U.S. patent application number 13/744962 was filed with the patent office on 2013-06-06 for use of ciclesonide for the treatment of respiratory diseases.
This patent application is currently assigned to NYCOMED GMBH. The applicant listed for this patent is NYCOMED GMBH. Invention is credited to Thomas BETHKE, Renate ENGELSTAETTER, Wilhelm WURST.
Application Number | 20130143849 13/744962 |
Document ID | / |
Family ID | 34312429 |
Filed Date | 2013-06-06 |
United States Patent
Application |
20130143849 |
Kind Code |
A1 |
WURST; Wilhelm ; et
al. |
June 6, 2013 |
USE OF CICLESONIDE FOR THE TREATMENT OF RESPIRATORY DISEASES
Abstract
Disclosed herein are novel methods of treating respiratory
diseases, and in particular the treatment of asthmatic
children.
Inventors: |
WURST; Wilhelm; (Konstanz,
DE) ; BETHKE; Thomas; (Konstanz, DE) ;
ENGELSTAETTER; Renate; (Allensbach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NYCOMED GMBH; |
Konstantz |
|
DE |
|
|
Assignee: |
NYCOMED GMBH
Konstantz
DE
|
Family ID: |
34312429 |
Appl. No.: |
13/744962 |
Filed: |
January 18, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10571311 |
Mar 9, 2006 |
8371292 |
|
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PCT/EP2004/052172 |
Sep 15, 2004 |
|
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13744962 |
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60502984 |
Sep 16, 2003 |
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Current U.S.
Class: |
514/174 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 31/00 20180101; A61P 37/08 20180101; A61P 11/02 20180101; A61K
31/58 20130101; A61P 11/00 20180101; A61K 9/0075 20130101; A61K
9/008 20130101; A61K 31/57 20130101 |
Class at
Publication: |
514/174 |
International
Class: |
A61K 31/58 20060101
A61K031/58 |
Claims
1. A method for treating or preventing a respiratory disease in a
child comprising administering to the child a dose of a composition
comprising ciclesonide, or a pharmaceutically acceptable salt,
solvate or physiologically functional derivative thereof, wherein
the dose of the composition comprises ciclesonide in an amount of
from 20 to 200 .mu.g.
2-10. (canceled)
11. The method according to claim 1 wherein ciclesonide is selected
from the group consisting of
[11.beta.,16.alpha.(R)]--16,17-[(Cyclohexylmethylen)bis(oxy)]-11-hydroxy--
21-(2-methyl-1-oxopropoxy)pregna-1,4-dien-3,20-dion,
[11.beta.,16.alpha.(S)]-16,17-[(Cyclohexylmethylen)bis(oxy)]-11-hydroxy-2-
1-(2-methyl-1-oxopropoxy)pregna-1,4-dien-3,20-dion,
[11.beta.,16.alpha.(R,S)]-16,17-[(Cyclohexyl-methylen)bis(oxy)]-11-hydrox-
y-21-(2-methyl-1-oxoprop-oxy)pregna-1,4-dien-3,20-dion,
16.alpha.,17-(22R)-Cyclohexylmethylendioxy-11.beta.,21-dihydroxypregna-1,-
4-dien-3,20-dion,
16.alpha.,17-(22S)-Cyclohexylmethylendioxy-11.beta.,21-dihydroxypregna-1,-
4-dien-3,20-dion and
16.alpha.,17-(22R,S)-Cyclohexylmethylendioxy-11.beta.,21-dihydroxy-pregna-
-1,4-dien-3,20-dion.
12-42. (canceled)
Description
FIELD OF THE INVENTION
[0001] This invention relates to a new method of treatment of
respiratory diseases, in particular the treatment of asthmatic
children.
BACKGROUND
[0002] U.S. Pat. No. 5,482,934 discloses
pregna-1,4-diene-3,20-dione-16-17-acetal-21 esfers and their use in
the treatment of inflammatory conditions. The compounds have the
general structure:
##STR00001##
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-2-
1-(2-methyl-1-oxopropoxy)pregna-1,4-dien-3,20-dion
[0003] Ciclesonide is a novel inhaled corticosteroid for asthma
treatment, which is undergoing clinical evaluation. Ciclesonide has
very low affinity for the glucocorticosteroid receptor but is
readily converted to the active metabolite
desisobutyryl-ciclesonide by esterases in the lung to provide local
activity in the target organ. This activation occurs by ester
cleavage at the C21 position of ciclesonide. The affinity of
desisobutyryl-ciclesonide to the glucocorticosteroid receptor is
approximately 100 times higher than that of ciclesonide.
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.
SUMMARY OF THE INVENTION
[0004] It has now been found that respiratory diseases in children
may be very effectively and safely treated by administering
ciclesonide to the children in need thereof in a dose of from 20 to
200 .mu.g. In particular systemic side effects possibly associated
with inhaled and intranasal corticosteroids such as growth
suppression in children after long-term exposure can be reduced or
completely avoided.
[0005] Subject of the invention is therefore a method for treating
or preventing a respiratory disease in a patient, which patient is
a child and the method comprising administering to the patient a
dose of a composition containing ciclesonide, a pharmaceutically
acceptable salt, solvates or physiologically functional derivative
thereof, wherein the dose of the composition comprises ciclesonide
in an amount of from 20 to 200 .mu.g.
[0006] Ciclesonide (herein also referred to as active ingredient)
is the INN for an active compound having the chemical name
[11.beta.,16.alpha.-(R)]-16,17-Rcyclohexylmethylene)bis(oxy))-11-hydroxy--
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)-cyclo-hexylmethylenedioxy-11.beta.,21-dihydroxypregn-
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-[(cyclohexylmethyl-ene)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%.
[0007] Administering ciclesonide in a daily dose range of from 20
to 200 .mu.g to a child afflicted with a respiratory disease
results in effective treatment and or prophylaxis of the
respiratory disease and avoiding systemic side effects such as
growth suppression which may occur in children after long-term
exposure to inhaled and intranasal corticosteroids.
[0008] Exemplary doses in connection with the invention comprise
20, 40, 60, 80, 100, 120, 140, 160, 180 or 200 .mu.g ciclesonide.
Preferably the dose comprises 40, 80 or 160 .mu.g ciclesonide. 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 in the
range of from 20 to 200 .mu.g 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.
[0009] 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 etc. Preferably child refers to a
pre-pubertal human, and in particular to a human from 6 to 12 years
of age.
[0010] Ciclesonide has been described for use in the treatment of
respiratory diseases. Therefore, formulations of ciclesonide have
use in the prophylaxis and treatment of clinical conditions for
which a glucocorticosteroid is indicated. Such conditions include
diseases associated with reversible airways obstruction such as
asthma, nocturnal asthma, exercise-induced asthma, chronic
obstructive pulmonary diseases (COPD) (e. g. chronic and wheezy
bronchitis, emphysema), respiratory tract infection and upper
respiratory tract disease (e. g. rhinitis, such as allergic and
seasonal rhinitis). In a preferred embodiment according to the
invention the respiratory disease in connection with the invention
refers to asthma, preferably mild to severe asthma.
[0011] The present invention also relates to the use of
ciclesonide, a pharmaceutically acceptable salt, solvates or
physiologically functional derivative thereof for the manufacture
of a medicament for the treatment or prevention of a respiratory
disease in a patient, which patient is a child and wherein the
medicament is administered at a dose of 20 to 200 .mu.g
ciclesonide.
[0012] The compositions comprising ciclesonide (also referred to as
formulations, medicaments or pharmaceutical compositions) include
those suitable for oral, parenteral including subcutaneous,
intradermal, intramuscular, intravenous and intraaarticular,
intranasal, inhalation (including fine particle dusts or mists
which may be generated by means of various types of metered dose
pressurised aerosols, nebulisers or insufflators), rectal and
topical (including dermal, buccal, sublingual and intraocular
administration) although the most suitable route may depend upon
for example the condition and disorder of the recipient. The
formulations may conveniently be presented in unit dosage form and
may be prepared by any of the methods well known in the art of
pharmacy. All methods include the step of bringing the active
ingredients into association with the carrier, which constitutes
one or more accessory ingredients/excipients. In general the
formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely
divided solid carriers or both and then, if necessary, shaping the
product into the desired formulation.
[0013] In one embodiment ciclesonide is provided in a form suitable
for inhalation. Formulations for inhalation include powder
compositions, which will preferably contain lactose, and spray
compositions which may be formulated, for example, as aqueous
solutions or suspensions or as aerosols delivered from pressurised
packs, with the use of a suitable propellant, e. g.
1,1,1,2-terafluorethane, 1,1,1,2,3,3,3-heptafluoropropane, carbon
dioxide or other suitable gas. A class of propellants, which are
believed to have minimal ozone-depleting effects in comparison to
conventional chlorofluorocarbons comprise hydrofluorocarbons and a
number of medicinal aerosol formulations using such propellant
systems are disclosed in, for example, EP 0372777, WO91/04011,
WO91/11173, WO91/11495, WO91/14422, WO93/11743, and EP-0553298.
These applications are all concerned with the preparation of
pressurised aerosols for the administration of medicaments and seek
to overcome problems associated with the use of this new class of
propellants, in particular the problems of stability associated
with the pharmaceutical formulations prepared. The applications
propose, for example, the addition of one or more of excipients
such as polar cosolvents or wetting agents (e.g. alcohols such as
ethanol), alkanes, dimethyl ether, surfactants (including
fluorinated and non-fluorinated surfactants, carboxylic acids such
as oleic acid, polyethoxylates etc.) or bulking agents such as a
sugar (see for example WO02/30394) and vehicles such as cromoglicic
acid and/or nedocromil which are contained at concentrations, which
are not therapeutically and prophylactically active (see
WO00/07567). For suspension aerosols, the active ingredients should
be micronised so as to permit inhalation of substantially all of
the active ingredients into the lungs upon administration of the
aerosol formulation, thus the active ingredients will have a mean
particle size of less than 100 microns, desirably less than 20
microns, and preferably in the range 0.7 to 10 microns, for
example, 1 to 5 microns.
[0014] WO 98/52542 is related to pharmaceutical compositions
comprising a therapeutically effective amount of ciclesonide or a
related compound and a hydrofluorocarbon propellant, preferably
selected from 1,1,1,2-tetrafluoroethane,
1,1,1,2,3,3,3-heptafluoropropane and a mixture thereof, and
cosolvent, preferably ethanol, in an amount effective to solubilize
ciclesonide and optionally a surfactant. In a preferred embodiment
ciclesonide is administered in a composition according to
WO98/52542.
[0015] Ciclesonide is generally present in the formulation at a
concentration, which allows administration of a dose of from 20 to
200 .mu.g. Such formulation generally comprises ethanol in an
amount effective to solubilize the ciclesonide. The propellant
preferably includes a hydrofluoroalkane, in particular Propellant
134a, Propellant 227 or a mixture thereof. In the case of a mixture
the ratio of Propellant 134a to Propellant 227 is generally in a
range from 75:25 w/w to 25:75 w/w. The formulations may contain
surfactant such as oleic acid, but may be also free of surfactant.
The formulations are preferably free of other excipients.
[0016] The formulations may be manufactured by preparing a drug
concentrate of the active ingredients with ethanol and adding this
concentrate to the pre-chilled propellant in a batching vessel.
Preferably a solution of the ciclesonide in the cosolvent is added
to the prechilled propellant in a batching vessel. The resulting
formulation is filled into vials. Alternatively the formulations
may be prepared by adding the required quantity of active
ingredient into an aerosol vial, crimping a valve on the vial and
introducing a pre-mixed blend of propellant and ethanol through the
valve. The vial is placed in an ultrasonic bath to ensure
solubilisation of ciclesonide.
[0017] In another embodiment preferred compositions for aerosol
delivery contain the active ingredient in particulate form, and
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or
mixtures thereof as propellant. Such formulation generally
comprises from 0.01 to 5% (w/w relative to the total weight of the
formulation) of polar cosolvent, in particular ethanol. In a
preferred embodiment no or less than 3% w/w of polar cosolvent, in
particular ethanol is contained. Especially preferred compositions
for aerosol delivery consist of particulate active ingredient, and
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluorpropane or
mixtures thereof as propellant and optionally a surfactant
(preferably oleic acid). In the case of a mixture the ratio of
Propellant 134a to Propellant 227 is generally in a range from
75:25 w/w to 25:75 w/w.
[0018] The formulations may be prepared by adding the required
quantity of active ingredient into an aerosol vial, crimping a
valve on the vial and introducing propellant or optionally a
pre-mixed blend of propellant and optionally the cosolvent and
surfactant through the valve.
[0019] Canisters generally comprise a container capable of
withstanding the vapour pressure of the propellant, such as plastic
or plastic-coated glass bottle or a metal can, for example an
aluminium can which may optionally be anodised, lacquer-coated
and/or plastic-coated, which container is closed with a metering
valve. Canisters may be coated with a fluorocarbon polymer as
described in WO 96/32150, for example, a co-polymer of
polyethersulphone (PES) and polytetrafluoroethylene (PTFE). Another
polymer for coating that may be contemplated is FEP (fluorinated
ethylene propylene).
[0020] The metering valves are designed to deliver a metered amount
of the formulation per actuation and incorporate a gasket to
prevent leakage of propellant through the valve. The gasket may
comprise any suitable elastomeric material such as for example low
density polyethylene, chlorobutyl, black and white
butadiene-acrylonitrile rubbers, butyl rubber and neoprene.
Thermoplastic elastomer valves as described in WO92/11190 and
valves containing EPDM rubber as described in WO95/02650 may be
suitable. Suitable valves are commercially available from
manufacturers well known in the aerosol industry, for example, from
Valois, France (eg. DF10, DF30, DF60), Bespak pic, UK (eg. BK300,
BK356, BK357) and 3M-Neotechnic Ltd, UK (eg. Spraymiser).
[0021] Valve seals, especially the gasket seal and also the seals
around the metering chamber, can be manufactured of a material,
which is inert to and resists extraction into the contents of the
formulation, especially when the contents include ethanol.
[0022] Valve materials, especially the material of manufacture of
the metering chamber, can be manufactured of a material, which is
inert to and resists distortion by contents of the formulation,
especially when the contents include ethanol. Particularly suitable
materials for use in manufacture of the metering chamber include
polyesters eg polybutyleneterephthalate (PBT) and acetals,
especially PBT.
[0023] Materials of manufacture of the metering chamber and/or the
valve stem may desirably be fluorinated, partially fluorinated or
impregnated with fluorine containing substances in order to resist
drug deposition.
[0024] Valves, which are entirely or substantially composed of
metal components (eg Spraymiser, 3M-Neotechnic), are especially
preferred for use according to the invention.
[0025] Intranasal sprays or nasal drops may be formulated with
aqueous or non-aqueous vehicles with or without the addition of
agents such as thickening agents, buffer salts or acid or alkali to
adjust the pH, isotonicity adjusting agents, preservatives or
anti-oxidants. Suitable aqueous formulations for ciclesonide for
application to mucosa are for example disclosed in WO01/28562 and
WO01/28563.
[0026] In another embodiment of the invention the pharmaceutical
formulation comprising the ciclesonide in as a dry powder, i.e.
ciclesonide is present in a dry powder comprising finely divided
ciclesonide optionally together with a finely divided
pharmaceutically acceptable carrier, which is preferably present
and may be one or more materials known as carriers in dry powder
inhalation compositions, for example saccharides, including
monosaccharides, disaccharides, polysaccharides and sugar alcohols
such as arabinose, glucose, fructose, ribose, mannose, sucrose,
trehalose, lactose, maltose, starches, dextran or mannitol. An
especially preferred carrier is lactose, particularly in the form
of the monohydrate. The dry powder may be in capsules of gelatine
or plastic, or in blisters, for use in a dry powder inhalation
device, preferably in dosage units of the ciclesonide together with
the carrier in amounts to bring the total weight of powder in each
capsule to from 5 mg to 50 mg. Alternatively the dry powder may be
contained in a reservoir of a multi-dose dry powder inhalation
device. Capsules and cartridges of for example gelatin, or blisters
of for example laminated aluminium foil, for use in an inhaler or
insulator may be formulated containing a powder mix of the active
ingredients and a suitable powder base such as lactose or starch,
preferably lactose. In this aspect, the active ingredient is
suitably micronised so as to permit inhalation of substantially all
of the active ingredients into the lungs upon administration of the
dry powder formulation, thus the active ingredient will have a
particle size of less than 100 .mu.m, desirably less than 20 .mu.m,
and preferably in the range 1 to 10 .mu.m. The solid carrier, where
present, generally has a maximum particle diameter of 300 .mu.m,
preferably 200 .mu.m, and conveniently has a mean particle diameter
of 40 to 100 .mu.m, preferably 50 to 75 .mu.m. The particle size of
the active ingredient and that of a solid carrier where present in
dry powder compositions, can be reduced to the desired level by
conventional methods, for example by grinding in an air-jet mill,
ball mill or vibrator mill, microprecipitation, spray drying,
lyophilisation or recrystallisation from supercritical media.
[0027] Where the inhalable form of the composition of the invention
is the finely divided particulate form, the inhalation device may
be, for example a dry powder inhalation device adapted to deliver
dry powder from a capsule or blister containing a dosage unit of
the dry powder or a multi-dose dry powder inhalation device. Such
dry powder inhalation devices are known in the art. Examples which
may be mentioned are Cyclohaler.RTM., Diskhaler.RTM. Rotadisk.RTM.,
Turbohaler.RTM. or the dry powder inhalation devices disclosed EP 0
505 321, EP 407028, EP 650410, EP 691865 or EP 725725
(Ultrahaler.RTM.).
[0028] Formulations for inhalation by nebulization may be
formulated with an aqueous vehicle with the addition of agents such
as acid or alkali, buffer salts, isotonicity adjusting agents or
antimicrobials. They may be sterilised by filtration or heating in
an autoclave. Suitable technologies for this type of administration
are known in the art. As an example the Mystic.RTM. technology is
to be mentioned (see for example U.S. Pat. No. 6,397,838, U.S. Pat.
No. 6,454,193 and U.S. Pat. No. 6,302,331).
[0029] Preferred unit dosage formulations are those containing a
pharmaceutical effective dose, as hereinbefore recited, or an
appropriate fraction thereof, of the active ingredient. Thus, in
the case of formulations designed for delivery by metered dose
pressurised aerosols, one actuation of the aerosol may deliver half
of the therapeutical effective amount such that two actuations are
necessary to deliver the therapeutically effective dose.
[0030] It should be understood that in addition to the ingredients
particularly mentioned above, the formulations of this invention
may include other agents conventional in the art having regard to
the type of formulation in question. Furthermore, the claimed
formulations include bioequivalents as defined by the US Food and
Drugs Agency.
[0031] The invention will now be illustrated by the following
examples without restricting it.
EXAMPLES
Example 1
Ciclesonide Metered Dose Inhaler (HFA-MDI)
[0032] Ciclesonide is provided as pharmaceutical product comprising
an aerosol vial equipped with a dispensing valve and containing the
following formulation:
TABLE-US-00001 Ciclesonide 1.000 mg/ml Ethanol 94.800 mg/ml P134a
1090.200 mg/ml
Example 2
Clinical Study in Children with Asthma
[0033] The present study was conducted to determine the effects of
ciclesonide at doses intended for the use in children on lower leg
growth rate and HPA function in children with mild asthma.
[0034] METHODS: In a double blind, randomized, placebo-controlled,
4-period cross-over study, 24 children, 6 to 12 years of age,
received ciclesonide 40, 80 and 160 .mu.g or placebo via HFA-MDI
once daily in the evening. Each 2-week treatment period was
followed by a 2-week washout. Knemometry was performed at the
beginning and the end of each treatment period. Cortisol levels in
12 h overnight urine were measured at the end of each treatment
period.
[0035] RESULTS: No statistically significant differences were seen
in lower-leg growth rates between any of the ciclesonide treatments
and placebo; lower leg growth rates were 0.412 mm/week (placebo),
0.425 mm/week (ciclesonide 40 .mu.g), 0.397 mm/week (80 .mu.g),
0.370 mm/week (160 .mu.g). There was no statistically significant
dose-response effect. Likewise, no difference between the various
treatments and no dose-dependency was found for urinary free
cortisol adjusted for creatinine. All treatments were well
tolerated.
[0036] CONCLUSIONS: Short-term lower leg growth rate and HPA-axis
function of pre-pubertal children with mild asthma are not affected
by treatment with ciclesonide in a dose range intended for the use
in children.
[0037] Although the invention has been described in terms of
preferred formulations and ingredients, it will be understood that
these are not intended to be limiting. To the contrary, those
skilled in the art will understand that various optional
ingredients may be included, such as flavouring agents,
preservatives, additional active ingredients, and the like, while
still embodying the present invention.
* * * * *