U.S. patent application number 13/688659 was filed with the patent office on 2013-04-18 for ciclesonide containing aqueous pharmaceutical composition.
This patent application is currently assigned to NYCOMED GmbH. The applicant listed for this patent is NYCOMED GmbH. Invention is credited to Atsuhiro NAGANO, Yoshihisa NISHIBE, Kazuya TAKANASHI.
Application Number | 20130095146 13/688659 |
Document ID | / |
Family ID | 17856339 |
Filed Date | 2013-04-18 |
United States Patent
Application |
20130095146 |
Kind Code |
A1 |
NAGANO; Atsuhiro ; et
al. |
April 18, 2013 |
CICLESONIDE CONTAINING AQUEOUS PHARMACEUTICAL COMPOSITION
Abstract
An aqueous pharmaceutical composition which comprises
ciclesonide, crystalline cellulose carmellose sodium and
hydroxypropylmethylcellulose is provided.
Inventors: |
NAGANO; Atsuhiro; (Tokyo,
JP) ; NISHIBE; Yoshihisa; (Iwakuni-shi, JP) ;
TAKANASHI; Kazuya; (Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NYCOMED GmbH; |
Konstanz |
|
DE |
|
|
Assignee: |
NYCOMED GmbH
Konstanz
DE
|
Family ID: |
17856339 |
Appl. No.: |
13/688659 |
Filed: |
November 29, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10110632 |
Jul 15, 2002 |
8383611 |
|
|
PCT/JP2000/007351 |
Oct 20, 2000 |
|
|
|
13688659 |
|
|
|
|
Current U.S.
Class: |
424/400 ;
514/171; 514/174 |
Current CPC
Class: |
A61K 31/14 20130101;
A61P 5/46 20180101; A61P 5/44 20180101; A61K 31/58 20130101; A61K
47/38 20130101; A61K 9/146 20130101; A61P 43/00 20180101; A61P
11/00 20180101 |
Class at
Publication: |
424/400 ;
514/174; 514/171 |
International
Class: |
A61K 31/58 20060101
A61K031/58; A61K 31/14 20060101 A61K031/14 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 20, 1999 |
JP |
11-298186 |
Claims
1-14. (canceled)
15. An aqueous pharmaceutical composition which comprises
ciclesonide, crystalline cellulose carmellose sodium and
hydroxypropylmethylcellulose, wherein said crystalline cellulose
carmellose sodium concentration is 1.7% w/w, and wherein said
hydroxypropylmethylcellulose concentration is from 0.1% w/w to 0.5%
w/w, relative to the total amount of the composition.
16. An aqueous pharmaceutical composition according to claim 15,
which further comprises one or more types of a water-insoluble
substance and/or water-low soluble substance which is one or more
types of cellulose.
17. An aqueous pharmaceutical composition according to claim 16,
which further comprises a water-soluble polymer substance.
18. An aqueous pharmaceutical composition according to claim 17,
wherein said water-soluble polymer substance is one or more types
selected from the group consisting of polyethylene glycol,
propylene glycol alginate, pectin, methoxyl pectin, guar gum, gum
arabic, carrageenan, methylcellulose, xanthan gum and
hydroxypropylcellulose.
19. An aqueous pharmaceutical composition according to claim 17,
wherein said water-soluble polymer substance is polyethylene
glycol.
20. An aqueous pharmaceutical composition according to claim 17,
wherein said water-soluble polymer substance is
hydroxypropylcellulose.
21. An aqueous pharmaceutical composition according to claim 15,
which further comprises a water-soluble polymer substance.
22. An aqueous pharmaceutical composition according to claim 21,
wherein said water-soluble polymer substance is one or more types
selected from the group consisting of polyethylene glycol,
propylene glycol alginate, pectin, methoxyl pectin, guar gum, gum
arabic, carrageenan, methylcellulose, xanthan gum and
hydroxypropylcellulose.
23. An aqueous pharmaceutical composition according to claim 21,
wherein said water-soluble polymer substance is polyethylene
glycol.
24. An aqueous pharmaceutical composition according to claim 21,
wherein said water-soluble polymer substance is
hydroxypropylcellulose.
25. An aqueous pharmaceutical composition according to claim 15,
wherein the ciclesonide particles have a size of between about 10
nm and about 100 .mu.m.
26. An aqueous pharmaceutical composition according to claim 15,
wherein the ciclesonide particles have a size of between about 10
nm and about 10 .mu.m.
27. An aqueous pharmaceutical composition according to claim 15,
further comprising at least one wetting agent.
28. An aqueous pharmaceutical composition according to claim 27,
wherein at least one wetting agent present is selected from the
group consisting of Polysorbate 80, glycerin monostearate, polyoxyl
stearate, lauromacrogol, sorbitan oleate and sucrose fatty acid
esters.
29. An aqueous pharmaceutical composition according to claim 15,
further comprising at least one osmotic-pressure controlling
agent.
30. An aqueous pharmaceutical composition according to claim 29,
wherein at least one osmotic-pressure controlling agent present is
a salt.
31. An aqueous pharmaceutical composition according to claim 30,
wherein the salt is sodium chloride.
32. An aqueous pharmaceutical composition according to claim 29,
wherein at least one osmotic-pressure controlling agent present is
a water-soluble sugar.
33. An aqueous pharmaceutical composition according to claim 32,
wherein the water-soluble sugar is glucose.
34. An aqueous pharmaceutical composition according to claim 15,
wherein the ciclesonide is present in a concentration of between
about 0.01% w/w and about 1% w/w, relative to the total amount of
the composition.
35. An aqueous pharmaceutical composition according to claim 15,
wherein the ciclesonide is present in a concentration of between
about 0.05% w/w and about 0.5% w/w, relative to the total amount of
the composition.
36. An aqueous pharmaceutical composition according to claim 15,
further comprising at least one antiseptic.
37. An aqueous pharmaceutical composition according to claim 36,
wherein at least one antiseptic present is benzalkonium
chloride.
38. An aqueous pharmaceutical composition according to claim 15,
further comprising at least one pH controlling agent.
39. An aqueous pharmaceutical composition according to claim 38,
wherein at least one pH controlling agent present is selected from
the group consisting of hydrochloric acid and sodium hydroxide.
40. An aqueous pharmaceutical composition according to claim 38,
wherein the at least one pH controlling agent is hydrochloric
acid.
41. An aqueous pharmaceutical composition according to claim 15,
further comprising at least one preservative.
42. An aqueous pharmaceutical composition according to claim 41,
wherein at least one preservative present is ascorbic acid.
43. An aqueous pharmaceutical composition according to claim 15,
further comprising at least one buffer.
44. An aqueous pharmaceutical composition according to claim 43,
wherein at least one buffer present is selected from the group
consisting of phosphoric acid and salts thereof.
45. An aqueous pharmaceutical composition according to claim 15,
further comprising (a) at least one pH controlling agent, and (b)
at least one antiseptic or at least one preservative.
Description
FIELD OF INVENTION
[0001] The present invention relates to a ciclesonide-containing
aqueous pharmaceutical composition for use in drug therapy that
contains ciclesonide and hydroxypropylmethylcellulose, wherein said
ciclesonide is dispersed in an aqueous medium in the form of solid
particles. More particularly, the present invention relates to a
ciclesonide-containing aqueous pharmaceutical composition having
excellent ciclesonide dispersivity during production as compared
with conventional aqueous pharmaceutical compositions.
BACKGROUND ART
[0002] Ciclesonide aqueous pharmaceutical compositions containing
ciclesonide dispersed in an aqueous medium in a form of solid
particles are expected to represent a useful drug form for reasons
that include 1) it is not necessary to completely dissolve
ciclesonide, 2) it can be directly administered to an affected site
by spraying and so forth for treatment of local diseases such as
those of the nasal mucosa, eyes and epidermis, and 3) they are
easier to swallow than tablets or granule and so forth.
[0003] When present in an aqueous medium, ciclesonide is resistant
to wetting and easily aggregates. The addition of wetting agent
such as Polysorbate 80 and powerful stirring and so forth during
production have been used in the prior art for the purpose of
dispersing drug having such properties in an aqueous medium in a
stable state.
[0004] Improvement of drug dispersivity of aqueous pharmaceutical
compositions containing a drug dispersed in an aqueous medium in
form of solid particles by addition of cellulose-based polymer is
disclosed in Morishima et al. patent specification of WO99-37286.
However, this patent relates to the redispersion of a drug that has
settled during storage, and is fundamentally different from the
present invention which relates to overcoming drawbacks of the
migration of ciclesonide towards bubbles formed by powerful
stirring during the production, and the adsorption of ciclesonide
to the walls of the production apparatus. Moreover, the
concentration of the cellulose-based polymer in the patent
specification of Morishima et al. is 0.0001 to 0.003%, and
methylcellulose can be used in place of
hydroxypropylmethylcellulose for the cellulose-based polymer, while
the addition of a nonionic surfactant is also required. It is not
easy to deduce the present invention from this patent in which the
optimum value of the hydroxypropylmethylcellulose concentration is
from 0.01% w/w to 0.5% w/w, and does not require a surfactant.
DISCLOSURE OF THE INVENTION
[0005] During the course of production of ciclesonide aqueous
pharmaceutical compositions, high shearing force is required to
disperse ciclesonide and it is necessary to powerfully stir
ciclesonide-containing aqueous pharmaceutical composition.
Ciclesonide migrates to the bubbles formed at this time. Since this
results in an increased concentration of ciclesonide in the upper
portion of the ciclesonide aqueous pharmaceutical composition being
higher than that in the lower portion, variation occurs in the
ciclesonide concentration of ciclesonide aqueous pharmaceutical
compositions produced. Moreover, the recovery rate decreases due to
adsorption of ciclesonide to the walls and so forth of the
production apparatus.
[0006] These variations in ciclesonide concentration and adsorption
of ciclesonide to the production apparatus were hardly improved at
all by the addition of wetting agents such as Polysorbate 80 that
have been used in the prior art. Conversely, the amount of formed
bubbles increases resulting in promotion of further variation in
ciclesonide concentration.
[0007] Therefore, there is a considerable need for the development
of a ciclesonide aqueous pharmaceutical composition that is able to
avoid variations in ciclesonide concentrations during production as
well as the decrease in ciclesonide recovery rate.
[0008] Namely, the object of the present invention is to provide a
ciclesonide aqueous pharmaceutical composition that avoids
variations in ciclesonide concentration during production as well
as decreases in the ciclesonide recovery rate.
[0009] As a result of earnest studies to solve the above problems,
the inventors of the present invention found that a ciclesonide
aqueous pharmaceutical composition can be provided that avoids
variations in ciclesonide concentrations during production as well
as decreases in the ciclesonide recovery rate, by using a
ciclesonide aqueous pharmaceutical composition containing
ciclesonide and hydroxypropylmethylcellulose, thereby leading to
completion of the present invention.
[0010] Namely, the present invention relates to an aqueous
pharmaceutical composition containing ciclesonide and
hydroxypropylmethylcellulose, wherein said ciclesonide is dispersed
in an aqueous medium in form of solid particles.
EMBODIMENT FOR CARRYING OUT THE INVENTION
[0011] It is essential that composition of the present invention
contain ciclesonide, while water-soluble, water-low soluble or
water-insoluble drugs other than ciclesonide can be added. Specific
examples of these include vasoconstrictors, bronchodilators,
anti-allergic agents and expectorants.
[0012] Although the ciclesonide particles that can be used in the
present invention may be of any size, they are preferably within
the range of 10 nm to 100 .mu.m, and particularly preferably within
the range of 10 nm to 10 .mu.m.
[0013] Although any substances may be used for the water-insoluble
or water-low soluble substance that can be used in the present
invention, a preferable example is a cellulose, and a particularly
preferable example is crystalline cellulose.
[0014] In the present invention, the concentration of
water-insoluble substance and/or water-low soluble substance
present in form of solid particles in an aqueous medium is
preferably 0.3% w/w and above, and particularly preferably 1% w/w
to 10% w/w, relative to the total amount of the composition.
[0015] In addition, an aqueous polymer substance can also be added
in the present pharmaceutical composition. Specific examples of
such include propylene glycol alginate, pectin, low methoxyl
pectin, gua gum, gum arabic, carrageenan, methylcellulose,
carboxymethylcellulose sodium, xanthan gum and
hydroxypropylcellulose, while particularly preferable examples
include carboxymethylcellulose sodium, polyethylene glycol and
hydroxypropylcellulose. In addition, crystalline cellulose
carmellose sodium, is an example of a combination of these
water-soluble substances and water-insoluble substances that can be
used in the present invention, and it consists of a mixture of
carboxymethylcellulose sodium and crystalline cellulose.
Furthermore, in the case of adding these water-soluble polymer
substances, the concentration of said substance is preferably 1%
w/w to 30% w/w relative to the water-insoluble substance and/or
water-low soluble substance.
[0016] The ciclesonide-containing aqueous pharmaceutical
composition of the present invention is also required to contain
hydroxypropylmethylcellulose. Although this may be of any grade, a
specific example is hydroxypropylmethylcellulose 2910.
[0017] Although said hydroxypropylmethylcellulose may be present at
any concentration, its concentration is preferably from 0.01% w/w
to 30% w/w, particularly preferably from 0.01% w/w to 5% w/w, more
particularly preferably from 0.01% w/w to 1% w/w, and most
preferably from 0.01% w/w to 0.5% w/w, relative to the total amount
of composition.
[0018] A wetting agent, although not essential in the present
invention, can be added, specific examples of which include
Polysorbate 80, glycerin monostearate, polyoxyl stearate,
lauromacrogol, sorbitan oleate and sucrose fatty acid esters.
[0019] In the present invention, a substance for controlling
osmotic pressure (osmotic pressure-controlling agent) can be added
to control osmotic pressure, specific examples of which include
salts such as sodium chloride and water-soluble sugars such as
glucose, with glucose being a particularly preferable example.
[0020] An effective amount of ciclesonide used in the present
invention can be determined according to the type and degree of the
respective disease, as well as the age and body weight of the
patient, and so forth.
[0021] The concentration of ciclesonide of the present invention is
preferably. from 0.01% w/w to 1% w/w, and particularly preferably
from 0.05% w/w to 0.5% w/w, relative to the total amount of the
composition.
[0022] Any method for dispersing a water-insoluble substance and/or
water-low soluble substance in an aqueous medium may be used for
the production of the ciclesonide-containing aqueous pharmaceutical
composition in the present invention, a specific example of which
is a method that uses a homomixer.
[0023] Known antiseptics, pH controlling agents, preservatives,
buffers, colorants, smell corrigents and so forth may be added as
necessary to the composition of the present invention to improve
its physical properties, appearance or odor and so forth of the
formulation. Examples of antiseptics include benzalkonium chloride,
examples of pH controlling agents include hydrochloric acid and
sodium hydroxide, examples of preservatives include ascorbic acid,
examples of buffers include phosphoric acid and its salt, examples
of colorants include red dye no. 2, and examples of smell
corrigents include menthol.
[0024] According to the present invention as described above, a
ciclesonide aqueous pharmaceutical composition is provided that
avoids variations in ciclesonide concentration during production as
well as decreases in the recovery rate of ciclesonide more
effectively than aqueous pharmaceutical compositions of the prior
art. These effects also lead to improved quality as well as
decreased production cost due to the higher recovery rate.
[0025] Thus, the present invention has extremely high significance
in terms of both quality and economy for the production of
ciclesonide aqueous pharmaceutical compositions.
EXAMPLES
[0026] The following provides an explanation of the present
invention through its Examples.
[0027] Ciclesonide used in the present invention was manufactured
by Byk Gulden Co., the crystalline cellulose carmellose sodium by
Asahi Chemical Industry Co., Ltd. (Avicel.TM. RC-A591NF),
hydroxypropylmethylcellulose 2910 by Shin-Etsu Chemical Co., Ltd.
(TC-5RW.TM. or Metrose 60SH-4000.TM.), Polysorbate 80 by Nippon
Surfactant Co., Ltd., and the sorbitan trioleate by Nikko Chemical
Co., Ltd. ROBOMICS.TM. manufactured by Tokushu Kika Kogyo Co., Ltd.
was used for the homomixer.
Example 1
[0028] Ciclesonide aqueous pharmaceutical compositions containing
the components indicated below were prepared on a 300 ml scale by
processing with a homomixer.
[0029] Homomixer processing was performed at 6000 rpm for 30
minutes.
[0030] Composition (1)
[0031] Ciclesonide: 0.1% w/w
[0032] Crystalline cellulose carmellose sodium: 1.7% w/w
[0033] Hydroxypropylmethylcellulose 2910 (TC-5RW.TM.): 0.01%
w/w
[0034] Composition (2)
[0035] Ciclesonide: 0.1% w/w
[0036] Crystalline cellulose carmellose sodium: 1.7% w/w
[0037] Hydroxypropylmethylcellulose 2910 (TC-5RW.TM.): 0.1% w/w
[0038] Composition (3)
[0039] Ciclesonide: 0.1% w/w
[0040] Crystalline cellulose carmellose sodium: 1.7% w/w
[0041] Hydroxypropylmethylcellulose 2910 (TC-5RW.TM.): 1% w/w
[0042] Composition (4)
[0043] Ciclesonide: 0.1% w/w
[0044] Crystalline cellulose carmellose sodium: 1.7% w/w
[0045] Hydroxypropylmethylcellulose 2910 (Metrose 60SH-4000.TM.):
0.01% w/w
[0046] Composition (5)
[0047] Ciclesonide: 0.1% w/w
[0048] Crystalline cellulose carmellose sodium: 1.7% w/w
[0049] Hydroxypropylmethylcellulose 2910 (Metrose 60SH-4000.TM.):
0.1% w/w
[0050] Immediately after processing compositions 1 to 5 with the
homomixer, the ciclesonide aqueous pharmaceutical compositions were
collected from the upper and lower portions of the emulsification
tank, followed by quantification of the ciclesonide concentrations
by HPLC. The value for the upper portion of the emulsification tank
was calculated by taking the ciclesonide concentration in the lower
portion of the emulsification tank to be 100%.
[0051] Subsequently, the ciclesonide concentrations of the
ciclesonide aqueous pharmaceutical compositions recovered from the
emulsification tank were quantified by HPLC, and the ciclesonide
recovery rates were determined based on the theoretical value of
the ciclesonide concentration as calculated from the charged
amount.
[0052] Those values are shown in Table 1.
Comparative Example 1
[0053] Ciclesonide aqueous pharmaceutical compositions containing
the components indicated below were prepared on a 300 ml scale by
processing with a homomixer. Homomixer processing was performed at
6000 rpm for 30 minutes.
[0054] Composition (6)
[0055] Ciclesonide: 0.1% w/w
[0056] Crystalline cellulose carmellose sodium: 1.7% w/w
[0057] Polysorbate 80: 0.1% w/w
[0058] Composition (7)
[0059] Ciclesonide: 0.1% w/w
[0060] Crystalline cellulose carmellose sodium: 1.7% w/w
[0061] Sorbitan trioleate: 0.1% w/w
[0062] Immediately after processing compositions 6 and 7 with the
homomixer, the ciclesonide aqueous pharmaceutical compositions were
collected from the upper and lower portions of the emulsification
tank, followed by quantification of the ciclesonide concentrations
by HPLC. The value for the upper portion of the emulsification tank
was calculated by taking the ciclesonide concentration in the lower
portion of the emulsification tank to be 100%.
[0063] Subsequently, the ciclesonide concentrations of the
ciclesonide aqueous pharmaceutical compositions recovered from the
emulsification tank were quantified by HPLC, and the ciclesonide
recovery rates were determined based on the theoretical value of
the ciclesonide concentration as calculated from the charged
amount.
[0064] Those values are shown in Table 1.
TABLE-US-00001 TABLE 1 Ciclesonide concentration immediately after
processing (%) Upper portion Lower portion of emulsi- of emulsi-
Recovery Preparation fication tank fication tank rate (%)
Embodiment 1 Composition 1 138.1 100.0 104.2 Composition 2 100.3
100.0 100.7 Composition 3 99.6 100.0 101.5 Composition 4 147.9
100.0 98.4 Composition 5 100.4 100.0 100.8 Comparative Composition
6 131.1 100.0 78.2 Example 1 Composition 7 438.7 100.0 43.0
[0065] In the case of compositions 2, 3 and 5, which contained 0.1
to 1% w/w of hydroxypropylmethylcellulose 2910, the ciclesonide
concentrations in the emulsification tank immediately after
homomixer processing were uniform, and the recovery rates were
almost 100%. In addition, in the case of compositions 1 and 4,
which contained 0.01% w/w of hydroxypropylmethylcellulose 2910,
although the ciclesonide concentrations in the emulsification tank
immediately after homomixer processing were somewhat non-uniform,
the recovery rates were almost 100%. In contrast, in the case of
composition 6, which contained 0.1% w/w of Polysorbate 80, the
ciclesonide concentration in the upper portion of the
emulsification tank immediately after homomixer processing was more
than 30% higher than in the lower portion. In addition, the
recovery rate decreased by about 20%. In the case of composition 7,
which contained 0.1% w/w of sorbitan trioleate, the ciclesonide
concentration in the upper portion of the emulsification tank
immediately after homomixer processing was more than 40% higher
than in the lower portion, and the recovery rate decreased by more
than half.
[0066] Based on these results, it was determined that the use of a
composition containing hydroxypropylmethylcellulose made it
possible to avoid variation in the concentration of ciclesonide
during production as well as avoid a decrease in the recovery rate
of ciclesonide.
* * * * *