U.S. patent application number 09/873348 was filed with the patent office on 2001-11-01 for aqueous suspension with good redispersibility.
Invention is credited to Inada, Katsuhiro, Matsuhisa, Keiichi, Terayama, Hideo, Yasueda, Shin-Ichi.
Application Number | 20010036966 09/873348 |
Document ID | / |
Family ID | 14878589 |
Filed Date | 2001-11-01 |
United States Patent
Application |
20010036966 |
Kind Code |
A1 |
Yasueda, Shin-Ichi ; et
al. |
November 1, 2001 |
Aqueous suspension with good redispersibility
Abstract
The aqueous suspension can be prepared by incorporating, in an
aqueous suspension of a hardly soluble drug, a water-soluble
polymer within the concentration range from the concentration at
which the surface tension of the aqueous suspension of the drug
begins to decrease up to the concentration at which the reduction
in surface tension ceases. The resulting aqueous suspension shows
ready redispersibility and will not undergo aggregation of
dispersed particles or caking. Because of its good
redispersibility, the suspension is useful as a parenteral
preparation, eye drops, nasal drops, a preparation for oral
administration, a lotion or the like.
Inventors: |
Yasueda, Shin-Ichi;
(Takarazuka, JP) ; Matsuhisa, Keiichi; (Himeji,
JP) ; Terayama, Hideo; (Itami, JP) ; Inada,
Katsuhiro; (Kobe, JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
14878589 |
Appl. No.: |
09/873348 |
Filed: |
June 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09873348 |
Jun 5, 2001 |
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09423558 |
Nov 10, 1999 |
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6274634 |
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09423558 |
Nov 10, 1999 |
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PCT/JP98/01998 |
Apr 30, 1998 |
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Current U.S.
Class: |
514/781 ;
514/772.7 |
Current CPC
Class: |
A61K 9/0048 20130101;
A61K 47/38 20130101; A61K 9/08 20130101; Y10S 514/846 20130101;
A61K 9/0014 20130101; Y10S 514/912 20130101; Y10S 514/937 20130101;
Y10S 514/914 20130101; A61K 9/0019 20130101; A61K 47/32 20130101;
A61K 9/0043 20130101 |
Class at
Publication: |
514/781 ;
514/772.7 |
International
Class: |
A61K 047/30; A61K
047/34 |
Foreign Application Data
Date |
Code |
Application Number |
May 14, 1997 |
JP |
124166/1997 |
Claims
1. An aqueous suspension which comprises a hardly soluble drug
together with a water-soluble polymer within a concentration range
from the concentration at which the surface tension of the aqueous
suspension of said drug begins to decrease up to the concentration
at which the reduction in surface tension ceases.
2. The aqueous suspension of claim 1, wherein the concentration of
the water-soluble polymer at which the surface tension of the
aqueous drug suspension begins to decrease is 0.00001 to 0.01%
(w/v: weight/volume) and the concentration of the water-soluble
polymer at which the reduction in surface tension ceases is 0.0001
to 0.1% (w/v).
3. The aqueous suspension of claim 1, wherein the concentration of
the water-soluble polymer is within the range of 0.00001 to 0.1%
(w/v).
4. The aqueous suspension of claim 1, wherein the water-soluble
polymer is a cellulose derivative or a water-soluble polyvinyl
polymer.
5. The aqueous suspension of claim 4 wherein the cellulose
derivative is at least one member selected from the group
consisting of hydroxypropylmethyl cellulose, methylcellulose,
hydroxyethylcellulose and hydroxypropylcellulose.
6. The aqueous suspension of claim 4 wherein the water-soluble
polyvinyl polymer is at least one member selected from the group
consisting of polyvinylpyrrolidone and polyvinyl alcohol.
7. The aqueous suspension of claim 3 wherein the ratio of the
water-soluble polymer to the hardly soluble drug is 0.0001 to 0.2
part by weight of the former to 1 part by weight of the latter.
8. The aqueous suspension of claim 1, said suspension being a
topical ophthalmic preparation.
9. The aqueous suspension of claim 1, said suspension being a
topical nasal preparation.
10. The aqueous suspension of claim 1, said suspension being a
parenteral preparation for injection.
11. The aqueous suspension of claim 1, said suspension being a
preparation for oral administration.
12. The aqueous suspension of claim 1, said suspension being a
lotion.
Description
TECHNICAL FIELD
[0001] The present invention relates to an aqueous suspension with
good redispersibility.
BACKGROUND ART
[0002] In preparing, for instance, an ophthalmic preparation, nasal
preparation or parenteral preparation containing a medicinal
compound hardly soluble in water, it is presumable that the drug be
suspended in an aqueous medium to give an aqueous suspension. When
such aqueous suspension is stored for a long period, the drug
occurring as dispersed particles (hereinafter sometimes referred to
merely as dispersed particles) tends to undergo aggregation,
resulting in increases in size of dispersed particles or
sedimentation of dispersed particles and further in secondary
aggregation of the dispersed particles that have settled, for
example caking. Therefore, efforts have been devoted to prevent the
aggregation or sedimentation of dispersed particles as far as
possible or, when such aggregation or sedimentation cannot be
prevented, to obtain suspensions capable of readily regaining their
original state.
[0003] One method so far proposed comprises making dispersed
particles smaller, decreasing the difference between the specific
gravity of dispersed particles with of the dispersion medium and
increasing the viscosity of the dispersion medium to thereby
prevent the particles from settling. In such cases, for increasing
the viscosity of the dispersion medium, the concentration of the
suspending agent and/or thickening agent, such as a water-soluble
polymer, has generally been selected within the range of 0.2 to
5.0% (w/v: weight/volume).
[0004] However, even when the concentration of the suspending agent
and/or thickening agent is within such range, the sedimentation of
particles cannot entirely be prevented. The problem which remains
is that dispersed particles settle and deposit, causing caking,
resulting in failure of uniform redispersion.
[0005] Another method which is conceivable comprises making drug
particles greater in size to thereby improve their
redispersibility. In the case of an ophthalmic preparation,
however, greater particle sizes may cause a foreign matter
sensation or eye irritation upon instillation. In the case of a
nasal preparation, greater particle sizes make it impossible to
apply it from a spray bottle. In the case of an injection, it is a
drawback that it cannot be administered through a needle.
DISCLOSURE OF INVENTION
[0006] Among the drugs recently developed and producing
pharmacological effects of value, many are hardly soluble ones. For
supplying these in the form of aqueous preparations such as
ophthalmic, nasal, parenteral and other preparations, it is
unavoidable in many instances to employ the aqueous suspension
form. However, the prior art aqueous suspensions have a
redispersibility problem; in many instances, it is difficult to
restore suspensions uniform in concentration without a long time of
shaking to effect redispersion. Thus, the advent of aqueous drug
suspensions which can be readily prepared and have good
redispersibility has been waited for. Accordingly, it is the
primary object of the present invention to provide an aqueous
suspension showing good redispersibility without undergoing
aggregation of dispersed particles or caking.
[0007] The present inventors made intensive investigations to solve
the above problems and, as a result, found that there is a certain
relationship between the surface tension of an aqueous suspension
and the redispersibility thereof. Based on such finding, they have
now completed the present invention.
[0008] The invention is thus concerned with an aqueous suspension
comprising a hardly soluble drug together with a water-soluble
polymer within the concentration range from the concentration at
which the surface tension of the drug suspension begins to decrease
up to the concentration at which the reduction in surface tension
ceases.
[0009] As will be shown later herein in Test Example 1, the surface
tension of an aqueous suspension begins to decrease with the
increase in the amount of a water-soluble polymer added thereto.
Upon continuation of the addition, the reduction in surface tension
ceases and, thereafter, a substantially constant surface tension is
maintained. On the contrary, the redispersibility of the dispersed
particles of an aqueous suspension becomes good at the point at
which the surface tension of the aqueous suspension begins to
decrease as a result of addition of the water-soluble polymer, and
the good redispersibility is maintained until the reduction in
surface tension ceases. Thereafter, as the reduction in surface
tension ceases and the surface tension becomes constant, the
redispersibility of the dispersed particles becomes gradually
worsened.
[0010] Where no water-soluble polymer is present, the dispersed
particles aggregate together and float on the surface of the
suspension and therefore no uniform suspension can be prepared.
[0011] The concentration of a water-soluble polymer at which the
surface tension of an aqueous drug suspension begins to decrease
and the concentration of the water-soluble polymer at which the
reduction in surface tension ceases generally increase according to
the contents of the hardly soluble drug used in the aqueous
suspension but vary depending on the physical properties, chemical
structure, and concentration and particle size of the hardly
soluble drug, among others. The water-soluble polymer concentration
at which the surface tension of the drug suspension begins to
decrease is generally 0.00001 to 0.01% (w/v), preferably 0.00005 to
0.005% (w/v), while the water-soluble polymer concentration at
which the reduction in surface tension of the suspension ceases is
generally 0.0001 to 0.1% (w/v), preferably 0.001 to 0.01%
(w/v).
[0012] The aqueous suspension of the present invention is generally
prepared at a water-soluble polymer concentration within the range
of 0.00001 to 0.1% (w/v), preferably 0.00005 to 0.05% (w/v), more
preferably 0.0001 to 0.01 w/v %.
[0013] The ratio of the water-soluble polymer to the hardly soluble
drug is generally 0.0001 to 0.2 part by weight, preferably 0.0005
to 0.1 part by weight, more preferably 0.0005 to 0.05 part by
weight of the former to 1 part by weight of the latter.
[0014] The water-soluble polymer to be used in the practice of the
present invention may be any pharmaceutically acceptable
water-soluble polymer, irrespective of type or category. Cellulose
derivatives and water-soluble polyvinyl polymers are suited for
use, however.
[0015] As the cellulose derivatives, there may be mentioned, for
example, hydroxypropylmethylcellulose, methylcellulose,
hydroxyethylcellulose and hydroxypropylcellulose. Particularly
preferred among them are hydroxypropylmethylcellulose and
methylcellulose.
[0016] As the water-soluble polyvinyl polymers, there may be
mentioned, among others, polyvinylpyrrolidone K25,
polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, and polyvinyl
alcohol (partial hydrolyzed product, complete hydrolyzed
product).
[0017] As used herein, the "hardly soluble drug" includes, within
the meaning thereof, those drugs which belong, in solubility
classification, to one of the groups "sparingly soluble", "slightly
soluble", "very slightly soluble" and "practically insoluble" as so
defined in the Japanese Pharmacopoeia. Thus, it includes all drugs
that can be provided in the final dosage form of aqueous
suspensions.
[0018] As specific examples of the hardly soluble drug to be used
in the practice of the present invention, there may be mentioned
steroidal antiinflammatory agents, antiinflammatory analgesics,
chemotherapeutic agents, synthetic antibacterial agents, antiviral
agents, hormones, anticataract agents, neovascularization
inhibitors, immunosuppressants, protease inhibitors, and aldose
reductase inhibitors, among others. The steroidal antiinflammatory
agents include, among others, cortisone acetate, hydrocortisone
acetate, betamethasone, prednisolone, fluticasone propionate,
dexamethasone, triamcinolone, loteprednol, fluorometholone,
difluprednate, momethasone furoate, clobetasol propionate,
diflorasone diacetate, diflucortolone valerate, fluocinonide,
amcinonide, halcinonide, fluocinolone acetonide, triamcinolone
acetonide, flumetasone pivalate and clobetasone butyrate. The
antiinflammatory analgesics include, among others, alclofenac,
aluminopropfen, ibuprofen, indomethacin, epirizole, oxaprozin,
ketoprofen, diclofenac sodium, diflunisal, naproxen, piroxicam,
fenbufen, flufenamic acid, flurbiprofen, floctafenine, pentazocine,
metiazinic acid, mefenamic acid and mofezolac. The chemotherapeutic
agents include, among others, sulfa drugs such as
salazusulfapyridine, sulfadimethoxine, sulfamethizole,
sulfamethoxazole, sulfamethopyrazine and sulfamonomethoxine,
synthetic antibacterial agents such as enoxacin, ofloxacin,
cinoxacin, sparfloxacin, thiamphenicol, nalidixic acid,
tosufloxacin tosilate, norfloxacin, pipemidic acid trihydrate,
piromidic acid, fleroxacin and levofloxacin, antiviral agents such
as aciclovir, ganciclovir, didanosine, didovudine and vidarabine,
and antifungal agents such as itraconazole, ketoconazole,
fluconazole, flucytosine, miconazole and pimaricin. The hormones
include, among others, insulin zinc, testosterone propionate and
estradiol benzoate. The anticataract agents include, among others,
pirenoxine and the like. The neovascularization inhibitors include,
among others, fumagillin and derivatives thereof. The
immunosuppressants include, among others, ciclosporin, rapamycin
and tacrolimus. The protease inhibitors include, among others,
[L-3-trans-ethoxycarbonyloxiran-2-carbonyl]-L-leucine
(3-methylbutyl)amide (E-64-d) and the like. The aldose reductase
inhibitors include, among others,
5-(3-ethoxy-4-pentyloxyphenyl)thiazolid- ine-2,4-dione and the
like.
[0019] The concentration of the hardly soluble drug to be used in
the practice of the invention may vary according to the drug
species, indication, dosage and other factors. Generally, however,
it is 0.01 to 10.0% (w/v), preferably 0.1 to 5.0% (w/v).
[0020] The aqueous suspension of the present invention may contain,
in addition to the hardly soluble drug and water-soluble polymer,
known compounds such as a buffer (e.g. carbonate salt, phosphate
salt, acetate salt, glutamic acid, citrate salt,
.epsilon.-aminocaproic acid), an isotonizing agent (e.g. glycerol,
mannitol, sorbitol, propylene glycol, sodium chloride, potassium
chloride, boric acid), a stabilizer (e.g. sodium edetate, sodium
citrate), a surfactant (e.g. polysorbate 80, polyoxyethylene(60)
hydrogenated castor oil, tyloxapol, benzalkonium chloride), a
preservative (p-hydroxybenzoate and it's analogs, benzalkonium
chloride, benzethonium chloride, chlorobutanol), a pH control agent
(e.g. hydrochloric acid, sodium hydroxide, phosphoric acid), and
other additives.
[0021] In cases where an additive which may influence the surface
tension of the aqueous suspension, for example a surfactant, is
used, it is preferred that the surface tension measurement be made
prior to addition of the surfactant and the surfactant be added
after selection of the concentration of the water-soluble
polymer.
[0022] The pH of the aqueous suspension of the present invention is
not critical but, generally, it is 4 to 9, preferably 5 to 8. It is
preferred that the surface tension be selected according to the
intended pH of the aqueous suspension.
[0023] The aqueous suspension of the invention has good
redispersibility without involving aggregation or caking of
dispersed particles and, therefore, can be used with advantage as,
for example, an ophthalmic preparation, a preparation for nasal
application, an injection, a preparation for oral administration or
a lotion.
BRIEF DESCRIPTION OF DRAWINGS
[0024] FIG. 1 is a graphic representation of the relationships
between the HPMC concentration and the surface tension and
redispersion time for a 0.1% (w/v) fluorometholone suspension as
found in Test Example 1. In the FIGURE, --.circle-solid.--
indicates the surface tension, and --.diamond-solid.-- indicates
the redispersion time.
BEST MODE FOR CARRYING OUT THE INVENTION
[0025] The following test examples and working examples illustrate
the invention in further detail. They are, however, by no means
limitative of the scope of the invention.
TEST EXAMPLE 1
Surface Tension-Redispersibility Test
[0026] Method
[0027] Solutions containing a suspending agent in concentrations
ranging from 0.000001 to 0.5 w/v % were first prepared. A test drug
was added to the solutions to prepare aqueous suspensions. The
surface tension of each aqueous suspension thus prepared was
measured with the Du Nouy tension meter K122 (Kruss). The
suspensions were then filled into 5 ml colorless polypropylene
bottles and allowed to stand at 25.degree. C. for 4 days. Each
bottle was caused to spin (60 rpm) on the variable mix rotor VMR-5
(60 rpm, manufactured by Iuchi) and the time required for
redispersion was measured. In addition, the condition of the
redispersed particles was visually examined.
[0028] As the suspending agent, hydroxypropylmethyl cellulose
[Metolose 60SH (TC-5E); manufactured by Shin-Etsu Chemical Co.,
Ltd.; hereinafter abbreviated as HPMC], methylcellulose (Metolose
SM-25; manufactured by Shin-Etsu Chemical Co., Ltd.; abbreviated as
MC), or polyvinylpyrrolidone (K30; manufactured by BASF;
abbreviated as PVP) was used. As the test drug, fluorometholone
0.05 w/v % or 0.1 w/v % or indomethacin 0.2 w/v % or 1.0 w/v % was
used.
[0029] Results
[0030] (1) Relationship of the concentration of HPMC to the surface
tension and redispersion time of fluorometholone 0.1 w/v %
suspension
[0031] The relation between the surface tension and
redispersibility of a fluorometholone 0.1 w/v % suspension is shown
in FIG. 1.
[0032] In the case of HPMC, the surface tension began to decline at
0.0001 w/v % and the decrease in surface tension almost ceased at
0.01 w/v. On the other hand, within the concentration range of
0.000005 to 0.0001 w/v % HPMC, the time required for redispersion
was 2 seconds but the dispersed particles aggregated and floated,
failing to give a uniform suspension. Over the range of 0.0001 to
0.01 w/v % HPMC, the redispersion time was less than 4 seconds and
a uniform suspension was obtained without aggregation of suspended
particles. When the concentration of HPMC was over 0.01 w/v %, the
redispersion time exceeded 5 seconds, indicating that the
redispersibility is adversely affected.
[0033] The preferred ratio of HPMC to fluorometholone was found to
be 0.001 to 0.1 part by weight of the former to 1 part by weight of
the latter.
[0034] (2) Relationship of the concentration of HPMC to the surface
tension of fluorometholone 0.05 w/v % suspension
[0035] With HPMC, the surface tension began to decline at 0.0001
w/v % (surface tension: 65.1 mN/m) and the decrease in surface
tension almost ceased at 0.002 w/v % HPMC (surface tension: 50.5
mN/m). The time required for redispersion of fluorometholone in
this concentration range of HPMC was about 6 seconds and the
condition of the dispersion was satisfactory.
[0036] The preferred ratio of HPMC to fluorometholone was 0.002 to
0.04 part by weight of the former to 1 part by weight to the
latter.
[0037] (3) Relationship of the concentration of MC to the surface
tension and redispersion time of fluorometholone 0.1 w/v %
suspension
[0038] With the concentration of MC being 0.0001 w/v % and below,
the surface tension was almost constant at 72.5 mN/m. The surface
tension began to decline at 0.0001 w/v % MC and the decrease in
surface tension almost ceased at 0.01 w/v %, when a tension value
of 54.5 mN/m was recorded. On the other hand, when the
concentration of MC was 0.0001 w/v % or less, the redispersion time
was as short as 2 seconds or less but the dispersed particles
aggregated and floated, failing to give a uniform suspension.
Within the concentration range of 0.0001 to 0.01 w/v % MC, the
necessary redispersion time was 9 to 10.7 seconds, with
redispersion taking place rapidly without aggregation of dispersed
particles. When the concentration of MC was over 0.01 w/v %, the
redispersion time was found to be close to 20 seconds, with
redispersibility being adversely affected.
[0039] The preferred ratio of MC to fluorometholone was 0.001 to
0.1 part by weight of the former to 1 part by weight of the
latter.
[0040] (4) Relationship of the concentration of HPMC to the surface
tension and redispersion time of indomethacin 0.2 w/v %
suspension
[0041] When the concentration of HPMC was less than 0.0001 w/v %,
the surface tension was almost constant at 72 mN/m. The surface
tension began to decline at 0.0001 w/v % HPMC and the decrease in
surface tension almost ceased at 0.01 w/v % HPMC, with a tension
value of 48 mN/m being recorded. On the other hand, when the
concentration of HPMC was below 0.0001 w/v %, the redispersion time
was as short as 7 seconds or less but the dispersed particles
aggregated and floated, failing to give a uniform suspension.
Within the concentration range of 0.0001 to 0.01 w/v % HPMC, the
redispersion time was 6.3 to 8.3 seconds, with the drug being
rapidly redispersed without aggregation. When the concentration of
HPMC was over 0.01 w/v %, the redispersibility was found to
deteriorate, with the redispersion time exceeding 12 seconds.
[0042] The preferred ratio of HPMC to indomethacin was 0.0005 to
0.05 part by weight of the former to 1 part by weight of the
latter.
[0043] (5) Relationship of the concentration of HPMC to the surface
tension and redispersion time of indomethacin 1.0 w/v %
suspension
[0044] When the concentration of HPMC was below 0.0005 w/v %, the
surface tension was almost constant at 72.73 mN/m. The surface
tension began to decline at 0.0005 w/v % HPMC and the decrease in
surface tension almost ceased at 0.005 w/v %, at which level a
tension value of 49.7 mN/m was recorded. On the other hand, when
the concentration of HPMC was less than 0.0005 w/v %, the
redispersion time was not more than 7 seconds but the dispersed
particles aggregated and floated, failing to give a uniform
suspension. Within the concentration range of 0.0005 to 0.005 w/v %
HPMC, the redispersion time was 7.3 to 16 seconds, with the drug
particles being rapidly redispersed without aggregation. When the
concentration of HPMC exceeded 0.005 w/v %, the redispersion time
was increased to more than 20 seconds, with the redispersibility
deteriorating.
[0045] The preferred ratio of HPMC to indomethacin was 0.0005 to
0.005 part by weight of the former to 1 part by weight of the
latter.
[0046] (6) Relationship of the concentration of PVP to the surface
tension of fluorometholone 0.05 w/v % suspension
[0047] The surface tension began to decline at 0.0002 w/v % PVC
(surface tension: 72.3 mN/m) and the decrease in surface tension
almost ceased at 0.001 w/v % (surface tension: 69.5 mN/m).
[0048] The preferred ratio of PVP to fluorometholone was 0.004 to
0.02 part by weight of the former to 1 part by weight of the
latter.
[0049] (7) Relationship of the concentration of PVP to the surface
tension of fluorometholone 0.1 w/v % suspension
[0050] When the concentration of PVP was less than 0.0003 w/v %,
the surface tension was almost constant at 72.5 mN/m. The surface
tension began to decline at 0.0003 w/v % and the decrease in
surface tension almost ceased at 0.002 w/v % where a tension value
of 69.5 mN/m was recorded. The time necessary for redispersion of
fluorometholone in this concentration range was about 6 seconds and
the condition of the dispersion was satisfactory. When the
concentration of PVP was in excess of 0.002 w/v %, the redispersion
time was prolonged to 18 seconds or longer, with the
redispersibility being found to deteriorate.
[0051] The preferred ratio of PVP to indomethacin was 0.003 to 0.02
part by weight of the former to 1 part by weight of the latter.
[0052] The above results indicate that although the surface tension
of the aqueous suspension is dependent on the kind of water-soluble
polymer added and the kind and concentration of hardly soluble
drug, suspensions of hardly soluble drugs with good
redispersibility can be prepared within the concentration range of
the water-soluble polymer from the level where the surface tension
begins to decline to the level where the decrease in surface
tension ceases, regardless of the kind of water-soluble
polymer.
TEST EXAMPLE 2
Redispersibility Test Under Accelerated Conditions
[0053] Method
[0054] Ophthalmic preparations were prepared according to Examples
2 and 4 presented below and each preparation was filled in a 5 ml
polypropylene bottle. After the bottle was centrifuged at 200 G for
10 minutes for forced sedimentation of the suspended particles, it
was caused to spin (60 rpm) on the variable mix rotor VMR-5 (60
rpm, Iuchi) and the redispersion time was measured.
[0055] Results
[0056] The redispersion times of the ophthalmic preparations of
Examples 2 and 4 were 4 seconds and 7 seconds, respectively. Gross
observation of each redispersed suspension showed a uniform
dispersion of fine particles.
[0057] The above results indicate that in the case of the aqueous
suspension according to the invention, its redispersibility is well
maintained even under the rugged condition of forced sedimentation
of the particles by centrifugation and is not affected by the
buffer and preservative ingredients, either.
1 Example 1: Ophthalmic preparation Fluorometholone 0.1 g
Methylcellulose 0.0006 g Sodium chloride 0.85 g Disodium
hydrogenphosphate dodecahydrate 0.1 g Benzalkonium chloride 0.005 g
0.1 N Hydrochloric acid q.s. to make pH 7.0 Purified water q.s. to
make 100 ml.
[0058] Methylcellulose was dissolved in about 80 ml of purified
water by effecting dispersion with warming, followed by cooling to
room temperature. Sodium chloride, Disodium hydrogenphosphate
dodecahydrate and benzalkonium chloride were added for dissolution.
The pH was adjusted to 7 by adding hydrochloric acid.
Fluorometholone was added and uniform suspension was effected using
a homogenizer. Purified water was added to make the whole volume
100 ml. A fluorometholone suspension ophthalmic preparation was
thus prepared.
2 Example 2: Ophthalmic preparation Fluorometholone 0.05 g
Methylcellulose 0.0003 g Sodium chloride 0.85 g Sodium dihydrogen
phosphate dihydrate 0.1 g Benzalkonium chloride 0.005 g 0.1 N
Sodium hydroxide q.s. to make pH 7.0 Purified water q.s. to make
100 ml.
[0059] A fluorometholone suspension ophthalmic preparation was
prepared in the same manner as in Example 1.
3 Example 3: Ophthalmic preparation Fluorometholone 0.02 g
Methylcellulose 0.0001 g Sodium chloride 0.85 g Disodium
hydrogenphosphate dodecahydrate 0.1 g Benzalkonium chloride 0.005 g
0.1 N Hydrochloric acid q.s. to make pH 7.0 Purified water q.s. to
make 100 ml.
[0060] A fluorometholone suspension ophthalmic preparation was
prepared in the same manner as in Example 1.
4 Example 4: Ophthalmic preparation Fluorometholone 0.05 g
Polyvinylpyrrolidone K30 0.0015 g Sodium chloride 0.9 g Sodium
dihydrogen phosphate dihydrate 0.1 g Benzalkonium chloride 0.005 g
0.1 N Sodium hydroxide q.s. to make pH 7.0 Purified water q.s. to
make 100 ml.
[0061] Polyvinylpyrrolidone, sodium chloride, sodium dihydrogen
phosphate dihydrate and benzalkonium chloride were added to about
80 ml of purified water and dissolution was effected. The pH was
adjusted to 7 by adding 0.1N sodium hydroxide. Fluorometholone was
added and uniform suspension was effected ultrasonically. The whole
volume was made 100 ml by adding purified water. A fluorometholone
suspension ophthalmic preparation was thus prepared.
5 Example 5: Ophthalmic preparation Sulfamonomethoxine 0.1 g
Hydroxypropylmethylcellulose 0.001 g Sodium acetate 0.1 g
Benzalkonium chloride 0.005 g Sodium chloride 0.9 g 0.1 N
Hydrochloric acid q.s. to make pH 5.0 Purified water q.s. to make
100 ml.
[0062] Hydroxypropylmethylcellulose was dissolved in about 80 ml of
purified water by effecting dispersion with warming, followed by
cooling to room temperature. Sodium chloride, sodium acetate and
benzalkonium chloride were added and dissolution was effected. The
pH was adjusted to 5 by adding hydrochloric acid.
Sulfamonomethoxine was added and uniform suspension was effected by
means of a mill. The whole amount was made 100 ml by adding
purified water. A sulfamonomethoxine suspension ophthalmic
preparation was thus prepared.
6 Example 6: Nasal drops Hydrocortisone acetate 0.1 g
Hydroxypropylmethylcellulose 0.0008 g Sodium dihydrogen phosphate
0.1 g Methylparaben 0.026 g Propylparaben 0.014 g Concentrated
glycerin 2.6 g 0.1 N Sodium hydroxide q.s. to make pH 7.0 Purified
water q.s. to make 100 ml.
[0063] Methylparaben and propylparaben were dissolved in about 80
ml of purified water with warming. Hydroxypropylmethylcellulose was
dispersed in the warm solution for effecting dissolution, followed
by cooling to room temperature. Concentrated glycerin and sodium
dihydrogen phosphate were added and dissolution was effected. The
pH was adjusted to 7 by adding sodium hydroxide. Hydrocortisone
acetate was added and uniform suspension was effected using a
mixer. The whole volume was made 100 ml by adding purified water. A
hydrocortisone acetate suspension for nasal application was thus
prepared.
7 Example 7: Parenteral preparation (injection) Estradiol benzoate
5.0 g Hydroxypropylcellulose 0.03 g Chlorobutanol 0.3 g Sodium
chloride 0.9 g Purified water q.s. to make 100 ml.
[0064] Chlorobutanol was dissolved in about 80 ml of purified water
with warming. Hydroxypropylcellulose was dissolved in the solution
by effecting dispersion with warming, followed by cooling to room
temperature. Sodium chloride was added for dissolution, estradiol
benzoate was added, and uniform suspension was effected using a
homogenizer. The whole volume was made 100 ml by adding purified
water. An estradiol benzoate suspension for parenteral
administration was thus prepared.
8 Example 8: Preparation for oral administration Mefenamic acid 3.0
g Methylcellulose 0.01 g Sorbitol 20 g 5% Ethylparaben solution 1
ml Purified water q.s. to make 100 ml.
[0065] Methylcellulose was dissolved in about 50 ml of purified
water by effecting dispersion with warming, followed by cooling to
room temperature. Sorbitol and 5% ethylparaben solution were added
for dissolution. Mefenamic acid was added and uniform suspension
was effected using a homogenizer. The whole volume was made 100 ml
by adding purified water. A mefenamic acid suspension for oral
administration was thus prepared.
9 Example 9: Lotion Indomethacin 7.5 g Hydroxypropylcellulose 0.04
g dl-Camphor 0.5 g Purified water q.s. to make 100 ml.
[0066] Hydroxypropylcellulose was dissolved in about 50 ml of
purified water by effecting dispersion with warming, followed by
cooling to room temperature. dl-Camphor was added for dissolution.
Indomethacin was added and uniform suspension was effected
ultrasonically. The whole volume was made 100 ml by adding purified
water. An indomethacin suspension lotion was thus prepared.
INDUSTRIAL APPLICABILITY
[0067] The aqueous suspension of the present invention has good
redispersibility and therefore can be utilized as an excellent
aqueous suspension preparation, for example ophthalmic preparation,
nasal drops, parenteral preparation, oral preparation, lotion or
the like.
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