U.S. patent application number 11/060564 was filed with the patent office on 2005-06-30 for pressurised metered dose inhalers (mdi).
This patent application is currently assigned to Chiesi Farmaceutici S.p.A.. Invention is credited to Brambilla, Gaetano, Ganderton, David, Garzia, Raffaella, Lewis, David, Meakin, Brian, Ventura, Paolo.
Application Number | 20050142071 11/060564 |
Document ID | / |
Family ID | 26331622 |
Filed Date | 2005-06-30 |
United States Patent
Application |
20050142071 |
Kind Code |
A1 |
Lewis, David ; et
al. |
June 30, 2005 |
Pressurised metered dose inhalers (MDI)
Abstract
The invention relates to the use of pressurised metered dose
inhalers (MDIs) having part or all of their internal surfaces
consisting of stainless steel, anodised aluminium or lined with an
inert organic coating; and to compositions to be delivered with
said MDIs.
Inventors: |
Lewis, David; (Parma,
IT) ; Ganderton, David; (Parma, IT) ; Meakin,
Brian; (Bath, GB) ; Ventura, Paolo; (Parma,
IT) ; Brambilla, Gaetano; (Parma, IT) ;
Garzia, Raffaella; (Parma, IT) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Chiesi Farmaceutici S.p.A.
Parma
IT
|
Family ID: |
26331622 |
Appl. No.: |
11/060564 |
Filed: |
February 18, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11060564 |
Feb 18, 2005 |
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10290225 |
Nov 8, 2002 |
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10290225 |
Nov 8, 2002 |
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09831888 |
Jul 19, 2001 |
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09831888 |
Jul 19, 2001 |
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PCT/EP99/09002 |
Nov 23, 1999 |
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Current U.S.
Class: |
424/45 ;
128/200.23; 514/171; 514/291 |
Current CPC
Class: |
A61M 15/009 20130101;
A61K 9/008 20130101; A61P 11/00 20180101; A61P 37/08 20180101; Y10S
514/958 20130101; A61K 9/12 20130101 |
Class at
Publication: |
424/045 ;
514/171; 514/291; 128/200.23 |
International
Class: |
A61L 009/04; A61K
031/573; A61K 031/4745 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 25, 1998 |
IT |
MI98A 002559 |
Jul 30, 1999 |
IT |
MI99A 001712 |
Claims
1-10. (canceled)
11. A medicinal aerosol steroid solution formulation product with
enhanced chemical stability, including: an aerosol container
equipped with a dispensing valve and containing a medicinal aerosol
formulation having a corticosteroid drug dissolved therein; said
corticosteroid being selected from the group consisting of
budesonide, triamcinolone acetonide, and rofleponide; and wherein
said container is provided with a non-metal interior surface so as
to reduce chemical degradation of the corticosteroid.
12. The product of claim 11, wherein said container is made of
aluminum having an inert interior coating.
13. The product of claim 12, wherein the interior coating is an
epoxy-phenolic lacquer.
14. The product of claim 11, wherein said dispensing valve is a
metered dose valve.
15. The product of claim 11, wherein said medicinal aerosol
formulation includes a hydrogen-containing propellant.
16. The product of claim 15, wherein the hydrogen-containing
propellant is a hydrofluorocarbon.
17. The product of claim 16, wherein the hydrofluorocarbon
propellant is selected from the group consisting of
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, and
mixtures thereof.
18. The product of claim 11, wherein said medicinal aerosol
formulation includes ethanol.
19. The product of claim 11, wherein the corticosteroid is selected
from the group consisting of budesonide and triamcinolone
acetonide.
20. The product of claim 11, wherein the corticosteroid is
budesonide.
21. The product of claim 11, wherein the corticosteroid is
triamcinolone acetonide.
22. A method of reducing the chemical degradation of a medicinal
corticosteroid dissolved in a formulation contained in a metal
container, said corticosteroid being selected from the group
consisting of budesonide, triamcinolone acetonide, and rofleponide,
comprising the step of providing a coating of inert material on the
interior surface of the metal container so as to reduce reaction of
the corticosteroid with the container.
23. A process for making a chemically stable steroid solution
aerosol product by filling into a container an aerosol formulation
comprising a dissolved corticosteroid, said corticosteroid being
selected from the group consisting of budesonide, triamcinolone
acetonide, and rofleponide, and said container having an inert
non-metal interior surface so as to avoid chemical degradation of
the corticosteroid due to interaction with the container.
24. A medicinal aerosol steroid solution formulation metered dose
inhaler product with enhanced chemical stability, including: an
aerosol container equipped with a metered dose dispensing valve and
containing a medicinal aerosol formulation including a
hydrofluoroalkane propellant selected from the group consisting of
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, and
mixtures thereof, and having a corticosteroid drug dissolved
therein, wherein the corticosteroid is selected from the group
consisting of budesonide, triamcinolone acetonide, and rofleponide.
Description
[0001] The invention relates to the use of pressurised metered dose
inhalers (MDIs) having part or all of their internal surfaces
consisting of stainless steel, anodised aluminium or lined with an
inert organic coating. The invention also relates to compositions
to be delivered with said MDIs.
[0002] Pressurised metered dose inhalers are well known devices for
administering pharmaceutical products to the respiratory tract by
inhalation.
[0003] Active materials commonly delivered by inhalation include
bronchodilators such as .beta.2 agonists and anticholinergics,
corticosteroids, anti-leukotrienes, anti-allergics and other
materials that may be efficiently administered by inhalation, thus
increasing the therapeutic index and reducing side effects of the
active material.
[0004] MDI uses a propellant to expel droplets containing the
pharmaceutical product to the respiratory tract as an aerosol.
[0005] For many years the preferred propellants used in aerosols
for pharmaceutical use have been a group of chlorofluorocarbons
which are commonly called Freons or CFCs, such as CCl.sub.3F (Freon
11 or CFC-11).sub.1 CCl.sub.2F.sub.2 (Freon 12 or CFC-12), and
CClF.sub.2--CClF.sub.2 (Freon 114 or CFC-114).
[0006] Recently, the chlorofluorocarbon (CFC) propellants such as
Freon 11 and Freon 12 have been implicated in the destruction of
the ozone layer and their production is being phased out.
[0007] Hydrofluoroalkanes [(HFAs) known also as
hydro-fluoro-carbons (HFCs)] contain no chlorine and are considered
less destructive to ozone and these are proposed as substitutes for
CFCs.
[0008] HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA 134a)
and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been
acknowledged to be the best candidates for non-CFC propellants and
a number of medicinal aerosol formulations using such HFA
propellant systems have been disclosed.
[0009] Many of these applications, in which HFAs are used as
propellant, propose the addition of one or more of adjuvants
including compounds acting as co-solvents, surface active agents
including fluorinated and non-fluorinated surfactants, dispersing
agents including alkylpolyethoxylates and stabilizers.
[0010] In the international application No. PCT/EP98/03533 filed on
Oct. 6, 1998 the applicant described solution compositions for use
in an aerosol inhaler, comprising an active material, a propellant
containing a hydrofluoroalkane (HFA), a cosolvent and further
comprising a low volatility component to increase the mass median
aerodynamic diameter (MMAD) of the aerosol particles on actuation
of the inhaler.
[0011] Compositions for aerosol administration via MDIs can be
solutions or suspensions. Solution compositions offer several
advantages: they are convenient to manufacture being completely
dissolved in the propellant vehicle and obviate physical stability
problems associated with suspension compositions.
[0012] The widespread use of these formulations is limited by their
chemical instability, causing the formation of degradation
products.
[0013] WO94/13262 proposes the use of acids as stabilisers
preventing the chemical degradation of the active ingredient in
aerosol solution formulations comprising HFAs. Among the selected
medicaments ipratropium bromide is comprised, for which many
composition examples are supplied, in which the active ingredient
is in combination with an organic or inorganic acid.
[0014] WO96/32099, WO96/32150, WO96/32151 and WO96/32345 disclose
metered dose inhalers for the administration of different active
ingredients in suspension in the propellant, wherein the internal
surfaces of the inhaler are partially or completely coated with one
or more fluorocarbon polymers optionally in combination with one or
more non-fluorocarbon polymers.
[0015] Said applications do not however address the technical
problem of the chemical stability of the active ingredient but they
rather concern a different problem, namely that of the adhesion of
micronized particles of the suspended active ingredient to the
internal surfaces of the inhaler, such as the can walls, valves and
sealings. It is also known from Eur. J. Pharm. Biopharm. 1997, 44,
195 that suspensions of drugs in HFA propellant are frequently
subjected to absorption of the drug particles on the valves and on
the internal walls of the inhaler. The properties of an epoxy
phenol resin coating of the aerosol cans have been studied to
circumvent this problem.
[0016] WO 95/17195 describes aerosol compositions comprising
flunisolide, ethanol and HFA propellants. It is stated in the
document that conventional aerosol canisters can be used to contain
the composition and that certain containers enhance its chemical
and physical stability. It is suggested that the composition can be
preferably contained in vials coated with resins such as epoxy
resins (e.g. epoxy-phenolic resins and epoxy-urea-formaldehyde
resins).
[0017] Actually the results reported in Tables 5, 6 and 8
respectively on pages 16 and 19 of the cited application
demonstrate that flunisolide decomposes only in plastic cans (Table
8), and that the percent drug recovery in compositions stored in
aluminium, glass or epoxy-phenol formaldehyde resin coated vials is
practically the same (Table 8). In other words there is no
difference between aluminium, glass type III or
epoxy/phenol-formaldehyde resin coated aluminium vials coated by
Cebal. No data are reported for other types of epoxy resins.
[0018] It has now been found that the chemical stability problems
of active ingredients in solution in HFA propellants can be
eliminated by storing and delivering said composition employing
metered-dose inhalers having part or all of their internal metallic
surfaces consisting of stainless steel, anodised aluminium or lined
with an inert organic coating.
[0019] The preferred material for the aerosol cans is anodised
aluminium.
[0020] In the case of epoxy-phenol resin coating the choice of the
suitable coating will be opportunely made on the basis of the
characteristics of the active ingredient.
[0021] The most widely used epoxy resins in can coatings are
produced by the reaction of epichlorohydrin and bisphenol A
(DGEBPA). Variations in the molecular weight and in the
polymerisation degree result in resins of different properties.
[0022] Phenoxy resins are other commercially important
thermoplastic polymers derived from bisphenols and epichlorohydrin,
characterized in that their molecular weights (MWs) are higher, ie,
ca 45000, than those of conventional epoxy resins, ie, 8000 and
lack terminal epoxide functionality.
[0023] Other multifunctional resins are epoxy-phenol-novolac and
epoxy-cresol-novolac resins obtained by glycidylation of the
phenol-formaldehyde (novolac) or of the o-cresol-formaldehyde
(o-cresol novolac) condensates respectively.
[0024] The inhalers according to the invention effectively prevent
the chemical degradation of the active ingredient.
[0025] Surprisingly and contrary to what reported in the prior art
with regard to flunisolide, we found a considerable degradation of
the tested active ingredients when their formulations were stored
in glass containers type III.
SUMMARY OF THE INVENTION
[0026] Pressurised metered dose inhalers for dispensing solution of
an active ingredient in a hydrofluorocarbon propellant, a
co-solvent and optionally a low-volatility component characterized
in that part or all of the internal surfaces of said inhalers
consist of stainless steel, anodised aluminium or are lined with an
inert organic coating.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Pressurised metered dose inhalers are known devices, usually
consisting of a main body or can, acting as a reservoir for the
aerosol formulation, a cap sealing the main body and a metering
valve fitted in the cap.
[0028] MDIs are usually made of a conventional material such as
aluminium, tin plate, glass, plastic and the like.
[0029] According to the invention, part or all of the internal
surfaces of the inhalers consists of stainless steel, anodised
aluminium or is lined with an inert organic coating. One of the
preferred coating consists of epoxy-phenol resin. Any kind of
stainless steel may be used. Suitable epoxy-phenol resins are
commercially available.
[0030] Active ingredients which may be used in the aerosol
compositions to be dispensed with the inhalers of the invention are
any ingredient which can be administered by inhalation and which
meets problems of chemical stability in solution in HFA propellants
giving rise to a decomposition when stored in conventional
materials cans and in particular in aluminium cans.
[0031] In the compositions to be delivered with the MDIs of the
invention the hydrofluorocarbon propellant is preferably selected
from the group of HFA 134a, HFA 227 and mixtures thereof.
[0032] The co-solvent is usually an alcohol, preferably ethanol.
The low volatility component, when present, is selected from the
group of glycols, particularly propylene glycol, polyethylene
glycol and glycerol, alkanols such as decanol (decyl alcohol),
sugar alcohols including sorbitol, mannitol, lactitol and maltitol,
glycofural (tetrahydro-furfurylalcohol) and dipropylene glycol,
vegetable oils, organic acids for example saturated carboxylic
acids including lauric acid, myristic acid and stearic acid;
unsaturated carboxylic acids including sorbic acid, and especially
oleic acid; saccharine, ascorbic acid, cyclamic acid, amino acids,
or aspartame, esters for example ascorbyl palmitate, isopropyl
myristate and tocopherol esters; alkanes for example dodecane and
octadecane; terpenes for example menthol, eucalyptol, limonene;
sugars for example lactose, glucose, sucrose; polysaccharides for
example ethyl cellulose, dextran; antioxidants for example
butylated hydroxytoluene, butylated hydroxyanisole; polymeric
materials for example polyvinyl alcohol, polyvinyl acetate,
polyvinyl pyrrolidone; amines for example ethanolamine,
diethanolamine, triethanolamine; steroids for example cholesterol,
cholesterol esters. The low-volatility component has a vapour
pressure at 25.degree. C. lower than 0.1 kPa, preferably lower than
0.05 kPa.
[0033] The aerosols compositions to be delivered with the
pressurised MDIs of the invention may contain from 0.2 to 2% by
weight of said low volatility component.
[0034] Propylene glycol, polyethylene glycol, isopropyl myristate
and glycerol are particularly preferred low-volatility
components.
[0035] The function of the low volatility component is to modulate
the MMAD of the aerosol particles. Being used at very low
concentrations, it does not substantially affect the chemical
stability of the compositions.
[0036] Examples of active ingredients include: anticholinergics
such as ipratropium bromide, oxitropium bromide, tiotropium
bromide; acetal corticosteroids such as budesonide, ciclesonide,
rofleponide; chetal corticosteroids such as flunisolide,
triamcinolone acetonide; other corticosteroids such as fluticasone
propionate, mometasone furoate; short or long acting
beta-adrenergic agonists such as salbutamol, formoterol,
salmeterol, TA 2005 and their combinations. The active ingredients
when possible may be present in racemic mixtures or in form of a
single enantiomer or epimer.
[0037] As said before, WO 94/13262 teaches that problems of
chemical stability of medicaments and in particular of ipratropium
bromide in aerosol solution compositions can be solved adding an
acid, either an inorganic acid or an organic acid, to the HFA
propellant/cosolvent system.
[0038] Examples of compositions containing ipratropium bromide in
HFA 134a/ethanol systems further containing an inorganic acid such
as hydrochloric, nitric, phosphoric or sulfuric acid or an organic
acid such as ascorbic or citric acid are provided.
[0039] We found that in solution compositions comprising
ipratropium bromide, a propellant containing a hydrofluoroalkane, a
cosolvent and further comprising a low volatility component:
[0040] a) different decomposition rates occur with different acids:
for example we found that ipratropium bromide (20 .mu.g/dose) in a
composition of 13% (w/w) ethanol, 1.0% (w/w) glycerol, 20 .mu.l/can
of 1N hydrochloric acid and HFA 134a to 12 ml/can rapidly
decomposes and after 3 months storage at 40.degree. C. gives 85.0%
average of drug remaining;
[0041] b) ipratropium bromide with or without acids is stable in
stainless steel, anodised aluminium or in some types of epoxy
phenol resin lined cans;
[0042] c) surprisingly certain kinds of materials, such as glass,
coatings proposed in the prior-art to overcome the physical
absorption phenomenon of the active ingredient, such as
perfluoroalkoxyalkanes and fluorinated-ethylene-propylene polyether
sulfone resins, or certain kinds of epoxy phenol coatings turned
out to be completely unsatisfactory and ineffective in preventing
its chemical degradation.
[0043] Another preferred active ingredient for the preparation of
solution compositions in a HFA/cosolvent system to be dispensed by
MDIs according to the present invention is budesonide.
[0044] Previously HFA/budesonide compositions have been described,
in which budesonide is present in suspension in the propellant
system and the composition further comprises additional ingredients
such as particular kinds of surfactants (EP 504112, WO 93/05765, WO
93/18746, Wo 94/21229).
[0045] In WO 98/13031 it is reported that suspension formulations
of budesonide have a propensity to rapidly form coarse flocs upon
dispersion and redispersion which may deleteriously affect dosage
reproducibility. There is also a tendency for budesonide to deposit
from suspension onto the walls of the container.
[0046] To achieve stable suspensions of particulate budesonide it
is employed in the prior art a composition containing a mixture of
HFA propellants to match the density of the propellant mixture to
be substantially identical to the density of budesonide, up to 3%
of an adjuvant such as ethanol and small amounts of surfactant.
[0047] It is stated in the document that the levels of the
adjuvants are low to avoid significant solubilization of drug,
leading to a problem of chemical degradation and particle size
increase on storage.
[0048] In the solution compositions of the present invention
budesonide is chemically and physically stable.
[0049] The aerosol compositions of the invention distributed in
inhalers having the internal surfaces consisting of stainless
steel, anodised aluminium or coated with an inert material and
preferably with epoxy-phenol resin are stable for long periods and
do not undergo chemical degradation.
[0050] Also in this case a considerable degradation of the active
ingredient was noticed when glass containers were used.
[0051] Analogously flunisolide and dexbudesonide (the 22R-epimer of
budesonide) solutions in HFA propellant containing ethanol and a
low-volatility component are stable when stored in inhalers having
the internal surfaces consisting of anodised aluminium or coated
with epoxy-phenol resin. Evident degradation of flunisolide was
noticed when glass containers were used.
[0052] It has been also found that the low volatility component may
also act as a co-solvent, thus increasing the solubility of the
drug in the formulation and increasing the physical stability
and/or allowing the possibility to decrease the quantity of
co-solvent required.
[0053] The following examples further illustrate the invention. In
the examples and tables the different types of epoxy phenol resins
are indicated with numbers in brackets corresponding to:
[0054] (1) Epoxy-phenol lacquered aluminium vials coated by
Cebal
[0055] (2) Epoxy-phenol lacquered aluminium vials coated by
Presspart
[0056] (3) Epoxy-phenol lacquered aluminium vials coated by
Nussbaum & Guhl
[0057] (4) Epoxy-phenol lacquered aluminium vials coated by
Presspart, other than (2)
EXAMPLE 1
[0058] A composition containing 4.8 mg of ipratropium bromide (20
.mu.g/dose), 13% (w/w) ethanol, 1.0% (w/w) glycerol and HFA 134a to
12 ml/can was distributed in stainless steel, anodised aluminium,
standard aluminium cans or in cans having different internal
coatings and were stored at various conditions.
[0059] The results are reported in Table 1 and Table 2.
[0060] The percent drug remaining in the composition, measured by
HPLC, shows that stainless steel and anodised aluminium cans as
well as epoxy-phenol resins (1), (2) and (4) coated cans are
effective in preventing the chemical degradation of ipratropium
bromide, differently from glass cans or other tested coatings.
EXAMPLE 2
[0061] The effect of different acids on the chemical stability of
the composition of Example 1 was studied.
[0062] Citric, ascorbic and hydrochloric acids were added to the
formulations in the amounts reported in Table 3.
[0063] The stability of the compositions was tested after 1, 2 and
5 months storage at 40.degree. C. in epoxy-phenol resin (4) coated
cans.
EXAMPLE 3
[0064] Compositions containing 12 mg of budesonide (50 .mu.g/dose),
13% or 15% (w/w) ethanol, 1.3% (w/w) glycerol in HFA 134a to 12
ml/can were distributed in stainless steel, anodised aluminium,
standard aluminium, glass cans or in cans having different internal
coatings and were stored at various conditions.
[0065] The results are reported in Table 4 and 5.
[0066] The percent drug remaining in the compositions, measured by
HPLC, shows the favourable effect of stainless steel, anodised
aluminium and inert coating on the chemical stability of the active
ingredient in respect to standard aluminium or glass cans. The best
results have been obtained with stainless steel, anodised aluminium
cans and with epoxy-phenol or perfluoroalkoxyalkane coatings.
EXAMPLE 4
[0067] A composition containing 48 mg of dexbudesonide (200
.mu.g/dose), 15% (w/w) ethanol, 1.3% (w/w) glycerol in HFA 134a to
12 ml can was distributed in epoxy-phenol lacquered aluminium cans
and was stored at 40.degree. C.
[0068] The percent drug remaining in the composition after 8
months, measured by HPLC, was 95.4% (average value referred to two
tests).
[0069] The control of the epimeric distribution showed that there
is no transfer from the 22R to the 22S epimer.
EXAMPLE 5
[0070] Compositions containing 7.2, 12, 16.8 mg of dexbudesonide
(corresponding to 30, 50 and 70 .mu.g/dose respectively), ethanol,
0.9 (w/w) PEG 400 or isopropyl myristate (IPM) in HFA 227 to 12 ml
can was distributed in aluminium anodised cans and was stored 70
days at 50.degree. C. The results are reported in Table 6.
[0071] The percent drug remaining in the composition measured by
HPLC shows the favourable effect of anodised aluminium cans on the
chemical stability of the active ingredient. The control of the
epimeric distribution showed that there is no transfer from the 22R
to the 22S epimer.
EXAMPLE 6
[0072] The fine particle dose (FPD: weight of particles having an
aerodynamic diameter lower than 4.7 .mu.m) of dexbudesonide
solution compositions in HFA 134a or HFA 227, prepared following
the examples 4 and 5, was determined.
[0073] The experiments were performed using the Andersen Cascade
Impactor and the data obtained are average values from 10
shots.
[0074] The results, reported in Table 7 and 8 show that
dexbudesonide formulations of the invention are characterized by a
very low dose and a very high fine particle dose.
[0075] The FPD gives a direct measure of the mass of particles
within the specified size range and is closely related to the
efficacy of the product.
EXAMPLE 7
[0076] A composition containing 60 mg of flunisolide (250
.mu.g/dose), 15% (w/w) ethanol, 1% (w/w) glycerol in HFA 134a to 12
ml/can was distributed in anodised aluminium, glass cans or in cans
having different internal coatings and were stored for 41 days at
50.degree. C.
[0077] The results are reported in Table 9.
[0078] The percent drug remaining in the composition, measured by
HPLC, shows the favourable effect of anodised aluminium and inert
coating with epoxy-phenol resins on the chemical stability of the
active ingredient in respect to glass cans.
EXAMPLE 8
[0079] The solubility of ipratropium bromide and micronized
budesonide in ethanol, glycerol and their mixtures has been
investigated.
[0080] The tests were carried out at room temperature.
[0081] a) Solubility in Ethanol.
[0082] About 8.5 g of absolute ethanol were weighed into a flask.
The active ingredient (Ipratropium Bromide or Budesonide) was added
in small amounts, under magnetic stirrer, until no further
dissolution occurred (i.e.: a saturated solution was obtained). The
flask was stirred for about 40 minutes, and left to settle
overnight prior to analysis, to let the system equilibrate. The
flask was kept sealed, to avoid evaporation.
[0083] The solution obtained was then filtered and tested for the
amount of active ingredient, according to the conventional
analytical procedure.
[0084] b) Solubility in Ethanol/Glycerol Mixtures.
[0085] The required amounts of ethanol and glycerol were weighted
into a flask, and mixed by a magnetic stirrer until a homogeneous
phase was obtained.
[0086] The solubility of ipratropium bromide in ethanol is 42.48
mg/g.
[0087] The solubility data of ipratropium bromide in
ethanol/glycerol mixtures are listed in Table 10.
[0088] The solubility of micronized budesonide in ethanol is 31.756
mg/g.
[0089] Solubility data of micronized budesonide in ethanol/glycerol
mixtures are listed in Table 11.
[0090] The data show that both the tested active ingredients are
rather soluble in ethanol, and that their solubility increases even
when small percentages of glycerol are added.
[0091] The increase in solubility is maintained also in presence of
HFA propellants.
1TABLE 1 Percent ipratropium bromide (IPBr) recovered after storing
the composition of Example 1 for 8 months at 40.degree. C. in cans
of different types CAN TYPE % RESIDUAL IPBr Epoxy-phenol resin (4)
96 Perfluoroalkoxyalkane 57 Fluorinated-ethylene-propylene/ 78
polyether sulphone (Xylan 8840.sup.(R)) Stainless steel 96 Standard
aluminium 46
[0092]
2TABLE 2 Percent ipratropium bromide (IPBr) recovered after storing
the composition of Example 1 for 30 and 60 days at 50.degree. C.,
or for 96 days at 40.degree. C. in cans of different types (average
values referred to two tests). % RESIDUAL IPBr (% RESIDUAL IPBr
RELATIVE TO t = 0) t = 30 days t = 60 days t = 96 days CAN TYPE t =
0 at 50.degree. C. at 50.degree. C. at 40.degree. C. Epoxy phenol
resin 99 89 88.5 93.5 (1) (90) (89.5) (94.5) Epoxy phenol resin
97.5 90 88.5 89 (2) (92) (90.5) (91) Epoxy phenol resin 98.5 56.5
46 52.5 (3) (57.5) (47) (53.5) Anodised aluminum 94 89 87 90.5 (95)
(92.5) (96.5) Glass type III* -- 48.5 41.5 47 (--) (--) (--)
*according to Eur Pharmacopoeia 3.sup.rd Ed Suppl 1999
[0093]
3TABLE 3 Percent ipratropium bromide (IPBr) recovered after storing
the compositions of Example 1, with different acids added, in
epoxy-phenol (4) coated cans (average values referred to two tests)
% RESIDUAL IPBr (% RESIDUAL IPBr RELATIVE TO t = 0) t = 1 month t =
2 months t = 5 months Acid t = 0 at 40.degree. C. at 40.degree. C.
at 40.degree. C. Citric (0.6% w/w) 98 98 99 94 (100) (101) (96)
(0.3% w/w) 99 99 100 97 (100) (101) (98) (0.07% w/w) 99 98 99 96
(99) (100) (97) Ascorbic 119 113 112 110 (95) (94) (92)
Hydrochloric (4 .mu.l-1 N) 101 100 104 96 (99) (102) (95) (10
.mu.l-1 N) 101 98 98 97 (97) (97) (96) (20 .mu.l-1 N) 100 95 98 97
(95) (98) (97) None 97 97 98 95 (100) (101) (98)
[0094]
4TABLE 4 Percent budesonide recovered after storing the composition
of Example 3 (13% ethanol) for 7 months at 40.degree. C. in cans of
different types CAN TYPE % RESIDUAL BUDESONIDE Epoxy-phenol resin
(4) 100 Fluorinated-ethylene-propylene/ 93.5 polyether sulphone
(Xylan 8840.sup.(R)) Stainless steel 97 Aluminium 68
Perfluoroalkoxyalkane 100
[0095]
5TABLE 5 Percent budesonide recovered after storing the composition
of Example 3 (15% ethanol) for 33 and 73 days at 50.degree. C. in
cans of different types (average values referred to two tests). %
RESIDUAL BUDESONIDE (% RESIDUAL BUDESONIDE RELATIVE TO t = 0) CAN
TYPE t = 0 T = 33 days t = 73 days Epoxy phenol 99.3 97.0 95.4
resin (1) (97.7) (96.1) Epoxy phenol 99.5 96.6 95.6 resin (2)
(97.0) (96.1) Epoxy phenol 99.3 96.6 95.9 resin (3) (97.2) (96.5)
Anodised 99.9 99.2 97.7 aluminium (99.3) (97.8) Glass type III* --
86.15 80.4 (--) (--) *according to Eur Pharmacopoeia 3.sup.rd Ed
Suppl 1999 These results have been confirmed storing the same
formulation up to 7 months at 30.degree. C., 40.degree. C.,
45.degree. C. and 50.degree. C.
[0096]
6TABLE 6 Percent dexbudesonide recovered after storing the
compositions of Example 5 for 70 days at 50.degree. C. in anodised
aluminium cans (average values referred to two tests). % Residual
dexbudesonide Metered (% residual dexbudesonide dose Ethanol Low
vol. comp. relative to t = 0) (.mu.g) % (w/w) 0.9% (w/w) t = 0 days
t = 70 days 30 5 PEG 400 95.8 95.8 (100) IPM 98.1 96.8 (98.7) 50 8
PEG 400 99.0 98.0 (98.9) IPM 98.0 99.4 (101) 70 7 PEG 400 95.7
93.75 (98.0) IPM 100.4 96.3 (96.0) IPM = Isopropyl myristate
[0097]
7TABLE 7 Fine particle dose (FPD) values of dexbudesonide solution
formulation in HFA 134a containing: dexbudesonide 14.4 mg/can (60
.mu.g/shot) ethanol 8% (w/w) low volatility compound 0.9% (w/w) HFA
134a to 12 ml can (valve chamber volume = 63 .mu.l) MMAD = 2.0
.mu.m Low volatility FPD FPF Metered dose Delivered dose Compound
(.mu.g) (%) (.mu.g) (.mu.g) IPM 39.9 73.6 57.9 54.2 IPM 39.4 77.4
53.2 50.9 IPM = isopropyl myristate FPF = fine particle fraction
(Fine particle dose/Delivered dose .times. 100) FPD = weight of
particles having an aerodynamic diameter lower than 4.7 .mu.m
Metered dose is given by the sum of delivered dose and actuator
residue. Delivered dose is the dose delivered ex actuator.
[0098]
8TABLE 8 Fine particle dose (FPD) values of dexbudesonide solution
formulation in HFA 227 containing: dexbudesonide 15.12 mg/can (63
.mu.g/shot) ethanol 7% (w/w) low volatility compound 0.9% (w/w) HFA
227 to 12 ml can (valve chamber volume = 63 .mu.l) MMAD = 2.0 .mu.m
Low volatility FPD FPF Metered dose Delivered dose Compound (.mu.g)
(%) (.mu.g) (.mu.g) IPM 45.0 75.5 63.9 59.7 PEG 400 48.5 78.9 65.5
61.5 IPM = isopropyl myristate FPF = fine particle fraction (Fine
particle dose/Delivered dose .times. 100) FPD = weight of particles
having an aerodynamic diameter lower than 4.7 .mu.m Metered dose is
given by the sum of delivered dose and actuator residue Delivered
dose is the dose delivered ex actuator
[0099]
9TABLE 9 Percent flunisolide recovered after storing the
composition of Example 7 for 41 days at 50.degree. C. in cans of
different types (average values referred to two tests). % RESIDUAL
FLUNISOLIDE (% RESIDUAL FLUNISOLIDE RELATIVE TO t = 0)) CAN TYPE t
= 0 t = 41 days t = 93 days Epoxy phenol 98.4 99.2 101.4 resin (1)
(101) (103) Epoxy phenol 101.9 99.7 101.9 resin (2) (97.8) (100)
Epoxy phenol 101.7 99.2 101.2 resin (3) (97.5) (99.6) Anodised
101.6 100.4 100.7 aluminum (98.8) (99.1) Glass type III* -- -- 97.5
(--) *according to Eur Pharmacopoeia 3.sup.rd Ed Suppl 1999
[0100]
10TABLE 10 Solubility of Ipratropium Bromide in ethanol/glycerol
mixtures Ipratropium Bromide Ethanol (%) Glycerol (%) solubility
(mg/g) 100 0 42.8 92.6 7.4 74.0 91.9 8.1 74.7 91.3 8.7 90.5 88.4
11.6 98.0 82.6 17.4 115.6 71.4 28.6 196.7 60 40 271.6 40 60 307.2
21.1 78.9 265.7 0 100 73.4
[0101]
11TABLE 11 Solubility of micronized Budesonide in ethanol/glycerol
mixtures Budesonide solubility Ethanol (%) Glycerol (%) (mg/g) 100
0 31.756 92.5 7.5 36.264 91.9 8.1 36.277 91.3 8.7 37.328 87.7 12.3
38.364 83.3 16.7 37.209 71.4 28.6 35.768 60 40 28.962 39.9 60.1
14.840 21.1 78.9 3.990 0 100 0.214
* * * * *