U.S. patent application number 10/582499 was filed with the patent office on 2007-05-24 for aqueous suspensions of ciclesonide for nebulisation.
This patent application is currently assigned to Altana Pharma AG. Invention is credited to Antje Brueck-Scheffler.
Application Number | 20070117783 10/582499 |
Document ID | / |
Family ID | 34684543 |
Filed Date | 2007-05-24 |
United States Patent
Application |
20070117783 |
Kind Code |
A1 |
Brueck-Scheffler; Antje |
May 24, 2007 |
Aqueous suspensions of ciclesonide for nebulisation
Abstract
This invention relates to a method for the preparation of
sterile aqueous suspensions of ciclesonide by sterilization with
moist heat. The invention further relates to pharmaceutical
compositions in particular to sterile aqueous suspensions of
ciclesonide for administration by nebulization in the prophylaxis
and/or treatment of respiratory diseases.
Inventors: |
Brueck-Scheffler; Antje;
(Konstanz, DE) |
Correspondence
Address: |
NATH & ASSOCIATES PLLC
112 South West Street
Alexandria
VA
22314
US
|
Assignee: |
Altana Pharma AG
Byk-Gulden-Str.2
Konstanz
DE
78467
|
Family ID: |
34684543 |
Appl. No.: |
10/582499 |
Filed: |
December 15, 2004 |
PCT Filed: |
December 15, 2004 |
PCT NO: |
PCT/EP04/53495 |
371 Date: |
June 9, 2006 |
Current U.S.
Class: |
514/174 |
Current CPC
Class: |
A61K 31/58 20130101;
A61K 47/26 20130101; A61P 5/38 20180101; C07J 71/00 20130101; A61P
11/06 20180101; A61K 47/10 20130101; A61P 11/00 20180101; C07J
71/0005 20130101; A61K 47/12 20130101; A61K 47/44 20130101; A61K
9/0078 20130101; A61K 47/14 20130101 |
Class at
Publication: |
514/174 |
International
Class: |
A61K 31/58 20060101
A61K031/58 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 16, 2003 |
EP |
03028848.4 |
Claims
1. A method for preparing a sterile aqueous suspension of
ciclesonide suitable for nebulization comprising the steps of: a.
providing an aqueous suspension of ciclesonide, containing one or
more pharmaceutically acceptable excipients, which one or more
excipients are all non-ionic excipients; and b. autoclaving the
aqueous suspension provided in (a).
2. A method for preparing a sterile aqueous suspension of
ciclesonide suitable for nebulization comprising the steps of: a.
providing an aqueous suspension of ciclesonide, containing at least
one non-ionic agent for adjusting osmolality and optionally further
pharmaceutically acceptable excipients; and b. autoclaving the
aqueous suspension provided in (a).
3. The method according to claim 1, wherein ciclesonide is selected
from the group consisting of
[11.beta.,16.alpha.(R)]-16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy--
21-(2-methyl-1-oxopropoxy)pregna-1,4diene-3,20-dione, mixtures of
the compounds
[11.beta.,16.alpha.(S)]-16,17-[(cyclohexylmethylene)bis(oxy)]-1-
1-hydroxy-21-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione)
and
[11.beta.,16.alpha.(R)]-16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy--
21-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione in any
desired mixing ratio, and mixtures of the compounds
[11.beta.,16.alpha.(S)]-16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy--
21-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione) and
[11.beta.,16.alpha.(R)]-16,17-[(cyclohexylmethylene)bis(oxy)]-1-hydroxy-2-
1-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione consisting
essentially of R epimers.
4. The method according to claim 1, wherein ciclesonide is selected
from the group consisting of ciclesonide, solvates of ciclesonide,
physiologically functional derivatives of ciclesonide, solvates of
physiologically functional derivates derivatives of ciclesonide and
mixtures thereof.
5. The method according to claim 4, wherein the physiologically
functional derivative of ciclesonide is selected from the group
consisting of
16.alpha.,17-(22R)-cyclohexylmethylenedioxy-11.beta.,21-dihydroxypregna-1-
,4-diene-3,20-dione,
16.alpha.,17-(22S)-cyclohexylmethylenedioxy-11.beta.,21-dihydroxypregna-1-
,4-diene-3,20-dione, and mixtures thereof in any mixing ratio.
6. The method according to claim 1, wherein the mean particle size
of ciclesonide is less than 12 .mu.m.
7. The method according to claim 2, wherein the non-ionic agent for
adjusting the osmolality is selected from the group consisting of
mannitol, glycerol, glucose, lactose, trehalose, sucrose, propylene
glycol, sorbitol, xylitol, polyethylene glycol, ethanol,
isopropanol, cyclodextrins, derivatives of cyclodextrins and
mixtures thereof.
8. The method according to claim 7, wherein the agent for adjusting
the osmolality is selected from the group consisting of mannitol,
glycerol, glucose and mixtures thereof.
9. The method according to claim 1, wherein the suitable excipients
are selected from the group consisting of agents for adjusting
osmolality, suspending agents, agents for modifying pH of the
suspension, chelating agents, preservatives and mixtures
thereof.
10. The method according to claim 2, wherein the suitable
excipients are selected from the group consisting of suspending
agents, agents for modifying pH of the suspension, chelating
agents, preservatives and mixtures thereof.
11. The method according to claim 10, wherein suitable excipients
are non-ionic excipients.
12. The method according to claim 9, wherein an agent for modifying
the pH of the suspension is present as excipients, which is an
organic acid selected from the group consisting of citric acid,
tartaric acid, lactic acid and mixtures thereof.
13. The method according to claim 9, wherein the suspending agent
is selected from the group consisting of polysorbates, tyloxapol,
poloxamers, poloxamines, polyoxyethylene castor oil derivatives,
phospholipids, hydroxypropylmethylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose,
polyvinylpyrrolidone, polyvinylalcohol and mixtures thereof.
14. The method according to claim 13, wherein the suspending agents
are polyoxyethylene sorbitan fatty acid esters.
15. The method according to claim 1, comprising the steps of a.
dissolving the non-ionic excipients or excipients in water; b.
optionally filtering the solution; c. homogeneously suspending
ciclesonide within the solution and d. autoclaving the aqueous
suspension provided in (c).
16. The method according to claim 2, comprising the steps of a.
dissolving the non-ionic agent for adjusting the osmolality and
optionally other excipients in water; b. optionally filtering the
solution; c. homogeneously suspending ciclesonide within the
solution; and d. autoclaving the aqueous suspension provided in
(c).
17. The method according to claim 1, wherein autoclaving is carried
out at a temperature above 90.degree. C.
18. The method according to claim 17, wherein autoclaving is
carried out at a temperature above 120.degree. C.
19. The method according to claim 17, wherein autoclaving is
carried out at 121.degree. C. for at least 15 minutes.
20. The method according to claim 1, wherein the sterile aqueous
suspension of ciclesonide suitable for nebulization has an
osmolality in the range of 225-430 mosmol/kg.
21. A sterile aqueous suspension of ciclesonide suitable for
nebulization containing one or more pharmaceutically acceptable
excipients, which one or more excipients are all non-ionic
excipients.
22. A sterile aqueous suspension of ciclesonide suitable for
nebulization containing at least one non-ionic agent for adjusting
osmolality and optionally further pharmaceutically acceptable
excipients.
23. The sterile aqueous suspension according to claim 21, having an
osmolality in the range of 225-430 mosmol/kg.
24. The sterile aqueous suspension according to claim 21, wherein
the ciclesonide has a mean particle size of less than 12 .mu.m.
25. The sterile aqueous suspension according to claim 22, wherein
the non-ionic agent for adjusting the osmolality is selected from
the group consisting of mannitol, glycerol, glucose, lactose,
trehalose, sucrose, propylene glycol, sorbitol, xylitol,
polyethylene glycol, ethanol, isopropanol, cyclodextrins,
derivatives of cyclodextrins and mixtures thereof.
26. The sterile aqueous suspension according to claim 25, wherein
the agent for adjusting the osmolality is selected from the group
consisting of mannitol, glycerol, glucose and mixtures thereof.
27. The sterile aqueous suspension according to claim 21, wherein
the suitable excipients are selected from the group consisting of
agents for adjusting osmolality, suspending agents, agents for
modifying pH of the suspension, chelating agents, preservatives and
mixtures thereof.
28. The sterile aqueous suspension according to claim 22, wherein
the suitable excipients are selected from the group consisting of
suspending agents, agents for modifying pH of the suspension,
chelating agents, preservatives and mixtures thereof.
29. The sterile aqueous suspension according to claim 22, wherein
suitable excipients are non-ionic excipients.
30. The sterile aqueous suspension according to claim 27, wherein
an agent for modifying the pH of the suspension is present as an
excipient which is an organic acid selected from the group
consisting of citric acid, tartaric acid, lactic acid and mixtures
thereof.
31. The sterile aqueous suspension according to claim 27, wherein
the suspending agent is selected from the group consisting of
polysorbates, tyloxapol, poloxamers, poloxamines, polyoxyethylene
castor oil derivatives, phospholipids,
hydroxypropylmethylcellulose, hydroxypropylcellulose,
hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone,
polyvinylalcohol and mixtures thereof.
32. The sterile aqueous suspension according to claim 31, wherein
the suspending agents are polyoxyethylene sorbitan fatty acid
esters.
33. An aqueous suspension of ciclesonide for administration by
nebulization, wherein the concentration of ciclesonide within the
suspension for nebulization is in the range of 0.005% to 0.5%
(w/v).
34. The aqueous suspension according to claim 21, wherein the
ciclesonide has a mean particle size of less than 12 .mu.m.
35. The aqueous suspension of ciclesonide according to claim 33,
which is a sterile suspension.
36. The sterile aqueous suspension according to claim 21 for
administration by nebulization, wherein the concentration of
ciclesonide within the suspension for nebulization is in the range
of 0.005% to 0.5% (w/v).
37. The sterile aqueous suspension according to claim 21 containing
as excipients mannitol and polysorbate or glycerol and
polysorbate.
38. The sterile aqueous suspension according to claim 37,
additionally containing hydrochloric acid or citric acid.
39. A method for the prophylaxis or treatment of a clinical
condition in a patient for which a glucocorticosteroid is
indicated, which comprises administration of a therapeutically
effective amount of a sterile aqueous suspension of ciclesonide
according to claim 21.
40. The method according to claim 39, wherein the clinical
condition is asthma the patient is a child and the treatment is a
continuous treatment regimen and the sterile aqueous suspension of
ciclesonide is administered by nebulization.
41. A drug product comprising a sealed container containing a
sterile aqueous suspension according to claim 21, and a label
indicating administration by nebulization in a continuous treatment
regimen.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a method for the preparation of
sterile aqueous suspensions of ciclesonide by sterilization with
moist heat. The invention further relates to pharmaceutical
compositions in particular to aqueous suspensions of ciclesonide
for administration by nebulization in the prophylaxis and/or
treatment of respiratory diseases.
BACKGROUND
[0002] U.S. Pat. No. 5,482,934 discloses
pregna-1,4-diene-3,20-dione-16-17-acetal-21 esters and their use in
the treatment of inflammatory conditions. The compounds have the
general structure: ##STR1## wherein R1 is 2-propyl, 1-butyl,
2-butyl, cyclohexyl or phenyl; and R2 is acetyl or isobutanoyl.
Ciclesonide is the INN for a compound of formula I in which R1 is
cyclohexyl and R2 is isobutanoyl with the chemical name
[11.beta.,16.alpha.(R)]-16,17[(Cyclohexylmethylen)bis(oxy)]-11-hydroxy-21-
-(2-methyl-1-oxopropoxy)pregna-1,4-dien-3,20-dion.
[0003] This compound has undergone evaluation as an antiasthmatic
and pharmacokinetic studies show that it will be useful in an
inhaler formulation. Ciclesonide is only moderately absorbed after
oral administration and has low systemic activity. Concentration of
the drug in the lungs is high and metabolism by liver oxidases is
very high, giving the drug a low plasma half-life. Systemic
activity of ciclesonide is three times lower than that of
budesonide, but anti-inflammatory activity is higher for the
former.
[0004] Suitable formulations for pressurized metered dose inhalers
(MDIs) for inhalation for ciclesonide are for example disclosed in
U.S. Pat. No. 6,264,923 and U.S. Pat. No. 6,120,752.
[0005] Besides dry powder inhalers (DPIs) and pressurized metered
dose inhalers (MDIs) nebulizers represent another class of devices
allowing inhalative drug administration. Especially in case of
children and elderly being not able to handle DPIs and MDIs
correctly, nebulization is the preferred way of drug administration
to the lungs. Thus it is desirable to provide ciclesonide in
formulations suitable for administration by nebulization. Whereas
in case of water-soluble drugs aqueous solutions are nebulized,
this is not possible in case of water-insoluble drugs such as
ciclesonide. Consequently these drug substances have to be applied
in the form of suspensions. In order to allow deposition within the
lungs the particle size of the aerosol droplets after nebulization
needs to be in the range of approximately 1-7 .mu.m. If suspensions
will be administered, the particle size of the suspended drug
particles is critical, since only particles being smaller than the
aerosol droplets themselves are nebulized. For example micronized
drug substance with a mean particle size of 2-6 .mu.m is suitable
for such suspensions.
[0006] Another requirement for suspension for nebulization is that
these suspensions have to be isoosmotic in order to avoid
irritation of the tissue coming into contact with the
formulation.
[0007] In addition formulations for administration by nebulization
have to be sterile. Whereas in case of solutions this can be
achieved by sterilization of the final formulation by moist heat or
by filtration through a bacteria retentive filter, achieving
sterile suspensions with a defined particle size is more difficult.
Sterilization by filtration is no option when micronized drug
substance with a mean particle size of 2-6 .mu.m is used, since the
particles are not able to pass the filter.
[0008] Sterilization of the (powdered) drug substance by dry heat
followed by preparation of the suspension under aseptic conditions
represents another manufacturing method. This is only possible, if
the drug substance is stable enough to withstand the high
temperature during this sterilization process (according to
European Pharmacopoeia 4.07, chapter 5.1.1. a temperature of
160.degree. C. for at least 2 h is required). WO99/25359 describes
a process for the sterilization of a powdered form of a gluco
corticosteroid. WO99/25359 discloses that the sterilization process
of glucocorticosteroids by dry heat can be carried out at a
significantly lower temperature than that considered necessary for
the heat sterilization of other substances. The drug substance is
exposed to 110-120.degree. C. for no longer than 10 h. WO99/25359
further discloses sterile pharmaceutical formulations comprising a
glucocorticosteroid and one or more pharmaceutically acceptable
additives, diluents or carriers. Examples of such additives include
surfactants, pH regulating agents, chelating agents, agents
rendering the suspension isoosmotic and thickening agents. These
sterile formulations can be produced by mixing the sterilized
glucocorticosteroid with any suitable additional ingredients, e.g.
a surfactant, pH regulating or chelating agent, an agent rendering
the suspension isoosmotic or a thickening agent. All components
other than the glucocorticosteroid, can be produced by sterile
filtration of their aqueous solutions. Examples 4 and 5 are related
to sterile formulations comprising budesonide.
[0009] WO00/25746 discloses a process for preparing a sterile
micronised glucocorticosteroid (beclomethasone dipropionate) by
gamma-irradiation.
[0010] To provide the sterile aqueous suspension however it is
needed that the suspension has to be prepared under aseptic
condition throughout the manufacturing process with the sterilized
ingredients including the steroid, indicating that a large and
special manufacturing plant is necessary.
[0011] Another method for providing sterile aqueous pharmaceutical
compositions is sterilization of the suspension by radiation. Ilium
et al (Pharm. Chemi. Sci., Ed. 2, 1974, pp. 167-174) recommend a
sterilization process for steroid-containing aqueous suspension by
beta ray or gamma ray irradiation.
[0012] Another very common sterilization process for sterilizing of
pharmaceutical compositions is autoclaving (sterilization by moist
heat). Since the autoclaving is done by heating usually at
121.degree. C., the method cannot be adopted for unstable drugs in
the presence of water at such high temperature. In case of
sterilization of the final suspension formulation by moist heat
there is a considerable risk of an increase of the particle size
during the sterilization process. Furthermore ciclesonide does not
seem to be stable chemically at such high temperature, because
ciclesonide has an acetal structure in its 16 and 17 positions.
[0013] WO 04/004739 is related to a ciclesonide-containing sterile
aqueous suspension sterilized by autoclaving, wherein the
concentration of ciclesonide after autoclaving is 95% or more
comparing to that before autoclaving. It is further disclosed that
it has been found that the uniformity of ciclesonide content can be
maintained when hydroxypropylmethylcellulose is present in the
suspension, even after sterilization by autoclaving.
[0014] Commercially available suspension formulations for
glucocorticosteroids for nebulization are e.g. available under the
tradenames Pulmicort.TM. and Flixotide.TM.. Pulmicort.TM. nebules
contain budesonide as drug substance. Besides the drug substance
the suspension is composed of sodium chloride (agent to adjust
osmolality) polysorbate 80 (suspending agent), sodium EDTA
(chelating agent) citric acid/sodium citrate (buffering agent) and
water. Flixotide.TM. nebules contain fluticasone propionate.
Besides the drug substance the suspension is composed of sodium
chloride (agent to adjust osmolality), polysorbate 20 and sorbitan
monolaurate (suspending agents), monosodium phosphate dihydrate and
dibasic sodium phosphate anhydrous (buffering agent) and water.
This formulation and its preparation are also disclosed in
WO95/31964. On page 4 it is stated that bulk suspensions are
sterilized by means of thermal sterilisation using steam.
[0015] It is an object of the present invention to provide an
aqueous suspension containing ciclesonide, in particular a sterile
aqueous suspension, which is suitable for inhalative
administration.
[0016] When autoclaving aqueous suspensions of ciclesonide for
nebulization containing excipients usually present in formulations
for nebulisation (such as sodium chloride as agent to adjust
osmolality), clogging of ciclesonide particles is observed during
sterilization process, making the suspension no longer suitable for
inhalative application.
DESCRIPTION OF THE INVENTION
[0017] Surprisingly it has been found now that sterile aqueous
suspensions of ciclesonide comprising agents for adjusting
osmolality can be prepared by autoclaving aqueous suspension of
ciclesonide when using non-ionic agents for adjusting the
osmolality as excipients in the suspension. No clogging of
ciclesonide particles and no significant increase of the particle
size of ciclesonide during the sterilization process is
observed.
[0018] Subject of the present invention is therefore a method for
preparing a sterile aqueous suspension of ciclesonide suitable for
nebulization comprising the steps of: [0019] (a) providing an
aqueous suspension of ciclesonide, containing at least one
non-ionic agent for adjusting the osmolality and optionally further
pharmaceutically acceptable excipients and [0020] (b) autoclaving
the aqueous suspension provided in (a).
[0021] Ciclesonide is the INN for an active compound having the
chemical name
[11.beta.,16.alpha.-(R)]-16,17-[(cyclohexylmethylene)bis(oxy)]-11-hy-
droxy-21-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione.
Ciclesonide and its preparation are described in U.S. Pat. No.
5,482,934. According to the invention, the name ciclesonide also
includes solvates of ciclesonide, physiologically functional
derivatives of ciclesonide or solvates thereof. Physiologically
functional derivatives of ciclesonide, which can be mentioned in
connection with the present invention, are preferably chemical
derivatives of ciclesonide, which have a similar physiological
function as ciclesonide or an active metabolite of ciclesonide, for
example the 21-hydroxy derivative of ciclesonide (hereinafter also
referred to as desisobutyryl-ciclesonide=des-CIC). The 21-hydroxy
compound has the chemical name
16.alpha.,17-(22R,S)-cyclohexylmethylenedioxy-11.beta.,21-dihydroxy-pregn-
a-1,4-diene-3,20-dione. This compound and its preparation are
disclosed in WO 94/22899. According to the invention, the name
"ciclesonide" is understood as meaning not only the pure R epimer
of the compound
[11.beta.,16.alpha.]16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy-21-(-
2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione but also R/S
epimer mixtures in any desired mixing ratio (that is the compounds
[11.beta.,16.alpha.(R)]-16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy--
21-(2-methyl-1-oxopropoxy) pregna-1,4diene3,20-dione and
[11.beta.,16.alpha.(S)]-16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy--
21-(2-methyl1-oxopropoxy)pregna-1,4-diene-3,20-dione), those being
preferred which essentially consist of R epimers. According to the
invention, essentially consisting of R epimers means that the
proportion of S epimers in the mixture is less than or equal to 5%,
preferably less than or equal to 1%.
[0022] The mean particle size of ciclesonide present in the aqueous
suspension is preferably within a range, which allows effective
administration of ciclesonide by nebulisalion. Preferably the mean
particle size of ciclesonide (as determined by laser diffraction)
is less than 12 .mu.m, preferably from 0.1 to 8 .mu.m, preferably 1
to 6 .mu.m, particularly preferably 2 to 4 .mu.m Ciclesonide with
such particle size can be obtained by micronization of ciclesonide
particles with greater particle size obtained in the manufacturing
process of ciclesonide (e.g. as described in WO98/009982) or
directly by crystallization processes leading to the desired mean
particle size.
[0023] The amount of ciclesonide, or a pharmaceutical acceptable
salt, solvate or physiologically functional derivative thereof
which is required to achieve a therapeutic effect will, of course,
vary with the subject under treatment, and the particular disorder
or disease being treated. It will further depend on the efficiency
of the nebulizer used and the deposition of the aerosol droplets in
the lung. Suitable concentrations of ciclesonide within the
suspension for nebulization can be in the range of 0.005% to 0.5%
(w/v) (i.e. 0.05 mg/ml to 5 mg/ml).
[0024] Non-ionic agent for adjusting the osmolality in connection
with the invention refers to pharmaceutically acceptable agent,
which is of non-ionic nature and which is customarily used to
render the Pharmaceutical solutions and/or suspensions isoosmotic
with body fluids. Examples for non-ionic agents for adjusting the
osmolality, which can be used in connection with the present
invention, are selected from the group of mannitol, glycerol,
glucose, lactose, trehalose, sucrose, propylene glycol, sorbitol,
xylitol, polyethylene glycol, ethanol, isopropanol, cyclodextrins,
derivatives of cyclodextrines and mixtures thereof. Preferred
examples are mannitol, glycerol, glucose or mixtures thereof. The
aim of adding an agent for adjusting the osmolatity is to provide a
suspension according to the invention, which is isoosmotic or close
to isoosmotic with body fluids, namely 290 mosmol/kg. In a
preferred embodiment of the invention the non-ionic agent for
adjusting osmolality is present in such an amount in the suspension
according to the invention to provide an osmolality of the
suspension in the range of 225-430 mosmol/kg, preferably in the
range of 250 to 350 mosmol/kg, particularly preferably in the range
of 280 to 300 mosmol/kg. As the person skilled in the art will
appreciate the amount of agents needed to adjust the osmolality
will depend on the presence of other excipients within the
formulation contributing to the overall osmolality of the
formulation.
[0025] Besides ciclesonide and the non-ionic agent to adjust the
osmolality the suspension used in the process according to the
invention may contain one ore more additional suitable
excipients.
[0026] Suitable excipients, which can be mentioned include
suspending agents, agents for modifying the pH of the suspension,
chelating agents and optionally preservatives. In this connection
it has been found that ionic excipients, (e.g. ionic buffer
systems), should be avoided in the process according to the
invention as these can lead to increase of particle size and
clogging of ciclesonide in the suspension during autoclaving
process. In a preferred embodiment according to the invention
suitable excipients are selected from the group of non-ionic
excipients.
[0027] In another embodiment the present invention therefore
relates to a method for preparing a sterile aqueous suspension of
ciclesonide suitable for nebulization comprising the steps of:
[0028] a. providing an aqueous suspension of ciclesonide,
containing one or more pharmaceutically acceptable excipients,
which one or more excipients are all non-ionic excipients; and
[0029] b. autoclaving the aqueous suspension provided in (a).
[0030] Suspending agents are used to obtain a uniform distribution
of single particles of ciclesonide within the formulation resulting
in a homogenous suspension. Examples for suspending agents, which
can be mentioned in connection with the invention include
polyoxyethylene sorbitan fatty acid esters (polysorbates), alkyl
aryl polyether alcohols such as tyloxapol, poloxamers, poloxamines,
polyoxyethylene castor oil derivatives, phospholipids,
hydroxypropylmethylcellulose, hydroxypropylcellulose,
hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone,
polyvinylalcohol and mixtures thereof. Preferred suspending agents
are polyoxyethylene castor oil derivatives, poloxamers,
polysorbates, tyloxapol and mixtures thereof. Particularly
preferred suspending agents are polysorbates, e.g. polysorbate 20
(=polyoxyethylene 20 sorbitan monolaurate), polysorbate 80
(=polyoxyethylene 20 sorbitan monooleate). The concentrations of
the suspending agents used within the formulation are largely
depended on the concentration of the suspended drug substance. The
suspending agent is added in an amount to achieve effective
suspension of ciclesonide to provide a homogeneous suspension. The
ratio between drug substance and suspending agent can usually vary
from 0.05 to 50.
[0031] If necessary, agents for modifying the pH of the suspension
can be added. Suitable examples, which may be mentioned are for
example inorganic and organic acids selected from the group of
hydrochloric acid, phosphoric acid, sulphuric acid, citric acid,
tartaric acid, lactic acid and mixtures thereof. Preferably organic
acids are present. As ciclesonide is known to be unstable under
alkaline conditions the pH-value of the suspension should
preferably be adjusted to yield neutral or slightly acidic
conditions.
[0032] Chelating agents such as editic acid or edetate salts can be
added in suitable concentrations (e.g. 0.01-0.1%). They can serve
as antioxidant synergists by sequestering the traces of heavy
metals thereby improving the chemical stability of the drug
substance or of the excipients. In addition, they have some
antimicrobial activity.
[0033] Optionally the formulation according to the invention might
contain one or more preservatives although made sterile by the
process according to the present invention. It is preferred to have
a preservative present in the formulations according to the
invention in order to preserve the microbiological quality during
use. This is especially important in case of multiple dose vials.
Suitable preservatives for example are benzoic acid, sorbic acids
and its salts, propionic acid and its salts, phenol and derivatives
such as cresol and chlorocresol, chlorobutanol, benzyl alcohol,
phenyl ethyl alcohol, butyl paraben and propyl paraben.
[0034] Preferred formulations according to the invention contain
the following components suspended/dissolved in water for
injections: TABLE-US-00001 Ciclesonide micronized 0.025-0.1% (w/v)
Glycerol 2.5% (w/v) Polysorbate 20 0.0125-0.05% (w/v) Ciclesonide
micronized 0.025-0.1% (w/v) Glycerol 2.5% (w/v) Polysorbate 80
0.0125-0.05% (w/v) Ciclesonide micronized 0.025-0.1% (w/v) Mannitol
5.0% (w/v) Polysorbate 20 0.0125-0.05% (w/v) Ciclesonide micronized
0.025-0.1% (w/v) Mannitol 5.0% (w/v) Polysorbate 80 0.0125-0.05%
(w/v)
[0035] In another aspect the present invention relates to a sterile
aqueous suspension of ciclesonide suitable for nebulization
containing one or more pharmaceutically acceptable excipients,
which one or more excipients are all non-ionic excipients.
[0036] In a further aspect the invention also relates to a sterile
aqueous suspension of ciclesonide, containing at least one
non-ionic agent to adjust the osmolality and optionally further
pharmaceutically acceptable excipients. Preferably the sterile
aqueous suspension is obtainable by a method of preparation
according to the present invention. In one embodiment according to
the invention the sterile aqueous suspension does not contain a
preservative.
[0037] In another aspect the invention relates to an aqueous
suspension of ciclesonide for administration by nebulization,
wherein the concentration of ciclesonide within the suspension for
nebulization is in the range of 0.005% to 0.5% (w/v) (i.e. 0.05
mg/ml to 5 mg/ml). In a preferred embodiment the suspension is a
sterile suspension.
[0038] Suspensions used in the process according to the invention
can be prepared by conventional methods for the preparation of
suspension formulations. In a preferred embodiment of the invention
the suspensions used in the process according to the invention can
be prepared by dissolving the non-ionic agent for adjusting the
osmolality and optionally other excipients (e.g. suspension agent)
in purified water or water for injections. If desired, this
solution of excipients can be filtered (sterile filtration).
Ciclesonide with a suitable particle size is homogenously suspended
within the solution (e.g. by stirring or by employing a
turboemulslfier, eg Ultraturrax). The final formulation is filled
into suitable containers (e.g. vials), sealed and sterilized by
moist heat. Alternatively the formulation can be sterilized by
moist heat as bulk and afterwards filled into sterile vials under
aseptic conditions and sealed. Instead of glass vials containers
prepared by a form-fill-seal process are also suitable. In this
case the formulation can be sterilized by moist heat as bulk and
filled under aseptic conditions afterwards. Filling into
form-fill-seal containers and terminal sterilization by moist heat
is also possible.
[0039] Sterilization by moist heat or autoclaving in connection
with the present invention refers to a method of sterilizing in a
suitable autoclaving equipment by steam with high pressure and
temperature which meets the criteria according to US Pharmacopoeia
26, chapter 1211 "Sterilization and sterility assurance of
compendial articles", European Pharmacopeia (Ph. Eur. 4.07, chapter
5.1.1. "Methods of preparation of sterile products"), or other
Pharmacopoelas. Sterile aqueous suspension in this context refers
to an aqueous suspension which meets the criteria according to US
Pharmacopoeia 26 chapter 71 "Sterility tests", European
Pharmacopeia (Ph. Eur. 4.07 chapter 2.6.1. "Sterility" . . . ), or
other Pharmacopoeias.
[0040] In connection with the process according to the invention it
is preferred to expose the formulation to a temperature above
90.degree. C., preferably 120.degree. C., particularly preferably
of at least 121.degree. C. In a still preferred embodiment the
formulation according to the invention is exposed to a temperature
of at least 121.degree. C. for at least 15 min in the presence of
saturated steam under pressure. Other suitable combinations of
temperatures (e.g. temperatures below 90.degree. C.) and time may
be used as well as long as they lead to a sterile formulation as
required by the standards set in the various pharmacopoeias.
[0041] Further subject of the invention is a process comprising the
steps of [0042] (a) dissolving the non-ionic agent for adjusting
the osmolality and optionally other excipients in water; [0043] (b)
optionally filtering the solution; [0044] (c) homogeneously
suspending ciclesonide within the solution and [0045] (d)
autoclaving the aqueous suspension provided in (c). [Amounts
expressed in percent (%) refer to percent of weight, based on the
total weight of the formulation (w/v) unless stated
differently].
[0046] The invention will now be illustrated by the following
examples without restricting it.
EXAMPLES
Example 1
[0047] 2.5 kg of glycerol and 12.5 g of Polysorbate 80 are
dissolved in 100 liters of water for injections. The solution is
filtered through a filter with a pore size of 0.2 .mu.m. 25 g of
micronized ciclesonide is added and the suspension is stirred for
at least 1 hour in order to yield a homogenous suspension. The
suspension is filled into glass vials. Each vial contains 2 ml of
the suspension. The vials are sterilized within an autoclave at a
temperature of 121.degree. C. for 15 min in the presence of
saturated steam.
Example 2
[0048] 5 kg of mannitol and 25 g of Polysorbate 20 are dissolved in
100 liters of water for injections. The solution is filtered
through a filter with a pore size of 0.21 .mu.m. 50 g of micronized
ciclesonide is added and the suspension is stirred for at least 1
hour in order to yield a homogenous suspension. The suspension is
filled into glass vials. Each vial contains 2 ml of the suspension.
The vials is sterilized within an autoclave at a temperature of
121.degree. C. for 15 min in the presence of saturated steam.
Example 3
[0049] 5.5 kg of glucose and 12.5 g of Tyloxapol are dissolved in
100 liters of water for injections. The solution has been filtered
through a filter with a pore size of 0.2 .mu.m. 25 g of micronized
ciclesonide is added and the suspension is stirred for at least 1
hour in order to yield a homogenous suspension. The suspension is
filled into glass bottles containing each about 1 liter. The
bottles are sterilized within an autoclave at a temperature of
121.degree. C. for 20 min in the presence of saturated steam. After
the sterilization process the sterile suspension is filled in a
form-fill-seal process under aseptic conditions. The final product
is composed of 2 ml of the suspension in a form-fill-seal container
made from polyethylene or polypropylene.
Example 4
[0050] 5 kg of mannitol and 25 g of Polysorbate 20 are dissolved in
100 liters of water for injections. The pH of the solution is
adjusted to pH 6 by addition of citric acid. The solution is
filtered through a filter with a pore size of 02 .mu.m. 50 g of
micronized ciclesonide is added and the suspension is stirred for
at least 1 hour in order to yield a homogenous suspension. The
suspension is filled into glass vials. Each vial contains 2 ml of
the suspension. The vials are sterilized within an autoclave at a
temperature of 115.degree. C. for 40 min in the presence of
saturated steam.
Comparative Examples
Example 5
[0051] Suspensions containing 0.05% of micronized ciclesonide,
0.025% of Polysorbate 20 (Formulation I), Polysorbate 80
(Formulation II) or Cremophor RH40 (Formulation II) as suspending
agents and 0.9% of sodium chloride as agent for adjusting the
osmolality in water for injections have been prepared. The
suspensions have been filled into glass vials and have been
sterilized by moist heat (121.degree. C., 20 min). Prior to the
sterilization and afterwards the size of the suspended particles
has been measured by laser diffraction (Particle sizer series 2600,
Malvern, suspension diluted with Polysorbate 80 solution 0.1% in
water, calculation according to Fraunhofer, ultrasound applied if
necessary). d10, d50 and d90 values are presented in the table
below. d10, d50 and d90 values in connection with this invention
mean, that for 10, 50 or 90% of the total volume of particles the
size is lower. Prior to the measurements the samples were shaken in
order to resuspend sedimented particles. TABLE-US-00002 Prior to
sterilization After sterilization Formulation d10 [.mu.m] d50
[.mu.m] d90 [.mu.m] d10 [.mu.m] d50 [.mu.m] d90 [.mu.m] I 1.98 4.15
8.83 13.53 80.06 110.12 II 2.27 4.74 9.32 11.39 79.01 109.92 III
2.05 4.29 8.81 10.37 74.05 108.88
[0052] As indicated in the table for all suspensions an increase of
particles was detected after the sterilization. Large, clogged
agglomerates of particles have been visible.
Example 6
[0053] Suspensions containing 0.05% of micronized ciclesonide,
0.025% of Polysorbate 20 as suspending agent and 2.5% of glycerol
(Formulation IV), 5% of mannitol (Formulation V) or 5% of glucose
(Formulation VI) as agent for adjusting the osmolality in water for
injections have been prepared. The suspensions have been filled
into glass vials and have been sterilized by moist heat
(121.degree. C., 20 min). Prior to the sterilization and afterwards
the size of the suspended particles has been measured by laser
diffraction (Mastersizer 2000, Malvern, suspension diluted with
water, calculation according to Mie, assumed refractive index of
suspended particles 1.52). Prior to the measurements the samples
were shaken in order to resuspend sedimented particles. d10, d50
and d90 values are presented in the table below. TABLE-US-00003
Prior to sterilization After sterilization Formulation d10 [.mu.m]
d50 [.mu.m] d90 [.mu.m] d10 [.mu.m] d50 [.mu.m] d90 [.mu.m] IV
0.432 2.357 4.854 1.260 2.317 3.980 V 0.447 2.260 4.638 1.248 2.281
3.871 VI 0.461 2.424 4.943 1.268 2.713 6.036
[0054] As shown in the table there is no significant increase of
the particle size when non-ionic agents for adjusting the
osmolality are employed. The purity of ciclesonide in all
formulations after the sterilization analysed by HPLC was higher
than 99.5% indicating that the drug substance is stable.
Example 7
[0055] Suspensions containing 0.05% of micronized ciclesonide,
0.025% of Polysorbate 20 as suspending agent and 0.9% of sodium
chloride (Formulation I) as ionic agent for adjusting the
osmolality or no ionic agent at all (Formulation VII) have been
prepared. The suspensions have been filled into glass vials and
have been sterilized by moist heat (121.degree. C., 20 min). Prior
to the sterilization and afterwards the size of the suspended
particles has been measured by laser diffraction (Mastersizer 2000,
Malvern, suspension diluted with water, calculation according to
Mie, assumed refractive index of suspended particles 1.52). Before
the measurements the samples were shaken in order to resuspend
sedimented particles. d10, d50 and d90 values are presented in the
table below. TABLE-US-00004 Prior to sterilization After
sterilization Formulation d10 [.mu.m] d50 [.mu.m] d90 [.mu.m] d10
[.mu.m] d50 [urn] d90 [.mu.m] I 0.382 2.581 5.623 Large white
agglomerates VII 0.393 2.508 5.483 1.259 2.268 3.887
[0056] As shown in the table the suspension containing no ionic
agent for adjusting the osmolality did not show any significant
increase of the particle size after the sterilization process.
Example 8
[0057] In order to evaluate if the sterilized suspensions with
nonionic agents for adjusting the osmolality are stable with regard
to the particle size during storage, the particle size of the
suspensions has been measured after 4 weeks storage at room
temperature. Before the measurements the samples were shaken in
order to resuspend sedimented particles. TABLE-US-00005 Initial
After 4 weeks storage Formulation d10 [.mu.m] d50 [.mu.m] d90
[.mu.m] d10 [.mu.m] d50 [.mu.m] d90 [.mu.m] IV 1.260 2.317 3.980
1.349 2.430 4.087 V 1.248 2.281 3.871 1.320 2.374 3.991 VI 1.268
2.713 6.036 1.223 2.727 6.236
[0058] No significant change of the particle size has been observed
during the storage indicative for the good stability of the
suspension formulations.
Example 9
[0059] Ciclesonide suspensions containing 0.05% of micronized
ciclesonide have been prepared by the method described in example 1
and 2. In addition, citric acid has been added to adjust be pH of
the suspension. Prior to and after sterilization the particle size
of the samples has been measured by the method described in example
6. TABLE-US-00006 Prior to sterilization After sterilization d10
d50 d90 d10 d50 d90 [.mu.m] [.mu.m] [.mu.m] [.mu.m] [.mu.m] [.mu.m]
Polysorbate 20 0.025% Mannitol 5% 0.455 2.355 4.894 1.302 2.806
6.573 Citric acid to pH 4 Polysorbate 20 0.025% Mannitol 5% 0440
2.351 4.810 1.299 2.636 5.002 Citric acid to pH 5 Polysorbate 20
0.025% Mannitol 5% 0.468 2.471 5.137 1.266 2.765 6.785 Citric acid
to pH 6 Polysorbate 20 0.025% 0.475 2.428 5.033 1.325 2.529 4.379
Mannitol 5% pH 7, no citric acid
[0060] As a result no significant change of the particle size after
the sterilization process has been observed.
Example 10
[0061] Ciclesonide suspensions containing 0.05% of micronized
ciclesonide have been prepared by the method described in example 5
and 6. In addition, citric acid buffers pH5 (citric acid/sodium
citrate) at various concentrations have been added to the
suspensions. Prior to and after sterilization the particle size of
the samples has been measured by the method described in example 6.
TABLE-US-00007 Prior to sterilization After sterilization d10 d50
d90 d10 d50 d90 [.mu.m] [.mu.m] [.mu.m] [.mu.m] [.mu.m] [.mu.m]
Polysorbate 20 0.025% Mannitol 5% 0.468 2.445 5.041 1.250 2.886
9.170 Citric acid buffer 0.0001 mol/l Polysorbate 20 0.025%
Mannitol 5% 0.484 2.545 5.241 1.270 4.479 21.788 Citric acid buffer
0.001 mol/l Polysorbate 20 0.025% Mannitol 5% 0.468 2.445 5.041
1.527 6.798 47.779 Citric acid buffer 0.01 mol/l
[0062] The measured particle sizes prior and after sterilization
indicate that with increasing buffer concentration the particle
size after sterilization increases. This shows that the suspensions
containing ionic buffering agents are susceptible to particle
growth during the sterilization process.
Example 11
[0063] Suspensions containing 0.05% of micronized ciclesonide,
0.025% of Polysorbate 20 as suspending agent and 2.5% of glycerol
(Formulation IV) or 5% of mannitol (Formulation V) as agent for
adjusting the osmolality in water for injections have been
prepared. The suspensions have been filled into glass via's and
have been sterilized by moist heat at 110.degree. C. for 120 min.
Prior to and after sterilization the particle size of the samples
has been measured by the method described in example 6.
TABLE-US-00008 After approx. 5 months After sterilization at
storage at room Prior to sterilization 110.degree. C., 120 min
temperature d10 d50 d90 d10 d50 d90 d10 d50 d90 [.mu.m] [.mu.m]
[.mu.m] [.mu.m] [.mu.m] [.mu.m] [.mu.m] [.mu.m] [.mu.m] Tween 20
0.025% 0.932 2.093 4.138 1.388 2.500 4.204 1.314 2.505 4.483
Glycerol 2.5% Tween 20 0.025% 0.785 1.825 4.133 1.269 2.415 4.255
1.255 2.388 4.352 Mannitol 5%
[0064] As a result no significant change of the particle size after
the sterilization process and after approx. 5 months storage of the
sterile formulations at room temperature has been observed.
Commercial Utility
[0065] The aqueous suspension of ciclesonide according to the
invention can be used for the prophylaxis or treatment of a
clinical condition in a mammal, such as a human (also referred to
as patient), for which a glucocorticosteroid is indicated.
Accordingly, the present invention provides a method for the
prophylaxis or treatment of a clinical condition in a mammal, such
as a human, for which a glucocorticosteroid is indicated, which
comprises administration of a therapeutically effective amount of
an aqueous suspension of ciclesonide, in particular a sterile
aqueous suspension of ciclesonide according to the invention.
[0066] The aqueous suspension of ciclesonide according to the
invention is particularly suitable in the prophylaxis and/or
treatment of respiratory diseases. Respiratory disease according to
the invention includes in particular diseases associated with
inflammatory airway diseases and/or reversible airways obstruction
such as asthma, nocturnal asthma, exercise-induced asthma, chronic
obstructive pulmonary diseases (COPD) (e.g. chronic and wheezy
bronchitis, emphysema), croup, respiratory tract infection and
upper respiratory tract disease (e.g. rhinitis, such as allergic
and seasonal rhinitis).
[0067] The aqueous suspensions according to the invention are
particularly suitable for intrapulmonal administration in
particular through administration by nebulization. The suspension
may also be administered by any other suitable route. For
administration by nebulization the suspension according to the
invention can be nebulized by means of suitable nebulizer, for
example a nebulizer connected to a compressor, (=jet nebulizer)
(e.g. nebulizers: Pani LC star.TM., Pan LC plus.TM., Omron VC.TM.,
Sidestream MS 2400 and 2200.TM., Halolite.TM., Circulaire.TM. and
compressors: eg Pari Proneb.TM. Ultra, DeVilbriss Pulmo Aide.TM.,
Medic Aid Portaneb.TM. Invacare Envoy.TM., MPV Truma MicroDrop.TM.)
and new generation nebulizers with different operation principles
(e.g. eflow.TM. by PARI, Omron U22 and Microair.TM. by Omron,
AeroNeb.TM. by Aerogen, Touchspray.TM. by Odem, Microhaler.TM. by
Pfeiffer).
[0068] Administration by nebulization is particularly suitable for
the treatment of patients suffering from a respiratory disease and
having difficulties to correctly use other devices for inhalation
such as infants and young children or elderly being not able to
handle DPIs and MDIs correctly. Preferably the patient in
connection with the invention is a child. Child in connection with
the invention refers to a human below eighteen years (e.g.
seventeen years, fifteen years, ten years, nine years, five years,
two years, 6 months etc.). Preferably child refers to a
pre-pubertal human, and in particular to a human from 6 months to
10 years of age, in particular 12 months to 8 years of age.
[0069] The amount of ciclesonide, or a pharmaceutical acceptable
salt, solvate or physiologically functional de rivative thereof
which is required to achieve a therapeutic effect will, of course,
vary with the patient under treatment, and the particular disorder
or disease being treated. As a monotherapy, ciclesonide is
generally administered to patients by inhalation at a daily dose of
from 0,05 mg to 2 mg, preferably 0.1 to 1 mg, which can be
administered in one or several doses. The dose is preferably a
daily dose and administered once or twice daily, preferably once
daily. A once daily dose may be administered any time of the day,
e.g. in the morning or preferably in the evening. The
administration of a daily dose of ciclesonide is preferably part of
a continuous treatment regimen, preferably a treatment period of
more than one day, particularly preferably more than one week, e.g.
a two week treatment period, a one month treatment period, a one
year treatment period or a life long treatment period. The dosage
of each administration can be the same or varied throughout the
continuous treatment regimen.
[0070] Further subject of the invention is a drug product
comprising a sealed container containing an aqueous suspension
according to the invention and a label indicating administration by
nebulization in a continuous treatment regimen. The container can
be of any suitable kind, e.g. a form-fill-seal container made from
polyethylene or polypropylene.
* * * * *