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Patent 2014401 Summary

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(12) Patent Application: (11) CA 2014401
(54) English Title: AEROSOLISED AZOLE ANTI FUNGALS
(54) French Title: COMPOSES ANTIFONGIQUES DE TYPE AZOTE, EN AEROSOL
Status: Dead
Bibliographic Data
(52) Canadian Patent Classification (CPC):
  • 167/158
  • 167/233
(51) International Patent Classification (IPC):
  • A61K 9/12 (2006.01)
  • A61K 31/40 (2006.01)
  • A61K 31/415 (2006.01)
(72) Inventors :
  • ORR, THOMAS S. C. (United Kingdom)
(73) Owners :
  • ORR, THOMAS S. C. (Not Available)
  • FISONS PLC (United Kingdom)
(71) Applicants :
(74) Agent: RIDOUT & MAYBEE LLP
(74) Associate agent:
(45) Issued:
(22) Filed Date: 1990-04-11
(41) Open to Public Inspection: 1990-10-12
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
89/08250 United Kingdom 1989-04-12

Abstracts

English Abstract




Abstract
Aerosolized Azole Antifungals
There are described pharmaceutical formulations
comprising as active ingredient, an azole antifungal in a
form suitable for administration by inhalation. Such
formulations include pressurised aerosol formulations,
non-pressurised aerosol formulations and
solutions/suspensions for use with a nebuliser device.
Also described is finely divided powdered azole antifungal
with a mass median diameter in the range 0.1 to 10 microns
and a method of prophylaxis of a fungal pulmonary infection
which comprises administering by inhalation a
therapeutically effective amount of an azole antifungal to
a patient predisposed to such an infection.


Claims

Note: Claims are shown in the official language in which they were submitted.


- 17 -

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical formulation comprising, as active
ingredient, an azole antifungal in a form suitable for
administration by inhalation.
2. A pharmaceutical formulation according to claim 1, in
the form of a dry powder.
3. A pharmaceutical formulation according to Claim 2
which contains a pharmaceutically acceptable liquefied gas
aerosol propellant.
4. A pharmaceutical formulation according to Claim 3
which contains from 0.1 to 12% by weight of the active
ingredient.
5. A pharmaceutical formulation according to Claim 3,
wherein at least 95% by weight of the particles of active
ingredient have a mass median diameter of from 0.1 to 10
microns.
6. A pharmaceutical formulation according to Claim 2
which is non-pressurised.
7. A pharmaceutical formulation according to Claim 6,
wherein the active ingredient is in admixture with a
pharmaceutically acceptable carrier.
8. A pharmaceutical formulation according to Claim 6,
wherein at least 95% by weight of the particles of the
active ingredient have a mass median diameter of from 0.1
to 10 microns.

- 18 -
9. A pharmaceutical formulation according to claim 1, in
the form of an aqueous solution or suspension for use with
a nebuliser device.
10. Finely divided powdered azole antifungal with a mass
median diameter in the range 0.1 to 10 microns.
11. A pharmaceutical formulation according to any one of
Claims 1 to 3, wherein the azole antifungal is selected
from clotrimazole, econazole nitrate, fluconazole,
itraconazole, ketoconazole, miconazole nitrate and
saperconazole.


Description

Note: Descriptions are shown in the official language in which they were submitted.


4~



Aerosolized Azole Antifungals
This invention relates to novel pharmaceutical
formulations and a novel therapeutic method of using them.
Invasive fungal infections cause significant morbidity
5 and mortality especially in patients with impaired immune
defenses. Because of the increasing number of
immunocompromised patients due to organ transplantation,
chemotherapy and AIDS, control of fungal infection is now a
major health issue.

In recent years, the development of the azole group of
antifungal agents hac contributed greatly to the treament
of fungal infections. Such compounds are normally
administered in suitable formulations orally, topically to
the skin, or by pessary or suppository. When administered
15 by such routes, however, even the potent azole antifungal
agents have little or no effect on an established, invasive
- fungal infection of the lung of an immunocompromised
patient.
We have now found that administration of an
~ 20aero~olised formulation of a suitable azole antifungal
- agent to the lungs of immunocompromised patients prevents
or greatly inhibits the onset of fungal disease.
; According to the invention we provide a pharmaceutical
formulation comprising, as active ingredient, an azole
25antifungal in a form suitable for administration by
inhalation.




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The prophylactic administration of azole antifungal
agents to the lung will be particulaxly effective in the
prevention of fungal infections whose main portal of entry
is the respiratory system, especially those caused by
5 asperaillus and cryptococcus species. In addition, use of
low doses applied directly to the lungs will minimise the
risks of the side effects seen with systemic antifungal
agents.
By azole antifungal agents we mean those having an

10 imidazole (structure I, X = CH) or triazole (structure I, X
= N) moiety.




l I




Particular azole antifungal agents which may be
mentioned are, for example, clotrimazole, econazole
nitrate, fluconazole, itraconazole, ketoconazole,

20miconazole nitrate and saperconazole.
Forms suitable for administration by inhalation
include aqueous solutions/suspensions, for use with a
nebuliser device; dry powder and pre~surised dry powder
aerosol.

Suitable nebuliser solutions/suspensions may be

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prepared by adding the azole antifungal agent to water,
which has preferably been distilled or sterilised. If
necessary or desired the aqueous medium may include
suspending agents, solubilising agents, stabilisers and/or
5 preservatives. The formulation may additionally contain
another prophylactic agent, such as pentamidine, or a
bronchodilator.
For inhalation as a powder formulation the active
ingredients in finely divided form may be used in admixture
10 with a larger sized carrier comprising particles, eg of up
to 400 microns diameter. We prefer at least 90% by weight
of the particles of the carrier to have an effective
particle size below 400 microns, and at least 50% by weight
of the particles of the carrier to have an effective
15 particle size above 30 microns. Effective particle size for
particles below 30 microns may be measured by a Coulter
counter. Effective particle size for particles above 30
microns may be measured by an Alpine air jet sieve.
Desirably, at least 95% by weight of the particles of
20 the active ingredients have an effective particle size in
the range 0.1 to 10 microns. Preferably at least 90% and
more desirably at least 95% by weight thereof have an
effective particle size in the range 1 to lO microns.
Suitably at least 50% by weight of the particles of the
25active ingredients have an effective particle size in the


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range 1 to 5 microns.
The particle size spectrum of the carrier will depend
on the particular inhalation device from which the
formulation is to be dispersed. It is however desirable to
5 avoid carrier particles of less than 10 microns in size,
thus minimising the number of non-drug particles which
penetrate deep into the lung. A large proportion of very
large particles may also cause a gritty feel in the mouth
of the user and is therefore less preferred. Use of a
10 carrier of large particle size may also cause problems in
filling when using filling machines which involve a dosator
which picks up powder by dipping into a powder bed from
above. ~owever, use of a carrier of large particle size may
ease filling when using machines in which a die is filled
15 from above, but may incline the composition to segregate
during transport or storage. Thus , desirably, at least 95%
by weight of the particles of the carrier have an effective
particle size below 400 microns. Preferably at least 50%,
and more desirably at least 70%, by weight of the carrier
20 particles have an effective particle size in the range 30
to 150, especially 30 to 80 microns.
The composition preferably contains ~rom 2 to 50% by
; ~ weight, more especially from 5 to 25% by weight and
particularly from 10 to 15% by weight of the active
~- 25 Lngredient, and from 50 to 98% by weight, more especially




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from 75 to 95% by weight and particularly from 85 to 90% by
weight of the carrier.
The finely divided active ingredients may be prepared
in the desired particle size range for example using a ball
5 mill, a fluid energy mill, by precipitation or by spray
drying. The carrier may be prepared by spray drying or
grinding and subsequently separating out the desired
fraction, for example by air classification and/or seiving.
The powder compositions may be prepared by mixing the
10 ingredients together in one or, preferably, more (eg two)
steps in a mixer, such as a planetary or other stirred
mixer.
The carrier may be any non-toxic material which is
chemically inert to the active ingredients and is
15 acceptable for inhalation. Examples of carriers which may
be used include inorganic salts, eg sodium chloride or
calcium carbonate; organic salts, eg sodium tartrate or
calcium lactate; organic compounds, eg urea or propylidone;
monosaccharides, eg lactose, mannitol, arabinose or
; 20 dextrose monohydrate; disaccharides, eg maltose or sucrose;
polysaccharides, eg starches, dextrins or dextrans. A
particularly preferred carrier is lactose, eg crystalline
lactose.
The powder compositions will generally be put in
, 25 sealed gelatine, plastic or other capsules. The container
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is preferably loosely filled to less than about 80% byvolume, preferably less than about 50% by volume with the
powder composition.
Alternatively, for inhalation the active ingredients
5 may be used in pellet or granule form, wherein the pellet
or granule is soft, is from 10 to 1,000, preferably from 30
to 500 microns in diameter and comprises an agglomeration
of individual medicament particles, at least 90% by weight
of which have a diameter of less than 10 microns.

The soft pellet or granule preferably has an internal
coherence such that the pellet or granule remains intact
when filled into a container, eg a capsule, using automatic
ox semi-automatic filling machines, under conditions of
transport and storage, and when fluidised within a
15 container in the device from which it is intended to
dispense ~he pellets or granules and yet may be broken up
into particles of a therapeutically effective size outside
the container as it discharges from the container.
We have found that satisfactory soft pellets or
. 20 granules for use in insufflators of the type described in
: British Patent No. 1,182,779 (commercially available under
the Registered Trade Mark "Spinhaler") and powdered by
human inhalation have a mean size in the range of from 50
to 250 microns, preferably a mean size in the range 120 to
25l60 microns aDd ~ost pr-e-rably a ~ an siz- of about 140


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mlcrons.
For pressurised aerosol formulations, the active
ingredients are preferably finely divided, eg at least 95%
by weight of the paticles of the active in~redient have an
5 effective particle size of from 1 to lO microns (and these
finely divided forms of the active ingredients are a
feature of the invention). We particularly prefer the
active ingredient to have a mass median diameter of less
than 5 microns and especially of less than 4 microns and
10 most preferably of less than 3.5 microns. We also prefer
not more than 5% by weight of the particles to have a
diameter of greater than 10 microns, and more preferably
not less than 90% by weight of the particles to have a
diameter of less than 6 microns.

We prefer the composition to contain from 0.1 to 12%,
more preferably from 0.2 to 5~, eg about 1 to 3.5% by
weight of the finely divided active ingredients.
By mass median diame~er we mean the diameter such that
half the particulate mass is in particles of lesser
20 diameter and half in particles of greater diameter. The
mass median diameter is essentially a Stokes diameter and
may be determined using a Joyce Loebl sedimentation disc
centrifuge either in a two layer or line start photometric
mode (Bagneso J and Ottaway A, Proc. Soc. Analyt. Chem.
Part 4, Vol 9, 1972 pages 83 -86).


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- 8 -


The active inqredients of mass median diameter less
than 4 microns when formulated as aerosol units and when
the units are examined using a single stage liquid impinger
(modification of that described in J. Pharm. Pharmac. 1973,
5 25, Suppl. 32P-36P) produce a greater dispersion than
exactly analogous units containing active ingredients of
larger mass median diameter. The single stage liquid
impinger samples the whole cloud delivered from the aerosol
; and separates it into two fractions by inertial impaction.
lO The fraction of smaller particle size is less than 10
microns in aerodynamic diameter and represents material
which is likely to penetrate into the deeper regions of the
human airways.
By providing a large proportion of fine particles of
15 active ingredient the invention enables effective lung
penetration to potential sites of organism colonisation.
The fine active ingredient(s) may be made by grinding
or milling and is (are) preferably dried thoraughly before
they are incorporated into the liquefied propellant medium.

The liquefied propellant is preferably a gas at room
temperature (20C) and atmospheric pressure ie it should
have a boiling point below 20C at atmospheric pressure.
The liquefied propellant should also be non-toxic. Among
the suitable liguefied propellants which may be employed
25 are dimethyl ether and alkanes containing up to 5 carbon
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atoms, eg butane or pentane, or a lower alkyl chloride, eg
methyl, ethyl or propyl chlorides. The most suitable
liquefied propellants are the fluorinated and
fluorochlorinated lower alkanes such as those sold under
5 the Registerd Trade Mark "Freon". Mixtures of the above
mentioned propellants may be suitably employed.
Examples of these propellants are:
dichlorodifluoromethane ("Propellant 12");
1,2-dichlorotetrafluoroethane ("Propellant 114");

trichloromonofluoromethane ("Propellant 11");
dichloromonofluoromethane ("Propellant 21");
monochlorodifluoromethane ("Propellant 22"):
trichlorotrifluoroethane ("Propellant 113"):
monochlorotrifluoromethane ("Propellant 13").

lS asymmetric dihydrotetrafluoroethane ("Propellant
134a")
Propellants with improved vapour pressure characteristics
may be obtained by using certain mixtures of these
compounds, eg "Propellant llU with "Propellant 12" or
20 "Propellant 12" with "Propellant 114". For example,
"Propellant 12", which has a vapour pressure of about
; 570kPa (absolute) at 20C, may be mixed in various
proportions to form a propellant having a desired
intermediate vapour pressure. We prefer compositions which
25do not contain trichloromonofluoromethane.
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It is desirable that the vapour pressure of the
propellant employed be between 380 and 500, and preferably
between 410 and 470kPa (absolute) at 20C. Such a
propellant mixture is usable safely with metallic
5 containers. Other mixtures of "Propellant 12" with
"Propellant 114", or of "Propellant 12" with "Propellant
11", or of "Propellant 12" with "Propellant 11" and
"Propellant 114" with absolute vapour pres-cures at 20C
in the range 230 to 380kPa are usable safely with

10 reinforced glass containers.
The composition may also contain a surface active
agent. The surface active agent may be a liquid or solid
non-ionic surface acti~e agent or may be a solid anionic
surface active a~ent.

The preferred solid anionic surface active agent is
sodium dioctylsulphosuccinate.
The amount of the surface active agent required is
related to the solids content of the suspension and to the
particle size of the solids. In general it is only
20 necessary to use 5-15%, and preferably 5-8% of the solid
surface active agent by weight of the solids content of the
suspension.
When a liquid non-ionic surface active agent is
employed it should have an hydrophile-lipophile balance
2s(HLB) ratio of less than 10. The HLB ratio is an empirical
'`

number which provides a guide to the surface active
properties of a surface active agent. The lower the HLB
ratio, the more lipophilic is the agent and, conversely,
the higher the HLB ratio, the more hydrophilic is the
5 agent. The HLB ratio is well known and understood by the
colloid chemist and its method of determination is
described by ~ C Griffin in the Journal of the Society of
Cosmetic Chemists, Vol 1, No 5, pages 311-326 (1949).
Preferably the surface active agent employed should have an
10 HLB ratio of 1 to 5. It is possible to employ mixtures of
surface active agents, the mixture having an HLB ratio
within the prescribed range.
Those surface active agents which are soluble or
dispersible in the propellant are effective. The more
15 propellant soluble surface active agents are the most
effective.
We prefer the liquid non-ionic surface active agent to
comprise from 0.1 to 2%, and more preferably from 0.2 to 1
by weight of the total composition. Such compositions tend
20 to be more physically stable on storage.
Among the liquid non-ionic surface active agents which
may be employed are the esters or partial esters of fatty
acids containing from 6 to 22 carbon atoms, such as
caproic, octoic, lauric, palmitic, stearic, linoleic,
25linolenic, oleostearic and oleic acids with an aliphatic

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polyhydric alcohol or its cyclic anhydride such as, forexample, ethylene glycol, glycerol, erythritol, arabitol,
mannitol, sorbitol, the hexitol anhydrides derived from
sorbitol tthe sorbitan esters sold under the Registered
5 Trade Mark "span") and the polyoxyethylene and
polyoxypropylene derivatives of these esters. Mixed esters,
such as mixed or natural glycerides, may be employed. The
preferred liquid non-ionic surface active agents are the
oleates of sorbitan, eg those sold under the Registered
10 Trade Marks "Arlacel C" (sorbitan sesquioleate), "Span 80"
(sorbitan monooleate) and "Span 85" (Sorbitan trioleate).
Specific examples of other liquid non-ionic surface active
agents which may be employed are sorbitan monolaurate,
polyoxyethylene sorbitol tetraoleate, polyoxyethylene
15 sorbitol pentaoleate and polyoxypropylene mannitol
dioleate. A solid non-ionic surface active agent which may
be mentioned is lecithin, eg soya lecithin, a vegetable
lecithin extracted from soya beans, but lecithin is not
preferred.

We particularly prefer compositions containing a
sorbitan or sorbitol ester, eg sorbitan trioleate in a
mixture of propellants 12 and 114. We prefer the ratio of
propellant 12 to 114 to be in the range 2 to 1:1 and
preferably 1.5:1 by weight, ie we prefer an excess of
2spropellant 12 over propellant 114.
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The preferred dosages of active drug will be dependent
on several factors including the particular azole
antifungal agent used and the patient's diagnosis. However,
when the treatment is to be used prophylactically, we
5 prefer that adequate levels of the drug are maintained in
the lung to prevent invasive fungal colonisation.
When the formulation is in the form of a
non-pressurised dry powder, eg a capsule for inhalation, a
unit dose of active ingredient may be from 0.05 to 40 mg,
lO more preferably 1 to 30 mg, particularly 5 to 20 mg.
When the formulation is in the form of a pressurised
aerosol formulation, the aerosol dispensing pack is
preferably provided with a valve adapted to deliver unit
dosages of between 0.025 and 0.25mls, and preferably 0.05
15 or O.lmls of composition. We prefer the valve to deliver
0.1, 1, 2, 3, 4 or 5mg of active ingredient and unit doses
of these quantities of the drug are provided.
The pressurised aerosol formulations of the invention
may be made by mixing the various components at a
20 temperature and pressure at which the propell~nt is in the
liquid phase and the active ingredients are in the solid
phase.
In producing the pressurised aerosol compositions and
packages of the invention, a container equipped with a
2svalve is filled with a propellant containing the finely




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divided active ingredient in suspension. A container mayfirst be charged with a weighed amount of dry active
ingredients which have been ground to a predetermined
particle size, or with a slurry of powder in the cooled
5 liquid propellant. A container may also be filled by
introducing powder and propellant by the normal cold
filling method, or a slurry of the powder in that component
of the propellant which boils above room temperature may be
placed in the container, the valve sealed in place, and the
10 balance of the propellant may be introduced by pressure
filling through the valve nozzle. As a further alternative
a bulk of the total composition may be made and portions of
this bulk compositon may be filled into the container
through the valve. Throughout the preparation of the
15 product care is desirably exercised to minimise the
absorption of moisture. On operating the valve, the powder
will be dispensed in a stream of propellant which will
vaporise providing an aerosol of dry powder.
It has not previously been suggested that azole
29 antifungals may be used as inhalation medicaments. As such
finely divided powdered azole antifungal is novel.
According to the invention, there is provided finely
divided powdered azole antifungal with a mass median
diameter in the range 0.1 to 10 microns. We prefer at
least 95% of such powdered antifungal to have a mass median




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diameter in this range.
The compositions of the invention may be used in the
remedial treatment or, more preferably, in the prophylaxis
of fungal infections of the airways. The compositions of
5 the invention, when administered via inhalation, will be
particularly useful for the prophylaxis of systemic fungal
infections whose portal of entry is the respiratory system.
According to a further aspect of the invention we
provide a composition for the prophylaxis of fungal
10 infections whose main portal of entry is the respiratory
system.
The formulations of the invention are advantageous in
that they are less toxic, more efficacious, give rise to
fewer side effects are better tolerated or have other
lS useful properties compared to known therapies.
Aspergillus and cryptococcus are significant mycotic
pathogens which enter the body via the lungs. The
compositions of the invention may, therefore, be used for
the prophylaxis and/or treatment of aspergillosis and
0cryptococcosis. Patients particularly susceptible to
invasive aspergillosis are those with defective neutrophil
~- function and/or neutropenia, for example those with
~; hematologic and lymphoreticular malignancy, organ
~; transplants, or high dose steroid use. Some asthmatic
~patients are also predispos-d to allergic bronchopulmonary
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- 16 -



aspergillosis (ABPA) for which thexe is no establishedtherapy. Treatment of the symptoms of asthma and/or ABPA
using steroids increases the risk of developing invasive
disease. Patients particularly at ris~ of developing
5 cryptococcosis are those with AIDS, lymphoreticular
malignancies, organ transplants, chronic steroid use,
sarcoidosis, chronic active hepatitis, connective tissue
disorders or severe diabetes mellitus. The treatment may be
administered by nasal inhalation: however we prefer oral

10 inhalation.
The dosage to be given will clearly vary with the
patient and with their condition. In general, however,
relatively low doses administered at an interval to
maintain adequate pulmonary drug concentration are

15 indicated.
According to the invention there is also provided a
method of prophylaxis of a fungal pulmonary infection,
especially infections caused by aspergillosis or
cryptococcosis, which comprises administering by inhalation
20 a therapeutically effective amount of an azole antifungal
agent to a patient predisposed to such an infection.




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Representative Drawing

Sorry, the representative drawing for patent document number 2014401 was not found.

Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date Unavailable
(22) Filed 1990-04-11
(41) Open to Public Inspection 1990-10-12
Dead Application 1993-10-11

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $0.00 1990-04-11
Registration of a document - section 124 $0.00 1990-10-03
Maintenance Fee - Application - New Act 2 1992-04-13 $100.00 1992-03-06
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
ORR, THOMAS S. C.
FISONS PLC
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Drawings 1990-10-12 1 8
Claims 1990-10-12 2 51
Abstract 1990-10-12 1 21
Cover Page 1990-10-12 1 15
Description 1990-10-12 16 557
Fees 1992-03-06 1 47