U.S. patent application number 10/627591 was filed with the patent office on 2005-04-28 for aerosolized active agent delivery.
Invention is credited to Clark, Andrew, Foulds, George H..
Application Number | 20050090798 10/627591 |
Document ID | / |
Family ID | 26760240 |
Filed Date | 2005-04-28 |
United States Patent
Application |
20050090798 |
Kind Code |
A1 |
Clark, Andrew ; et
al. |
April 28, 2005 |
Aerosolized active agent delivery
Abstract
The present invention is directed to methods and devices for
delivering an active agent formulation to the lung of a human
patient. The active agent formulation may be in dry powder form, it
may be nebulized, or it may be in admixture with a propellant. The
active agent formulation is delivered to a patient at an
inspiratory flow rate of less than 17 liters per minute. The
bioavailability of the active agent was found to increase at these
flow rates when compared to inspiratory flow rates of 17 liters per
minute or more.
Inventors: |
Clark, Andrew; (Half Moon
Bay, CA) ; Foulds, George H.; (Chester, CT) |
Correspondence
Address: |
NEKTAR THERAPEUTICS
150 INDUSTRIAL ROAD
SAN CARLOS
CA
94070
US
|
Family ID: |
26760240 |
Appl. No.: |
10/627591 |
Filed: |
July 25, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10627591 |
Jul 25, 2003 |
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09266720 |
Mar 11, 1999 |
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6655379 |
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60078212 |
Mar 16, 1998 |
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60078214 |
Mar 16, 1998 |
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Current U.S.
Class: |
604/500 ;
514/11.1; 514/11.2; 514/11.4; 514/11.8; 514/11.9; 514/14.1;
514/20.5; 514/5.9; 514/7.7; 514/9.9 |
Current CPC
Class: |
A61M 15/002 20140204;
A61M 15/00 20130101; A61K 9/0073 20130101 |
Class at
Publication: |
604/500 ;
514/002 |
International
Class: |
A61K 038/00; A61M
031/00 |
Claims
1-22. (cancelled)
23. A device for increasing the bioavailability of an aerosolized
active agent, said device comprising a flow restrictor for limiting
the flow of an aerosolized active agent formulation to a human
patient to less than 17 liters per minute, wherein the device is
adapted to aerosolize the active agent formulation and wherein the
active agent formulation is (i) a powder, (ii) a solution,
suspension, or slurry that may be nebulized, or (iii) suspended or
dissolved in a propellant.
24. The device of claim 23 wherein the flow restrictor comprises an
orifice.
25. The device of claim 24 wherein the flow restictor comprises
apertures of 0.5 to 0.9 mm in diameter.
26. The device of claim 23 wherein the flow restrictor is a valve
that provides for decreasing resistance with increasing flow
rate.
27. The device of claim 23 wherein the flow restictor is a valve
that provides for high resistance at all flow rates except a
desired flow rate range.
28. The device of claim 23 wherein the device is adapted to be used
with an active agent selected from the group consisting of insulin,
cyclosporin, parathyroid hormone, follicle stimulating hormone,
alpha-1-antitrypsin, budesonide, human growth hormone, growth
hormone releasing hormone, interferon alpha, interferon beta,
growth colony stimulating factor, leutinizing hormone releasing
hormone, calcitonin, low molecular weight heparin, somatostatin,
respiratory syncytial virus antibody, erythropoietin, Factor VIII,
Factor IX, ceredase, cerezyme and analogues, agonists and
antagonists thereof.
29. The device of claim 23 wherein the active agent formulation is
a powder and wherein the device is adapted to aerosolize the active
agent formulation.
30. The device of claim 23 wherein the active agent formulation is
contained in a blister and wherein the device is adapted to receive
the blister.
31. The device of claim 23 wherein the device is adapted to
aerosolize a powder active agent formulation.
32. The device of claim 31 wherein the device is adapted to
aerosolize the powder active agent formulation using compressed
air.
33. A device for delivering an aerosolized active agent to the
lungs of a human patient, wherein said device is adapted to deliver
an aerosolized active agent formulation at an inspiratory flow rate
of less than 17 liters per minute, wherein the device is adapted to
aerosolize the active agent formulation and wherein the active
agent formulation is (i) a powder, (ii) a solution, suspension, or
slurry that may be nebulized, or (iii) suspended or dissolved in a
propellant.
34. The device of claim 33 wherein the device is adapted to be used
with an aerosolized active agent formulation in dry powder
form.
35. The device of claim 33 wherein the device is adapted to deliver
the aerosolized active agent formulation at an inspiratory flow
rate of 10 liters per minute or less.
36. The device of claim 33 wherein the active agent formulation is
a powder and wherein the device is adapted to aerosolize the active
agent formulation.
37. The device of claim 33 wherein the active agent formulation is
contained in a blister and wherein the device is adapted to receive
the blister.
38. A device for delivering aerosolized insulin to the lungs of a
human patient, wherein said device comprises a flow restrictor to
restrict an inspiratory flow rate of an aerosolized insulin
formulation to less than 17 liters per minute and wherein the
device is adapted to aerosolize the insulin.
39. The device of claim 38 wherein the inspiratory flow rate is 10
liters per minute or less.
40. The device of claim 38 wherein the active agent formulation is
a powder and wherein the device is adapted to aerosolize the active
agent formulation.
41. The device of claim 38 wherein the active agent formulation is
contained in a blister and wherein the device is adapted to receive
the blister.
42. A device for delivering an aerosolized active agent to the
lungs of a human patient, wherein said device comprises one or more
orifices sized so that au aerosolized active agent formulation may
be delivered at an inspiratory flow rate of less than 17 liters per
minute, wherein the device is adapted to aerosolize the active
agent formulation and wherein the active agent formulation is (i) a
powder, (ii) a solution, suspension, or slurry that may be
nebulized, or (iii) suspended or dissolved in a propellant.
43. The device of claim 42 wherein the device is adapted to deliver
an aerosolized insulin formulation to the lungs.
44. The device of claim 42 wherein the orifices are sized so that
the aerosolized active agent formulation may be delivered at an
inspiratory flow rate of 10 liters per minute or less.
45. The device of claim 42 wherein the active agent formulation is
a powder and wherein the device is adapted to aerosolize the active
agent formulation.
46. The device of claim 42 wherein the active agent formulation is
contained in a blister and wherein the device is adapted to receive
the blister.
47. A device for delivering an aerosolized active agent to the
lungs of a human patient, said device comprising: a chamber in flow
communication with a mouthpiece; means for aerosolizing the active
agent; and means for limiting an inspiratory flow rate through the
mouthpiece to less than 17 liters per minute, whereby an
aerosolized active agent formulation in the chamber may be
delivered to the human patient, the active agent formulation being
(i) a powder, (ii) a solution, suspension, or slurry that may be
nebulized, or (iii) suspended or dissolved in a propellant.
48. The device of claim 47 wherein the inspiratory flow rate is
limited to 10 liters per minute or less.
49. The device of claim 47 wherein the device is adapted to deliver
an aerosolized insulin formulation to the lungs.
50. The device of claim 47 further comprising means for
aerosolizing the active agent.
51. The device of claim 47 wherein the active agent formulation is
a powder and wherein the device is adapted to aerosolize the active
agent formulation.
52. The device of claim 47 wherein the active agent formulation is
contained in a blister and wherein the device is adapted to receive
the blister.
Description
FIELD OF THE INVENTION
[0001] The present invention is related to the pulmonary delivery
of an active agent formulation. More particularly, it is a method
and device for pulmonary delivery of an active agent formulation
for increased systemic bioavailability of the active agent via
absorption in the deep lung. Average inspiratory flow rates of less
than 17 liters per minute of active agent formulation must be
maintained in order to achieve increased bioavailability.
BACKGROUND OF THE INVENTION
[0002] Effective delivery to a patient is a critical aspect of any
successful drug therapy. Various routes of delivery exist, and each
has its own advantages and disadvantages. Oral drug delivery of
pills, capsules, elixirs, and the like is perhaps the most
convenient method, but many drugs are degraded in the digestive
tract before they can be absorbed. Subcutaneous injection is
frequently an effective route for systemic drug delivery, including
the delivery of proteins, but enjoys a low patient acceptance.
Since injection of drugs, such as insulin, one or more times a day
can frequently be a source of poor patient compliance, a variety of
alternative routes of administration have also been developed,
including transdermal, intranasal, intrarectal, intravaginal, and
pulmonary delivery.
[0003] Insulin is a 50 amino acid polypeptide hormone having a
molecular weight of about 6,000 daltons which is produced in the
pancreatic .beta.-cells of normal (non-diabetic) individuals.
Insulin is necessary for regulating carbohydrate metabolism by
reducing blood glucose levels. Where the body's ability to regulate
blood glucose levels has been impaired, diabetes will result. There
are two main types of diabetes. In Type I, the insulin-secreting
cells of the pancreas are destroyed. Insulin production is
therefore nearly completely halted. In Type II, either the body
produces insulin but in quantities that are insufficient to
regulate blood sugar levels to within a normal range or the insulin
receptors are unable to adequately process the insulin in the
blood. Survival of Type I diabetic patients depends on the frequent
and long-term administration of insulin to maintain acceptable
blood glucose levels. Type II diabetics may require insulin
administration, but diet, exercise or oral medications are often
used to avoid the necessity of daily injections of insulin.
[0004] Insulin is most commonly administered by subcutaneous
injection, typically into the abdomen or upper thighs, in order to
maintain acceptable blood glucose levels, it is often necessary to
inject basal insulin at least once or twice per day, with
supplemental injections of rapid-acting insulin being administered
when necessary, usually prior to meals. Blood glucose levels should
typically remain between 50 mg/dl and 300 mg/dl, preferably between
about 80 mg/dl and 1120 mg/dl with a target blood glucose level of
100 mg/dl. Aggressive treatment of diabetes can require even more
frequent injections, in conjunction with the close monitoring of
blood glucose levels by patients using home diagnostic kits.
[0005] The administration of insulin by injection is undesirable in
a number of respects. First, many patients find it difficult and
burdensome to inject themselves as frequently as necessary to
maintain acceptable blood glucose levels. Such reluctance can lead
to non-compliance with recommended therapeutic regimens, which in
the most serious cases can be life-threatening. Moreover, systemic
absorption of insulin from subcutaneous injection is relatively
slow when compared to the normal release of insulin by the
pancreas, frequently requiring from 45 to 90 minutes, even when
fast-acting insulin formulations are employed. Thus, it has long
been a goal to provide alternative insulin formulations and routes
of administration which avoid the need for physically invasive
injections and which can provide rapid systemic blood levels of the
insulin as seen in normal subjects.
[0006] Elliot et al, Aust. Paediatr. J.(1987)23:293-297 described
the nebulized delivery of semi-synthetic human insulin to the
respiratory tracts of six diabetic children and determined that it
was possible to control diabetes in these children, although the
efficiency of absorption was low (20-25%) as compared to
subcutaneous delivery. Laube et al. U.S. Pat. No. 5,320,094, noting
Elliot and a number of other studies, stressed that although
insulin had been delivered to the lung, none of the patients had
responded to the pulmonary insulin therapy sufficient for lowering
of blood glucose levels to within a normal range. Laube et al.
hypothesized that this problem resulted from the loss of drug in
the delivery system and/or in the oropharynx as a result of the
method of delivery and that the maximization of deposition within
the lungs should improve glucose control in the blood. In order to
achieve maximum delivery, Laube et al controlled the inspiratory
flow rate at the time of aerosol inhalation at flow rates of less
than 30 liters/minute and, preferably about 17 liters/minute. The
delivery system included a medication chamber for receiving the
insulin, an outlet aperture through which the insulin was
withdrawn, and a flow rate limiting aperture to control the
inspiratory flow rate.
[0007] Rubsamen et al. U.S. Pat. Nos. 5,364,838 and 5,672,581
describe the delivery of a measured amount of aerosolized insulin.
The insulin is automatically released into the inspiratory flow
path in response to information obtained from determining the
inspiratory flow rate and inspiratory volume of a patient. A
monitoring device continually sends information to a
microprocessor, and when the microprocessor determines that an
optimal point in the respiratory cycle is reached, the
microprocessor actuates the opening of a valve allowing release of
insulin. The inspiratory flow rate is in the range of from about
0.1 to 2.0 liters/second and the volume is in the range of from
about 0.1 to 0.8 liters.
[0008] Even with the amount of work that has been done to optimize
delivery of inhaled insulin, there has not been a system and method
of delivery that has provided sufficient delivery of insulin to the
lung for maintaining target blood glucose levels in diabetic
patients. Such a system and method for delivery would be useful for
the delivery of many other active agents as well.
SUMMARY OF THE INVENTION
[0009] Accordingly, in one aspect, the present invention is
directed to a method for delivering an active agent formulation to
the lungs of a human patient, said method comprising providing the
active agent formulation at an inspiratory flow rate of below 17
liters per minute. The active agent formulation may be provided in
dry powder or nebulized form, or it may be in the form of
aerosolized particles in admixture with a propellant.
[0010] In another aspect, the present invention is directed to a
method for delivering insulin to the lungs of a human patient, said
method comprising providing insulin at an inspiratory flow rate of
below 17 liters per minute. The is preferably provided in dry
powder form, but it may also be in nebulized form, or it may be in
the form of aerosolized particles in admixture with a
propellant.
[0011] In yet another aspect, the present invention is directed to
a device for increasing the bioavailability of an aerosolized
active agent, said device comprising a flow restricter for limiting
the flow of the aerosolized active agent formulation to below 17
liters per minute. The flow restricter may be in the form of a
simple orifice, a valve that provides for increasing resistance
with increasing flow rate, a valve that provides for decreasing
resistance with increasing flow rate, or a valve that provides for
high resistance at all flow rates except the desired flow rate.
[0012] In a further aspect, the present invention is directed to a
device for delivering an active agent to the lungs of a human
patient wherein the device delivers an aerosolized active agent
formulation at an inspiratory flow rate of less than 17 liters per
minute.
[0013] The present invention is also directed to a device for
delivering insulin to the lungs of a human patient wherein the
device delivers an aerosolized insulin formulation at an
inspiratory flow rate of less than 17 liters per minute.
DESCRIPTION OF THE FIGURES
[0014] FIG. 1A is a perspective view and FIG. 1B is an elevational
view of an embodiment of a dry powder active agent formulation
delivery device of the invention.
[0015] FIG. 2A is a cross-sectional view and FIG. 2B is an
elevational view of an embodiment of a nebulized active agent
formulation delivery device of the invention.
[0016] FIG. 3A is a perspective view and FIG. 3B is an elevational
view of an embodiment of a propellant driven active agent
formulation delivery device of the invention.
[0017] FIG. 4A is a perspective view of a simple orifice and FIG.
41B is a graph showing the type of resistance obtained
therefrom.
[0018] FIG. 5A is a perspective view of a valve that provides for
increasing resistance with increasing flow rate and FIG. 5B is a
graph showing the type of resistance obtained therefrom.
[0019] FIG. 6A is a perspective view of a valve that provides for
decreasing resistance with increasing flow rate and FIG. 6B is a
graph showing the type of resistance obtained therefrom.
[0020] FIG. 7A is a perspective view of a valve that provides for
high resistance at all flow rates except the desired flow rate and
FIG. 7B is a graph showing the type of resistance obtained
therefrom.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The present invention provides a method and device for the
pulmonary delivery of an active agent formulation where inspiratory
flow rate of the active agent formulation is less than 17
liters/min. The invention is surprising in that it provides for
increased blood levels of active agent than observed following
higher inspiratory flow rates.
Definitions
[0022] "Active agent" as described herein includes an agent, drug,
compound, composition of matter or mixture there which provides
some pharmacologic, often beneficial, effect. This includes foods,
food supplements, nutrients, drugs, vaccines, vitamins, and other
beneficial agents. As used herein, the terms further include any
physiologically or pharmacologically active substance that produces
a localized or systemic effect in a patient. The active agent that
can be delivered includes antibiotics, antiviral agents,
anepileptics, analgesics, anti-inflammatory agents and
bronchodilators, and may be inorganic and organic compounds,
including, without limitation, drugs which act on the peripheral
nerves, adrenergic receptors, cholinergic receptors, the skeletal
muscles, the cardiovascular system, smooth muscles, the blood
circulatory system, synoptic sites, neuroeffector junctional sites,
endocrine and hormone systems, the immunological system, the
reproductive system, the skeletel system, autacoid systems, the
alimentary and excretory systems, the histamine system the central
nervous system. Suitable agents may be selected from, for example,
polysaccharides, steroid, hypnotics and sedatives, psychic
energizers, tranquilizers, anticonvulsants, muscle relaxants,
antiparkinson agents, analgesics, anti-inflammatories, muscle
contractants, antimicrobials, antimalarials, hormonal agents
including contraceptives, sympathomimetics, polypeptides, and
proteins capable of eliciting physiological effects, diuretics,
lipid regulating agents, antiandrogenic agents, antiparasitics,
neoplastics, antineoplastics, hypoglycemics, nutritional agents and
supplements, growth supplements, fats, antienteritis agents,
electrolytes, vaccines and diagnostic agents.
[0023] Examples of active agents useful in this invention include
but are not limited to insulin, calcitonin, erythropoietin (EPO),
Factor VIII, Factor IX, ceredase, cerezyme cyclosporin, granulocyte
colony stimulating factor (GCSF), alpha-1 proteinase inhibitor,
elcatonin, granulocyte macrophage colony stimulating factor
(GMCSF), growth hormone human growth hormone (HGH), growth hormone
releasing hormone (GHRH) heparin low molecular weight heparin
(LMWH) interferon alpha interferon beta interferon gamma
interleukin-2, luteinizing hormone releasing hormone (LHRH)
somatostatin somatostatin analogs including octreotide, vasopressin
analog, follicle stimulating hormone (FSH), insulin-like growth
factor, insulintropin, interleukin-1 receptor antagonist
interleukin-3, interleukin-4, interleukin-6, macrophage colony
stimulating factor (M-CSF), nerve growth factor parathyroid hormone
(PTH), thymosin alpha I, IIb/IIIa inhibitor, alpha-1 antitrypsin
respiratory syncytial virus antibody, cystic fibrosis transmembrane
regulator (CFTR) gene deoxyreibonuclease (Dnase),
bactericidal/permeabili- ty increasing protein (BPI), anti-CMV
antibody, interleukin-1 receptor. 13-cis retinoic acid, pentamidine
isethiouate, albuterol sulfate metaproterenol sulfate
beclomethasone diprepionate triamcinolone acetamide budesonide
acetonide, ipratropium bromide, flunisolide, fluticasone, cromolyn
sodium, ergotamine tartrate and the analogues, agonists and
antagonists of the above. Active agents may further comprise
nucleic acids, present as bare nucleic acid molecules viral
vectors, associated viral particles, nucleic acids associated or
incorporated within lipids or a lipid-containing material, plasmid
DNA or RNA or other nucleic acid construction of a type suitable
for transfection or transformation of cells, particularly cells of
the alveolar regions of the lungs. The active agents may be in
various forms, such as soluble and insoluble charged or uncharged
molecules, components of molecular complexes or pharmacologically
acceptable salts. The active agents may be naturally occurring
molecules or they may be recombinantly produced, or they may be
analogs of the naturally occurring or recombinantly produced active
agents with one or more amino acids added or deleted. Further, the
active agent may comprise live attenuated or killed viruses
suitable for use as vaccines. Where the active agent is insulin,
the term includes natural extracted human insulin, recombinantly
produced human insulin insulin extracted from bovine and/or porcine
sources, recombinantly produced porcine and bovine insulin and
mixtures of any of the above. The insulin may be neat that is in
its substantially purified form, but may also include excipients as
commercially formulated. Also included in the term "insulin" are
insulin analogs where one or more of the amino acids of the
naturally occurring or recombinantly produced insulin has been
deleted or added.
[0024] "Aerosolized active agent formulation" means the active
agent as defined above in a formulation that is suitable for
pulmonary delivery. The aerosolized active agent formulation may be
in the dry powder form, it may be a solution suspension or slurry
to be nebulized, or it may be in admixture with a suitable low
boiling point, highly volatile propellant. It is to be understood
that more than one active agent may be incorporated into the
aerosolized active agent formulation and that the use of the term
"agent" in no way excludes the use of two or more such agents.
[0025] The "inspiratory flow rate" or "average inspiratory flow
rate" are used interchangeably here to mean the flow rate at which
the aerosolized active agent formulation is delivered. For a
continuous nebulizer, this is the flow rate over the entire breath.
For a device that gives an aerosol bolus such as a dry powder
inhaler or an MDI, this is the average flow rate throughout the
period during which the aerosol bolus is delivered plus the time
taken for the aerosol to traverse the anatomical dead space, i.e.
from the lips to beyond generation 6 or 8 of the airways
(approximately 150 mls).
[0026] The amount of active agent in the aerosolized active agent
formulation will be that amount necessary to deliver a
therapeutically effective amount of the active agent to achieve the
desired result. In practice this will vary widely depending upon
the particular agent the severity of the condition, and the desired
therapeutic effect. However, the device is generally useful for
active agents that must be delivered in doses of from 0.001 mg/day
to 100 mg/day, preferably 0.01 mg/day to 50 mg/day.
[0027] The present invention is based at least in part on the
unexpected observation that when an active agent is delivered to a
patient at an inspiratory flow rate of less than 17 liters per
minute or preferably less than 12 liters per minute and more
preferably 10 liters per minute or less and often between 5 and 10
liters per minute, the lung deposition and thus the bioavailability
of the active agent increases as opposed to when the active agent
is delivered at an inspiratory flow rate of 17 liters per minute or
more. It was surprising that the lower flow rate would lead to a
higher bioavailability since Laube et al (U.S. Pat. No. 5,320,094)
determined the optimal flow rate of aerosolized insulin to be 17
liters per minute and that up to 30 liters per minute was
desirable.
[0028] Active agent formulations suitable for use in the present
invention include dry powders, solutions, suspensions or slurries
for nebulization and particles suspended or dissolved within a
propellant. Dry powders suitable for use in the present invention
include amorphous active agents, crystalline active agents and
mixtures of both amorphous and crystalline active agents. The dry
powder active agents have a particle size selected to permit
penetration into the alveoli of the lungs, that is, preferably 10
.mu.m mass median diameter (MMD), preferably less than 7.5 .mu.m,
and most preferably less than 5 .mu.m, and usually being in the
range of 0.1 .mu.m to 5 .mu.m in diameter. The to delivered dose
efficiency (DDE) of these powders is >30%, usually >40%,
preferably >50 and often >60% and the aerosol particle size
distribution is 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. These dry powder active agents have a moisture content
below about 10% by weight, usually below about 5% by weight, and
preferably below about 3% by weight. Such active agent powders are
described in WO 95/24183 and WO 96/32149, which are incorporated by
reference herein.
[0029] Dry powder active agent formulations are preferably prepared
by spray drying under conditions which result in a substantially
amorphous powder. Bulk active agent, no usually in crystalline
form, is dissolved in a physiologically acceptable aqueous buffer,
typically a citrate buffer having a pH range from about 2 to 9. The
active agent is dissolved at a concentration from 0.01% by weight
to 1% by weight, usually from 0.1% to 0.2%. The solutions may then
be spray dried in a conventional spray drier available from
commercial suppliers such as Niro A/S (Denmark), Buchi
(Switzerland) and the like, resulting in a substantially amorphous
powder. These amorphous powders may also be prepared by
lyophilization, vacuum drying, or evaporative drying of a suitable
active agent solution under conditions to produce the amorphous
structure. The amorphous active agent formulation so produced can
be ground or milled to produce particles within the desired size
range. Dry powder active agents may also be in a crystalline form.
The crystalline dry powders may be prepared by grinding or jet
milling the bulk crystalline active agent.
[0030] The active agent 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 active agent concentration in the powder which is
being delivered to a patient, but may also serve to improve the
dispersabilty of the powder within a powder dispersion device in
order to provide more efficient and reproducible delivery of the
active agent and to improve handling characteristic of the active
agent such as flowability and consistency to facilitate
manufacturing and powder filling. Such excipients include but are
not limited to (a) carbohydrates, e.g., monosaccharides such as
fructose, galactose, glucose, D-mannose, sorbose, and the like:
disaccharides, such as lactose, trehalose, cellobiose, and the
like: cyclodextrins, such as 2-hydroxypropyl-.beta.-cyclodextrin:
and polysaccharides, scuh as raffinose, maltodextrins, dextrans,
and the like: (b) amino acids, such as glycine, arginine, aspartic
acid, glutamic acid, cysteine, lysine, and the like: (c) organic
salts prepared from organic acids and bases, such as sodium
citrate, sodium ascorbate, magnesium gluconate, sodium gluconate,
tromethamin hydrochloride, and the like: (d) peptides and proteins
such as aspartame, human serum albumin, gelatin, and the like: and
(e) alditols, such as mannitol, xylitol, and the like. A preferred
group of carriers includes lactose, trehalose, raffinose,
maltodextrins, glycine, sodium citrate, human serum albumin and
mannitol.
[0031] The dry powder active agent formulations may be delivered
using Inhale Therapeutic Systems' dry powder inhaler as described
in WO 96/09085 which is incorporated herein by reference, but
adapted to control the flow rate to 17 liters per minute or less as
described below. The dry powders may also be delivered using a
metered dose inhaler as described by Laube et al in U.S. Pat. No.
5,320,094, which is incorporated by reference herein.
[0032] Nebulized solutions may be prepared by aerosolizing
commercially available active agent formulation solutions. These
solutions may be delivered by a jet nebulizer such as the Raindrop,
produced by Puritan Bennett, the use of which is described by Laube
et al. Other methods for delivery of solutions, suspensions of
slurries are described by Rubsamen et al. U.S. Pat. No. 5,672,581.
A device that uses a vibrating, piezoelectric member is described
in Ivri et al. U.S. Pat. No. 5,586,550, which is incorporated by
reference herein.
[0033] Propellant systems may include an active agent dissolved in
a propellant or particles suspended in a propellant. Both of these
types of formulations are described in Rubsamen et al. U.S. Pat.
No. 5,672,581, which is incorporated herein by reference.
[0034] In order to obtain the increased bioavailabilities of active
agent, the devices described above must be modified in order to
restrict the inspiratory flow rate of the active agent formulation
to 10 liters per minute or less. FIGS. 1A, 1B, 2A, 2B, 3A, 3B, 4A
and 4B show this restriction achieved by devices using a simple
orifice. FIGS. 5A, 5B, 6A, 6B, 7A and 7B show alternative flow
control methods useful in any of the FIG. 1A, 2A or 3A devices.
With regard to the devices for delivering the dry powder active
agent formulation as shown in FIGS. 1A and 1B, the device 100
contains a flow restricter 102 with apertures 103 that limits the
inspiratory flow to 10 liters per minute or less according to the
invention. FIG. 1A shows an exploded view of the device described
in WO 96/09085. Briefly, a patient inserts a blister of active
agent into the base 106 of the device. The handle 108 is cocked to
compress air for dispersion of the active agent. Lever 110 is
lowered to lift the blister 104 into place. Button 116 is depressed
which punctures the blister 104 and releases the active agent with
the compressed air into the capture chamber 112. The patient puts
his mouth over mouthpiece 114 and the aerosolized active agent
formulation is withdrawn through flow restricter 102 at a rate of
10 liters per minute or less.
[0035] FIGS. 2A and 2B show a rigid chamber 200 suitable for
restricting the inspiratory flow rate delivered by a nebulizer
according to the invention. As described in Laube et al, a rigid
chamber 200 is provided having a proximal end 202, a distal end 204
and a main body 206. The proximal end 202 has an aperture 208 that
is sized to accept standard disposable mouthpieces for use with
hospital nebulizers. The body of the device 206 has an opening has
an opening 210 of a size suitable for coupling to an external
source of aerosolized active agent. The aerosolized active agent
formulation is delivered to the chamber 200 through opening 210.
The opening 210 is then covered such that the aerosolized active
agent is contained within the chamber 200. The distal end 204
contains a flow restricter 212, in this case a series of apertures
214 such that when a patient inhales the active agent formulation
through a mouthpiece attached to the aperture 208, the inspiratory
flow rate of the active agent formulation is maintained at or below
10 liters per minute.
[0036] In order to restrict the inspiratory flow rate on a
propellant driven system, a metered dose inhaler (MDI) 300 may be
provided with a flow restricter 302 as shown in FIGS. 3A and 3B and
further described in Laube et al. The MIDI 300 is shown with a
mouthpiece 304 and a rigid chamber 306. The proximal end 308 of the
mouthpiece 304 is adapted to be placed in the mouth of a patient.
The distal end 310 of the mouthpiece 304 is rigidly attached to the
proximal end 312 of chamber 306. The MDI is attached such that when
operated, a dose of aerosolized active agent formulation is
released into chamber 306. The distal end 314 of chamber 306
contains a flow restricter 302, in this case a series of apertures
318 as shown in FIG. 3B, such that when a patient inhales the
active agent formulation through the proximal end 308 of the
mouthpiece 304, the inspiratory flow rate of the active agent
formulation is maintained at or below 10 liters per minute.
[0037] The devices of FIGS. 1-3 use a simple orifice as shown in
FIG. 4A to achieve the desired inspiratory flow rate. The rate of
air flow through the orifice is proportional to the square root of
the pressure drop across it, and in this case the resistance (R) is
constant-as shown in FIG. 4B. In order to obtain a flow rate of 10
liters per minute, the resistance required is approximately 1 cm
H.sub.2O.sup.1/2/Lmin.sup.-1. This is accomplished by including a
flow restricter with a total orifice area of approximately 2 to 4
mm.sup.2. In the embodiments shown in FIGS. 1-3, there are 8-12
apertures of 0.5-0.9 mm diameter which will provide for this type
of flow.
[0038] FIG. 5A shows a valving arrangement where the resistance
increases with increasing flow rate. The proportionality of
resistance to flow rate is shown in FIG. 5B. Such an arrangement
allows for comfortable inhalation at the desired flow rate. As with
the arrangement of FIG. 4A, the resistance at 10 liters per minute
would be approximately 1 cm H.sub.2O.sup.1/2/Lmin.sup.-1.
[0039] FIG. 6A shows a valving arrangement where the resistance
decreases with increasing flow rate. This arrangement is useful
where an aerosol bolus can be delivered slowly enough to ensure
that it has entered the lower airway prior to the flow being
allowed to increase to over 10 liters per minute. The
proportionality of resistance to flow rate is shown in FIG. 6B.
[0040] FIG. 7A shows a valving arrangement where the resistance is
high at all flow rates except for the desired flow rate. The
proportionality of resistance to flow rate is shown in FIG. 7B. The
resistance at 10 liters per minute would be 0.25 cm
H.sub.2O.sup.1/2/Lmin.sup.-1 and greater than 1 cm
H.sub.2O.sup.1/2/Lmin.sup.-1 at other than the desired flow
rate.
[0041] It is also possible, but somewhat less desirable to provide
training to a patient using a device which is not restricted such
that the patient learns to inspire at a flow rate at or below 10
liters per minute.
[0042] The following examples are illustrative of the present
invention. It is not to be construed as limiting the scope of the
invention. Variations and equivalents of this example will be
apparent to those of skill in the art in light of the present
disclosure, the drawings and the claims herein.
EXAMPLES
[0043] Materials and Methods
[0044] Materials
[0045] Crystalline human zinc insulin. 26.3 U/mg was obtained from
Eli Lilly and Company, Indianapolis. Ind. and found to be >99%
pure as measured by rpHPLC.
[0046] Human calcitonin was obtained from Ciba-Geigy.
[0047] Low molecular weight heparin sodium salt (average molecular
weight .about.6000) was obtained from Sigma Chemical, St. Louis,
Mo.
[0048] Cyclosporin A, BMP grade was obtained as a powder
crystallized from acetone (melting point 148-150.degree. C.) from
Poli Industria Chemica, S.p.A.
[0049] Human serum albumin (HSA) (Tentex Fr V. Low Endotoxin. Fatty
Acid Free) was obtained from Miles Inc. (Kankakee. Ill.).
[0050] Albuterol sulfate was obtained from Profarmaco (Milano,
Italy).
[0051] USP mannitol was obtained from Roquette Corporation (Gurnee,
Ill.).
[0052] USP lactose was obtained from Spectrum (New Brunswick,
N.J.).
[0053] Glycine was purchased from Sigma Chemical Company (St.
Louis, Mo.).
[0054] Sodium citrate dihydrate. USP was obtained from J. T. Baker
(Phillipsburg, N.J.).
[0055] Ethanol (200 proof, USP, NF grade) was obtained from
Spectrum (New Brunswick, NJ).
[0056] Powder Production
[0057] Insulin powders were made by dissolving bulk crystalline
insulin in sodium citrate buffer containing mannitol and glycine to
give final solids concentration of 7.5 mg/ml and pH of 6.7+0.3. The
spray dryer was operated with an inlet temperature between
110.degree. C. and 120.degree. C. and a liquid feed rate of 5
ml/min, resulting in an outlet temperature between 70.degree. C.
and 80.degree. C. The solutions were then filtered through a 0.22
.mu.m filter and spray dried in a Buchi Spray Dryer to form a fine
white amorphous powder. The resulting powders were stored in
tightly capped containers in a dry environment (<10% RH).
[0058] Powders containing 26.7% human calcitonin were made by spray
drying an aqueous mixture containing human calcitonin. The mixture
was prepared by combining 1.9 mg human calcitonin per 1.0 mL
deionized water with 4.3 mg/mL mannitol and 0.9 m/mL citrate buffer
at a pH of 3.85. The mixture was spray dried in a Buchi Spray Dryer
that was operated with an inlet temperature between 110.degree. C.
and 120.degree. C. and a liquid feed rate of 5.5 ml/min, resulting
in an outlet temperature between 70.degree. C. and 80.degree. C.
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. The
resulting powders were stored in tightly capped containers in a dry
environment (<10% RH).
[0059] Powders containing 93% low molecular weight (lmw) heparin
powders were made by spray drying an aqueous mixture containing lmw
heparin. The mixture was prepared by combining 6.9 mg 1 mw heparin
per 1.0 mL deionized water with 0.5 mg/mL HSA a pH of 6.9. The
mixture was spray dried in a Buchi Spray Dryer that was operated
with an inlet temperature of 140.degree. C. and a liquid feed rate
of 3.8 ml/min, resulting in an outlet temperature of 85.degree. C.
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. The
resulting powders were stored in tightly capped containers in a dry
environment (<10% RH).
[0060] Powders containing cyclosporin were made by spray drying an
organic solution containing 1.5 g cyclosporin A and 50 mL ethanol.
The solution was spray dried in a Buchi Spray Dryer using a
nitrogen atmosphere containing less than 5% oxygen (with N.sub.2
atm <5% O.sub.2 that was operated with an inlet temperature of
100.degree. C. and a liquid feed rate of 5 mL/min, resulting in an
outlet temperature of 70.degree. C. The resulting powders were
stored in tightly capped containers in a dry environment (<10%
RH).
[0061] Powders containing 2.3% albuterol sulfate were made by spray
drying an aqueous mixture containing albuterol sulfate. The mixture
was prepared by combining 0.60 mg albuterol sulfate and 25.68 mg
lactose per 1.0 mL deionized water at a pH of 4.6. The mixture was
spray dried in a Niro Spray Dryer that was operated with an inlet
temperature of 120.degree. C. and a liquid feed rate of 50 mL/min,
resulting in an outlet temperature between 64.7.degree. C. and
67.2.degree. C. The resulting powders were stored in tightly capped
containers in a dry environment (<10% RH).
[0062] Powder Analysis
[0063] The particle size distribution of the powders was measured
by liquid centrifugal sedimentation in a Horiba CAPA-700 Particle
Size Analyzer following dispersion of the powders in Sedisperse
A-11 (Micrometrics, Norcross, Ga.). The moisture content of the
powders was measured by the Karl Fischer technique using a
Mitsubishi CA-06 Moisture Meter. The aerosol particle size
distribution was measured using a cascade impactor (Graseby
Andersen, Smyrna, Ga.). The delivered dose efficiency (DDE) is
evaluated using the Inhale Therapeutic Systems aerosol devices,
similar to that described in WO96/09085. The DDE is defined as the
percentage of the nominal dose contained within a blister package
that exited the mouthpiece of the aerosol device and was captured
on a glass fiber filter (Gelman, 47 mm diameter) through which a
vacuum was drawn (30 L/min) for 2.5 seconds following device
actuation. DDE was calculated by dividing the mass of the powder
collected on the filter by the mass of the powder in the blister
pack.
[0064] In the case of insulin, the integrity of insulin before and
after powder processing was measured against a reference standard
of human insulin by redissolving weighed portions of powder in
distilled water and comparing the redissolved solution with the
original solution put into the spray dryer. Retention time and peak
area by rpHPLC were used to determine whether the insulin molecule
had been chemically modified or degraded in the process. UV
absorbance was used to determine insulin concentration (at 278 nm)
and presence of absence of insoluble aggregates (at 400 nm). In
addition, the pHs of the starting and reconstituted solutions were
measured. The amorphous nature of the insulin powder was confirmed
by polarized light microscopy.
[0065] In Vivo Testing
[0066] In order to examine the effect of changes in the rate of
inhalation on the bioavailability of inhaled active agent, 12
individuals were dosed with insulin at the following peak sustained
flow rates in a randomized sequence:
[0067] 10 L/min.+-.5 L/min
[0068] 25 L/min.+-.5 L/min
[0069] 35 L/min or greater.
[0070] Inhale Therapeutic Systems' (San Carlos, Calif.) dry powder
inhaler was used to administer the aerosolized active agent powder.
In the case of insulin, 3 mg of the amorphous insulin powders
described above were filled into blister packages and inserted into
the inhaler. The inhaler dispersed the powder and produced an
aerosol cloud of medication which was held in a volume of
approximately 240 ml in a holding chamber. The volume of the
holding chamber was a minor fraction of a deep inspiratory breath
(>2 liters). The chamber was designed so that during inhalation
of the aerosol cloud, ambient air was pulled into the chamber
thereby pushing the aerosol cloud out of the chamber and deep into
the lungs. Each 3 mg dose of the dry powder contained 82.5 U of
insulin.
[0071] The subjects were trained in the breathing maneuvers for
inhalation of active agent. The steps were: (1) Subject exhaled to
functional residual capacity and wrapped lips around the mouthpiece
of the inhaler: (2) A cloud of aerosolized active agent was
dispersed from the blister pack into the holding chamber of the
inhaler: (3) Subject inhaled at the designated rate until total
lung capacity was reached (this should have removed all of the
aerosol from the chamber): (4) Subject removed mouth from the
inhaler and held breath for 5 seconds: and (5) Subject exhaled
gently to normal expiratory level and resumed normal breathing.
[0072] All subjects fasted at least eight (8) hours prior to
insulin dosing and were required to refrain from lying down, eating
or drinking caffeinated beverages during the first six (6) hours
after dosing in order to standardize experimental conditions. Blood
was collected at 30 and 15 minutes prior to insulin dosing; and 0
(just prior to insulin dosing), 5, 10, 20, 30, 45, 60, 90, 120,
180, 240, 300 and 360 minutes after the start of the
inhalation.
[0073] Spirometery was performed on each subject prior to dosing to
determine their pulmonary function. FEV was at least 70% of
predicted normal values. To determine whether inhalation of active
agent powder caused bronchoconstriction or other change in
pulmonary function, spirometry was also performed prior to and 30,
60 and 360 minutes after the start of each administration of active
agent. At each time point, each subject performed 3 forced
expiratory volume tests.
[0074] In order to obtain the appropriate inhaled flow rates,
subjects were able to view the output from the inhalation
measurement device and were instructed to try to match their
inhalation rate to the desired rate on the output from the device.
For the 10 L/min rate, inhalation lasted approximately 15 seconds.
For the 25 L/min inhalation rate, inhalation required approximately
6 seconds. For the >35 L/min inhalation rate, the subjects were
instructed to inhale as rapidly as possible.
EXAMPLE 1
Insulin Powders
[0075] Insulin powders were prepared as described above and
administered to patients also as described above. The
bioavailibilities, peak insulin concentrations and time to peak
insulin concentrations were as shown in Table I below. The figures
show, surprisingly, that inspiratory flow rates of 10 liters per
minute or less achieved higher bioavailabilities of insulin (AUC),
and higher peak concentrations of insulin (Cmax) than did
inspiratory flow rates of 17.0 liters per minute or greater.
Further, blood glucose level control (AUC) was greater for an
inspiratory flow rate of 9.1 liters per minute than for the higher
flow rates, and the maximum concentration (Cmax) was lower for the
lower flow rate. Accordingly, a flow rate below 17 liters per
minute, preferably 10 liters per minute or less is desired for
optimal insulin delivery and glucose blood level control.
1TABLE 1 Summary of Pharmacokinetics and Pharmacodynamic Factors
for Insulin aerosol Inhaled at Different Inspiratoy Flow rates.
Peak Average flow sustained during aerosol Insulin values Glucose
values flow rate administration t.sub. C.sub. AUC.sub.U 360 t.sub.
C.sub. AUC .sub.U [l/min] [l/min] [min] [mU/ml] [mU .multidot.
min/ml] [min] [mU/ml] [mU .multidot. min/ml] >35 21.1 .+-. 4.5
48.8 .+-. 13.0 21.0 .+-. 8.0 2052 .+-. 1342 28.7 .+-. 6.6 77.5 .+-.
29.2 5588 .+-. 747 .congruent.25 17.0 .+-. 4.9 46.3 .+-. 26.0 21.7
.+-. 7.4 2555 .+-. 873 30.9 .+-. 12.8 91.3 .+-. 28.9 5461 .+-. 2931
.congruent.10 9.1 .+-. 1.7 41.7 .+-. 8.1 31.6 .+-. 16.0 3502 .+-.
1342 38.8 .+-. 13.2 67.5 .+-. 17.5 6230 .+-. 1908
EXAMPLE 2
Human Calcitonin Powders
[0076] Human calcitonin powders are prepared as described above.
Upon administration to patients, flow rates below 17 liters per
minute will result in higher bioavailabilities and lower times to
peak concentration than those above 17 liters per minutes.
EXAMPLE 3
Heparin Powders
[0077] Low molecular weight heparin powders are prepared as
described above. Upon administration to patients, flow rates below
17 liters per minute will result in higher bioavailabilities and
lower times to peak concentration than those above 17 liters per
minutes.
EXAMPLE 4
Cyclosporin Powders
[0078] Cyclosporin A powders are prepared as described above. Upon
administration to patients, flow rates below 17 liters per minute
will result in higher lung deposition and thus increased
therapeutic effect than those above 17 liters per minutes.
EXAMPLE 5
Albuterol Sulfate Powders
[0079] Albuterol sulfate powders are prepared as described above.
Upon administration to patients, flow rates below 17 liters per
minute will result in higher lung deposition and thus increased
therapeutic effect than those above 17 liters per minutes.
[0080] The disclosure of each publication patent or patent
application mentioned in this specification is incorporated by
reference herein to the same extent as if each individual
publication, patent or patent application were specifically and
individually indicated to be incorporated by reference.
* * * * *