 6. The temperature of
the vials was increased to the shelf temperature of 40.degree. C.
and the vials were maintained at the same pressure and the same
temperature for 15 hours.
Comparative Example 2
[0366] To a suspension of Compound A (12.0 g) in Water for
Injection (70 mL) was added 1 mol/L aqueous sodium hydroxide
solution, and the mixture was stirred to dissolve Compound A.
Thereafter, 1 mol/L aqueous sodium hydroxide solution was further
added to adjust the pH to 8.5. To the solution was added Water for
Injection to give a total volume of 160 mL. Thereafter, the mixture
was filtered through a 0.22-.mu.m membrane filter to obtain a
liquid preparation (pH 8.5). Each vial was filled with the liquid
preparation (8 mL), lyophilized and then closed airtight to obtain
a lyophilized preparation of an amorphous product.
[0367] Lyophilization method [0368] 1. Vials were cooled at the
shelf temperature of -60.degree. C. to freeze the content. [0369]
2. The temperature of the vials was increased to the shelf
temperature of 50.degree. C. under vacuum (50 Pa or below) and the
vials were maintained at the same pressure and the same temperature
for 39 hours.
Test Example 1
Solubility
[0370] To the each vial obtained in Comparative Examples and
Examples was added Water for Injection (10 mL) and the vials were
shaken by hand. Thus, the dissolution time of the solid substance
was measured. The results are shown in Table 3.
TABLE-US-00003 TABLE 3 Example No. Dissolution time (seconds) 2 5 5
5 6 18 7 28 8 25 9 18 10 9 11 10 12 18 13 17 14 14 15 9 16 13 17 17
18 16 19 16 20 8 21 18 22 14 23 21 24 9 25 12 26 11 27 20 28 12 29
18 30 8 31 4 32 4 33 5 34 7 35 4 36 3 37 5 38 5 39 8 40 8 41 19 42
10 43 31 44 17 45 9 46 5 47 5 48 13 49 9 50 5 51 5 52 7 53 5 54 5
55 5 56 9 57 5 58 5 59 7 60 5 61 5 62 5 63 9 64 5 65 5 66 5 67 6 68
8 69 7 Comparative 60 Example 1 Comparative 65 Example 2
[0371] The dissolution time of an amorphous sodium salt
(Comparative Example 1) was 60 seconds. The dissolution time of an
amorphous sodium salt (Comparative Example 2) was 65 seconds.
[0372] The dissolution time of a milled crystal of a meglumine salt
monohydrate (Example 2) was 5 seconds. The milled crystal of a
meglumine salt exhibited more superior solubility than the
amorphous sodium salt.
[0373] The dissolution time of an amorphous meglumine salt (Example
5) was 5 seconds. The amorphous meglumine salt exhibited more
superior solubility than the amorphous sodium salt.
[0374] The dissolution time of preparations (Examples 6 to 9, 41 to
44) produced by lyophilization including an annealing step was 10
to 31 seconds. The preparation produced by this process exhibited
more superior solubility than the amorphous sodium salt even though
it is not milled.
[0375] The dissolution time of preparations (Examples 10 to 13)
containing amino acids as an additive; preparations (Examples 14 to
19) containing saccharides as an additive; preparations (Examples
20 to 23) containing sugar alcohols as an additive; preparations
(Examples 24 to 26) containing salts as an additive; a preparation
(Example 27) containing creatinine as an additive, a preparation
(Example 28) containing urea as an additive; a preparation (Example
29) containing nicotinic acid amide as an additive; and a
preparation (Example 30) containing trometamol as an additive
demonstrate that these preparations exhibit much more superior
solubility than an amorphous sodium salt.
[0376] Furthermore, the dissolution time of preparations (Examples
31 to 34, 45, 46, 49 to 59, 64 to 68) containing amino acids and
saccharides, and preparations (Examples 35 to 40, 47, 60 to 63)
containing amino acids and sugar alcohols all fall within the range
of 10 seconds and thus exhibited extremely superior solubility.
Test Example 2
Appearance
[0377] Appearance was observed. As a result, lyophilized
preparations of Examples 7 and 8 looked uniform without a melting
mark. Furthermore, the preparations of Examples 12, 15, 27, 31 to
33, 36, 38, 51, 55 and 59 were uniform cakes without a melting
mark. The surface of the preparations was smooth and appearance was
more satisfactory. Lyophilized preparations having more preferable
appearance were obtained by blending additives.
Test Example 3
Stability (1)
[0378] The lyophilized preparations of Examples 7, 8, 10, 11, 13,
15, 20, 23, 31, 32, 36 and 40 were allowed to stand still at
40.degree. C. for 6 months and then checked for appearance and
residual ratio of Compound A. As a result, appearance change and
reduction of the content of Compound A were not observed.
Test Example 4
Stability (2)
[0379] The lyophilized preparations of Examples 69 and Comparative
Example 1 were irradiated (1,200,000 lxhr) by a D65 lamp
(FLR20S-D-EDL-D65/M) and then their appearance was observed. As a
result, appearance change was not observed in the preparation of
Example 69; whereas the preparation of Comparative Example 1 turned
into orange-yellow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0380] FIG. 1 is a powder X-ray diffraction pattern of a crystal of
a meglumine salt (monohydrate) of
6-fluoro-3-hydroxy-2-pyrazinecarboxamide;
[0381] FIG. 2 is a powder X-ray diffraction pattern of an amorphous
meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide; and
[0382] FIG. 3 is a powder X-ray diffraction pattern of a crystal of
an anhydrous meglumine salt of
6-fluoro-3-hydroxy-2-pyrazinecarboxamide.
INDUSTRIAL APPLICABILITY
[0383] A preparation filled with a meglumine salt of
6-fluoro-3-hydroxy-2-pyrazinecarboxamide of the present invention
is superior in solubility and useful as an injectable
preparation.
* * * * *