Note: Descriptions are shown in the official language in which they were submitted.
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PROCATEROL MICROSPHERES CONTROLLED-RELEASE
AEROSOL
FIELD OF INVENTION
The present invention relates to a method of making
a composition for delivery by aerosol inhalation
comprising albumin microsphere~, preferably in a
propellant, that provides controlled-release delivery of
pharmaceutically active agents, particularly
bronchodilating agents such as procaterol or procaterol
hydrochloride; the composition for use in the delivery;
its use and a device for this use.
BACKGROUND OF INVENTION
Internaticnal application published under the
Patent Cooperation Treaty (PCT~ publication number ~O
87/05803 describes pharmaceutical compositions for
administration of ~2-receptor active substances
including procaterol by inhalation and comprising
liposomes. The description provides for aerosolizing a
composition of a selected quantity of lipid-based solid
material which is said to spontaneously form or
reconstitute liposomes in an aqueous milieu. The
present invention differs from the described composition
as the invention does not provide a lipid-based material
for aerosolizing and further does not provide for
delivery by the formation of liposomes. The composition
also differs from the present invention by the
controlled-release property of the present invention.
International application published under the PCT
publication number WO 87/05213 also describes
preparation of pharmaceutical compositions for
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inhalation containinq microgranu]es of solid
water-soluble diluents and a lubricant. Although the
compositions may include procaterol, the other
components are different from the present invention.
For example, W0 87/05213 teaches the preparation of an
excipient called a conglomerate in the form of
microgranules of a solid water-soluble vehicle such as
lactose, xylitol, arabinose, dextran, mannitol or the
like with a suitable lubricant such as sodium benzoate,
magnesium stearate, colloidal silica, hydrogenated oils,
fatty bases, etc.
In contrast, the present invention provides
controlled release of a pharmaceutically active agent,
preferably procaterol or procaterol hydrochloride in a
water insoluble matrix.
U.S. Patent No. 4,696,938 describes insecticidal
aerosol compositions. Although many of the components
of this composition are the same as or similar to those
employed .in the present invention, various components
acceptable in an insecticidal application are included
which are not suitable for pharmaceutical use. No
details of the preparation of an aerosol composition are
described. The Example for an aerosol in the disclosure
of the patent indicates the components, a toxicant and
toxicant impurities and Freon 12, are mixed and packaged
under pressure in a suitable container e~lipped with a
release spraly valve. This teaching is not suitable for
the present controlled-release aerosol for procaterol.
S.R. Walker et al., "The Clinical Pharmacology of
Oral and Inhaled ~albutamol", Clinical Pharmacology and
Therapeutics, Vol.13, No. 6, p.861 (1972) describes the
pharmacology of inhaled salbutamol which is a selective
~2-receptor stimulant, i.e., an effective
bronchodilator. However, no description shows
preparation o an aerosol and therefore differs from the
present invention or controlled-release of procaterol.
Yarious references describe albumin for delivery
of drugs in parenteral applications, particularly for
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cancer treatment. These include, CRC Critical Reviews
n Therapeutic Drug Carrier_Systems, Yasunori Morimoto
and Shlgeru Fujimoto, "Albumin Microspheres as Drug
Carriers," Volume 2, Issue 1, pp.19-63; Microspheres and
Druq TheraPy. Pharmaceutical, Immunolo~ical and Medical
Aspects, edited by S. S. Davis, L. Illum, J. G. McVie
and E. Tomlinson ~1984), Elsevier Science Publishers B.
V., Chapter 1 "Human serum albumin microspheres for
intraarterial drug targeting of cytostatic compounds.
Pharmaceutical aspects and release characteristics,"
pp 75-89 by E Tomlinson et al., Chapter 4 "De~elopment
and testing of proteinaceous nanoparticles containinq
cytotoxics," pp.117-128 by R. C. Oppenheim et al.,
Chapter 3 "Adriamycin-loaded albumin microspheres: Lung
entrapment and fate in the rat," pp.205-215 by N.
~illmott et al., Chapter 9 "Drug entrapment within
native albumin beads," pp.295-307 by T.D. Sokoloski and
G.P. Royer, and Chapter 10 "Hydrophili~ albumin and
dextran ion-exchange microspheres for localized
chemotherapy,l- pp.309-325 by ~.P. Goldberg et al.;
Biomedical Applications of Microencapsulation, Editor:
Franklin Lim, CRC Press Inc., Boca Raton, Florida
(1983), Chapter 3 "Biodegradable Microspheres for
Parenteral Administration," pp.53-75 at 66 by C. Thies
and M. Bissery; E. Tomlinson and J. G. McVie, "New
directions in Cancer Chemotherapy 2. Targeting with
Microspheres," Pharmacy International, November, 1983,
pp. 281-284; and N. Willmott and P. J. Harrison,
"Characterization of reeze-dried albumin microspheres
containing the anti-cancer drug adriamycin,"
International Journal of Pharmaceutics, 43 (1988)
161-166.
Extended-Release Dosaqe Forms by Leszek Krowczynski
translator Dorota Porebska Brozyna, CRC Press, Inc.,
Boca Raton, Florida, pp. 71-72 describes an aqueous
suspension (0.5 ml) of human serum albumin and
staphylococcal protein A mixed with cottonseed oil (6Q
-4~
ml) and homogenization of the emulsion by sonification
for 1 min. at 60C ollowed by denaturation at 120 to
125C for 10 min. Use of egg albumin is also ~entioned
by Krowczynski. The resultant microspheres were air
dried for parenteI-al administration. Although these
microspheres comprise a pharmacological component the
reference teaches intraarticular injection of the
microspheres which is different from an aerosol delivery
of a pharmacologically active component. Thus, the
article does not provide microspheres for extended-
release delivery of procaterol in an aerosol as set out
in the present invention.
SUMMARY OF INVENTION
The present invention provides a controlled-release
pharmaceutical formulation for use in an inhalation
aexosol comprising a pharmaceutically active agent,
preferably procaterol, and albumin in the form of
microspheres.
The present invention provides a novel method for
preparing a composition for controlled-release d~livery
of a pharmaceutically active agent by inhalation aerosol
which comprises dispersing microspheres, wherein the
microspheres are a controlled-release formulation
comprising a pharmaceutically active agent and albumin;
in an aerosol-type propellant.
The present invention also provides a composition
for controlled-release delivery of a pharmaceutically
active agent by inhalation aerosol which comprises a
dispersion of microspheres, wherein the micro~pheres are
a controlled-release pharmaceutical formulation of a
pharmaceutically active agent and albumin; in an
aerosol-type propellant.
The present invention is al~o a method of treating
a disease condition which comprises administering
microspheres by inhalation aerosol, wherein the
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microspheres are a controlled-release formulation
comprising a pharmaceutically active agent effective for
treating the disease or condition and albumin; by
metered-dose.
Finally, the pre~ent invention i~ an inhalation
device for delivery by inhalation aerosol. The
inhalation device may be a powder-inhalator such a~
Spinhaler~, Rotahaler~, Turbuhaler~, etc. or a
pressurized dose-aerosol. The powder-inhalator provides
a selected quantity of microspheres in a form suitable
for inhalation. The microspheres are a
controlled-release formulation comprising a
pharmaceutically active agent together with albumin. No
powder-inhalers containing a controlled-relea~e
formulation exist on the market.
The pressurized dose-aerosol is a pressure-tight
container having a valve-controlled opening, option~lly
equipped with a ~etered dose device, and containing a
self-propelling composition capable of providing
microsphere5 in aerosol form. The self-propelling
composition comprises a pharmaceutically acceptable
propellant in which the microspheres are dispersed. The
microspheres are a controlled-release phar~aceutical
formulation preferably comprising a pharm~ceutically
active agent: toget}ler with albumin. On operating the
metering valve of the aerosol container, the
microspheres are dispensed in a stream of propellant.
No pressurized dose-aerosols containing controlled-
release microspheres exist on the market. However,
controlled-release microspheres having pharmaceutically
active agents together with albumin are present in
various other suspending a~ents particularly ~uitable
for parenteral use.
The pharmaceutically açtive agents of the present
invention are compounds appropriate for delivery by
inhalation aerosol, preferably such agents having high
potency. More preferably the agent i~ a bronchodilating
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agent and most preferably i9 procaterol or procate~ol
hydrochloride.
Stabilizing agents may be present on each of the
above described microspheres having a pharmaceutically
active agent and albumin.
DETAILE~ DESCRIPTION OF INVENTION
Pharmaceutically active agents for inhalation
aerosol which may be incorporated into the microspheres
of the present invention are 5-lipoxygenase or
cyclooxygenase inhibitors and antiallergy agents
generally; antiinflammatory agents; alld particularly
bronchodilating agents. For example, isoprote~enol
hydrochloride~ isoetharine hydrochloride,
metaproterenol, albuterol, terbutaline, cromolyn
atropine sulfate, and preferably procaterol
hydrochloride may be used.
The albumin microspheres suitable for use in the
inhalation a~rosol of the present invention
micr~encapsulate the active agent which may be prepared
either by thermal denaturation at elevated temperatures,
80 to 140C' for from 2 to 60 min., or chemical
cross-linking in vegetable oil or isooctane solution.
For example, an a~leous solution or suspension of the
active agent, 2 to 200 mg/ml, and serum albumin, 18 to
lBOO mg/ml, is mixed with an oil, 10 to 1000 ml,
preferably vegetable oil~ and an emulsion prepared by
sonification for 0.5 to 3 min. The e~ulsion i5 added to
an ~dditional 50-50,000 ml oil and heated for ~.5 to ~0
min. at 80 to 140C. The resultant microspheres are
washed with n-hexane and separated by centrifugation.
Procaterol hydrochloride may not be sufficiently
stable to resist elevated temperatures used for albumin
denaturation. Thus, it is suygested a stabîlizer may be
added, either in the oil or aqueous phase or both oil
and aqueous phases in the above description.
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Specifically, for example, in a procaterol hydrochlorid~
concentration of 20 ng/ml in water, the procaterol i5
decomposed ca. 5% in 100 minutes at 98C. With the
addition of ascorbic acid ~0.05%) as a stabilizer in the
aqueous phase, no decomposition occurs. One of ordinary
skill would recognize use of other stabilizers may
include sodium metabisulfite, ~odium sulfite, sodium
bisulfite, isoascorbic acid, sodium isoascorbate,
ascorbyl palmitate, ethyl gallate, propyl gallate,
gallic acid, cysteine hydrochloride, thioglycollic acid,
thiosorbitol, sodium thiosulphate, tocopherols,
butylated hydroxytoluene, butylated hydroxyanisole,
t-butylhydroquinone and the like.
The microspheres may be stored in hexane or washed
with a propellant for dispersion in the propellant. The
microspheres and compressed air or microspheres and
propellant in a dispersion composition is filled into a
device for inhalation aerosols and appropriately charged
to an appropriate air pressure or with additional
propellant to an appropriate pressure. This microsphere
containing a pharmaceutically acceptable agent
~icroencapsulated in albumin is ready for compressed air
delivery inhalation use or metered-dose inhalation use.
The oils for forming the emulsion include edible
animal and vegetable oils such as various fish oils,
soybean, safflower, sunflower, corn, cottonseed,
rapeseed, sesame, and bran oils, preferably cottonseed
oil.
The serum albumin suitable for use in the
microspheres include human, egg, or other animal such as
rabbit or bovine, preerably human or bovine serum
albumin.
The propellants that may be used in the present
invention are either compre~sed air or pharmaceutically
3~ acceptable propellants for metered-dos2 inhalants such
as various chlorofluorocarbons, fluorocarbons or
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hydrocarbons which generate a po~itive pressure within a
sealed container.
The oil phase will typically contain emulsifiers,
preferable emulsifiers having a low HLB (Hydrophile-
Lipophile Balance). Examples of such emulsifiersinclude glyceryl monostearate, glyceryl monoleate,
sucrose distearate, sorbitan monostearate, sorbitan,
monopalmitate, sorbitan monolaurate, and sorbitan esters
marketed under the trade name Span.
The preferred microspheres of the present invention
microencapsulate a potent bronchodilator in albumin.
The most preferred microspheres of the present
invention microencapsulate the potent bronchodilator,
procaterol hydrochloride.
The release profile can be controlled depending on
the amount of albumin that is used for
microencapsulation.
The encapsulation process i8 preferably optimized to
prepare microspheres in the particle size range of 1 to
10 ~m(microns) and preferably in the range of 1 to 3
microns. The overall ratio of active agent to albumin
is typically from 1 to 10. A relatively large amount of
albumin, i.e., up to 20 milligrams, can be used to
encapsulate the most preferred active agent, procaterol
hydrochloride.
P. E. Morrow in Chapter 21 of Airway DYnamics
entitled, "Dynamics of Dust Removal From The Lower
Airways: Measurements and Interpretations Based upon
Radioactive Aerosols," describes size-deposition
relationships for dust deposition and removal for a dust
cloud or aerosol. This article teaches that dust or
aerosol of size ranges, for example from 1 to 10
microns, preferably 1 to 3 microns, such as the
microspheres which are the present invention, could stay
in the lung for an extended period of time. That is, in
the light of this teaching, the microspheres of the
present invention would provide a control],ed release of
a pharmaceutically active agent by aerosol inhalation.
Generally, an ordinarily skilled physician will
readily determine and prescribe an effective amount of
the il~halation aerosol having the microspheres for
prophylactic or therapeutic treatment of the condition
for which such treatment is ac~inistered.
The composition described below is a dispersion of
microspheres containing procaterol hydrochloride
microencapsulated in seru~ albumin which microspheres
are dispersed in a propellant having the trade name
Freon 11 and/or Freon 12.
EXAMPLE 1
Preparation of Albumin Microspheres
An aqueous solution ~1 ml) containing 20 mg of
procaterol hydrochlc~ride and 180 ml of bovine serum
albumin is mixed with cottonseed oil (100~1) and the
emulsion is prepared by sonication for 1.5 minutes at
50~C. This water/oil emulsion is added to 200 ml of
constantly stirred cottonseed oil at 110C for 30
minutes. T'he resultant microspheres are washed with
n-hexane and separated by centrifugation. The
microspheres may be stored in hexane.
Dispersion of Drug-Loaded A bumin Microspheres in
Propellant
Albumin microspheres dispersed in hexane are
centrifuged and washed with Freon 11. The microspheres
are then dispersed in 6 g of Freon 11 and placed in
pressurizable aerosol device. Fourteen yra~s of Freon
12 is filled into the above device and mixed well after
the devise is crimped. The dispersion of the
microspheres containiny procaterol hydrochloride in the
propellant Freon 11 anc~ Freon 12 is ready for
metered-dose inhalation use.
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E~MPLE 2
An aqueous solution (1 ml) contailing 20 mg of
procaterol hydrochloride, 10 mg o ascorbic acid and 170
ml of bovine serum albumin is mixed with lOQ ml
cottonseed oil containing 0.2 ml of ~-tocopherol and the
mixture is sonicated or 1.5 minutes at 50C to prepare
an emulsion. The microspheres are then prepared as
described in the above example.
