U.S. patent application number 10/245705 was filed with the patent office on 2003-05-08 for devices, compositions and methods for the pulmonary delivery of aerosolized medicaments.
Invention is credited to Eljamal, Mohammed, Foster, Linda, Patton, John S., Platz, Robert M..
Application Number | 20030086877 10/245705 |
Document ID | / |
Family ID | 29220122 |
Filed Date | 2003-05-08 |
United States Patent
Application |
20030086877 |
Kind Code |
A1 |
Platz, Robert M. ; et
al. |
May 8, 2003 |
Devices, compositions and methods for the pulmonary delivery of
aerosolized medicaments
Abstract
According to the subject invention, dispersible dry powder
pharmaceutical-based compositions are provided, including methods
for their manufacture and dry powder dispersion devices. A
dispersible dry powder pharmaceutical-based composition is one
having a moisture content of less than about 10% by weight (%w)
water, usually below about 5%w and preferably less than about 3%w;
a particle size of about 1.0-5.0 .mu.m mass median diameter (MMD),
usually 1.0-4.0 .mu.m MMD, and preferably 1.0-3.0 .mu.m MMD; a
delivered dose of about >30%, usually >40%, preferably
>50%, and most preferred >60%: and an aerosol particle size
distribution of about 1.0-5.0 .mu.m mass median aerodynamic
diameter (MMAD), usually 1.5-4.5 .mu.m MMAD, and preferably 1.5-4.0
MMAD. Such composition are of pharmaceutical grade purity.
Inventors: |
Platz, Robert M.; (Half Moon
Bay, CA) ; Patton, John S.; (San Carlos, CA) ;
Foster, Linda; (Sunnyvale, CA) ; Eljamal,
Mohammed; (San Jose, CA) |
Correspondence
Address: |
Mary Ann Dillahunty
BURNS, DOANE, SWECKER & MATHIS, L.L.P.
P.O. Box 1404
Alexandria
VA
22313-1404
US
|
Family ID: |
29220122 |
Appl. No.: |
10/245705 |
Filed: |
September 18, 2002 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10245705 |
Sep 18, 2002 |
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09616236 |
Jul 14, 2000 |
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09616236 |
Jul 14, 2000 |
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09447753 |
Nov 22, 1999 |
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6372258 |
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09447753 |
Nov 22, 1999 |
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09427075 |
Oct 26, 1999 |
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6509006 |
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09427075 |
Oct 26, 1999 |
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08423515 |
Apr 14, 1995 |
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08423515 |
Apr 14, 1995 |
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07910048 |
Jul 8, 1992 |
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5458135 |
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08423515 |
Apr 14, 1995 |
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08417507 |
Apr 4, 1995 |
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08417507 |
Apr 4, 1995 |
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08044358 |
Apr 7, 1993 |
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08417507 |
Apr 4, 1995 |
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08232849 |
Apr 25, 1994 |
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5607915 |
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08417507 |
Apr 4, 1995 |
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08309691 |
Sep 21, 1994 |
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5785049 |
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08417507 |
Apr 4, 1995 |
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08246034 |
May 18, 1994 |
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08417507 |
Apr 4, 1995 |
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08313707 |
Sep 27, 1994 |
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08417507 |
Apr 4, 1995 |
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08383475 |
Feb 1, 1995 |
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Current U.S.
Class: |
424/46 |
Current CPC
Class: |
A61K 9/1658 20130101;
A61M 15/0033 20140204; A61K 9/1617 20130101; A61K 9/0075 20130101;
A61K 9/1611 20130101; A61K 38/28 20130101; A61K 47/544 20170801;
A61K 9/1652 20130101; A61M 15/0051 20140204; A61M 15/0045 20130101;
A61M 2202/064 20130101; A61M 2205/0233 20130101; A61K 9/1623
20130101; B82Y 5/00 20130101; A61K 38/215 20130101; A61M 2205/073
20130101; A61M 15/0086 20130101; A61K 38/21 20130101; A61K 9/1694
20130101 |
Class at
Publication: |
424/46 |
International
Class: |
A61L 009/04; A61K
009/14 |
Claims
The subject matter claimed is:
1. A dispersible pharmaceutical-based dry powder composition for
pulmonary delivery, said composition comprising a therapeutically
effective amount of the pharmaceutical in combination with a
pharmaceutically acceptable carrier.
2. The composition of claim 1, wherein the composition is
substantially free from penetration enhancers.
3. The composition of claim 2, wherein the carrier comprises
HSA.
4. The composition of claim 3, wherein the carrier further
comprises a carbohydrate bulking agent.
5. The composition of claim 1, wherein about 95% of the mass of the
dry powder composition has a particle size of less than 10
.mu.m.
6. The composition of claim 5, wherein about 80% of the mass of the
dry powder composition has a particle size of less than 5.mu.m.
7. A unit dosage form for pulmonary delivery of a pharmaceutical,
which dosage form comprises a unit dosage receptacle containing a
dispersible pharmaceutical-based dry powder composition which
composition comprises a therapeutically effective amount of the
pharmaceutical in combination with a pharmaceutically acceptable
carrier.
8. The unit dosage form of claim 7 wherein the carrier comprises
HSA and a carbohydrate bulking agent, the composition is
substantially free from penetration enhancers and about 95% of the
mass of the dry powder composition has a particle size of less than
about 10 .mu.m.
9. A method of treating a disease state responsive to treatment by
a pharmaceutical, which method comprises pulmonarily administering
to a subject in need thereof a physiologically effective amount of
a dispersible pharmaceutical-based dry powder composition that
comprises a therapeutically effective amount of the macromolecule
in combination with a pharmaceutically acceptable carrier.
10. The method of claim 9, wherein the carrier comprises HSA and a
carbohydrate bulking agent, the composition is substantially free
from penetration enhancers and about 95% of the mass of the dry
powder composition has a particle size of less than about 10
.mu.m.
11. A method for aerosolizing a pharmaceutical-based dry powder
composition that comprises a therapeutically effective amount of
the pharmaceutical in combination with a pharmaceutically
acceptable carrier, which method comprises: dispersing an amount of
the dry powder composition in a gas stream to form an aerosol and
capturing the aerosol in a chamber suitable for subsequent
inhalation by a patient.
12. The method of claim 11, wherein the carrier comprises HSA and a
carbohydrate bulking agent, the composition is substantially free
from penetration enhancers and about 95% of the mass of the dry
powder composition has a particle size of less than about 10
.mu.m.
13. A method for preparing a spray-dried, pharmaceutical-based dry
powder composition that comprises a therapeutically effective
amount of the macromolecule and a pharmaceutically acceptable
carrier, which method comprises spray-drying an aqueous mixture of
the macromolecule and the carrier under conditions to provide a
respirable dry powder.
14. The method of claim 13 wherein the composition is substantially
free from penetration enhancers.
15. The method of claim 14, wherein the carrier comprises HSA.
16. The method of claim 15, wherein the carrier further comprises a
carbohydrate bulking agent.
17. The method of claim 16, wherein the bulking agent is
mannitol.
18. The method of claim 13, wherein 95% of the mass of the
spray-dry composition has a particle size less than 10 .mu.m.
19. A spray-dried, macromolecule-based dry powder composition for
pulmonary delivery, said composition comprising a therapeutically
effective amount of the macromolecule in combination with a
pharmaceutically acceptable carrier that comprises HSA and a
carbohydrate bulking agent, wherein the composition is substanually
free from penetration enhancers and about 95% of the mass of the
dry powder composition has a particle size of less than 10
.mu.m.
20. The composition of claim 19, wherein the bulking agent is
mannitol.
21. The composition according to any of claims 1, 7, 9, 13, and 19
wherein the macromolecule is selected from the group comprising
insulin, interlukin 1 receptor, parathyroid hormone (PTH-34),
alpha-1 antitrypsin, calcitonin, low molecular weight heparin,
heparin, interferon, and nucleic acids.
Description
[0001] This application is a continuation in part of the following
U.S. patent applications: Ser. No. 07/910,048. filed Jul. 8, 1992;
Ser. No. 08/______ (attorney docket No. 15225-000410), filed Apr.
4, 1995, which is a file wrapper continuation of Ser. No.
08/044,358, filed Apr. 7, 1993; Ser. No. 08/232,849, filed Apr. 25,
1994; Ser. No. 08/309,691, filed Sep. 21, 1994; Ser. No.
08/246,034, filed May 18, 1994; Ser. No. 08/313,707, filed Sep. 27,
1994; and, Ser. No. 08/383,475, filed Feb. 1, 1995, the full
disclosures of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to methods and
compositions for the dry powder formulation of pharmaceuticals,
including macromolecules, for pulmonary delivery.
[0004] Over the years, certain drugs have been sold in compositions
suitable for forming a drug dispersion for oral inhalation
(pulmonary delivery) to treat various conditions in humans. Such
pulmonary drug delivery compositions are designed to be delivered
by inhalation by the patient of a drug dispersion so that the
active drug within the dispersion can reach the lung. It has been
found that certain drugs delivered to the lung are readily absorbed
through the alveolar region directly into blood circulation.
Pulmonary delivery is particularly promising for the delivery of
macromolecules (proteins, polypeptides and nucleic acids) which are
difficult to deliver by other routes of administration. Such
pulmonary delivery can be effective both for systemic delivery and
for localized delivery to treat diseases of the lungs.
[0005] Pulmonary drug delivery can itself be achieved by different
approaches, including liquid nebulizers, aerosol-based metered dose
inhalers (MDI's), and dry powder dispersion devices. Aerosol-based
MDI's are losing favor because they rely on the use of
chlorofluorocarbons (CFC's), which are being banned because of
their adverse effect on the ozone layer. Dry powder dispersion
devices, which do not rely on CFC aerosol technology, are promising
for delivering drugs that may be readily formulated as dry powders.
Many otherwise labile macromolecules may be stably stored as
lyophilized or spray-dried powders by themselves or in combination
with suitable powder carriers. The ability to deliver
pharmaceutical compositions as dry powders, however, is problematic
in certain respects. The dosage of many pharmaceutical compositions
is often critical so it is necessary that any dry powder delivery
system be able to accurately, precisely, and reliably deliver the
intended amount of drug. Moreover, many pharmaceutical compositions
are quite expensive. Thus, the ability to efficiently deliver the
dry powders with a minimal loss of drug is critical. It is also
essential that the powder be readily dispersible prior to
inhalation by the patient in order to assure adequate distribution
and systemic absorption.
[0006] A particularly promising approach for the pulmonary delivery
of dry powder drugs utilizes a hand-held device with a hand pump
for providing a source of pressurized gas. The pressurized gas is
abruptly released through a powder dispersion device, such as a
venturi nozzle, and the dispersed powder made available for patient
inhalation. While advantageous in many respects, such hand-held
devices are problematic in a number of other respects. The
particles being delivered are less than 10 .mu.m in size, usually
in the range from 1 .mu.m to 5 .mu.m, making powder handling and
dispersion more difficult than with larger particles. The problems
are exacerbated by the relatively small volumes of pressurized gas,
which are available using hand-actuated pumps. In particular,
venturi dispersion devices are unsuitable for difficult-to-disperse
powders when only small volumes of pressurized gas are available.
Another equirement for hand-held and other powder delivery devices
is efficiency. It is important that the concentration of drug in
the bolus of gas be relatively high to reduce the number of breaths
required to achieve a total dosage. The ability to achieve both
adequate dispersion and small dispersed volumes is a significant
technical challenge that requires in part that each unit dosage of
the powdered composition be readily and reliably dispersible.
[0007] 2. Description of the Relevant Literature
[0008] Dry powder dispersion devices for medicaments are described
in a number of patent documents. U.S. Pat. No. 3,921,637 describes
a manual pump with needles for piercing through a single capsule of
powdered medicine. The use of multiple receptacle disks or strips
of medication described in EP467172 (where a reciprocatable punch
is used to open a blister pack); WO91/02558; WO93/09832; U.S. Pat.
Nos. 4,627,432; 4,811,731; 5,035,237; 5,048,514; 4,446,862;
5,048,514; and 4,446,862. Other patents which show puncturing of
single medication capsules include U.S. Pat. Nos. 4,338,931;
3,991,761; 4,249,526; 4,069,819; 4,995,385; 4,889,114; and
4,884,565; and EP469,814, WO90/07351 describes a hand-held pump
device with a loose powder reservoir.
[0009] A dry powder sonic velocity disperser is described in Witham
and Gates, Dry Dispersion with Sonic Velocity Nozzles, presented at
the workshop on Dissemination Techniques for Smoke and Obscurants,
Chemical Systems Laboratory, Aberdeen Proving Ground, Maryland,
Mar. 14-16, 1983.
[0010] U.S. Pat. Nos. 4,926,852 and 4,790,305, describe a type of
"spacer" for use with a metered dose inhaler. The spacer defines a
large cylindrical volume which receives an axially directed burst
of drug from a propellant-driven drug supply. U.S. Pat. No.
5,027,806, is an improvement over the '852 and '305 patents, having
a conical holding chamber which receives an axial burst of drug.
U.S. Pat. No. 4,624,251, describes a nebulizer connected to a
mixing chamber to permit a continuous recycling of gas through the
nebulizer. U.S. Pat. No. 4,677,975, is described above. European
patent application 347,779 describes an expandable spacer for a
metered dose inhaler having a one-way valve on the mouthpiece. WO
90/07351 describes a dry powder oral inhaler having a pressurized
gas source (a piston pump) which draws a measured amount of powder
into a venturi arrangement.
[0011] The respiratory delivery of aerosolized aqueous insulin
solutions is described in a number of references, beginning with
Gnsslen (1925) Klin. Wochenschr. 4:71 and including Laube et al.
(1993) JAMA 269:2106-21-9; Elliott et al. (1987) Aust. Paediatr. J.
23:293-297; Wigley et al. (1971) Diabetes 20:552-556. Corthorpe et
al. (1992) Pharm Res 9:764-768; Govinda (1959) Indian J. Physiol.
Pharmacol. 3:161-167; Hastings et al. (1992) J. Appl. Physiol.
73:1310-1316; Liu et al. (1993) JAMA 269:2106-2109; Nagano et al.
(1985) Jikeikai Med. J. 32:503-506; Sakr (1992) Int. J. Phar.
86:1-7; and Yoshida et al. (1987) Clin. Res. 35:160-166. Pulmonary
delivery of dry powder medicaments, such as insulin, in a large
particle carrier vehicle is described in U.S. Pat. No. 5,254,330. A
metered dose inhaler (MDI) for delivering crystalline insulin
suspended in a propellant is described in Lee and Sciara (1976) J.
Pharm. Sci. 65:567-572. A MDI for delivering insulin into a spacer
for regulating inhalation flow rate is described in U.S. Pat. No.
5,320,094. The intrabronchial administration of recombinant insulin
is briefly described in Schluter et al. (Abstract) (1984) Diabetes
33:75A and Kohler et al. (1987) Atemw. Lungenkrkh. 13:230-232.
Intranasal and respiratory delivery of a variety of polypeptides,
including insulin, in the presence of an enhancer, are described in
U.S. Pat. No. 5,011,678 and Nagai et al. (1984) J. Contr. Rel.
1:15-22. Intranasal delivery of insulin in the presence of
enhancers and/or contained in controlled release formulations are
described in U.S. Pat. Nos. 5,204,108; 4,294,829; and 4,153,689;
PCT Applications WO 93/02712, WO 91/02545, WO 90/09780, and WO
88/04556; British Patent 1,527,605; Rydn and Edman (1992) Int. J.
Pharm. 83:1-10; and Bjork and Edman (1988) Int. J. Pharm.
47:233-238. The preparation and stability of amorphous insulin were
described by Rigsbee and Pikal at the American Association of
Pharmaceutical Sciences (AAPS), Nov. 14-18, 1993, Lake Buena Vista,
Fla. Methods for spray drying polypeptide, polynucleotide and other
labile drugs in a carrier which forms an amorphous structure which
stabilizes the drug are described in European patent application
520 748. (AAPS), Nov. 14-18, 1993, Lake Buena Vista, Fla.
[0012] Stribling et al. (1992) J. Biopharm. Sci. 3:255-263,
describes the aerosol delivery of plasmids carrying a
chloramphenicol acetyltransferase (CAT) reporter gene to mice. The
plasmids were incorporated in DOTMA or cholesterol liposomes, and
aqueous suspensions of the liposomes were nebulized into a small
animal aerosol delivery chamber. Mice breathing the aerosol were
found to at least transiently express CAT activity in their lung
cells. Rosenfeld et al. (1991) Science: 252:431-434, describes the
in vivo delivery of an alpha-1 antitrypsin gene to rats, with
secretion of the gene product being observable for at least one
week. The gene was diluted in saline and instilled directly into
the rat trachea. Friedman (1989) Science 244:1275-1281 is a review
article describing human gene therapy strategies.
[0013] U.S. Pat. Nos. 4,833,125 and 4,698,328, describe the
administration of active parathyroid hormone fragments in
combination with vitamin D or a dietary calcium supplement.
Suggested administration routes include parenteral by injection,
rapid infusion, nasopharyngeal absorption, dermal absorption, or
oral. See also, Neer et al. (1987) Osteoporosis 53:829-835. U.S.
Pat. No. 5,011,678, describes the use of amphophilic steroids as a
penetration enhancer for nasal or bronchopulmonary delivery of
proteins and polypeptides, listing parathyroid hormone as one of a
"veritable host" of proteins which could be delivered with the
enhancer. Parathyroid hormone (full length) is secreted naturally
from the parathyroid gland as a series of spikes in a pulsatile
fashion which is analogous to pituitary hormones (Harms et al.
(1987) Int. Symp. on Osteoporosis, Aalborg, Abstract 232). The full
length hormone is rapidly broken down in the circulation into
several fragments which are the dominant serum forms. It is
hypothesized that an intermittent or pulsatile secretion pattern
for parathyroid hormone is necessary to maintain its bone restoring
properties (Hesch et al. (1988) Calcif. Tissue Int. 42:341-344 and
Habener et al. (1971), Proc. Natl. Acad. Sci. USA 68:2986-2991).
Patton and Platz (1992) Adv. Drug Deliver. Rev. 8: 179-196,
describe methods for delivering proteins and polypeptides by
inhalation through the deep lung.
[0014] The aerosolization of protein therapeutic agents, including
alpha-1 antitrypsin, is disclosed in EP0289336. The use of alpha-1
antitrypsin for treating pulmonary inflamnmation is disclosed in
U.S. Pat. No. 5,093,316.
[0015] Therapeutic aerosol formulations, including calcitonin, are
disclosed in WO90/09781.
[0016] Methods and compositions for inhibiting neutrophil elastase
and cathespin G employing aerosolized 2-0-desulfated heparin is
disclosed in WO94/02107.
[0017] Interleukin-1 receptor compositions are disclosed in U.S.
Pat. Nos. 4,968,607, 5,081,228 and 5,180,812.
[0018] Aerosol formulations of interferons have been produced for
pulmonary delivery as described in WO 91/16038. WO 91/16038 teaches
adding a surfactant or the like to improve the dispersibility of a
human interferon from a CFC delivery system. Methods and
compositions for the preparation of solid polypeptide
microparticles as a pharmaceutical aerosol formulation are
disclosed in WO 91/16038. The purification of proteins of molecular
weight in excess of 12,000, including human IFN is disclosed in
U.S. Pat. No.: 4,503,035. Low pH pharmaceutical compositions of
recombinant IFN-beta are disclosed in WO 89/05158.
[0019] 3. Objects of the Invention
[0020] An object of the present invention is to provide a
pharmaceutical composition suitable for long-term pulmonary
administration to a patient in need thereof.
[0021] Another object of this invention is to provide a
pharmaceutical-containing dispersible dry powdered composition that
is administered by inhalation in a manner that is free of a liquid
propellant such as a CFC, HFC or carbon dioxide.
[0022] Another object of this invention is to provide a
pharmaceutical-containing dispersible dry powdered composition that
can be easily manufactured by a method that maintains a high
percentage of pharmaceutical activity.
[0023] Another object of this invention is to provide a
manufacturable method for the production of pharmaceutical
composition of sufficient purity.
[0024] Still another object of this invention is to provide a
pharmaceutical-containing dispersible dry powdered composition that
exhibits a high level of stability.
[0025] Other objects may be apparent to one of ordinary skill upon
reviewing the following specification and claims.
SUMMARY OF THE INVENTION
[0026] According to the subject invention, dispersible dry powder
pharmaceutical-based compositions are provided, including methods
for their manufacture and dry powder dispersion devices. A
dispersible dry powder pharmaceutical-based composition is one
having a moisture content of less than about 10% by weight (%w)
water, usually below about 5%w and preferably less than about 3%w;
a particle size of about 1.0-5.0 .mu.m mass median diameter (MMD),
usually 1.0-4.0 .mu.m MMD, and preferably 1.0-3.0 .mu.m MMD; a
delivered dose of about >30%, usually >40%, preferably
>50%, and most preferred >60%; and an aerosol particle size
distribution of about 1.0-5.0 .mu.m mass median aerodynamic
diameter (MMAD), usually 1.5-4.5 .mu.m MMAD, and preferably 1.5-4.0
MMAD. Such composition are of pharmaceutical grade purity.
DESCRIPTION OF SPECIFIC EMBODIMENTS
[0027] The present invention is based at least in part on the
dispersibility characteristics of the pharmaceutical-based dry
powder compositions produced according to the present invention.
The dispersibility characteristics of the subject
pharmaceutical-based compositions means that they are more suitable
for use in pulmonary delivery devices than compositions prepared by
other methods. The compositions of the invention are readily
aerosolized and rapidly absorbed through the lungs of a host when
delivered by a dry powder inhaler.
Definitions
[0028] In interpreting the claims to the various aspects of this
invention, there are several important definitions that should be
considered.
[0029] The term "dispersibility" or "dispersible" means a dry
powder having a moisture content of less than about 10% by weight
(%w) water, usually below about 5%w and preferably less than about
3%w; a particle size of about 1.0-5.0 .mu.m mass median diameter
(MMD), usually 1.0-4.0 .mu.m MMD, and preferably 1.0-3.0 .mu.m MMD;
a delivered dose of about >30%, usually >40%, preferably
>50%, and most preferred >60%; and an aerosol particle size
distribution of about 1.0-5.0 .mu.m mass median aerodynamic
diameter (MMAD), usually 1.5-4.5 .mu.m MMAD, and preferably 1.5-4.0
.mu.m MMAD. Methods and compositions for improving dispersibility
are disclosed in U.S. application Ser. No.: 08/______, filed Apr.
14, 1995 (attorney docket no.: ITSY-003/00US), the disclosures of
which are hereby incorporated by reference.
[0030] The term "powder" means a composition that consists of
finely dispersed solid particles that are free flowing and capable
of being readily dispersed in an inhalation device and subsequently
inhaled by a subject so that the particles reach the lungs to
permit penetration into the alveoli. Thus, the powder is said to be
"respirable." Preferably the average particle size is less than
about 10 microns (.mu.m) in diameter with a relatively uniform
spheroidal shape distribution. More preferably the diameter is less
than about 7.5 .mu.m and most preferably less than about 5.0 .mu.m.
Usually the particle size distribution is between about 0.1 .mu.m
and about 5 .mu.m in diameter, particularly about 0.3 .mu.m to
about 5 .mu.m.
[0031] The term "dry" means that the composition has a moisture
content such that the particles are readily dispersible in an
inhalation device to form an aerosol. This moisture content is
generally below about 10% by weight (%w) water, usually below about
5%w and preferably less than about 3%w.
[0032] The term "therapeutically effective amount" is the amount
present in the composition that is needed to provide the desired
level of drug in the subject to be treated to give the anticipated
physiological response. This amount is determined for each drug on
a case-by-case basis. Guidelines are given hereafter.
[0033] The term "physiologically effective amount" is that amount
delivered to a subject to give the desired palliative or curative
effect. This amount is specific for each drug and its ultimate
approved dosage level. Guidelines are given hereafter.
[0034] The term "pharmaceutically acceptable carrier" means that
the carrier can be taken into the lungs with no significant adverse
toxicological effects on the lungs.
Compositions of the Invention
[0035] One aspect of this invention is a dispersible
pharmaceutical-based dry powder composition for pulmonary delivery,
the composition comprising a therapeutically effective amount of a
pharmaceutical in combination with a pharmaceutically acceptable
carrier.
[0036] In general, the compositions of this invention have a
suitable for pulmonary delivery because of their dispersibility
characteristics. Such compositions were not previously known in the
art. In the dry state, the pharmaceutical may be in crystalline or
amorphous form. Pharmaceutical compositions suitable for
formulation into dispersible dry powders are listed in Table 1.
These include macromolecule and non-macromolecule-based
pharmaceuticals, usually macromolecules, with insulin,
interleukin-1 receptor, parathyroid hormone (PTH-34), alpha-1
antitrypsin, calcitonin, low molecular weight heparin, heparin,
interferon, and nucleic acids being preferred.
[0037] A therapeutically effective amount of active pharmaceutical
will vary in the composition depending on the biological activity
of the drug employed and the amount needed in a unit dosage form.
Because the subject compounds are dispersible, it is highly
preferred that they be manufactured in a unit dosage form in a
manner that allows for ready manipulation by the formulator and by
the consumer. This generally means that a unit dosage will be
between about 0.5 mg and 15 mg of total material in the dry powder
composition, preferably between about 2 mg and 10 mg. Generally,
the amount of drug in the composition will vary from about 0.05%w
to about 99.0%w. Most preferably the composition will be about 0.2%
to about 97.0%w drug.
[0038] The amount of the pharmaceutically acceptable carrier is
that amount needed to provide the necessary stability,
dispersibility, consistency and bulking characteristics to ensure a
uniform pulmonary delivery of the composition to a subject in need
thereof. Numerically the amount may be from about 0.05%w to about
99.95%w, depending on the activity of the drug being employed.
Preferably about 5%w to about 95%w will be used.
[0039] The carrier may be one or a combination of two or more
pharmaceutical excipients, but will generally be substantially free
of any "penetration enhancers." Penetration enhancers are surface
active compounds which promote penetration of a drug through a
mucosal membrane or lining and are proposed for use in intranasal,
intrarectal, and intravaginal drug formulations. Exemplary
penetration enhancers include bile salts, e.g., taurocholate,
glycocholate, and deoxycholate; fusidates, e.g.,
taurodehydrofusidate; and biocompatible detergents, e.g., Tweens,
Laureth-9, and the like. The use of penetration enhancers in
formulations for the lungs, however, is generally undesirable
because the epithelial blood barrier in the lung can be adversely
affected by such surface active compounds. The dry powder
compositions of the present invention are readily absorbed in the
lungs without the need to employ penetration enhancers.
[0040] The types of pharmaceutical excipients that are useful as
carriers in this invention include stabilizers such as human serum
albumin (HSA), bulking agents such as carbohydrates, amino acids
and polypeptides; pH adjusters or buffers; salts such as sodium
chloride; and the like. These carriers may be in a crystalline or
amorphous form or may be a mixture of the two.
[0041] It has been found that HSA is particularly valuable as a
carrier in that it provides improved dispersibility.
[0042] Bulking agents that are particularly valuable include
compatible carbohydrates, polypeptides, amino acids or combinations
thereof. Suitable carbohydrates include monosaccharides such as
galactose, D-mannose, sorbose, and the like; disaccharides, such as
lactose, trehalose, and the like; cyclodextrins, such as
2-hydroxypropyl-.beta.-cy- clodextrin; and polysaccharides, such as
raffinose, maltodextrins, dextrans, and the like; alditols, such as
mannitol, xylitol, and the like. A preferred group of carbohydrates
includes lactose, threhalose, raffinose maltodextrins, and
mannitol. Suitable polypeptides include aspartame. Amino acids
include alanine and glycine, with glycine being preferred.
[0043] Additives, which are minor components of the composition of
this invention, may be included for conformational stability during
spray drying and for improving dispersibility of the powder. These
additives include hydrophobic amino acids such as tryptophan,
tyrosine, lucine, phenylalanine, and the like.
[0044] Suitable pH adjusters or buffers include organic salts
prepared from organic acids and bases, such as sodium citrate,
sodium ascorbate, and the like; sodium citrate is preferred.
[0045] The unit dosage form, method of treatment, and process of
preparation of this invention are described hereafter.
[0046] Unit Dosage Form.
[0047] Another aspect of this invention is a unit dosage form for
pulmonary delivery of dispersible dry powder pharmaceutical-based
compositions, which dosage form comprises a unit dosage receptacle
containing a pharmaceutical-based dry powder composition, which
composition comprises a therapeutically effective amount of a
pharmaceutical in combination with a pharmaceutically acceptable
carrier.
[0048] In this aspect of the invention, the composition of this
invention (as discussed hereinbefore) is placed within a suitable
dosage receptacle in an amount sufficient to provide a subject with
drug for a unit dosage treatment. The dosage receptacle is one that
fits within a suitable inhalation device to allow for the
aerosolization of the interferon-based dry powder composition by
dispersion into a gas stream to form an aerosol and then capturing
the aerosol so produced in a chamber having a mouthpiece attached
for subsequent inhalation by a subject in need of treatment. Such a
dosage receptacle includes any container enclosing the composition
known in the art such as gelatin or plastic capsules with a
removable portion that allows a stream of gas (e.g., air) to be
directed into the container to disperse the dry powder composition.
Such containers are exemplified by those shown in U.S. Pat. No.
4,227,522 issued Oct. 14, 1980; U.S. Pat. No. 4,192,309 issued Mar.
11, 1980; and U.S. Pat. No. 4,105,027 issued Aug. 8, 1978. Suitable
containers also include those used in conjunction with Glaxo's
Ventolin Rotohaler brand powder inhaler or Fison's Spinhaler brand
powder inhaler. Another suitable unit-dose container which provides
a superior moisture barrier is formed from an aluminum foil plastic
laminate. The pharmaceutical-based powder is filled by weight or by
volume into the depression in the formable foil and hermetically
sealed with a covering foil-plastic laminate. Such a container for
use with a powder inhalation device is described in U.S. Pat. No.
4,778,054 and is used with Glaxo's Diskhaler.RTM. (U.S. Pat. Nos.
4,627,432; 4,811,731; and 5,035,237). All of these references are
incorporated herein by reference.
[0049] Method of Treating a Disease State.
[0050] Another aspect of this invention is a method of treating a
condition responsive to treatment by a pharmaceutical of interest,
which method comprises pulmonarily administering to a subject in
need thereof a physiologically effective amount of a dispersible
pharmaceutical-based dry powder composition that comprises a
therapeutically effective amount of drug in combination with a
pharmaceutically acceptable carrier.
[0051] Conditions that may be treated by the compositions of this
are described in Table 1.
[0052] The physiologically effective amount needed to treat a
particular condition or disease state will depend on the
individual, the condition, length of treatment, the regularity of
treatment, the type of drug, and other factors, but can be
determined by one of ordinary skill in the medicinal arts.
[0053] It is presently believed that the effective absorption by a
host of dry powder composition according to the present invention
results from a rapid dissolution in the ultra-thin (<0.1 .mu.m)
fluid layer of the alveolar lining of the lung. The particles of
the present invention thus have a mean size which is from 10 to 50
times larger than the lung fluid layer, making it unexpected that
the particles are dissolved and the interferon systemically
absorbed in a rapid manner for either local lung or systemic
treatment. An understanding of the precise mechanism, however, is
not necessary for practicing the present invention as described
herein.
[0054] The aerosolized pharmaceutical-based dry powders of this
invention are particularly useful in place of parenteral delivery.
Thus, the methods and compositions of the present invention will be
particularly valuable in chronic treatment protocols where a
patient can self-medicate. The patient can achieve a desired dosage
by inhaling an appropriate amount of drug, as just described. The
efficiency of systemic delivery via the method as just described
will typically be in the range from about 15% to 50%.
[0055] Method for Aerosolizing the Powder.
[0056] Still another aspect of this invention is a device and
method for aerosolizing a pharmaceutical-based dry powder
composition that comprises a therapeutically effective amount of
drug in combination with a pharmaceutically acceptable carrier,
which method comprises dispersing an amount of the dry powder
composition in a gas stream to form an aerosol and capturing the
aerosol in a chamber having a mouthpiece for subsequent inhalation
by a patient.
[0057] A further detailed description of this method is found in
pending U.S. patent application Ser. Nos.: 07/910,048 and
08/207,472, both of which are incorporated herein by reference.
[0058] Preparing the Compositions.
[0059] Still another aspect of this invention is a method for
preparing a dispersible pharmaceutical-based dry powder composition
of this invention that comprises spray drying an aqueous mixture of
the drug and a pharmaceutically acceptable carrier under conditions
to provide a respirable dry powder composition.
[0060] Spray drying is a process in which a homogeneous aqueous
mixture of drug and the carrier is introduced via a nozzle (e.g., a
two fluid nozzle), spinning disc or an equivalent device into a hot
gas stream to atomize the solution to form fine droplets. The
aqueous mixture may be a solution, suspension, slurry, or the like,
but needs to be homogeneous to ensure uniform distribution of the
components in the mixture and ultimately the powdered composition.
Preferably the aqueous mixture is a solution. The solvent,
generally water, rapidly evaporates from the droplets producing a
fine dry powder having particles 1 to 5 .mu.m in diameter.
Surprisingly, the drug is not degraded when it is exposed to the
hot drying gas, and the interferon powders can be prepared having
sufficient purity for pharmaceutical use. An acceptable purity is
defined as less than 5% degradation products and contaminates,
preferably less than 3% and most preferably less than 1%.
[0061] The spray drying is done under conditions that result in
substantially amorphous powder of homogeneous constitution having a
particle size that is respirable, a low moisture content and flow
characteristics that allow for ready aerosolization. Preferably the
particle size of the resulting powder is such that more than about
98% of the mass is in particles having a diameter of about 10 .mu.m
or less with about 90% of the mass being in particles having a
diameter less than 5 .mu.m. Alternatively, about 95% of the mass
will have particles with a diameter of less than 10 .mu.m with
about 80% of the mass of the particles having a diameter of less
than 5 .mu.m.
[0062] The solutions may then be sprayed dried in conventional
spray drying equipment from commercial suppliers, such as Buchi,
Niro, Yamato Chemical Co., Okawara Kakoki Co., and the like,
resulting in a substantially amorphous particulate product.
[0063] For the spraying process, such spraying methods as rotary
atomization, pressure atomization and two-fluid atomization can be
used. Examples of the devices used in these processes include
"Parubisu [phonetic rendering] Mini-Spray GA-32" and "Parubisu
Spray Drier DL-41", manufactured by Yamato Chemical Co., or "Spray
Drier CL-8." "Spray Drier L-8," "Spray Drier FL-12," "Spray Drier
FL-16" or "Spray Drier FL-20." manufactured by Okawara Kakoki Co.,
can be used for the method of spraying using rotary-disk
atomizer.
[0064] While no special restrictions are placed on the nozzle of
the atomizer used in the process of spraying, it is recomnmended to
use a nozzle which can produce a spray-dry composition with a grain
diameter suitable for nasal, pharyngeal or pulmonary
administration. For example, nozzle types "1A," "1," "2A," "2," "3"
and the like, manufactured by Yamato Chemical Co., can be used for
the above-mentioned spray-drier, manufactured by the same company.
In addition, disks type "MC-50," "MC-65" or "MC-85," manufactured
by Okawara Kakoki Co., can be used as rotary disks of the
spray-drier atomizer, manufactured by the same company.
[0065] While no particular restrictions are placed on the gas used
to dry the sprayed material, it is recommended to use air, nitrogen
gas or an inert gas. The temperature of the inlet of the gas used
to dry the sprayed materials such that it does not cause heat
deactivation of the sprayed material. The range of temperatures may
vary between about 50.degree. C. to about 200.degree. C.,
preferably between about 50.degree. C. and 100.degree. C. The
temperature of the outlet gas used to dry the sprayed material, may
vary between about 0.degree. C. and about 150.degree., preferably
between 0.degree. C. and 90.degree. C., and even more preferably
between 0.degree. C. and 60.degree. C. The fact that inlet and
outlet temperatures above about 55.degree. C. can be used is
surprising in view of the fact that most macromolecule-based drugs
deactivate at that temperature, with nearly complete deactivation
occurring at about 70.degree. C.
[0066] The dispersible pharmaceutical-based dry powders of the
present invention may optionally be combined with pharmaceutical
carriers or excipients which are suitable for respiratory and
pulmonary administration. Such carriers may serve simply as bulking
agents when it is desired to reduce the interferon concentration in
the powder which is being delivered to a patient, but may also
serve to enhance the stability of the interferon compositions and
to improve the dispersibility of the powder within a powder
dispersion device in order to provide more efficient and
reproducible delivery of the interferon and to improve handling
characteristics of the interferon such as flowability and
consistency to facilitate manufacturing and powder filling.
[0067] Such carrier materials may be combined with the drug prior
to spray drying, i.e., by adding the carrier material to the
purified bulk solution. In that way, the carrier particles will be
formed simultaneously with the drug particles to produce a
homogeneous powder. Alternatively, the carriers may be separately
prepared in a dry powder, form and combined with the dry powder
drug by blending. The powder carriers will usually be crystalline
(to avoid water absorption), but might in some cases be amorphous
or mixtures of crystalline and amorphous. The size of the carrier
particles may be selected to improve the flowability of the drug
powder, typically being in the range from 25 .mu.m to 100 .mu.m. A
preferred carrier material is crystalline lactose having a size in
the above-stated range.
[0068] Alternatively, dry powder compositions may be prepared by
other processes such as lyophilization and jet milling as disclosed
in WO 91/16038, the disclosures of which are hereby incorporated by
reference.
1TABLE 1 DRUG INDICATIONS SELECTED MACROMOLECULE DRUGS FOR SYSTEMIC
APPLICATIONS Calcitonin Osteoporosis Prophylaxis Paget's Disease
Hypercalcemia Erythropoietin (EPO) Anemia Factor IX Hemophilia B
Granulocyte Colony Stimulating Neutropenia Factor (G-CSF)
Granulocyte Macrophage Colony Bone Marrow Engraftment/ Stimulating
Factor (GM-CSF) Transplant Failure Growth Hormone Short Stature
Renal Failure Heparin Blood Clotting Heparin (Low Molecular Weight)
Blood Clotting Insulin Type I and Type II Diabetes Interferon Alpha
Hepatitis B and C Hairy Cell Leukemia Kaposi's Sarcoma Interferon
Beta Multiple Sclerosis Interferon Gamma Chronic Granulomatous
Disease Interleukin-2 Renal Cancer Luteinizing Hormone Releasing
Prostate Cancer Hormone (LHRH) Endometriosis Somatostatin Analog
Gastrointestinal Cancers Vasopressin Analog Diabetes Insipidus Bed
Wetting FSH Fertility Amylin Type I Diabetes Ciliary Neurotrophic
Factor Lou Gehrig's Disease Growth Hormone Releasing Factor Short
Stature (GRF) Insulin-Like Growth Factor Osteoporosis Nutritional
Support Insulinotropin Type II Diabetes Interferon Beta Hepatitis B
and C Interferon Gamma Rheumatoid Arthritis Interleukin-1 Receptor
Antagonist Rheumatoid Arthritis Interleukin-3 Adjuvant to
Chemotherapy Interleukin-4 Immunodeficiency Disease Interleukin-6
Thrombocytopenia Macrophage Colony Stimulating Fungal Disease
Factor (M-CSF) Cancer Hypercholesterolemia Nerve Growth Factor
Peripheral Neuropathies Parathyroid Hormone Osteoporosis
Somatostatin Analog Refractory Diarrheas Thymosin Alpha 1 Hepatitis
B and C IIb/IIIa Inhibitor Unstable Angina Alpha-1 Antitrypsin
Cystic Fibrosis Anti-RSV Antibody Respiratory Syncytial Virus
Cystic Fibrosis Transmembrane Cystic Fibrosis Regulator (CFTR) Gene
Deoxyribonuclase (DNase) Chronic Bronchitis Heparin Asthma
Bactericidal/Permeability Adult Respiratory Distress Syndrome
(ARDS) Increasing Protein (BPI) Anti-CMV Antibody Cytomegalovirus
Interleukin-1 Receptor Asthma SELECTED NON-MACROMOLECULE DRUGS FOR
SYSTEMIC AND LOCAL LUNG APPLICATIONS Pentamidine isethiouate
Pneumocystis carini peneumonia Albuterol sulfate Broncospasm
Metaproterenol sulfate Bronchial asthma Beclomethasone dipreoionate
Trimcinoline acetonide Budesonide acetonide Ipratropium bromide
Flunisolide Cromolyn sodium Ergotamine Tartrate Migranes
[0069] The following exmples are offered by way of illustration and
not limitation.
EXPERIMENTAL
[0070] According the the subject invention, the following
dispersible dry powder formulations were prepared as described. All
compositions produced according to the present invention meet the
strict specifications for content and purity required of
pharmaceutical products.
EXAMPLE I
20.0% Insulin Formulation for Pulmonary Delivery
[0071] A. Formulation.
[0072] Bulk crystalline human zinc insulin, was obtained from Eli
Lilly and Company, Indianapolis, Ind. A 20% insulin formulation was
acheived by combining 1.5 mg insulin per 1.0 mL deionized water
with 4.96 mg/mL USP mannitol and 1.04 mg/mL citrate buffer (sodium
citrate dihydrate USP and citric acid monohydrate USP) for a total
solids concentration of 7.5 mg/mL at pH 6.7.+-.0.3.
[0073] B. Spray Drying.
[0074] A dry powder of the 20% insulin formulation described above
was produced by spray drying the aqueous mixture using a Buchi
Laboratory Spray Dryer under the following conditions:
2 Temperature of aqueous mixture 2-8.degree. C. Inlet temperature
120-122.degree. C. Feed rate .sup. 5.3 mL/min Outlet temperature
80-81.degree. C.
[0075] Once the aqueous mixture was consumed, the outlet
temperature was maintained at <80.degree. C. for about 10
minutes by slowly decreasing the inlet temperature to provide a
secondary drying.
[0076] C. Characterization.
[0077] The above 20% insulin dry powder composition contained 66.1
% mannitol and 13.9% citrate. The composition was found to contain
1.1 to 2.0% moisture as measured by a coulombic Karl Fischer method
using a Mitsubishi CA-06 Moisture Meter.
[0078] The particle size distribution of the composition was
measured by liquid centrifugal sedimentation in a Horiba CAPA-700
Particle Size Analyzer following dispersion of the powder on
Sedisperse A-11 (Micrometrics, Norcross, Ga.) and was determined to
be 1.3 .mu.m to 1.5 .mu.m MMD.
[0079] The delivered dose of the insulin powder composition was
measured by collecting the aerosol powder produced by a dry powder
dispersion device, similar to devices described in co-pending U.S.
application Ser. Nos. 07/910,048; 08/313,707; 08/309,691 and
PCT/US92/05621, the disclosures of which are hereby incorporated by
reference, on a filter placed over the device mouthpiece. The
delivered dose of the insulin powder composition was determined to
be 563.+-.16 .mu.g or 60 to 64% of the total powder (5.0 mg) loaded
into the device.
[0080] The aerosol particle size distribution, measured using a
cascade impactor (California Measurements IMPAQ-6), was determined
to be 2.0 .mu.m MMAD, with 86% to 90% of the particles <5.0
.mu.m in diameter.
[0081] The insulin content of the powder, measured by reverse phase
HPLC (rpHPLC) was determined to be 197 .mu.g/mg powder, accounting
for 99% of the expected insulin. No degradation peaks were detected
in the chromatogram.
EXAMPLE II
5.0% Parathyroid Hormone Formulation for Pulmonary Delivery
[0082] A. Formulation.
[0083] Bulk 34 amino acid active fragment of parathyroid hormon,
PTH (1-34), was obtained from BACHEM CALIFORNIA. Torrance, Calif. A
5.0% PTH (1-34) formulation was acheived by combining 0.375 mg PTH
(1-34) per 1.0 mL deionized water with 6.06 mg/mL mannitol USP and
1.04 mg/mL citrate buffer (sodium citrate dihydrate USP and citric
acid monohydrate USP) for a total solids concentration of 7.48
mg/mL at pH 6.3.
[0084] B. Spray Drying.
[0085] A dry powder of the 5.0% PTH (1-34) formulation described
above was produced by spray drying the aqueous mixture using a
Buchi Laboratory Spray Dryer under the following conditions:
3 Temperature of aqueous mixture 2-8.degree. C. Inlet temperature
122-124.degree. C. Feed rate .sup. 5.2 mL/min Outlet temperature
73-74.degree. C.
[0086] Once the aqueous mixture was consumed, the outlet
temperature was maintained at <80.degree. C. for about 5 minutes
by slowly decreasing the inlet temperature to provide a secondary
drying.
[0087] C. Characterization.
[0088] The following characterization of the dry powder formulation
described above was carried out using the methods described in
Example I unless indicated otherwise.
[0089] The above 5.0% PTH (1-34) dry powder composition contained
81.0% mannitol and 13.9% citrate. The formulation contained 0.5%
moisture.
[0090] The particle size distribution of the composition was
determined to be 2.4 .mu.m and 21.71 m MMD in separate
measurements.
[0091] The delivered dose of the PTH (1-34) powder was determined
to be 161 .mu.g or 64.5% and 175 .mu.g or 69.2% in separate
measurements.
[0092] The PTH (1-34) content of the powder, measured by rpHPLC was
determined to be 48.5 .mu.g/mg powder, accounting for 97% of the
expected value. No degradation peaks were detected in the
chromatogram.
EXAMPLE III
0.7% Interleukin-1 Receptor Formulation for Pulmonary Delivery
[0093] A. Formulation.
[0094] Bulk interleukin-1 receptor, IL-1 receptor, was obtained
from Immunex Corporation, Seattle, Wash. A 0.7% IL-1 receptor
formulation was acheived by combining 0.053 mg IL-1 receptor per
1.0 mL deionized water with 7.07 mg/mL raffinose (Pfanstiehl,
Waukegan, Ill.) and 0.373 mg/mL Tris buffer at pH 7.18.
[0095] B. Spray Drying.
[0096] A dry powder of the 0.7% IL-1 receptor formulation described
above was produced by spray drying the aqueous mixture using a
Buchi Laboratory Spray Dryer under the following conditions:
4 Temperature of aqueous mixture 2-8.degree. C. Inlet temperature
135-137.degree. C. Feed rate .sup. 4.9 mL/min Outlet temperature
92-93.degree. C.
[0097] Once the aqueous mixture was consumed, the outlet
temperature was maintained at 90.degree. C. for about 15 minutes by
slowly decreasing the inlet temperature to provide a secondary
drying.
[0098] C. Characterization.
[0099] The following characterization of the dry powder formulation
described above was carried out using the methods described in
Example I unless indicated otherwise.
[0100] The above 0.7% IL-1 receptor dry powder composition
contained 94.3% raffinose and 5.0% Tris. The formulation contained
1.84.+-.0.25% moisture.
[0101] The particle size distribution of the composition was
determined to be 1.95 .mu.m MMD with 100% of the particles <5.0
.mu.m.
[0102] The delivered dose of the IL-1 receptor powder was
determined to be 22.3.+-.2.0 .mu.g or 53.4.+-.4.7%.
[0103] The aerosol particle size distribution, was determined to be
3.2 .mu.m MMAD, with 77% of the particles <5.0 .mu.m in
diameter.
[0104] The IL-1 receptor content of the powder as measured by
rpHPLC was determined to be 8.4 .mu.g/mg, accounting for 120% of
the expected IL-1 receptor. No degradation peaks were detected in
the chromatogram.
EXAMPLE IV
5.0% Interleukin-1 Receptor Formulation for Pulmonary Delivery
[0105] A. Formulation.
[0106] Bulk interleukin-1 receptor, IL-1 receptor, was obtained
from Immunex Corporation, Seattle, Wash. A 5.0% IL-1 receptor
formulation was acheived by combining 0.375 mg IL-1 receptor per
1.0 ml deionized water with 6.77 mg/mL raffinose and 0.351 mg/nmL
Tris buffer at pH 7.35.
[0107] B. Spray Drying.
[0108] A dry powder of the 5.0% IL-1 receptor formulation described
above was produced by spray drying the aqueous mixture using a
Buchi Laboratory Spray Dryer under the following conditions:
5 Temperature of aqueous mixture 2-8.degree. C. Inlet temperature
138.degree. C. Feed rate .sup. 4.9 mL/min Outlet temperature
91.degree. C.
[0109] Once the aqueous mixture was consumed, the outlet
temperature was maintained at 90.degree. C. for about 15 minutes by
slowly decreasing the inlet temperature to provide a secondary
drying.
[0110] C. Characterization.
[0111] The following characterization of the dry powder formulation
described above was carried out using the methods described in
Example I unless indicated otherwise.
[0112] The above 5.0% IL-1 receptor dry powder composition
contained 90.3% raffinose and 4.7% Tris. The formulation contained
1.75.+-.0.26% moisture.
[0113] The particle size distribution of the composition was
determined to be 2.74 .mu.m MMD with 97% of the particles <5.0
.mu.m.
[0114] The delivered dose of the IL-1 receptor powder was
determined to be 123.4.+-.24.5 .mu.g or 49.3.+-.9.8 %.
[0115] The aerosol particle size distribution, was determined to be
4.1 .mu.m MMAD, with 64% of the particles <5.0 .mu.m in
diameter.
[0116] The IL-1 receptor content of the powder as measured by
rpHPLC was determined to be 52.7.+-.1.81 .mu.g/mg, accounting for
105% of the expected IL-1 receptor. No degradation peaks were
detected in the chromatogram.
EXAMPLE V
26Human Calcitonin Formulation for Pulmonary Delivery
[0117] A. Formulation.
[0118] Bulk human calcitonin was obtained from Ciba-Geigy. A 26.7%
human calcitonin formulation was acheived by combining 1.9 mg human
calcitonin per 1.0 mL deionized water with 4.3 mg/mL mannitol and
0.9 mg/mL citrate buffer at pH 3.85.
[0119] B. Spray Drying.
[0120] A dry powder of the 26.7% human calcitonin formulation
described above was produced by spray drying the aqueous mixture
using a Buchi Laboratory Spray Dryer under the following
conditions:
6 Temperature of aqueous mixture 4.degree. C. Inlet temperature
119.degree. C. Feed rate .sup. 5.5 mL/min Outlet temperature
78.degree. C. Atomizer coolant temperature 0-5.degree. C. Cyclone
coolant temperature 25-30.degree. C.
[0121] Once the aqueous mixture was consumed, the outlet
temperature was maintained at 80.degree. C. for about 10 minutes by
slowly decreasing the inlet temperature to provide a secondary
drying.
[0122] C. Characterization.
[0123] The following characterization of the dry powder formulation
described above was carried out using the methods described in
Example I unless indicated otherwise.
[0124] The above 26.7% human calcitonin dry powder composition
contained 60% mannitol and 13.3% citrate. The formulation contained
0.71% moisture.
[0125] The particle size distribution of the composition was
determined to be 1.33.+-.0.63 .mu.m MMD.
[0126] The delivered dose of the human calcitonin powder was
determined to be 76.8.+-.6.7%.
[0127] The human calcitonin content of the powder as measured by
rpHPLC was determined to be 272.0 .mu.g/mg, accounting for
102.+-.1.7% of the expected human calcitonin. No degradation peaks
were detected in the chromatogram.
EXAMPLE VI
90% Alpha-1 Antitrypsin Formulation For Pulmonary Delivery
[0128] A. Formulation.
[0129] Bulk alpha-1 antitrypsin, A1A, was obtained from Armour
Pharmaceutical Company, Kankakee. Ill. A 90% A1A formulation was
acheived by combining 4.89 mg A1A per 1.0 mL deionized water with
0.54 mg/mL citrate buffer at pH 6.0.
[0130] B. Spray Drying.
[0131] A dry powder of the 90% A1A formulation described above was
produced by spray drying the aqueous mixture using a Buchi
Laboratory Spray Dryer under the following conditions:
7 Temperature of aqueous mixture 4.degree. C. Inlet temperature
98-101.degree. C. Feed rate 5.0 mL/min Outlet temperature
65.degree. C. Atomizer coolant temperature 2-8.degree. C. Cyclone
coolant temperature 30.degree. C.
[0132] Once the aqueous mixture was consumed, the outlet
temperature was maintained at 69.degree. C. for about 10 minutes by
slowly decreasing the inlet temperature to provide a secondary
drying.
[0133] C. Characterization.
[0134] The following characterization of the dry powder formulation
described above was carried out using the methods described in
Example I unless indicated othenwise.
[0135] The above 90% A1A dry powder composition contained 10.0%
citrate. The formulation contained 4.79% moisture.
[0136] The particle size distribution of the composition was
determined to be 1.71.+-.0.87 .mu.m MMD.
[0137] The delivered dose of the 90% A1A powder was determined to
be 67.0.+-.5.0%.
[0138] The aerosol particle size distribution, was determined to be
1.0 .mu.m MMAD, with 90% of the particles <5.0 .mu.m in
diameter.
[0139] The A1A content of the powder as measured by rpHPLC was
determined to be 80% of the expected value. No degradation peaks
were detected in the chromatogram. The activity after spray drying
was determined to be 74.+-.1%
EXAMPLE VII
0.3% Beta Interferon Formulation for Pulmonary Delivery Containing
Human Serum Albumin
[0140] A. Formulation.
[0141] Bulk beta interferon, IFN-.beta., was obtained from Toray
Industries, Inc., Tokyo, Japan. A 0.3% IFN-.beta. formulation was
acheived by combining 0.025 mg IFN-.beta. per 1.0 mL deionized
water with 5.54 mg/mL human serum albuman (HSA), 2.3 mg/mL citrate
buffer and 0.345 mg/mL of NaCl at pH 4.5.
[0142] B. Spray Drying.
[0143] A dry powder of the 0.3% IFN-.beta. formulation described
above was produced by spray drying the aqueous mixture using a
Buchi Laboratory Spray Dryer under the following conditions:
8 Temperature of aqueous mixture 2-8.degree. C. Inlet temperature
93.degree. C. Feed rate 2.7 mL/min Outlet temperature 62.degree.
C.
[0144] C. Characterization.
[0145] The following characterization of the dry powder formulation
described above was carried out using the methods described in
Example I unless indicated otherwise.
[0146] The above 0.3% IFN-.beta. dry powder composition contained
66.0% HSA, 27.4% citrate, 4.1% NaCl. The formulation contained
4.22% moisture.
[0147] The particie size distribution of the composition was
determined to be 1.62 .mu.m MMD with 94.8% of the particles <5
.mu.m.
[0148] The delivered dose of the 0.3% IFN-.beta. powder was
determined to be 9.9 .mu.g/mg or 66.0.+-.4.0%.
[0149] The aerosol particle size distribution, was determined to be
2.0 .mu.m MMAD, with 85% of the particles <5.0 .mu.m in
diameter.
[0150] The IFN-.beta. activity of the powder as measured by
IFN-.beta. enzyme immunoassay (Toray-Fuji Bionics) and was
determined to be 109.+-.8% of the expected activity.
EXAMPLE VIII
0.3% Beta Interferon Formulation for Pulmonary Delivery Containing
Raffinose
[0151] A. Formulation.
[0152] Bulk beta interferon, IFN-.beta., was obtained from Toray
Industries, Inc., Tokyo, Japan. A 0.3% IFN-.beta. formulation was
acheived by combining 0.025 mg IFN-.beta. per 1.0 mL deionized
water with 4.7 mg/mnL raffinose, 1.0 mg/mL human serum albuman
(HSA), 2.3 mg/mL citrate buffer and 0.3 mg/mL of NaCl at pH
4.5.
[0153] B. Spray Drying.
[0154] A dry powder of the 0.3% IFN-.beta. formulation described
above was produced by spray drying the aqueous mixture using a
Buchi Laboratory Spray Dryer under the following conditions:
9 Temperature of aqueous mixture 8.degree. C. Inlet temperature
145.degree. C. Feed rate .sup. 5.0 mL/min Outlet temperature
87.degree. C.
[0155] Once the aqueous mixture was consumed, the outlet
temperature was maintained at 97.degree. C. for about 5 minutes by
slowly decreasing the inlet temperature to provide a secondary
drying.
[0156] C. Characterization.
[0157] The following characterization of the dry powder formulation
described above was carried out using the methods described in
Example I unless indicated otherwise.
[0158] The above 0.3% IFN-.beta. dry powder composition contained
56.4% raffinose, 11.9% HSA, 27.4% citrate, 3.5% NaCl. The
formulation contained 0.69% moisture.
[0159] The particle size distribution of the composition was
determined to be 2.06 .mu.m MMD with 88.9% of the particles
<5.mu.m.
[0160] The delivered dose of the 0.3% IFN-.beta. powder was
determined to be 10.2 .mu.g/mg or 68.0.+-.2.0%.
[0161] The aerosol particle size distribution, was determined to be
2.5 .mu.m MMAD, with 84% of the particles <5.0 .mu.m in
diameter.
[0162] The IFN-.beta. activity of the powder as measured by
IFN-.beta. enzyme immunoassay (Toray-Fuji Bionics) and was
determined to be 109.+-.8% of the expected activity.
EXAMPLE IX
93% Low Molecular Weight Heparin Formulation for Pulmonary
Delivery
[0163] A. Formulation.
[0164] Bulk low molecular weight heparin sodium salt (Av. Mol. Wt.:
Approx. 6000) from porcine intestinal mucosa, heparin (LMW), was
obtained from Sigma Chemical, St. Louis, Mo.. A 93% heparin (LMW)
formulation was acheived by combining 6.9 mg heparin (LMW) per 1.0
mL deionized water with 0.5 mg/mL HSA at pH 6.9.
[0165] B. Spray Drying.
[0166] A dry powder of the 93% heparin (LMW) formulation described
above was produced by spray drying the aqueous mixture using a
Buchi Laboratory Spray Dryer under the following conditions:
10 Temperature of aqueous mixture 2-8.degree. C. Inlet temperature
140.degree. C. Feed rate .sup. 3.8 mL/min Outlet temperature
85.degree. C. Atomizer coolant temperature 2-8.degree. C. Cyclone
coolant temperature 20.degree. C.
[0167] Once the aqueous mixture was consumed, the outlet
temperature was maintained at 80.degree. C. for about 10 minutes by
slowly decreasing the inlet temperature to provide a secondary
drying.
[0168] C. Characterization.
[0169] The following characterization or the dry powder formulation
described above was carried out using the methods described in
Example I unless indicated otherwise.
[0170] The above 93% heparin (LMW) dry powder composition contained
7.0% HSA.
[0171] The delivered dose of the 93% heparin (LMW) powder was
determined to be 60.0.+-.1.0%.
[0172] The aerosol particle size distribution, was determined to be
3.5 .mu.m MMAD, with 70% of the particles <5.0 .mu.m in
diameter.
EXAMPLE X
97% Unfractionated Heparin Formulation for Pulmonary Delivery
[0173] A. Formulation.
[0174] Bulk unfractionated heparin sodium salt from porcine
intestinal mucosa, heparin, was obtained from Sigma Chemical, St.
Louis, Mo. A 97% heparin formulation was acheived by combining 7.0
mg heparin per 1.0 mL deionized water with 0.25 mg/mL HSA at pH
6.55.
[0175] B. Spray Drying.
[0176] A dry powder of the 97% heparin formulation described above
was produced by spray drying the aqueous mixture using a Buchi
Laboratory Spray Dryer under the following conditions:
11 Temperature of aqueous mixture 2-8.degree. C. Inlet temperature
150.degree. C. Feed rate 4.0 mL/min Outlet temperature 85.degree.
C. Atomizer coolant temperature 2-8.degree. C. Cyclone coolant
temperature 20.degree. C.
[0177] Once the aqueous mixture was consumed, the outlet
temperature was maintained at 80.degree. C. for about 10 minutes by
slowly decreasing the inlet temperature to provide a secondary
drying.
[0178] C. Characterization.
[0179] The following characterization of the dry powder formulation
described above was carried out usine the methods described in
Example I unless indicated otherwise.
[0180] The above 97% heparin dry powder composition contained 3.0%
HSA. The formulation contained 5.11% moisture.
[0181] The particle size distribution of the composition was
determined to be 2.0 to 2.5 .mu.m MMD.
[0182] The delivered dose of the 97% heparin powder was determined
to be 79.0.+-.6.0%.
[0183] The aerosol particle size distribution, was determined to be
3.2 .mu.m MMAD, with 70% of the particles <5.0 .mu.m in
diameter.
EXAMPLE XI
Lipid Vector Gene Formulation for Pulmonary Delivery
[0184] A. Formulation.
[0185] Bulk pCMV.beta. DNA:Lipid vector as described in U.S.
application Ser. No.: 08/______ (attorney docket no. 15225-000410
filed Apr. 14, 1995 entitled COMPOSITIONS AND METHODS FOR NUCLEIC
ACID DELIVERY TO THE LUNG, the disclosures of which are hereby
incorporated by reference. Was obtained from Genzyme Corporation,
Cambridge, Mass. A 0.71% DNA:Lipid vector formulation was acheived
by combining 0.005:0.03 mg DNA:Lipid vector per 1.0 mL deionized
water with 5.3 mg/mL glycine (J. T. Baker) 0.3 mg/mL HSA at pH
6.4.
[0186] B. Spray Drying.
[0187] A dry powder of the DNA:Lipid vector formulation described
above was produced by spray drying the aqueous mixture using a
Buchi Laboratory Spray Dryer under the following conditions:
12 Temperature of aqueous mixture 2-8.degree. C. Inlet temperature
120.degree. C. Feed rate 3.8 mL/min Outlet temperature 71.degree.
C. Atomizer coolant temperature 2-8.degree. C. Cyclone coolant
temperature 2-8.degree. C.
[0188] Once the aqueous mixture was consumed, the outlet
temperature was maintained at 65.degree. C. for about 5 minutes by
slowly decreasing the inlet temperature to provide a secondary
drying.
[0189] C. Characterization.
[0190] The following characterization of the dry powder formulation
described above was carried out using the methods described in
Example I unless indicated otherwise.
[0191] The above 0.71% DNA:Lipid vector dry powder composition
contained 93.97% glycine, and 5.32% HSA.
[0192] The particle size distribution of the composition was
determined to be 2.0 .mu.m MMD.
[0193] The delivered dose of the 97% heparin (HMW) powder was
determined to be 64.0.+-.1.0%.
[0194] The aerosol particle size distribution, was determined to be
2.4 .mu.m MMAD, with 75% of the particles <5.0 .mu.m in
diameter.
[0195] Activity after spray drying was determined to be 160% of the
expected value.
EXAMPLE XII
Adenoviral Vector Gene Formulation for Pulmonary Delivery
[0196] A. Formulation.
[0197] Bulk pCMV.beta. DNA:Adenovirous vector as described in U.S.
application Ser. No.: 08/______ (attorney docket no. 15225-000410)
filed Apr. 14, 1995 entitled COMPOSITIONS AND METHODS FOR NUCLEIC
ACID DELIVERY TO THE LUNG, the disclosures of which are hereby
incorporated by reference, was obtained from Genzyme Corporation,
Cambridge, Mass. A DNA:adenovirous vector formulation was acheived
by combining 10.sup.8 PFU/mL DNA:Lipid vector per 1.0 mL deionized
water with 6.1 mg/mL glycine J. T. Baker) 2.5 mg/mL HSA, 1.9 mg/mL
phosphate buffer at pH 7.4.
[0198] B. Spray Drying.
[0199] A dry powder of the DNA:Lipid vector formulation described
above was produced by spray drying the aqueous mixture using a
Buchi Laboratory Spray Dryer under the following conditions:
13 Temperature of aqueous mixture 2-8.degree. C. Inlet temperature
105.degree. C. Feed rate 2.9 mL/min Outlet temperature 72.degree.
C. Atomizer coolant temperature 2-8.degree. C. Cyclone coolant
temperature 20.degree. C.
[0200] Once the aqueous mixture was consumed, the outlet
temperature was maintained at 70.degree. C. for about 10 minutes by
slowly decreasing the inlet temperature to provide a secondary
drying.
[0201] C. Characterization.
[0202] The following characterization of the dry powder formulation
described above was carried out using the methods described in
Example I unless indicated otherwise.
[0203] The above DNA:adenovirous vector dry powder composition
contained 58% glycine, and 24% HSA and 18% phosphate buffer.
[0204] The particle size distribution of the composition was
determined to be 2.3 .mu.m MMD.
[0205] The delivered dose of the 97% heparin (HMW) powder was
determined to be 51.0.+-.1.0%.
[0206] The aerosol particle size distribution, was determined to be
1.8 .mu.m MMAD, with 80% of the particles <5.0 .mu.m in
diameter.
[0207] Activity after spray drying was determined to be 76% of the
expected value.
[0208] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
[0209] The invention now being fully described, it will be apparent
to one of ordinary skill in the art that many changes and
modifications can be made thereto without departing from the spirit
or scope of the appended claims.
* * * * *