U.S. patent application number 14/849950 was filed with the patent office on 2016-03-03 for pulmonary delivery for levodopa.
The applicant listed for this patent is Civitas Therapeutics, Inc.. Invention is credited to Raymond T. Bartus, David J. Bennett, Dwaine F. Emerich, Blair C. Jackson.
Application Number | 20160058727 14/849950 |
Document ID | / |
Family ID | 28454804 |
Filed Date | 2016-03-03 |
United States Patent
Application |
20160058727 |
Kind Code |
A1 |
Jackson; Blair C. ; et
al. |
March 3, 2016 |
Pulmonary Delivery for Levodopa
Abstract
In one aspect, the invention is related to a method of treating
a patient with Parkinson's disease, the method including
administering to the respiratory tract of the patient particles
that include more than about 90 weight percent (wt %) of levodopa.
The particles are delivered to the patient's pulmonary system,
preferably to the alveoli or the deep lung.
Inventors: |
Jackson; Blair C.; (South
Grafton, MA) ; Bennett; David J.; (Brighton, MA)
; Bartus; Raymond T.; (San Diego, CA) ; Emerich;
Dwaine F.; (Glocester, RI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Civitas Therapeutics, Inc. |
Chelsea |
MA |
US |
|
|
Family ID: |
28454804 |
Appl. No.: |
14/849950 |
Filed: |
September 10, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14055959 |
Oct 17, 2013 |
9155699 |
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14849950 |
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13773054 |
Feb 21, 2013 |
8586093 |
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14055959 |
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12972824 |
Dec 20, 2010 |
8404276 |
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13773054 |
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10392342 |
Mar 19, 2003 |
7879358 |
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12972824 |
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60366471 |
Mar 20, 2002 |
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Current U.S.
Class: |
424/489 ;
514/567 |
Current CPC
Class: |
A61K 31/137 20130101;
A61K 9/0073 20130101; A61K 9/1611 20130101; A61P 25/00 20180101;
A61K 9/1623 20130101; A61P 25/16 20180101; A61K 31/70 20130101;
A61K 31/198 20130101; A61K 9/1617 20130101; A61K 9/0075
20130101 |
International
Class: |
A61K 31/198 20060101
A61K031/198; A61K 9/00 20060101 A61K009/00; A61K 9/16 20060101
A61K009/16 |
Claims
1. A composition of dry powder particles formulated for pulmonary
delivery comprising about 75 weight percent levodopa or more and
sodium chloride.
2. The composition of claim 1, wherein the particles further
comprise a phospholipid or a combination of phospholipids.
3. The composition of claim 1, wherein the particles have a tap
density about 0.4 g/cm.sup.3 or less.
4. The composition of claim 1, wherein the particles have a volume
median geometric diameter about 5 micrometers or more.
5. The composition of claim 1, wherein the particles have an
aerodynamic diameter of from about 1 micrometer to about 5
micrometers.
6. The composition of claim 1, wherein the particles have an
aerodynamic diameter of from about 1 micrometer to about 3
micrometers.
7. The composition of claim 1, wherein the particles have an
aerodynamic diameter of from about 3 micrometer to about 5
micrometers.
8. The composition of claim 1, wherein the particles have a tap
density about 0.3 g/cm.sup.3 or less.
9. The composition of claim 1, wherein the particles have a tap
density about 0.2 g/cm.sup.3 or less.
10. The composition of claim 1, wherein the particles have a tap
density about 0.1 g/cm.sup.3 or less.
11. The composition of claim 1, wherein the particles comprise
about 10% or less by weight of sodium chloride.
12. The composition of claim 1, wherein the particles comprise
about 5% or less by weight of sodium chloride.
13. The composition of claim 1, wherein the particles comprise
about 2% or less by weight of sodium chloride.
14. The composition of claim 2, wherein the phospholipid is
dipalmitoyl phosphatidylcholine (DPPC).
15. A composition of dry powder particles consisting essentially of
about 75% or more levodopa, sodium chloride and
dipalmitoylphosphatidylcholine.
16. A composition of dry powder particles consisting essentially of
levodopa, sodium chloride and dipalmitoylphosphatidylcholine,
wherein the ratio of levodopa:dipalmitoylphosphatidylcholine:sodium
chloride is about 90:8:2.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/055,959, filed Octt. 17, 2013 which is a continuation of
U.S. application Ser. No. 13/773,054, filed Feb. 21, 2013, now U.S.
Pat. 8,586,093, issued Nov. 19, 2013, which is a continuation of
U.S. application Ser. No. 12/972,824, filed Dec. 20, 2010 now U.S.
Pat. 8,404,276, issued Mar. 26, 2013, which is a divisional of U.S.
application Ser. No. 10/392,342, filed Mar. 19, 2003, now U.S.
Patent 7,879,358, issued Feb. 1, 2011, (now RE43,711, issued Oct.
2, 2012), which claims the benefit of U.S. Provisional Application
No. 60/366,471, filed Mar. 20, 2002. The entire teachings of the
above applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Parkinson's disease is characterized neuropathologically by
degeneration of dopamine neurons in the basal ganglia and
neurologically by debilitating tremors, slowness of movement and
balance problems. It is estimated that over one million people
suffer from Parkinson's disease. Nearly all patients receive the
dopamine precursor levodopa or L-Dopa, often in conjunction with
the dopa-decarboxylase inhibitor, carbidopa. L-Dopa adequately
controls symptoms of Parkinson's disease in the early stages of the
disease. However, it tends to become less effective after a period
which can vary from several months to several years in the course
of the disease.
[0003] It is believed that the varying effects of L-Dopa in
Parkinson's disease patients are related, at least in part, to the
plasma half life of L-Dopa which tends to be very short, in the
range of 1 to 3 hours, even when co-administered with carbidopa. In
the early stages of the disease, this factor is mitigated by the
dopamine storage capacity of the targeted striatal neurons. L-Dopa
is taken up and stored by the neurons and is released over time.
However, as the disease progresses, dopaminergic neurons
degenerate, resulting in decreased dopamine storage capacity.
Accordingly, the positive effects of L-Dopa become increasingly
related to fluctuations of plasma levels of L-Dopa. In addition,
patients tend to develop problems involving gastric emptying and
poor intestinal uptake of L-Dopa. Patients exhibit increasingly
marked swings in Parkinson's disease symptoms, ranging from a
return to classic Parkinson's disease symptoms, when plasma levels
fall, to the so-called dyskinesis, when plasma levels temporarily
rise too high following L-Dopa administration.
[0004] As the disease progresses, conventional L-Dopa therapy
involves increasingly frequent, but lower dosing schedules. Many
patients, for example, receive L-Dopa every two to three hours. It
is found, however, that even frequent doses of L-Dopa are
inadequate in controlling Parkinson's disease symptoms. In
addition, they inconvenience the patient and often result in
non-compliance.
[0005] It is also found that even with as many as six to ten L-Dopa
doses a day, plasma L-Dopa levels can still fall dangerously low,
and the patient can experience very severe Parkinson's disease
symptoms. When this happens, additional L-Dopa is administered as
intervention therapy to rapidly increase brain dopamine activity.
However, orally administered therapy is associated with an onset
period of about 30 to 45 minutes during which the patient suffers
unnecessarily. In addition, the combined effects of the
intervention therapy, with the regularly scheduled dose can lead to
overdosing, which can require hospitalization. For example,
subcutaneously administered dopamine receptor agonist
(apomorphine), often requiring a peripherally acting dopamine
antagonist, for example, domperidone, to control dopamine-induced
nausea, is inconvenient and invasive.
[0006] Therefore, a need exists for methods of treating patients
suffering with Parkinson's disease which are at least as effective
as conventional therapies yet minimize or eliminate the
above-mentioned problems.
SUMMARY OF THE INVENTION
[0007] The invention relates to methods of treating disorders of
the central nervous system (CNS). More specifically the invention
relates to particles and methods for delivering a drug suitable in
treating Parkinson's disease, e.g., levodopa, to the pulmonary
system.
[0008] In one aspect, the invention is related to a method of
treating a patient with Parkinson's disease, the method including
administering to the respiratory tract of the patient particles
that include more than about 90 weight percent (wt %) of levodopa.
The particles are delivered to the patient's pulmonary system,
preferably to the alveoli region of the deep lung.
[0009] In one embodiment of the invention, the particles also
include a non-reducing sugar, e.g., trehalose and, optionally, a
salt, e.g., sodium chloride (NaCl).
[0010] In another embodiment of the invention, the particles also
include a phospholipid, e.g., DPPC, or a combination of
phospholipids, and optionally a salt, e.g., NaCl.
[0011] The invention is also related to a method of preparing spray
dried particles that have a high content of L-Dopa, e.g., more than
about 90 wt %. The method includes combining L-Dopa, trehalose,
NaCl and water to form an aqueous solution and preparing an organic
solution (e.g., ethanol), mixing the aqueous solution and organic
solution to form a liquid feed mixture and spray drying the liquid
feed mixture, thereby forming spray dried particles.
[0012] The invention further is related to methods for
administering to the pulmonary system a therapeutic dose of L-Dopa
in a small number of steps, and preferably in a single, breath
activated step. The invention also is related to methods of
delivering a therapeutic dose of L-Dopa to the pulmonary system, in
a small number of breaths, and preferably in a single breath.
[0013] The invention has numerous advantages. The particles of the
invention are useful in treating all stages of Parkinson's disease,
e.g., ongoing management of the disease, as well as providing
rescue therapy. The particles have a high content of L-Dopa and,
therefore, the amount of drug that can be contained and
administered from a given inhaler capsule is increased, thereby
reducing the number of puffs required to deliver a clinically
effective dose. The methods of the invention result in forming dry,
non-sticky particles in high yields, minimizing material losses and
manufacturing costs. The particles have aerodynamic and dispersive
properties that render them useful in pulmonary delivery, in
particular delivery to the deep lung.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The features and other details of the invention, either as
steps of the invention or as combination of parts of the invention,
will now be more particularly described and pointed out in the
claims. It will be understood that the particular embodiments of
the invention are shown by way of illustration and not as
limitations of the invention. The principle feature of this
invention may be employed in various embodiments without departing
from the scope of the invention.
[0015] The invention is generally related to methods of treating
Parkinson's disease. The methods and particles disclosed herein can
be used in the ongoing (non-rescue) treatment of Parkinson's
disease or during the late stages of the disease, when the methods
described herein are particularly well suited to provide rescue
therapy. As used herein, "rescue therapy" means on demand, rapid
delivery of a drug to a patient to help reduce or control disease
symptoms.
[0016] Compounds used for treating Parkinson's disease include
levodopa (L-Dopa) and carbidopa. The structure of Carbidopa is
shown below:
##STR00001##
The structure of Levodopa is shown below:
##STR00002##
[0017] Other drugs generally administered in the treatment of
Parkinson's disease and which may be suitable in the methods of the
invention include, for example, ethosuximide, dopamine agonists
such as, but not limited to carbidopa, apomorphine, sopinirole,
pramipexole, pergoline, bronaocriptine, and ropinirole. The L-Dopa
or other dopamine precursor or agonist may be any form or
derivative that is biologically active in the patient being
treated. Combinations of drugs also can be employed.
[0018] In one embodiment of the invention the particles consist
include L-Dopa or other dopamine precursor or agonist as described
above. Particularly preferred are particles that include more than
about 90 weight percent (wt %), for instance, at least 93 wt %
L-Dopa. In one embodiment, the particles include at least 95 wt %
L-Dopa. In other embodiments, the presence of a non-reducing sugar
or the presence of a salt, as will be described herein, facilitates
a lower L-Dopa wt % while maintaining favorable features. The wt %
of L-Dopa can be lower to about 75 wt %, or to about 50 wt %, or to
about 20 wt %.
[0019] In further embodiments, the particles of the invention can
also include one or more additional component(s), generally in an
amount that is less than 10 weight percent.
[0020] In one embodiment the additional component is a non-reducing
sugar, for example, but not limited to, trehalose, sucrose,
fructose. Trehalose is preferred. Combinations of non-reducing
sugars also can be employed. The amount of non-reducing sugar(s),
e.g., trehalose, present in the particles of the invention
generally is less than 10 wt %, for example, but not limited to,
less than 8 wt %, or less than 6 wt %.
[0021] Without wishing to be held to a particular interpretation of
the invention, it is believed that non-reducing sugars enhance the
stability of a drug, such as L-Dopa, that has chemical groups,
e.g., amine group, that can potentially react with a sugar that is
reducing, e.g., lactose. It is further believed the presence of
non-reducing sugars rather than reducing sugars also can benefit
compositions that include other bioactive agents or drugs, such as,
for example, Carbidopa, epinephrine and other catecholamines.
[0022] In another embodiment, the particles of the invention
include, in addition to L-Dopa, one or more phospholipids. Specific
examples of phospholipids include but are not limited to
phosphatidylcholines dipalmitoyl phosphatidylcholine (DPPC),
dipalmitoyl phosphatidylethanolamine (DPPE), distearoyl
phosphatidylcholine (DSPC), dipalmitoyl phosphatidyl glycerol
(DPPG) or any combination thereof. The amount of phospholipids,
e.g., DPPC, present in the particles of the invention generally is
less than 10 wt %.
[0023] The phospholipids or combinations thereof and methods of
preparing particles having desired release properties are described
in U.S. application Ser. No. 09/792,869 entitled "Modulation of
Release from Dry Powder Formulations", filed on Feb. 23, 2001 under
Attorney Docket No. 2685.1012-004, which is a continuation-in-part
of U.S. application Ser. No. 09/644,736 entitled "Modulation of
Release from Dry Powder Formulations", filed on Aug. 23, 2000 under
Attorney Docket No. 2685.1012-001, both of which claim the benefit
of U.S. Provisional Patent Application No. 60/150,742 entitled
"Modulation of Release From Dry Powder Formulations by Controlling
Matrix Transition", filed on Aug. 25, 1999. The contents of all
three applications are incorporated herein by reference in their
entirety.
[0024] Optionally, the particles include, in addition to a
non-reducing sugar(s) or phospholipid(s), a small amount of a
strong electrolyte salt, such as, but not limited to, sodium
chloride (NaCl). Other salts that can be employed include sodium
phosphate, sodium fluoride, sodium sulfate and calcium carbonate.
Generally, the amount of salt present in the particles is less than
10 wt %, for example, less than 5 wt %.
[0025] Particles that comprise, by weight, greater than 90% of an
agent, e.g., L-Dopa, can have local areas of charges on the surface
of the particles. This electrostatic charge on the surface of the
particles causes the particles to behave in undesirable ways. For
example, the presence of the electrostatic charge will cause the
particles to stick to the walls of the spray drying chamber, or to
the pipe leading from the spray dryer, or to stick within the
baghouse, thereby, significantly reducing the percent yield
obtained. Additionally, the electrostatic charge can tend to cause
the particles to agglomerate when placed in a capsule based system.
Dispersing these agglomerates can be difficult and that can
manifest itself by either poor emitted doses, poor fine particle
fractions, or both. Moreover, particle packing can also be affected
by the presence of an electrostatic charge. Particles with like
charges in close proximity will repel each other, leaving void
spaces in the powder bed. This results in a given mass of particles
with an electrostatic charge taking up more space than a given mass
of the same powder without an electrostatic charge. Consequently,
this limits the upper dose that can be delivered in a single
receptacle.
[0026] Without wishing to be held to a particular interpretation of
the invention, it is believed that a salt, such as NaCl, provides a
source of mobile counter-ions. It is believed that the addition of
a small salt to particles that have local areas of charge on their
surface will reduce the amount of static present in the final
powder by providing a source of mobile counter-ions that would
associate with the charged regions on the surface. Thereby the
yield of the powder produced is improved by reducing powder
agglomeration, improving the Fine Particle Fraction (FPF) and
emitted dose of the particles and allowing for a larger mass of
particles to be packed into a single receptacle. As seen in Table
1, particles comprising L-Dopa and either trehalose or DPPC, with
the addition of sodium chloride, show an increased yield of
approximately 50-60 fold.
TABLE-US-00001 TABLE 1 Formulation Ratio Yield L-Dopa/Trehalose
95/5 <1% L-Dopa/Trehalose/NaCl 93/5/2 50% L-Dopa/DPPC 95/5
<1% L-Dopa/DPPC/NaCl 90/8/2 62%
[0027] Table 2 depicts the effects of sodium chloride on the fine
particle fraction and emitted dose of particles comprising L-Dopa
and either trehalose or DPPC.
TABLE-US-00002 TABLE 2 Formulation Ratio FPF < 5.6 FPF < 3.4
L-Dopa/Trehalose 95/5 33 12 L-Dopa/Trehalose/NaCl 93/5/2 59 40
L-Dopa/DPPC 95/5 29 10 L-Dopa/DPPC/NaCl 90/8/2 70 54
[0028] It is believed that the salt effect described above also
benefits compositions that include bioactive agents other than
L-Dopa. Examples of such active agents include, but are not limited
to, Carbidopa, epinephrine, other catecholamines, albuterol,
salmeterol, ropinirole and piroxican. Furthermore, compositions
that include 90% or less of a bioactive agent, e.g., L-Dopa, also
can benefit from adding a salt such as described above.
[0029] The particles of the invention can include a surfactant. As
used herein, the term "surfactant" refers to any agent which
preferentially absorbs to an interface between two immiscible
phases, such as the interface between water and an organic polymer
solution, a water/air interface or organic solvent/air interface.
Surfactants generally possess a hydrophilic moiety and a lipophilic
moiety, such that, upon absorbing to microparticles, they tend to
present moieties to the external environment that do not attract
similarly-coated particles, thus reducing particle agglomeration.
Surfactants may also promote absorption of a therapeutic or
diagnostic agent and increase bioavailability of the agent.
[0030] Suitable surfactants which can be employed in fabricating
the particles of the invention include but are not limited to
Tween-20; Tween-80; hexadecanol; fatty alcohols such as
polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a
surface active fatty acid such as palmitic acid or oleic acid;
glycocholate; surfactin; a poloxamer; a sorbitan fatty acid ester
such as sorbitan trioleate (Span 85); and tyloxapol.
[0031] Other materials which promote fast release kinetics of the
medicament can also be employed. For example, biocompatible, and
preferably biodegradable polymers can be employed. Particles
including such polymeric materials are described in U.S. Pat. No.
5,874,064, issued on Feb. 23, 1999 to Edwards et al., the teachings
of which are incorporated herein by reference in their
entirety.
[0032] The particles can also include a material such as, for
example, dextran, polysaccharides, lactose, cyclodextrins,
proteins, peptides, polypeptides, amino acids, fatty acids,
inorganic compounds, phosphates.
[0033] Particles of the invention are suitable for delivering
L-Dopa to the pulmonary system. Particles administered to the
respiratory tract travel through the upper airways (oropharynx and
larynx), the lower airways which include the trachea followed by
bifurcations into the bronchi and bronchioli and through the
terminal bronchioli which in turn divide into respiratory
bronchioli leading then to the ultimate respiratory zone, the
alveoli or the deep lung. The particles can be engineered such that
most of the mass of particles deposits in the deep lung or
alveoli.
[0034] The particles of the invention can be administered as part
of a pharmaceutical formulation or in combination with other
therapies be they oral, pulmonary, by injection or other mode of
administration. As described herein, particularly useful pulmonary
formulations are spray dried particles having physical
characteristics which favor target lung deposition and are
formulated to optimize release and bioavailability profiles.
[0035] The particles of the invention can be employed in
compositions suitable for drug delivery to the pulmonary system.
For example, such compositions can include the particles and a
pharmaceutically acceptable carrier for administration to a
patient, preferably for administration via inhalation.
[0036] The particles of the invention are useful for delivery of
L-Dopa to the pulmonary system, in particular to the deep lung. The
particles are in the form of a dry powder and are characterized by
a fine particle fraction (FPF), geometric and aerodynamic
dimensions and by other properties, as further described below.
[0037] Gravimetric analysis, using Cascade impactors, is a method
of measuring the size distribution of airborne particles. The
Andersen Cascade Impactor (ACI) is an eight-stage impactor that can
separate aerosols into nine distinct fractions based on aerodynamic
size. The size cutoffs of each stage are dependent upon the flow
rate at which the ACI is operated. Preferably the ACI is calibrated
at 60 L/min.
[0038] In one embodiment, a two-stage collapsed ACI is used for
particle optimization. The two-stage collapsed ACI consists of
stages 0, 2 and F of the eight-stage ACI and allows for the
collection of two separate powder fractions. At each stage an
aerosol stream passes through the nozzles and impinges upon the
surface. Particles in the aerosol stream with a large enough
inertia will impact upon the plate. Smaller particles that do not
have enough inertia to impact on the plate will remain in the
aerosol stream and be carried to the next stage.
[0039] The ACI is calibrated so that the fraction of powder that is
collected on a first stage is referred to as fine particle fraction
FPF (5.6). This FPF corresponds to the % of particles that have an
aerodynamic diameter of less than 5.6 .mu.m. The fraction of powder
that passed the first stage of the ACI and is deposited on the
collection filter is referred to as FPF(3.4). This corresponds to
the % of particles having an aerodynamic diameter of less than 3.4
.mu.m.
[0040] The FPF (5.6) fraction has been demonstrated to correlate to
the fraction of the powder that is deposited in the lungs of the
patient, while the FPF(3.4) has been demonstrated to correlate to
the fraction of the powder that reaches the deep lung of a
patient.
[0041] The FPF of at least 50% of the particles of the invention is
less than about 5.6 .mu.m. For example, but not limited to, the FPF
of at least 60%, or 70%, or 80%, or 90% of the particles is less
than about 5.6 .mu.m.
[0042] Another method for measuring the size distribution of
airborne particles is the multi-stage liquid impinger (MSLI). The
Multi-stage liquid Impinger (MSLI) operates on the same principles
as the Anderson Cascade Impactor (ACI), but instead of eight stages
there are five in the MSLI. Additionally, instead of each stage
consisting of a solid plate, each MSLI stage consists of an
methanol-wetted glass frit. The wetted stage is used to prevent
bouncing and re-entrainment, which can occur using the ACI. The
MSLI is used to provide an indication of the flow rate dependence
of the powder. This can be accomplished by operating the MSLI at
30, 60, and 90 L/min and measuring the fraction of the powder
collected on stage 1 and the collection filter. If the fractions on
each stage remain relatively constant across the different flow
rates then the powder is considered to be approaching flow rate
independence.
[0043] The particles of the invention have a tap density of less
than about 0.4 g/cm.sup.3. Particles which have a tap density of
less than about 0.4 g/cm.sup.3 are referred to herein as
"aerodynamically light particles". For example, the particles have
a tap density less than about 0.3 g/cm.sup.3, or a tap density less
than about 0.2 g/cm.sup.3, a tap density less than about 0.1
g/cm.sup.3. Tap density can be measured by using instruments known
to those skilled in the art such as the Dual Platform
Microprocessor Controlled Tap Density Tester (Vankel, NC) or a
GEOPYCTM instrument (Micrometrics Instrument Corp., Norcross, Ga.
30093). Tap density is a standard measure of the envelope mass
density. Tap density can be determined using the method of USP Bulk
Density and Tapped Density, United States Pharmacopia convention,
Rockville, Md, 10.sup.th Supplement, 4950-4951, 1999. Features
which can contribute to low tap density include irregular surface
texture and porous structure.
[0044] The envelope mass density of an isotropic particle is
defined as the mass of the particle divided by the minimum sphere
envelope volume within which it can be enclosed. In one embodiment
of the invention, the particles have an envelope mass density of
less than about 0.4 g/cm.sup.3.
[0045] The particles of the invention have a preferred size, e.g.,
a volume median geometric diameter (VMGD) of at least about 1
micron (.mu.m). In one embodiment, the VMGD is from about 1 .mu.m
to 30 .mu.m, or any subrange encompassed by about 1 .mu.m to 30
.mu.m, for example, but not limited to, from about 5 .mu.m to about
30 .mu.m, or from about 10 .mu.m to 30 .mu.m. For example, the
particles have a VMGD ranging from about 1 .mu.m to 10 .mu.m, or
from about 3 .mu.m to 7 .mu.m, or from about 5 .mu.m to 15 .mu.m or
from about 9 .mu.m to about 30 .mu.m. The particles have a median
diameter, mass median diameter (MMD), a mass median envelope
diameter (MMED) or a mass median geometric diameter (MMGD) of at
least 1 .mu.m, for example, 5 .mu.m or near to or greater than
about 10 .mu.m. For example, the particles have a MMGD greater than
about 1 .mu.m and ranging to about 30 .mu.m, or any subrange
encompassed by about 1 .mu.m to 30 .mu.m, for example, but not
limited to, from about 5 .mu.m to 30 .mu.m or from about 10 .mu.m
to about 30 .mu.m.
[0046] The diameter of the spray-dried particles, for example, the
VMGD, can be measured using a laser diffraction instrument (for
example Helos, manufactured by Sympatec, Princeton, N.J.). Other
instruments for measuring particle diameter are well know in the
art. The diameter of particles in a sample will range depending
upon factors such as particle composition and methods of synthesis.
The distribution of size of particles in a sample can be selected
to permit optimal deposition to targeted sites within the
respiratory tract.
[0047] Aerodynamically light particles preferably have "mass median
aerodynamic diameter" (MMAD), also referred to herein as
"aerodynamic diameter", between about 1 .mu.m and about 5 .mu.m or
any subrange encompassed between about 1 .mu.m and about 5 .mu.m.
For example, but not limited to, the MMAD is between about 1 .mu.m
and about 3 .mu.m, or the MMAD is between about 3 .mu.m and about 5
.mu.m.
[0048] Experimentally, aerodynamic diameter can be determined by
employing a gravitational settling method, whereby the time for an
ensemble of particles to settle a certain distance is used to infer
directly the aerodynamic diameter of the particles. An indirect
method for measuring the mass median aerodynamic diameter (MMAD) is
the multi-stage liquid impinger (MSLI).
[0049] The aerodynamic diameter, 4, can be calculated from the
equation:
d.sub.aer=d.sub.g .rho..sub.tap
[0050] where d.sub.g is the geometric diameter, for example the
MMGD, and p is the powder density.
[0051] Particles which have a tap density less than about 0.4
g/cm.sup.3, median diameters of at least about 1 .mu.m, for eample,
at least about 5 .mu.m, and an aerodynamic diameter of between
about 1 .mu.m and about 5 .mu.m, preferably between about 1 .mu.m
and about 3 .mu.m, are more capable of escaping inertial and
gravitational deposition in the oropharyngeal region, and are
targeted to the airways, particularly the deep lung. The use of
larger, more porous particles is advantageous since they are able
to aerosolize more efficiently than smaller, denser aerosol
particles such as those currently used for inhalation
therapies.
[0052] In comparison to smaller, relatively denser particles the
larger aerodynamically light particles, preferably having a median
diameter of at least about 5 .mu.m, also can potentially more
successfully avoid phagocytic engulfment by alveolar macrophages
and clearance from the lungs, due to size exclusion of the
particles from the phagocytes' cytosolic space. Phagocytosis of
particles by alveolar macrophages diminishes precipitously as
particle diameter increases beyond about 3 .mu.m. Kawaguchi, H., et
al., Biomaterials, 7: 61-66 (1986); Krenis, L. J. and Strauss, B.,
Proc. Soc. Exp. Med., 107: 748-750 (1961); and Rudt, S. and Muller,
R. H., J. Contr. Rel., 22: 263-272 (1992). For particles of
statistically isotropic shape, such as spheres with rough surfaces,
the particle envelope volume is approximately equivalent to the
volume of cytosolic space required within a macrophage for complete
particle phagocytosis.
[0053] The particles may be fabricated with the appropriate
material, surface roughness, diameter and tap density for localized
delivery to selected regions of the respiratory tract such as the
deep lung or upper or central airways. For example, higher density
or larger particles may be used for upper airway delivery, or a
mixture of varying sized particles in a sample, provided with the
same or different therapeutic agent may be administered to target
different regions of the lung in one administration. Particles
having an aerodynamic diameter ranging from about 3 to about 5
.mu.m are preferred for delivery to the central and upper airways.
Particles having and aerodynamic diameter ranging from about 1 to
about 3 .mu.m are preferred for delivery to the deep lung.
[0054] Inertial impaction and gravitational settling of aerosols
are predominant deposition mechanisms in the airways and acini of
the lungs during normal breathing conditions. Edwards, D. A., J.
Aerosol Sci., 26: 293-317 (1995). The importance of both deposition
mechanisms increases in proportion to the mass of aerosols and not
to particle (or envelope) volume. Since the site of aerosol
deposition in the lungs is determined by the mass of the aerosol
(at least for particles of mean aerodynamic diameter greater than
approximately 1 .mu.m), diminishing the tap density by increasing
particle surface irregularities and particle porosity permits the
delivery of larger particle envelope volumes into the lungs, all
other physical parameters being equal.
[0055] The low tap density particles have a small aerodynamic
diameter in comparison to the actual envelope sphere diameter. The
aerodynamic diameter, d.sub.aer, is related to the envelope sphere
diameter, d (Gonda, I., "Physico-chemical principles in aerosol
delivery," in Topics in Pharmaceutical Sciences 1991 (eds. D. J. A.
Crommelin and K. K. Midha), pp. 95-117, Stuttgart: Medpharm
Scientific Publishers, 1992)), by the formula:
d.sub.aer=d .rho.
[0056] where the envelope mass_is in units of g/cm.sup.3. Maximal
deposition of monodispersed aerosol particles in the alveolar
region of the human lung (.about.60%) occurs for an aerodynamic
diameter of approximately d.sub.aer=3 .mu.m. Heyder, J. et al., J.
Aerosol Sci., 17: 811-825 (1986). Due to their small envelope mass
density, the actual diameter d of aerodynamically light particles
comprising a monodisperse inhaled powder that will exhibit maximum
deep-lung deposition is:
d=3/ .rho..mu.m (where .rho..sub.--<1 g/cm.sup.3);
[0057] where d is always greater than 3 .mu.m. For example,
aerodynamically light particles that display an envelope mass
density, .mu.=0.1 g/cm.sup.3, will exhibit a maximum deposition for
particles having envelope diameters as large as 9.5 .mu.m. The
increased particle size diminishes interparticle adhesion forces.
Visser, J., Powder Technology, 58: 1-10. Thus, large particle size
increases efficiency of aerosolization to the deep lung for
particles of low envelope mass density, in addition to contributing
to lower phagocytic losses.
[0058] The aerodynamic diameter can be calculated to provide for
maximum deposition within the lungs. Previously this was achieved
by the use of very small particles of less than about five microns
in diameter, preferably between about one and about three microns,
which are then subject to phagocytosis. Selection of particles
which have a larger diameter, but which are sufficiently light
(hence the characterization "aerodynamically light"), results in an
equivalent delivery to the lungs, but the larger size particles are
not phagocytosed. Improved delivery can be obtained by using
particles with a rough or uneven surface relative to those with a
smooth surface.
[0059] In another embodiment of the invention, the particles have
an envelope mass density, also referred to herein as "mass density"
of less than about 0.4 g/cm.sup.3. Mass density and the
relationship between mass density, mean diameter and aerodynamic
diameter are discussed in U.S. Pat. No. 6,254,854, issued on Jul.
3, 2001, to Edwards, et al., which is incorporated herein by
reference in its entirety.
[0060] The invention also is related to producing particles that
have compositions and aerodynamic properties described above. The
method includes spray drying. Generally, spray-drying techniques
are described, for example, by K. Masters in "Spray Drying
Handbook", John Wiley & Sons, New York, 1984.
[0061] The present invention is related to a method for preparing a
dry powder composition. In this method, first and second components
are prepared, one of which comprises an active agent. For example,
the first component comprises an active agent dissolved in an
aqueous solvent, and the second component comprises an excipient
dissolved in an organic solvent. The first and second components
are combined either directly or through a static mixer to form a
combination. The first and second components are such that
combining them causes degradation in one of the components. For
example, the active agent is incompatible with the other component.
In such a method, the incompatible active agent is added last. The
combination is atomized to produce droplets that are dried to form
dry particles. In one aspect of this method, the atomizing step is
performed immediately after the components are combined in the
static mixer.
[0062] Suitable organic solvents that can be present in the mixture
being spray dried include, but are not limited to, alcohols for
example, ethanol, methanol, propanol, isopropanol, butanols, and
others. Other organic solvents include, but are not limited to,
perfluorocarbons, dichloromethane, chloroform, ether, ethyl
acetate, methyl tert-butyl ether and others. Aqueous solvents that
can be present in the feed mixture include water and buffered
solutions. Both organic and aqueous solvents can be present in the
spray-drying mixture fed to the spray dryer. In one embodiment, an
ethanol/water solvent is preferred with the ethanol:water ratio
ranging from about 20:80 to about 80:20. The mixture can have an
acidic or alkaline pH. Optionally, a pH buffer can be included.
Preferably, the pH can range from about 3 to about 10, for example,
from about 6 to about 8.
[0063] A method for preparing a dry powder composition is provided.
In such a method, a first phase is prepared that comprises L-Dopa
and trehalose and optionally salts. A second phase is prepared that
comprises ethanol. The first and second phases are combined in a
static mixer to form a combination. The combination is atomized to
produce droplets that are dried to form dry particles. In an
Alternative, only the first phase is prepared and atomized to
produce droplets that are dried to form dry particles.
[0064] A method for preparing a dry powder composition is provided.
In such a method, a first phase is prepared that comprises L-Dopa
and optionally salts. A second phase is prepared that comprises
DPPC in ethanol. The first and second phases are combined in a
static mixer to form a combination. The combination is atomized to
produce droplets that are dried to form dry particles.
[0065] An apparatus for preparing a dry powder composition is
provided. The apparatus includes a static mixer (e.g., a static
mixer as more fully described in U.S. Pat. No. 4,511,258, the
entirety of which is incorporated herein by reference, or other
suitable static mixers such as, but not limited to, model 1/4-21,
made by Koflo Corporation) having an inlet end and an outlet end.
The static mixer is operative to combine an aqueous component with
an organic component to form a combination. Means are provided for
transporting the aqueous component and the organic component to the
inlet end of the static mixer. An atomizer is in fluid
communication with the outlet end of the static mixer to atomize
the combination into droplets. The droplets are dried in a dryer to
form dry particles. The atomizer can be a rotary atomizer. Such a
rotary atomizer may be vaneless, or may contain a plurality of
vanes. Alternatively, the atomizer can be a two-fluid mixing
nozzle. Such a two-fluid mixing nozzle may be an internal mixing
nozzle or an external mixing nozzle. The means for transporting the
aqueous and organic components can be two separate pumps, or a
single pump. The aqueous and organic components are transported to
the static mixer at substantially the same rate. The apparatus can
also include a geometric particle sizer that determines a geometric
diameter of the dry particles, and an aerodynamic particle sizer
that determines an aerodynamic diameter of the dry particles.
[0066] The aqueous solvent and the organic solvent that make up the
L-Dopa solution are combined either directly or through a static
mixer. The L-Dopa solution is then transferred to the rotary
atomizer (aka spray dryer) at a flow rate of about 5 to 28 g/min
(mass) and about 6 to 80 ml/min (volumetric). For example, the
L-Dopa solution is transferred to the spray drier at a flow rate of
30 g/min and 31 ml/min. The 2-fluid nozzle disperses the liquid
solution into a spray of fine droplets which come into contact with
a heated drying air or heated drying gas (e.g., Nitrogen) under the
following conditions.
[0067] The pressure within the nozzle is from about 10 psi to 100
psi; the heated air or gas has a feed rate of about 80 to 110 kg/hr
and an atomization flow rate of about 13 to 67 g/min (mass) and a
liquid feed of 10 to 70 ml/min (volumetric); a gas to liquid ratio
from about 1:3 to 6:1; an inlet temperature from about 90.degree.
C. to 150.degree. C.; an outlet temperature from about 40.degree.
C. to 71.degree. C.; a baghouse outlet temperature from about
42.degree. C. to 55.degree. C. For example, but not limited to, the
pressure within the nozzle is set at 75 psi; the heated gas has a
feed rate of 95 kg/hr; and an atomizer gas flow rate of 22.5 g/min
and a liquid feed rate of 70 ml/min; the gas to liquid ratio is
1:3; the inlet temperature is 121.degree. C.; the outlet
temperature is 48.degree. C.; the baghouse temperature is
43.degree. C.
[0068] The contact between the heated nitrogen and the liquid
droplets causes the liquid to evaporate and porous particles to
result. The resulting gas-solid stream is fed to the product
filter, which retains the fine solid particles and allows that hot
gas stream, containing the drying gas, evaporated water and
ethanol, to pass. The formulation and spray drying parameters are
manipulated to obtain particles with desirable physical and
chemical characteristics. Other spray-drying techniques are well
known to those skilled in the art. An example of a suitable spray
dryer using rotary atomization includes the Mobile Niro spray
dryer, manufactured by Niro, Denmark. The hot gas can be, for
example, air, nitrogen, carbon dioxide or argon.
[0069] The particles of the invention are obtained by spray drying
using an inlet temperature between about 90.degree. C. and about
150.degree. C. and an outlet temperature between about 40.degree.
C. and about 70.degree. C.
[0070] The particles can be fabricated with a rough surface texture
to reduce particle agglomeration and improve flowability of the
powder. The spray-dried particles have improved aerosolization
properties. The spray-dried particle can be fabricated with
features which enhance aerosolization via dry powder inhaler
devices, and lead to lower deposition in the mouth, throat and
inhaler device.
[0071] Methods and apparatus suitable for forming particles of the
present invention are described in U.S. Patent Application entitled
"Method and Apparatus for Producing Dry Particles", filed
concurrently herewith under Attorney Docket No. 00166.0115-US01,
which is a Continuation-in-part of U.S. patent application Ser. No.
10/101,563 entitled "Method and Apparatus for Producing Dry
Particles", filed on Mar. 20, 2002, under the Attorney Docket No.
00166.0115-US00. Methods and apparatus suitable for forming
particles of the present invention are described in PCT Patent
Application entitled "Method and Apparatus for Producing Dry
Particles", filed concurrently herewith under Attorney Docket No
00166.0115-WO01. The entire contents of these applications are
incorporated by reference herein.
[0072] Administration of particles to the respiratory system can be
by means such as known in the art. For example, particles are
delivered from an inhalation device such as a dry powder inhaler
(DPI). Metered-dose-inhalers (MDI), nebulizers or instillation
techniques also can be employed.
[0073] Various suitable devices and methods of inhalation which can
be used to administer particles to a patient's respiratory tract
are known in the art. For example, suitable inhalers are described
in U.S. Pat. No. 4,069,819, issued Aug. 5, 1976 to Valentini, et
al., U.S. Pat. No.4,995,385 issued Feb. 26, 1991 to Valentini, et
al., and U.S. Pat. No. 5,997,848 issued Dec. 7, 1999 to Patton, et
al. Other examples include, but are not limited to, the
SPINHALER.RTM. (Fisons, Loughborough, U.K.), ROTAHALER.RTM.
(Glaxo-Wellcome, Research Triangle Technology Park, North
Carolina), FLOWCAPS.RTM. (Hovione, Loures, Portugal),
INHALATOR.RTM. (Boehringer-Ingelheim, Germany), and the
AEROLIZER.RTM. (Novartis, Switzerland), the diskhaler
(Glaxo-Wellcome, RTP, NC) and others, such as known to those
skilled in the art. In one embodiment, the inhaler employed is
described in U.S. patent application Ser. No. 09/835,302, entitled
"Inhalation Device and Method", by David A. Edwards, et al., filed
on Apr. 16, 2001 under Attorney Docket No. 00166.0109.US00 and in
U.S. patent application Ser. No. 10/268,059, entitled "Inhalation
Device and Method", by David A. Edwards, et al., filed on Oct. 10,
2002. The entire contents of these applications are incorporated by
reference herein.
[0074] Delivery to the pulmonary system of particles is by the
methods described in U.S. Patent Application, "High Efficient
Delivery of a Large Therapeutic Mass Aerosol", application Ser. No.
09/591,307, filed Jun. 9, 2000, and U.S. Patent Application,
"Highly Efficient Delivery of A Large Therapeutic Mass Aerosol",
application Ser. No. 09/878,146, filed Jun. 8, 2001. The entire
contents of both these applications are incorporated herein by
reference. As disclosed therein, particles are held, contained,
stored or enclosed in a receptacle. The receptacle, e.g. capsule or
blister, has a volume of at least about 0.37cm.sup.3 and can have a
design suitable for use in a dry powder inhaler. Larger receptacles
having a volume of at least about 0.48 cm.sup.3, 0.67 cm.sup.3 or
0.95 cm.sup.3 also can be employed.
[0075] The methods of the invention also relate to administering to
the respiratory tract of a subject, particles and/or compositions
comprising the particles of the invention, which can be enclosed in
a receptacle. As described herein, the invention is drawn to
methods of delivering the particles of the invention, or the
invention is drawn to methods of delivering respirable compositions
comprising the particles of the invention. As used herein, the term
"receptacle" includes but is not limited to, for example, a
capsule, blister, film covered container well, chamber and other
suitable means of storing particles, a powder or a respirable
composition in an inhalation device known to those skilled in the
art. Receptacles containing the pharmaceutical composition are
stored 2-8.degree. C.
[0076] The invention is also drawn to receptacles which are
capsules, for example, capsules designated with a particular
capsule size, such as 2, 1, 0, 00 or 000. Suitable capsules can be
obtained, for example, from Shionogi (Rockville, MD). Blisters can
be obtained, for example, from Hueck Foils, (Wall, NJ). Other
receptacles and other volumes thereof suitable for use in the
instant invention are known to those skilled in the art.
[0077] In a specific example, dry powder from a dry powder inhaler
receptacle, e.g., capsule, holding 25 mg nominal powder dose having
at 95% L-Dopa load, i.e., 23.75 mg L-Dopa, could be administered in
a single breath. Based on a conservative 4-fold dose advantage, the
23.75 mg delivered in one breath would be the equivalent of about
95 mg of L-Dopa required in oral administration. Several such
capsules can be employed to deliver higher doses of L-Dopa. For
instance a size 4 capsule can be used to deliver 50 mg of L-Dopa to
the pulmonary system to replace (considering the same conservative
4-fold dose advantage) a 200 mg oral dose.
[0078] The invention further is related to methods for
administering to the pulmonary system a therapeutic dose of the
medicament in a small number of steps, and preferably in a single,
breath activated step. The invention also is related to methods of
delivering a therapeutic dose of a drug to the pulmonary system, in
a small number of breaths, and preferably in one or two single
breaths. The method includes administering particles from a
receptacle having, holding, containing, storing or enclosing a mass
of particles, to a subject's respiratory tract.
[0079] In one example, at least 80% of the mass of the particles
stored in the inhaler receptacle is delivered to a subject's
respiratory system in a single, breath-activated step. In another
embodiment, at least 1 milligram of L-Dopa is delivered by
administering, in a single breath, to a subject's respiratory tract
particles enclosed in the receptacle. Preferably at least 10
milligrams of L-Dopa is delivered to a subject's respiratory tract.
Amounts as high as 15, 20, 25, 30, 35, 40 and 50 milligrams can be
delivered.
[0080] Delivery to the pulmonary system of particles in a single,
breath-actuated step is enhanced by employing particles which are
dispersed at relatively low energies, such as, for example, at
energies typically supplied by a subject's inhalation. Such
energies are referred to herein as "low." As used herein, "low
energy administration" refers to administration wherein the energy
applied to disperse and/or inhale the particles is in the range
typically supplied by a subject during inhaling.
[0081] The invention also is related to methods for efficiently
delivering powder particles to the pulmonary system. For example,
but not limited to, at least about 70% or at least about 80% of the
nominal powder dose is actually delivered. As used herein, the term
"nominal powder dose" is the total amount of powder held in a
receptacle, such as employed in an inhalation device. As used
herein, the term nominal drug dose is the total amount of
medicament contained in the nominal amount of powder. The nominal
powder dose is related to the nominal drug dose by the load percent
of drug in the powder.
[0082] Properties of the particles enable delivery to patients with
highly compromised lungs where other particles prove ineffective
for those lacking the capacity to strongly inhale, such as young
patients, old patients, infirm patients, or patients with asthma or
other breathing difficulties. Further, patients suffering from a
combination of ailments may simply lack the ability to sufficiently
inhale. Thus, using the methods and particles for the invention,
even a weak inhalation is sufficient to deliver the desired dose.
This is particularly important when using the particles of the
instant invention as rescue therapy for a patient suffering from
debilitating illness of Parkinson's disease.
[0083] Aerosol dosage, formulations and delivery systems may be
selected for a particular therapeutic application, as described,
for example, in Gonda, I. "Aerosols for delivery of therapeutic and
diagnostic agents to the respiratory tract," in Critical Reviews in
Therapeutic Drug Carrier Systems, 6: 273-313, 1990; and in Moren,
"Aerosol dosage forms and formulations," in: Aerosols in Medicine.
Principles, Diagnosis and Therapy, Moren, et al., Eds, Esevier,
Amsterdam, 1985.
[0084] The method of the invention includes delivering to the
pulmonary system an effective amount of a medicament such as, for
example, a medicament described above. As used herein, the term
"effective amount" means the amount needed to achieve the desired
effect or efficacy. The actual effective amounts of drug can vary
according to the specific drug or combination thereof being
utilized, the particular composition formulated, the mode of
administration, and the age, weight, condition of the patient, and
severity of the episode being treated. In the case of a dopamine
precursor, agonist or combination thereof it is an amount which
reduces the Parkinson's symptoms which require therapy. Dosages for
a particular patient are described herein and can be determined by
one of ordinary skill in the art using conventional considerations,
(e.g. by means of an appropriate, conventional pharmacological
protocol). For example, effective amounts of oral L-Dopa range from
about 50 milligrams (mg) to about 500 mg. In many instances, a
common ongoing (oral) L-Dopa treatment schedule is 100 mg eight (8)
times a day.
[0085] It has been discovered in this invention that pulmonary
delivery of L-Dopa doses, when normalized for body weight, result
in at least a 2-fold increase in plasma level as well as in
therapeutical advantages in comparison with oral administration.
Significantly higher plasma levels and therapeutic advantages are
possible in comparison with oral administration. In one example,
pulmonary delivery of L-Dopa results in a plasma level increase
ranging from about 2-fold to about 10-fold when compared to oral
administration. Plasma levels that approach or are similar to those
obtained with intravenous administration can be obtained.
[0086] Assuming that bioavailability remains the same as dosage is
increased, the amount of oral drug, e.g. L-Dopa, required to
achieve plasma levels comparable to those resulting from pulmonary
delivery by the methods of the invention can be determined at a
given point after administration. In a specific example, the plasma
levels 2 minutes after oral and administration by the methods of
the invention, respectively, are 1 .mu.g/m1L-Dopa and 5
.mu.g/m1L-Dopa. Thus 5 times the oral dose would be needed to
achieve the 5 .mu.g/ml level obtained by administering the drug
using the methods of the invention. In another example, the L-Dopa
plasma levels at 120 minutes after administration are twice as high
with the methods of the invention when compared to oral
administration. Thus twice as much L-Dopa is required after
administration 1 .mu.g/ml following oral administration in
comparison to the amount administered using the methods of the
invention.
[0087] To obtain a given drug plasma concentration, at a given time
after administration, less drug is required when the drug is
delivered by the methods of the invention than when it is
administered orally. Generally, at least a two-fold dose reduction
can be employed in the methods of the invention in comparison to
the dose used in conventional oral administration. A much higher
dose reduction is possible. In one embodiment of the invention, a
five fold reduction in dose is employed and reductions as high as
about ten fold can be used in comparison to the oral dose.
[0088] At least a two-fold dose reduction also is employed in
comparison to other routes of administration, other than
intravenous, such as, for example, intramuscular, subcutaneous,
buccal, nasal, intra-peritoneal, and rectal.
[0089] In addition or alternatively to the pharmacokinetic effect,
(e.g., serum level, dose advantage) described above, the dose
advantage resulting from the pulmonary delivery of a drug, e.g.,
L-Dopa, used to treat Parkinson's disease, also can be described in
terms of a pharmacodynamic response. Compared to the oral route,
the methods of the invention avoid inconsistent medicament uptake
by intestines, avoidance of delayed uptake following eating,
avoidance of first pass catabolism of the drug in the circulation
and rapid delivery from lung to brain via aortic artery.
[0090] Preferably, the effective amount is delivered on the "first
pass" of the blood to the site of action. The "first pass" is the
first time the blood carries the drug to and within the target
organ from the point at which the drug passes from the lung to the
vascular system. Generally, L-Dopa is released in the blood stream
and delivered to its site of action within a time period which is
sufficiently short to provide therapy to the patient being treated.
In many cases, L-Dopa can reach the central nervous system in less
than about 10 minutes, often as quickly as two minutes and even
faster.
[0091] Preferably, the patient's symptoms abate within minutes and
generally no later than one hour. In one embodiment of the
invention, the release kinetics of the medicament are substantially
similar to the drug's kinetics achieved via the intravenous route.
In another embodiment of the invention, the T. of L-Dopa in the
blood stream ranges from about 1 to about 10 minutes. As used
herein, the term T. means the point at which levels reach a maximum
concentration. In many cases, the onset of treatment obtained by
using the methods of the invention is at least two times faster
than onset of treatment obtained with oral delivery. Significantly
faster treatment onset can be obtained. In one example, treatment
onset is from about 2 to about 10 times faster than that observed
with oral administration.
[0092] Particles and methods for delivering L-Dopa to the pulmonary
system are described in U.S. patent application Ser. No. 09/665,252
entitled "Pulmonary Delivery In Treating Disorders of the Central
Nervous System", filed on Sep. 19, 2000, now U.S. Pat. No.
6,514,482 issued on Jan. 4, 2003, and U.S. patent application Ser.
No. 09/877,734 entitled "Pulmonary Delivery In Treating Disorders
of the Central Nervous System", filed, Jun. 8, 2001; the contents
of both is incorporated herein by reference in their entirety.
[0093] If desired, particles which have fast release kinetics,
suitable in rescue therapy, can be combined with particles having
sustained release, suitable in treating the chronic aspects of a
condition. For example, in the case of Parkinson's disease,
particles designed to provide rescue therapy can be co-administered
with particles having controlled release properties.
[0094] The administration of more than one dopamine precursor,
agonist or combination thereof, in particular L-Dopa, carbidopa,
apomorphine, and other drugs can be provided, either simultaneously
or sequentially in time. Carbidopa, for example, is often
administered to ensure that peripheral carboxylase activity is
completely shut down. Intramuscular, subcutaneous, oral and other
administration routes can be employed. In one embodiment, these
other agents are delivered to the pulmonary system. These compounds
or compositions can be administered before, after or at the same
time. In a preferred embodiment, particles that are administered to
the respiratory tract include both L-Dopa and carbidopa. The term
"co-administration" is used herein to mean that the specific
dopamine precursor, agonist or combination thereof and/or other
compositions are administered at times to treat the episodes, as
well as the underlying conditions described herein.
[0095] In one embodiment chronic L-Dopa therapy includes pulmonary
delivery of L-Dopa combined with oral carbidopa. In another
embodiment, pulmonary delivery of L-Dopa is provided during the
episode, while chronic treatment can employ conventional oral
administration of L-Dopa/carbidopa.
[0096] The present invention will be further understood by
reference to the following non-limiting examples.
EXEMPLIFICATIONS
Preparation of Dry Particles Containing L-Dopa
Example 1
Particles Comprising L-Dopa and Trehalose
[0097] Particles with a formulation containing L-Dopa and trehalose
were prepared as follows:
[0098] The aqueous solution was formed by adding 2.375 g L-Dopa and
125 mg trehalose to 700 ml of USP water. The organic solution
comprised 300 ml of ethanol. The aqueous solution and the organic
solution were combined in a static mixer. A 1 L total combination
volume was used, with a total solute concentration of 2.5 g/L in
30/70 ethanol/water. The combined solution flowed from the static
mixer into a 2 fluid atomizer and the resulting atomized droplets
were spray dried under the following process conditions: [0099]
Inlet temperature .about.135.degree. C. [0100] Outlet temperature
from the drying drum .about.49 to 53.degree. C. [0101] Nitrogen
drying gas=95 kg/hr [0102] Atomization rate=14 g/min [0103] 2 Fluid
internal mixing nozzle atomizer [0104] Liquid feed rate=70 ml/min
[0105] Pressure in drying chamber=-2.0 in water
[0106] The resulting particles had a FPF(5.6) of 33%, and a
FPF(3.4) of 12%, both measured using a 2-stage ACI.
[0107] The combination solution flowing out of the static mixer was
fed into a rotary atomizer.
[0108] The contact between the atomized droplets from the atomizer
and the heated nitrogen caused the liquid to evaporate from the
droplets, resulting in dry porous particles. The resulting
gas-solid stream was fed to bag filter that retained the resulting
dry particles, and allowed the hot gas stream containing the drying
gas (nitrogen), evaporated water, and ethanol to pass. The dry
particles were collected into a product collection vessel.
[0109] In order to obtain dry particles of particular physical and
chemical characteristics, in vitro characterization tests can be
carried out on the finished dry particles, and the process
parameters adjusted accordingly, as described above. Particles
containing 95 wt % L-Dopa and 5 wt % trehalose were produced using
this method. In this manner, the desired aerodynamic diameter,
geometric diameter, and particle density could be obtained for
these particles in real-time, during the production process.
Example 2
Particles Comprising L-Dopa, Trehalose and Sodium Chloride
[0110] Particles with a formulation containing L-Dopa, trehalose
and sodium chloride were prepared as follows: The aqueous solution
was formed by adding 2.325 g L-Dopa, 125 mg trehalose and 50 mg
sodium chloride to 700 ml of USP water. The organic solution
comprised 300 ml of ethanol. The aqueous solution and the organic
solution were combined in a static mixer. A 1 L total combination
volume was used, with a total solute concentration of 2.5 g/L in
30/70 ethanol/water. The combined solution flowed from the static
mixer into a 2 fluid atomizer and the resulting atomized droplets
were spray dried under the following process conditions: [0111]
Inlet temperature .about.135.degree. C. [0112] Outlet temperature
from the drying drum .about.49 to 53.degree. C. [0113] Nitrogen
drying gas=95 kg/hr [0114] Atomization rate=14 g/min [0115] 2 Fluid
internal mixing nozzle atomizer [0116] Liquid feed rate=70 ml/min
[0117] Liquid feed temperature .about.50.degree. C. [0118] Pressure
in drying chamber=-2.0 in water
[0119] The resulting particles had a FPF(5.6) of 59%, and a
FPF(3.4) of 40%, both measured using a 2-stage ACI. The volume mean
geometric diameter was 17 .mu.m at 1.0 bar.
[0120] The combination solution flowing out of the static mixer was
fed into a 2-fluid atomizer. The contact between the atomized
droplets from the atomizer and the heated nitrogen caused the
liquid to evaporate from the droplets, resulting in dry porous
particles. The resulting gas-solid stream was fed to bag filter
that retained the resulting dry particles, and allowed the hot gas
stream containing the drying gas (nitrogen), evaporated water, and
ethanol to pass. The dry particles were collected into a product
collection vessel.
[0121] In order to obtain dry particles of particular physical and
chemical characteristics, in vitro characterization tests can be
carried out on the finished dry particles, and the process
parameters adjusted accordingly, as described above. Particles
containing 93 wt % L-Dopa, 5 wt % trehalose and 2 wt % sodium
chloride produced using this method had a VMGD of 17 .mu.m measured
by Rodos at 1 bar and a VMGD of 12 .mu.m at 2 bar, FPF(5.6) of 59%.
In this manner, the desired aerodynamic diameter, geometric
diameter, and particle density could be obtained for these
particles in real-time, during the production process.
Example 3
Particles Comprising L-Dopa and DPPC
[0122] Particles with a formulation containing L-Dopa and DPPC were
prepared as follows: The aqueous solution was formed by adding
1.1875 g L-Dopa to 300 ml of USP water. The organic solution
comprised 62.5 mg DPPC in 700 ml of ethanol. The aqueous solution
and the organic solution were combined in a static mixer. A 1 L
total combination volume was used, with a total solute
concentration of 1.25 g/L in 70/30 ethanol/water. The combined
solution flowed from the static mixer into a 2 fluid atomizer and
the resulting atomized droplets were spray dried under the
following process conditions: [0123] Inlet temperature
.about.108.degree. C. [0124] Outlet temperature from the drying
drum .about.49 to 53.degree. C. [0125] Nitrogen drying gas=95 kg/hr
[0126] Atomization rate=18 g/min [0127] 2 Fluid internal mixing
nozzle atomizer [0128] Liquid feed rate=70 ml/min [0129] Liquid
feed temperature .about.50.degree. C. [0130] Pressure in drying
chamber=-2.0 in water
[0131] The resulting particles had a FPF(5.6) of 29%, and a
FPF(3.4) of 10%, both measured using a 2-stage ACI. The volumetric
mean geometric diameter was 7.9 .mu.m at 1 bar.
[0132] The combination solution flowing out of the static mixer was
fed into a rotary atomizer. The contact between the atomized
droplets from the atomizer and the heated nitrogen caused the
liquid to evaporate from the droplets, resulting in dry porous
particles. The resulting gas-solid stream was fed to bag filter
that retained the resulting dry particles, and allowed the hot gas
stream containing the drying gas (nitrogen), evaporated water, and
ethanol to pass. The dry particles were collected into a product
collection vessel.
[0133] In order to obtain dry particles of particular physical and
chemical characteristics, in vitro characterization tests can be
carried out on the finished dry particles, and the process
parameters adjusted accordingly, as described above. Particles
containing 95 wt % L-Dopa and 5 wt % DPPC were produced using this
method. In this manner, the desired aerodynamic diameter, geometric
diameter, and particle density could be obtained for these
particles in real-time, during the production process.
Example 4
Particles Comprising L-Dopa, DPPC and Sodium Chloride
[0134] Particles with a formulation containing L-Dopa, DPPC and
sodium chloride were prepared as follows: The aqueous solution was
formed by adding 1.125 g L-Dopa and 25 mg sodium chloride to 300 ml
of USP water. The organic solution comprised 100 mg DPPC in 700 ml
of ethanol. The aqueous solution and the organic solution were
combined in a static mixer. A 1 L total combination volume was
used, with a total solute concentration of 1.25 g/L in 70/30
ethanol/water. The combined solution flowed from the static mixer
into a 2 fluid atomizer and the resulting atomized droplets were
spray dried under the following process conditions: [0135] Inlet
temperature .about.108.degree. C. [0136] Outlet temperature from
the drying drum .about.49 to 53.degree. C. [0137] Nitrogen drying
gas=95 kg/hr [0138] Atomization rate=18 g/min [0139] 2 Fluid
internal mixing nozzle atomizer [0140] Liquid feed rate=70 ml/min
[0141] Liquid feed temperature .about.50.degree. C. [0142] Pressure
in drying chamber=-2.0 in water
[0143] The resulting particles had a FPF(5.6) of 70%, and a
FPF(3.4) of 40%, both measured using a 2-stage ACI. The volume mean
geometric diameter was 14 .mu.m at 1.0 bar.
[0144] The combination solution flowing out of the static mixer was
fed into a rotary atomizer. The contact between the atomized
droplets from the atomizer and the heated nitrogen caused the
liquid to evaporate from the droplets, resulting in dry porous
particles. The resulting gas-solid stream was fed to bag filter
that retained the resulting dry particles, and allowed the hot gas
stream containing the drying gas (nitrogen), evaporated water, and
ethanol to pass. The dry particles were collected into a product
collection vessel.
[0145] In order to obtain dry particles of particular physical and
chemical characteristics, in vitro characterization tests can be
carried out on the finished dry particles, and the process
parameters adjusted accordingly, as described above. Particles
containing 90 wt % L-Dopa, 8 wt % DPPC and 2 wt % sodium chloride
produced using this method had a VMGD of 14 .mu.m measured by Rodos
at 1 bar and a VMGD of 11 .mu.m at 2 bar, FPF(5.6) of 70%. In this
manner, the desired aerodynamic diameter, geometric diameter, and
particle density could be obtained for these particles in
real-time, during the production process.
[0146] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *