U.S. patent application number 11/873467 was filed with the patent office on 2008-07-03 for use of simple amino acids to form porous particles.
This patent application is currently assigned to Advanced Inhalation Research, Inc.. Invention is credited to Richard P. Batycky, Michael M. Lipp, Ralph W. Niven.
Application Number | 20080160092 11/873467 |
Document ID | / |
Family ID | 23511119 |
Filed Date | 2008-07-03 |
United States Patent
Application |
20080160092 |
Kind Code |
A1 |
Batycky; Richard P. ; et
al. |
July 3, 2008 |
USE OF SIMPLE AMINO ACIDS TO FORM POROUS PARTICLES
Abstract
Particles having a tap density of less than 0.4 g/cm.sup.3
include a hydrophobic amino acid or salt thereof and a therapeutic,
prophylactic or diagnostic agent or any combination thereof.
Preferred particles include a phospholipid, have a median geometric
diameter between about 5 and about 30 microns and an aerodynamic
diameter between about 1 and about 5 microns. The particles can be
formed by spray-drying and are useful for delivery to the pulmonary
system.
Inventors: |
Batycky; Richard P.;
(Newton, MA) ; Lipp; Michael M.; (Framingham,
MA) ; Niven; Ralph W.; (Half Moon Bay, CA) |
Correspondence
Address: |
ELMORE PATENT LAW GROUP, PC
515 Groton Road, Unit 1R
Westford
MA
01886
US
|
Assignee: |
Advanced Inhalation Research,
Inc.
Cambridge
MA
|
Family ID: |
23511119 |
Appl. No.: |
11/873467 |
Filed: |
October 17, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11637353 |
Dec 12, 2006 |
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11873467 |
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09644320 |
Aug 23, 2000 |
7252840 |
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11637353 |
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09382959 |
Aug 25, 1999 |
6586008 |
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09644320 |
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Current U.S.
Class: |
424/489 ;
514/1.7; 514/1.8; 514/10.2; 514/10.3; 514/11.1; 514/11.4; 514/11.8;
514/11.9; 514/5.9 |
Current CPC
Class: |
A61K 9/0075 20130101;
A61K 47/183 20130101; A61K 9/0082 20130101; A61K 9/145 20130101;
A61K 9/1617 20130101; A61K 31/137 20130101; A61P 11/06 20180101;
A61P 11/00 20180101; A61K 31/685 20130101 |
Class at
Publication: |
424/489 ;
514/2 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 38/00 20060101 A61K038/00 |
Claims
1. A method of preparing particles having a tap density less than
0.4 g/cm.sup.3 comprising: (a) forming a mixture including a
therapeutic, prophylactic or diagnostic agent, or any combination
thereof, and an amino acid or a salt thereof; and (b) spray-drying
said mixture to produce particles having a tap density less than
about 0.4 g/cm.sup.3.
2. The method of claim 1, wherein the particles have a median
geometric diameter of between about 5 micrometers and about 30
micrometers.
3. The method of claim 1, wherein the particles have an aerodynamic
diameter of between about 1 and about 5 microns.
4. The method of claim 3, wherein the particles have an aerodynamic
diameter of between about 1 and about 3 microns.
5. The method of claim 3, wherein the particles have an aerodynamic
diameter of between about 3 and 5 microns.
6. The method of claim 1, wherein the amino acid is
hydrophobic.
7. The method of claim 6, wherein the hydrophobic amino acid is
selected form the group consisting of leucine, isoleucine, alanine,
valine, phenylalanine and any combination thereof.
8. The method of claim 3, wherein the hydrophobic amino acid is
present in the particles in an amount of at least 10% weight.
9. The method of claim 1, wherein the therapeutic, prophylactic or
diagnostic agent is present in the particles in an amount ranging
from about 1 to about 90% weight.
10. The method of claim 1, wherein the mixture comprises a
surfactant.
11. The method of claim 1, wherein the mixture comprises a
phospholipid.
12. The method of claim 11, wherein the phospholipid is endogenous
to the lung.
13. The method of claim 11, wherein the phospholipid is selected
from the group consisting of phosphatidylcholines,
phosphatidylethanolamines, phosphatidylglycerols,
phosphatidylserines, phosphatidylinositols and combinations
thereof.
14. The method of claim 1, wherein the mixture comprises an organic
solvent.
15. The method of claim 1, wherein the mixture comprises a
co-solvent including an organic solvent and an aqueous solvent.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 11/637,353, filed on Dec. 12, 2006, which is a continuation of
U.S. application Ser. No. 09/644,320, filed Aug. 23, 2000, now U.S.
Pat. No. 7,252,840, which is a continuation-in-part of U.S. patent
application Ser. No. 09/382,959, filed Aug. 25, 1999, now U.S. Pat.
No. 6,586,008. The entire teachings of the above applications are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Aerosols for the delivery of therapeutic agents to the
respiratory tract have been described, for example, Adjei, A. and
Garren, J. Pharm. Res., 7: 565-569 (1990); and Zanen, P. and Lamm,
J.-W. J. Int. J. Pharm., 114: 111-115 (1995). The respiratory tract
encompasses the upper airways, including the oropharynx and larynx,
followed by the lower airways, which include the trachea followed
by bifurcations into the bronchi and bronchioli. The upper and
lower airways are called the conducting airways. The terminal
bronchioli then divide into respiratory bronchioli which then lead
to the ultimate respiratory zone, the alveoli, or deep lung. 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). The deep lung, or alveoli, are
the primary target of inhaled therapeutic aerosols for systemic
drug delivery.
[0003] Inhaled aerosols have been used for the treatment of local
lung disorders including asthma and cystic fibrosis (Anderson, Am.
Rev. Respir. Dis., 140: 1317-1324 (1989)) and have potential for
the systemic delivery of peptides and proteins as well (Patton and
Platz, Advanced Drug Delivery Reviews, 8: 179-196 (1992)). However,
pulmonary drug delivery strategies present many difficulties for
the delivery of macromolecules; these include protein denaturation
during aerosolization, excessive loss of inhaled drug in the
oropharyngeal cavity (often exceeding 80%), poor control over the
site of deposition, lack of reproducibility of therapeutic results
owing to variations in breathing patterns, the frequent too-rapid
absorption of drug potentially resulting in local toxic effects,
and phagocytosis by lung macrophages.
[0004] Considerable attention has been devoted to the design of
therapeutic aerosol inhalers to improve the efficiency of
inhalation therapies. Timsina et. al., Int. J. Pharm., 101: 1-13
(1995); and Tansey, I. P., Spray Technol. Market, 4: 26-29 (1994).
Attention has also been given to the design of dry powder aerosol
surface texture, regarding particularly the need to avoid particle
aggregation, a phenomenon which considerably diminishes the
efficiency of inhalation therapies. French, D. L., Edwards, D. A.
and Niven, R. W., J. Aerosol Sci., 27: 769-783 (1996). Dry powder
formulations ("DPFs") with large particle size have improved
flowability characteristics, such as less aggregation (Visser, J.,
Powder Technology, 58: 1-10 (1989)), easier aerosolization, and
potentially less phagocytosis. Rudt, S. and R. H. Muller, J.
Controlled Release, 22: 263-272 (1992); Tabata, Y. and Y. Ikada, J.
Biomed. Mater. Res., 22: 837-858 (1988). Dry powder aerosols for
inhalation therapy are generally produced with mean geometric
diameters primarily in the range of less than 5 .mu.m. Ganderton,
D., J. Biopharmaceutical Sciences, 3: 101-105 (1992); and Gonda, I.
"Physico-Chemical Principles in Aerosol Delivery," in Topics in
Pharmaceutical Sciences 1991, Crommelin, D. J. and K. K. Midha,
Eds., Medpharm Scientific Publishers, Stuttgart, pp. 95-115, 1992.
Large "carrier" particles (containing no drug) have been
co-delivered with therapeutic aerosols to aid in achieving
efficient aerosolization among other possible benefits. French, D.
L., Edwards, D. A. and Niven, R. W., J. Aerosol Sci., 27: 769-783
(1996).
[0005] The human lungs can remove or rapidly degrade hydrolytically
cleavable deposited aerosols over periods ranging from minutes to
hours. In the upper airways, ciliated epithelia contribute to the
"mucociliary escalator" by which particles are swept from the
airways toward the mouth. Pavia, D. "Lung Mucociliary Clearance,"
in Aerosols and the Lung: Clinical and Experimental Aspects,
Clarke, S. W. and Pavia, D., Eds., Butterworths, London, 1984.
Anderson, Am. Rev. Respir. Dis., 140: 1317-1324 (1989). In the deep
lungs, alveolar macrophages are capable of phagocytosing particles
soon after their deposition. Warheit, M. B. and Hartsky, M. A.,
Microscopy Res. Tech., 26: 412-422 (1993); Brain, J. D.,
"Physiology and Pathophysiology of Pulmonary Macrophages," in The
Reticuloendothelial System, S. M. Reichard and J. Filkins, Eds.,
Plenum, New York, pp. 315-327, 1985; Dorries, A. M. and Valberg, P.
A., Am. Rev. Resp. Disease 146: 831-837 (1991); and Gehr, P.,
Microscopy Res. and Tech., 26: 423-436 (1993). As the diameter of
particles exceeds 3 .mu.m, there is increasingly less phagocytosis
by macrophages. Kawaguchi, H., 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). However, increasing the particle size also has been found
to minimize the probability of particles (possessing standard mass
density) entering the airways and acini due to excessive deposition
in the oropharyngeal or nasal regions. Heyder, J., J. Aerosol Sci.,
17: 811-825 (1986).
[0006] Local and systemic inhalation therapies can often benefit
from a relatively slow controlled release of the therapeutic agent.
Gonda, I., "Physico-chemical principles in aerosol delivery," in:
Topics in Pharmaceutical Sciences 1991, D. J. A. Crommelin and K.
K. Midha, Eds., Stuttgart: Medpharm Scientific Publishers, pp.
95-117 (1992). Slow release from a therapeutic aerosol can prolong
the residence of an administered drug in the airways or acini, and
diminish the rate of drug appearance in the bloodstream. Also,
patient compliance is increased by reducing the frequency of
dosing. Langer, R., Science, 249: 1527-1533 (1990); and 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).
[0007] Controlled release drug delivery to the lung may simplify
the way in which many drugs are taken. Gonda, I., Adv. Drug Del.
Rev., 5: 1-9 (1990); and Zeng, X., et al., Int. J. Pharm., 124:
149-164 (1995). Pulmonary drug delivery is an attractive
alternative to oral, transdermal, and parenteral administration
because self-administration is simple, the lungs provide a large
mucosal surface for drug absorption, there is no first-pass liver
effect of absorbed drugs, and there is reduced enzymatic activity
and pH mediated drug degradation compared with the oral route.
Relatively high bioavailability of many molecules, including
macromolecules, can be achieved via inhalation. Wall, D. A., Drug
Delivery, 2: 1-20 1995); Patton, J. and Platz, R., Adv. Drug Del.
Rev., 8: 179-196 (1992); and Byron, P., Adv. Drug. Del. Rev., 5:
107-132 (1990). As a result, several aerosol formulations of
therapeutic drugs are in use or are being tested for delivery to
the lung. Patton, J. S., et al., J. Controlled Release, 28: 79-85
(1994); Damms, B. and Bains, W., Nature Biotechnology (1996);
Niven, R. W., et al., Pharm. Res., 12(9): 1343-1349 (1995); and
Kobayashi, S., et al., Pharm. Res., 13(1): 80-83 (1996).
[0008] Drugs currently administered by inhalation come primarily as
liquid aerosol formulations. However, many drugs and excipients,
especially proteins, peptides (Liu, R., et al, Biotechnol. Bioeng.,
37: 177-184 (1991)), and biodegradable carriers such as
poly(lactide-co-glycolides) (PLGA), are unstable in aqueous
environments for extended periods of time. This can make storage as
a liquid formulation problematic. In addition, protein denaturation
can occur during aerosolization with liquid formulations.
Mumenthaler, M., et al., Pharm. Res., 11: 12-20 (1994). Considering
these and other limitations, dry powder formulations (DPF's) are
gaining increased interest as aerosol formulations for pulmonary
delivery. Damms, B. and W. Bains, Nature Biotechnology (1996);
Kobayashi, S., et al., Pharm Res., 13(1): 80-83 (1996); and
Timsina, M., et al., Int. J. Pharm., 101: 1-13 (1994). However,
among the disadvantages of DPF's is that powders of ultrafine
particulates usually have poor flowability and aerosolization
properties, leading to relatively low respirable fractions of
aerosol, which are the fractions of inhaled aerosol that escape
deposition in the mouth and throat. Gonda, I., in Topics in
Pharmaceutical Sciences 1991, D. Crommelin and K. Midha, Editors,
Stuttgart: Medpharm Scientific Publishers, 95-117 (1992). A primary
concern with many aerosols is particulate aggregation caused by
particle-particle interactions, such as hydrophobic, electrostatic,
and capillary interactions.
[0009] An effective dry-powder inhalation therapy for both short
and long term release of therapeutics, either for local or systemic
delivery, requires a powder that displays minimum aggregation, as
well as a means of avoiding or suspending the lung's natural
clearance mechanisms until drugs have been effectively
delivered.
[0010] One formulation for dry powder pulmonary delivery involves
the separation of active particles from a carrier on actuation of
the inhaler. Due to blending requirements, preparing these powders
is associated with an increased number of steps. Furthermore, the
method of delivery of these powders is associated with several
disadvantages. For example, there are inefficiencies in the release
of active particles from the carrier. Moreover, the carrier takes
up significantly more volume than the active particle, thus high
drug doses are difficult to achieve. In addition, the large lactose
particles can impact the back of the throat, causing coughing.
[0011] Therefore, a need exists for dry-powders suitable for
inhalation which minimize or eliminate the above-mentioned
problems.
SUMMARY OF THE INVENTION
[0012] The invention relates to particles having a tap density of
less than about 0.4 g/cm.sup.3. The particles include an amino acid
or a salt thereof. In one embodiment, the particles include a
therapeutic, prophylactic or diagnostic agent or any combination
thereof. In another embodiment, the particles include a
phospholipid. In still another embodiment, the particles have a
median geometric diameter of between about 5 micrometers and about
30 micrometers. In a further embodiment, the particles have an
aerodynamic diameter of between about 1 and about 5 microns.
[0013] The invention also relates to a method of producing
particles having a tap density of less than about 0.4 g/cm.sup.3.
The method includes forming a mixture which includes a therapeutic,
prophylactic or diagnostic agent, or any combination thereof, and
an amino acid or a salt thereof and spray-drying the mixture to
form particles having a tap density of less than about 0.4
g/cm.sup.3. In one embodiment of the invention, the mixture
includes a phospholipid. In other embodiments, the mixture includes
an organic solvent or an organic-aqueous co-solvent.
[0014] The invention further relates to a method for drug delivery
to the pulmonary system. The method includes administering to the
respiratory tract of a patient in need of treatment, prophylaxis or
diagnosis an effective amount of particles having a tap density of
less than about 0.4 g/cm.sup.3. The particles include a
therapeutic, prophylactic or diagnostic agent, or any combination
thereof, and an amino acid or salt thereof In one embodiment, the
particles include a phospholipid. In another embodiment, delivery
to the respiratory system includes delivery to the deep lung. In
still another embodiment of the invention, delivery to the
respiratory system includes delivery to the central airways. In a
further embodiment of the invention, delivery to the respiratory
system includes delivery to the upper airways.
[0015] The invention relates also to a composition for drug
delivery to the pulmonary system. The composition includes
particles which incorporate a therapeutic, prophylactic or
diagnostic agent and an amino acid or salt thereof and which have a
tap density of less than about 0.4 g/cm.sup.3.
[0016] Preferred amino acids include hydrophobic amino acids.
Examples include but are not limited to leucine, isoleucine,
alanine, valine and phenylalanine. Other amino acids that can be
employed are amino acids which are insoluble in the solvent system
employed to form the particles.
[0017] Preferred phospholipids include but are not limited to
phosphatidic acid, phosphatidylcholines, phosphatidylethanolamines,
phosphatidylglycerols, phosphatidylserines, phosphatidylinositols
and combinations thereof
[0018] The invention has several advantages. For example, the
particles of the invention incorporate amino acids which, in the
amounts that are administered to the respiratory system of a
patient, are expected to be non-toxic. Furthermore, amino acids are
relatively inexpensive thus lowering overall particle manufacturing
costs. Still further, the invention is capable of conferring
extended release properties as well as improved formulability. In
contrast to methods in which active particles are released from the
carrier on actuation of the inhaler, the entire particles of the
invention go to the desired site of the pulmonary system. Drugs can
be delivered in higher doses and with higher efficiency. Lodging of
particle material in the back of the throat is avoided. The method
of forming particles can be carried out using simple, inexpensive
solvents which do not raise emission and solvent recovery concerns.
The method permits the use of Class 3 or better solvents.
Furthermore, the method requires less process steps than methods
employed to form powders which release active particles from the
carrier upon actuation of the inhaler.
DETAILED DESCRIPTION OF THE INVENTION
[0019] 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.
[0020] The invention is directed to particles having a tap density
of less than about 0.4 g/cm.sup.3 which include an amino acid or a
salt thereof and methods of producing such particles. The invention
is also directed to methods of delivering the particles to the
pulmonary system of a patient.
[0021] In a preferred embodiment the amino acid is hydrophobic.
Suitable hydrophobic amino acids include naturally occurring and
non-naturally occurring hydrophobic amino acids. Non-naturally
occurring amino acids include, for example, beta-amino acids, Both
D, L configurations and racemic mixtures of hydrophobic amino acids
can be employed. Suitable hydrophobic amino acids can also include
amino acid derivatives or analogs. As used herein, an amino acid
analog includes the D or L configuration of an amino acid having
the following formula: --NH--CHR--CO--, wherein R is an aliphatic
group, a substituted aliphatic group, a benzyl group, a substituted
benzyl group, an aromatic group or a substituted aromatic group and
wherein R does not correspond to the side chain of a
naturally-occurring amino acid. As used herein, aliphatic groups
include straight chained, branched or cyclic C1-C8 hydrocarbons
which are completely saturated, which contain one or two
heteroatoms such as nitrogen, oxygen or sulfur and/or which contain
one or more units of unsaturation. Aromatic groups include
carbocyclic aromatic groups such as phenyl and naphthyl and
heterocyclic aromatic groups such as imidazolyl, indolyl, thienyl,
furanyl, pyridyl, pyranyl, pyranyl, oxazolyl, benzothienyl,
benzofuranyl, quinolinyl, isoquinolinyl and acridintyl.
[0022] Suitable substituents on an aliphatic, aromatic or benzyl
group include --OH, halogen (--Br, --Cl, --I and --F)
--O(aliphatic, substituted aliphatic, benzyl, substituted benzyl,
aryl or substituted aryl group), --CN, --NO.sub.2, --COOH,
--NH.sub.2, --NH(aliphatic group, substituted aliphatic, benzyl,
substituted benzyl, aryl or substituted aryl group), --N(aliphatic
group, substituted aliphatic, benzyl, substituted benzyl, aryl or
substituted aryl group).sub.2, --COO(aliphatic group, substituted
aliphatic, benzyl, substituted benzyl, aryl or substituted aryl
group), --CONH.sub.2, --CONH(aliphatic, substituted aliphatic
group, benzyl, substituted benzyl, aryl or substituted aryl
group)), --SH, --S(aliphatic, substituted aliphatic, benzyl,
substituted benzyl, aromatic or substituted aromatic group) and
--NH--C(=NH)--NH.sub.2. A substituted benzylic or aromatic group
can also have an aliphatic or substituted aliphatic group as a
substituent. A substituted aliphatic group can also have a benzyl,
substituted benzyl, aryl or substituted aryl group as a
substituent. A substituted aliphatic, substituted aromatic or
substituted benzyl group can have one or more substituents.
Modifying an amino acid substituent can increase, for example, the
lypophilicity or hydrophobicity of natural amino acids which are
hydrophillic.
[0023] A number of the suitable amino acids, amino acids analogs
and salts thereof can be obtained commercially. Others can be
synthesized by methods known in the art. Synthetic techniques are
described, for example, in Green and Wuts, "Protecting Groups in
Organic Synthesis", John Wiley and Sons, Chapters 5 and 7,
1991.
[0024] Hydrophobicity is generally defined with respect to the
partition of an amino acid between a nonpolar solvent and water.
Hydrophobic amino acids are those acids which show a preference for
the nonpolar solvent. Relative hydrophobicity of amino acids can be
expressed on a hydrophobicity scale on which glycine has the value
0.5. On such a scale, amino acids which have a preference for water
have values below 0.5 and those that have a preference for nonpolar
solvents have a value above 0.5. As used herein, the term
hydrophobic amino acid refers to an amino acid that, on the
hydrophobicity scale has a value greater or equal to 0.5, in other
words, has a tendency to partition in the nonpolar acid which is at
least equal to that of glycine.
[0025] Examples of amino acids which can be employed include, but
are not limited to: glycine, proline, alanine, cysteine,
methionine, valine, leucine, tyrosine, isoleucine, phenylalanine,
tryptophan. Preferred hydrophobic amino acids include leucine,
isoleucine, alanine, valine, phenylalanine and glycine.
Combinations of hydrophobic amino acids can also be employed.
Furthermore, combinations of hydrophobic and hydrophilic
(preferentially partitioning in water) amino acids, where the
overall combination is hydrophobic, can also be employed.
[0026] In a preferred embodiment of the invention, the amino acid
is insoluble in the solvent system employed, such as, for example,
in a 70:30 (vol/vol) ethanol:water co-solvent.
[0027] The amino acid can be present in the particles of the
invention in an amount of at least 10 weight %. Preferably, the
amino acid can be present in the particles in an amount ranging
from about 20 to about 80 weight %. The salt of a hydrophobic amino
acid can be present in the particles of the invention in an amount
of at least 10% weight. Preferably, the amino acid salt is present
in the particles in an amount ranging from about 20 to about 80
weight %.
[0028] Examples of therapeutic, prophylactic or diagnostic agents
include synthetic inorganic and organic compounds, proteins,
peptides, polypeptides, polysaccharides and other sugars, lipids,
and DNA and RNA nucleic acid sequences having therapeutic,
prophylactic or diagnostic activities. Nucleic acid sequences
include genes, antisense molecules which bind to complementary DNA
or RNA and inhibit transcription, and ribozymes. The agents to be
incorporated can have a variety of biological activities, such as
vasoactive agents, neuroactive agents, hormones, anticoagulants,
immunomodulating agents, cytotoxic agents, prophylactic agents,
antibiotics, antivirals, antisense, antigens, and antibodies. In
some instances, the proteins may be antibodies or antigens which
otherwise would have to be administered by injection to elicit an
appropriate response. Compounds with a wide range of molecular
weight can be encapsulated, for example, between 100 and 500,000
grams or more per mole.
[0029] The particles can include a therapeutic agent for local
delivery within the lung, such as agents for the treatment of
asthma, chronic obstructive pulmonary disease (COPD), emphysema, or
cystic fibrosis, or for systemic treatment. For example, genes for
the treatment of diseases such as cystic fibrosis can be
administered, as can beta agonists steroids, anticholinergics and
leukotriene modifiers for asthma. Other specific therapeutic agents
include, but are not limited to, human growth hormone, insulin,
calcitonin, gonadotropin-releasing hormone ("LHRH"), granulocyte
colony-stimulating factor ("G-CSF"), parathyroid hormone-related
peptide, somatostatin, testosterone, progesterone, estradiol,
nicotine, fentanyl, norethisterone, clonidine, scopolamine,
salicylate, cromolyn sodium, salmeterol, formoterol, albuterol, and
Valium.
[0030] Any of a variety of diagnostic agents can be incorporated
within the particles, which can locally or systemically deliver the
incorporated agents following administration to a patient.
Biocompatible or pharmacologically acceptable gases can be
incorporated into the particles or trapped in the pores of the
particles using technology known to those skilled in the art. The
term gas refers to any compound which is a gas or capable of
forming a gas at the temperature at which imaging is being
performed. In one embodiment, retention of gas in the particles is
improved by forming a gas-impermeable barrier around the particles.
Such barriers are well known to those of skill in the art.
[0031] Diagnostic agents also include but are not limited to
imaging agents which include commercially available agents used in
positron emission tomography (PET), computer assisted tomography
(CAT), single photon emission computerized tomography, x-ray,
fluoroscopy, and magnetic resonance imaging (MRI).
[0032] Examples of suitable materials for use as contrast agents in
MRI include but are not limited to the gadolinium chelates
currently available, such as diethylene triamine pentacetic acid
(DTPA) and gadopentotate dimeglumine, as well as iron, magnesium,
manganese, copper and chromium.
[0033] Examples of materials useful for CAT and x-rays include
iodine based materials for intravenous administration, such as
ionic monomers typified by diatrizoate and iothalamate, non-ionic
monomers such as iopamidol, isohexol, and ioversol, non-ionic
dimers, such as iotrol and iodixanol, and ionic dimers, for
example, ioxagalte.
[0034] The particles of the invention can also be precursors to
tablet formulations.
[0035] Preferably, a therapeutic, prophylactic, diagnostic agent or
a combination thereof can be present in the spray-dried particles
in an amount ranging from less than about 1 weight % to about 90
weight %.
[0036] In another embodiment of the invention, the particles
include a phospholipid, also referred to herein as
phosphoglyceride. In a preferred embodiment, the phospholipid, is
endogenous to the lung. In another preferred embodiment the
phospholipid includes, among others, phosphatidic acid,
phosphatidylcholines, phosphatidylethanolamines,
phosphatidylglycerols, phosphatidylserines, phosphatidylinositols
and combinations thereof. 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.
[0037] The phospholipid, can be present in the particles in an
amount ranging from about 0 to about 90 weight %. Preferably, it
can be present in the particles in an amount ranging from about 10
to about 60 weight %.
[0038] Suitable methods of preparing and administering particles
which include phospholipids, are described in U.S. Pat. No.
5,855,913, issued on Jan. 5, 1999 to Hanes et al. and in U.S. Pat.
No. 5,985,309, issued on Nov. 16, 1999 to Edwards et al. The
teachings of both are incorporated herein by reference in their
entirety.
[0039] In still another embodiment of the invention the particles
include a surfactant such as, but not limited to the phospholipids
described above. Other surfactants, such as, for example,
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
poloxomer; a sorbitan fatty acid ester such as sorbitan trioleate
(Span 85); tyloxapol can also be employed.
[0040] 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.
[0041] The surfactant can be present in the particles in an amount
ranging from about 0 to about 90 weight %. Preferably, it can be
present in the particles in an amount ranging from about 10 to
about 60 weight %.
[0042] The a preferred embodiment of the invention, the particles
include a therapeutic, prophylactic or diagnostic agent, or
combinations thereof, a hydrophobic amino acid or a salt thereof,
and a phospholipid.
[0043] In one embodiment of the invention, the phospholipid or
combination or phospholipids present in the particles can have a
therapeutic, prophylactic or diagnostic role. For example, the
particles of the invention can be used to deliver surfactants to
the lung of a patient. This is particularly useful in medical
indications which require supplementing or replacing endogenous
lung surfactants, for example in the case of infant respiratory
distress syndrome.
[0044] The particles of the invention can have desired drug release
properties. In one embodiment, the particles include one or more
phospholipids selected according to their transition temperature.
For example, by administering particles which include a
phospholipid or combination of phospholipids which have a phase
transition temperature higher than the patient's body temperature,
the release of the therapeutic, prophylactic or diagnostic agent
can be slowed down. On the other hand, rapid release can be
obtained by including in the particles phospholipids having low
transition temperatures. Particles having controlled release
properties and methods of modulating release of a biologically
active agent are described in U. S Provisional Application
60/150,742, filed on Aug. 25, 1999, and U.S. patent application
Ser. No. 09/644,736, filed concurrently herewith under Attorney
Docket No. 2685.1012-001, entitled "Modulation of Release From Dry
Powder Formulations;" the contents of both are incorporated herein
by reference in their entirety.
[0045] Particles, and in particular particles having controlled or
sustained release properties, also can include other materials. For
example, the particles can include a biocompatible, and preferably
biodegradable polymer, copolymer, or blend. Such polymers are
described, for example, 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. Preferred polymers are those
which are capable of forming aerodynamically light particles having
a tap density less than about 0.4 g/cm.sup.3, a mean diameter
between about 5 .mu.m and about 30 .mu.m and an aerodynamic
diameter between approximately one and five microns, preferably
between about one and about three microns. The polymers can be
tailored to optimize different characteristics of the particle
including: i) interactions between the agent to be delivered and
the polymer to provide stabilization of the agent and retention of
activity upon delivery; ii) rate of polymer degradation and,
thereby, rate of drug release profiles; iii) surface
characteristics and targeting capabilities via chemical
modification; and iv) particle porosity.
[0046] Surface eroding polymers such as polyanhydrides can be used
to form the particles. For example, polyanhydrides such as
poly[(p-carboxyphenoxy)-hexane anhydride] (PCPH) may be used.
Suitable biodegradable polyanhydrides are described in U.S. Pat.
No. 4,857,311.
[0047] In another embodiment, bulk eroding polymers such as those
based on polyesters including poly(hydroxy acids) can be used. For
example, polyglycolic acid (PGA), polylactic acid (PLA), or
copolymers thereof may be used to form the particles. The polyester
may also have a charged or functionalizable group, such as an amino
acid. In a preferred embodiment, particles with controlled release
properties can be formed of poly(D,L-lactic acid) and/or
poly(D,L-lactic-co-glycolic acid) ("PLGA") which incorporate a
phospholipid such as DPPC.
[0048] Still other polymers include but are not limited to
polyamides, polycarbonates, polyalkylenes such as polyethylene,
polypropylene, poly(ethylene glycol), poly(ethylene oxide),
poly(ethylene terephthalate), poly vinyl compounds such as
polyvinyl alcohols, polyvinyl ethers, and polyvinyl esters,
polymers of acrylic and methacrylic acids, celluloses and other
polysaccharides, and peptides or proteins, or copolymers or blends
thereof. Polymers may be selected with or modified to have the
appropriate stability and degradation rates in vivo for different
controlled drug delivery applications.
[0049] In one embodiment, the particles include functionalized
polyester graft copolymers, as described in Hrkach et al.,
Macromolecules, 28: 4736-4739 (1995); and Hrkach et al.,
"Poly(L-Lactic acid-co-amino acid) Graft Copolymers: A Class of
Functional Biodegradable Biomaterials" in Hydrogels and
Biodegradable Polymers for Bioapplications, ACS Symposium Series
No. 627, Raphael M. Ottenbrite et al, Eds., American Chemical
Society, Chapter 8, pp. 93-101, 1996.
[0050] Materials other than biodegradable polymers can be included
in the spray-dried particles of the invention. Suitable materials
include various non-biodegradable polymers and various excipients.
Examples of excipients include, but are not limited to: a sugar,
such as lactose, polysaccharides, cyclodextrins and/or a
surfactant.
[0051] In yet another embodiment of the invention, the particles
also include a carboxylate moiety and a multivalent metal salt.
Such compositions are described in U.S. Provisional Application
60/150,662, filed on Aug. 25, 1999, and U.S. patent application
Ser. No. 09/644,105, entitled "Formulation for Spray-Drying Large
Porous Particles," filed concurrently herewith under Attorney
Docket No. 2685.1010-001; the teachings of both are incorporated
herein by reference in their entirety. In a preferred embodiment,
the particles include sodium citrate and calcium chloride.
[0052] 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. The
particles can be co-delivered, for example, with larger carrier
particles, not carrying a therapeutic agent, having, for example, a
mean diameter ranging between about 50 .mu.m and about 100
.mu.m.
[0053] The particles of the invention have a tap density less than
about 0.4 g/cm.sup.3. As used herein, the phrase "aerodynamically
light particles" refers to particles having a tap density less than
about 0.4 g/cm.sup.3. Particles having a tap density of less than
about 0.1 g/cm.sup.3 are preferred. The tap density of particles of
a dry powder can be obtained using a GeoPyc.TM. instrument
(Micrometrics Instrument Corp., Norcross, Ga. 30093). A Dual
Platform Microprocessor Controlled Tap Density Tester (Vankel,
N.C.) can also be used. Tap density is a standard measure of the
envelope mass density. 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. 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.
[0054] Aerodynamically light particles have a preferred size, e.g.,
a volume median geometric diameter (VMGD) of at least about 5
microns (.mu.m). In one embodiment, the VMGD is from about 5 .mu.m
to about 30 .mu.m. In another embodiment of the invention, the
particles have a VMGD ranging from about 10 .mu.m to about 30
.mu.m. In other embodiments, 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 5 .mu.m, for
example from about 5 .mu.m and about 30 .mu.m.
[0055] The diameter of the particles, for example, their MMGD or
their VMGD, can be measured using an electrical zone sensing
instrument such as a Multisizer IIe, (Coulter Electronic, Luton,
Beds, England), or a laser diffraction instrument (for example
Helos, manufactured by Sympatec, Princeton, N.J.). Other
instruments for measuring particle diameter are well known 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 within targeted sites within the
respiratory tract.
[0056] 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. In
one embodiment of the invention, the MMAD is between about 1 .mu.m
and about 3 .mu.m. In another embodiment, the MMAD is between about
3 .mu.m and about 5 .mu.m.
[0057] 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).
[0058] Process conditions as well as efficiency of inhaler, in
particular with respect to dispersibility, can contribute to the
size of particles that can be delivered to the pulmonary
system.
[0059] Aerodynamically light particles may be fabricated or
separated, for example by filtration or centrifugation, to provide
a particle sample with a preselected size distribution. For
example, greater than about 30%, 50%, 70%, or 80% of the particles
in a sample can have a diameter within a selected range of at least
about 5 .mu.m. The selected range within which a certain percentage
of the particles must fall may be for example, between about 5 and
about 30 .mu.m, or optimally between about 5 and about 15 .mu.m. In
one preferred embodiment, at least a portion of the particles have
a diameter between about 9 and about 11 .mu.m. Optionally, the
particle sample also can be fabricated wherein at least about 90%,
or optionally about 95% or about 99%, have a diameter within the
selected range. The presence of the higher proportion of the
aerodynamically light, larger diameter particles in the particle
sample enhances the delivery of therapeutic or diagnostic agents
incorporated therein to the deep lung. Large diameter particles
generally mean particles having a median geometric diameter of at
least about 5 .mu.m.
[0060] Aerodynamically light particles with a tap density less than
about 0.4 g/cm.sup.3, median diameters of at least about 5 .mu.m,
and an aerodynamic diameter of between about 1 and about 5 .mu.m,
preferably between about 1 and about 3 .mu.m, are more capable of
escaping inertial and gravitational deposition in the oropharyngeal
region, and are targeted to the airways or 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.
[0061] 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.
[0062] Aerodynamically light particles thus are capable of a longer
term release of an encapsulated agent in the lungs. Following
inhalation, aerodynamically light biodegradable particles can
deposit in the lungs, and subsequently undergo slow degradation and
drug release, without the majority of the particles being
phagocytosed by alveolar macrophages. The drug can be delivered
relatively slowly into the alveolar fluid, and at a controlled rate
into the blood stream, minimizing possible toxic responses of
exposed cells to an excessively high concentration of the drug. The
aerodynamically light particles thus are highly suitable for
inhalation therapies, particularly in controlled release
applications.
[0063] 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.
[0064] 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.
[0065] 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.
where the envelope mass .rho. 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=.sup.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.<1 g/cm.sup.3);
where d is always greater than 3 .mu.m. For example,
aerodynamically light particles that display an envelope mass
density, .rho.=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.
[0066] In one embodiment of the invention, the spray-dried
particles have a tap density less than about 0.4 g/cm.sup.3 and a
median diameter between about 5 .mu.m and about 30 .mu.m, which in
combination yield an aerodynamic diameter of between about 1 and
about 5 .mu.m, and for delivery to the deep lung, preferably
between about 1 and about 3 .mu.m. The aerodynamic diameter is
calculated to provide for maximum deposition within the lungs,
previously 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.
[0067] In another embodiment of the invention, the particles have a
mass density of less than about 0.4 g/cm.sup.3 and a mean diameter
of between about 5 .mu.m and about 30 .mu.m. Mass density and the
relationship between mass density, mean diameter and aerodynamic
diameter are discussed in U. S. application Ser. No. 08/655,570,
filed on May 24, 1996, which is incorporated herein by reference in
its entirety. In a preferred embodiment, the aerodynamic diameter
of particles having a mass density less than about 0.4 g/cm.sup.3
and a mean diameter of between about 5 .mu.m and about 30 .mu.m is
between about 1 .mu.m and about 5 .mu.m.
[0068] The invention also relates to methods of preparing particles
having a tap density less than about 0.4 g/cm.sup.3. In one
embodiment, the method includes forming a mixture including a
therapeutic, prophylactic or diagnostic agent, or a combination
thereof, and an amino acid or a salt thereof The therapeutic,
prophylactic or diagnostic agents which can be employed include but
are not limited to those described above. The amino acids or salts
thereof, include but are not limited to those described before.
[0069] In a preferred embodiment, the mixture includes a
surfactant, such as, for example, the surfactants described above.
In another preferred embodiment, the mixture includes a
phospholipid, such as, for example the phospholipids described
above. An organic solvent or an aqueous-organic solvent can be
employed to form the mixture.
[0070] Suitable organic solvents that can be employed include but
are not limited to alcohols such as, 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.
[0071] Co-solvents that can be employed include an aqueous solvent
and an organic solvent, such as, but not limited to, the organic
solvents as described above. Aqueous solvents include water and
buffered solutions. In one embodiment, an ethanol water solvent is
preferred with the ethanol:water ratio ranging from about 50:50 to
about 90:10 ethanol:water.
[0072] The mixture can have a neutral, acidic or alkaline pH.
Optionally, a pH buffer can be added to the solvent or co-solvent
or to the formed mixture. Preferably, the pH can range from about 3
to about 10.
[0073] The mixture is spray-dried. Suitable spray-drying techniques
are described, for example, by K. Masters in "Spray Drying
Handbook", John Wiley & Sons, New York, 1984. Generally, during
spray-drying, heat from a hot gas such as heated air or nitrogen is
used to evaporate the solvent from droplets formed by atomizing a
continuous liquid feed.
[0074] In a preferred embodiment, a rotary atomizer is employed. An
example of suitable spray driers using rotary atomization includes
the Mobile Minor spray drier, manufactured by Niro, Denmark. The
hot gas can be, for example, air, nitrogen or argon.
[0075] Preferably, the particles of the invention are obtained by
spray drying using an inlet temperature between about 100.degree.
C. and about 400.degree. C. and an outlet temperature between about
50.degree. C. and about 130.degree. C.
[0076] Without being held to any particular theory, it is believed
that due to their hydrophobicity and low water solubility,
hydrophobic amino acids facilitate the formation of a shell during
the drying process when an ethanol:water co-solvent is employed. It
is also believed that the amino acids may alter the phase behavior
of the phospholipids in such a way as to facilitate the formation
of a shell during the drying process.
[0077] The particles of the invention can be used for delivery to
the pulmonary system. They can be used to provide controlled
systemic or local delivery of therapeutic or diagnostic agents to
the respiratory tract via aerosolization. Administration of the
particles to the lung by aerosolization permits deep lung delivery
of relatively large diameter therapeutic aerosols, for example,
greater than about 5 .mu.m in median diameter. 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.
[0078] The particles may be administered alone or in any
appropriate pharmaceutically acceptable carrier, such as a liquid,
for example saline, or a powder, for administration to the
respiratory system. They can be co-delivered with larger carrier
particles, not including a therapeutic agent, the latter possessing
mass median diameters for example in the range between about 50
.mu.m and about 100 .mu.m.
[0079] 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.
[0080] The use of biodegradable polymers permits controlled release
in the lungs and long-time local action or systemic
bioavailability. Denaturation of macromolecular drugs can be
minimized during aerosolization since macromolecules can be
contained and protected within a polymeric shell. Coencapsulation
of peptides with peptidase-inhibitors can minimize peptide
enzymatic degradation. Pulmonary delivery advantageously can reduce
or eliminate the need for injection. For example, the requirement
for daily insulin injections can be avoided.
[0081] The invention is also related to a method for drug delivery
to the pulmonary system. The method comprises administering to the
respiratory tract of a patient in need of treatment, prophylaxis or
diagnosis an effective amount of particles comprising a
therapeutic, prophylactic or diagnostic agent and a hydrophobic
amino acid. In a preferred embodiment, the particles include a
phospholipid. As used herein, the term "effective amount" means the
amount needed to achieve the desired effect or efficacy.
[0082] Porous or aerodynamically light particles, having a
geometric size (or mean diameter) in the range of about 5 to about
30 .mu.m, and tap density less than about 0.4 g/cm.sup.3, such that
they possess an aerodynamic diameter of about 1 and about 3 .mu.m,
have been shown to display ideal properties for delivery to the
deep lung. Larger aerodynamic diameters, ranging, for example, from
about 3 to about 5 .mu.m are preferred, however, for delivery to
the central and upper airways. According to one embodiment of the
invention the particles have a tap density of less than about 0.4
g/cm.sup.3 and a mean diameter of between about 5 .mu.m and about
30 .mu.m. According to another embodiment of the invention, the
particles have a mass density of less than about 0.4 g/cm.sup.3 and
a mean diameter of between about 5 .mu.m and about 30 .mu.m. In one
embodiment of the invention, the particles have an aerodynamic
diameter between about 1 .mu.m and about 5 .mu.m. In another
embodiment of the invention, the particles have an aerodynamic
diameter between about 1 .mu.m and about 3 .mu.m microns. In still
another embodiment of the invention, the particles have an
aerodynamic diameter between about 3 .mu.m and about 5 .mu.m.
[0083] Particles including a medicament, for example one or more of
the drugs listed above, are administered to the respiratory tract
of a patient in need of treatment, prophylaxis or diagnosis.
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. In a preferred embodiment,
particles are administered via a dry powder inhaler (DPI).
Metered-dose-inhalers (MDI), nebulizers or instillation techniques
also can be employed.
[0084] Such devices are known in the art. For example, a DPI is
described in U.S. Pat. No. 4,069,819 issued on Aug. 5, 1976 and
U.S. Pat. No. 4,995,385, issued on Feb. 26, 1991, both to
Valentini, et al. Examples of other suitable inhalers are described
in U.S. Pat. No. 5,997,848 issued Dec. 7, 1999 to Patton, et al.
Various other suitable devices and methods of inhalation which can
be used to administer particles to a patient's respiratory tract
are known in the art. Examples include, but are not limited to, the
Spinhaler.RTM. (Fisons, Loughborough, U.K.), Rotahaler.RTM.
(Glaxo-Wellcome, Research Triangle Technology Park, N.C.),
FlowCaps.RTM. (Hovione, Loures, Portugal), Inhalator.RTM.
(Boehringer-Ingelheim, Germany), and the Aerolizer.RTM. (Novartis,
Switzerland), Diskhaler.RTM. (Glaxo-Wellcome, RTP, NC) and others,
such as known to those skilled in the art. Preferably, the
particles are administered as a dry powder via a dry powder
inhaler.
[0085] In one embodiment of the invention, delivery to the
pulmonary system of particles is in a single, breath-actuated step,
as described in U.S. patent application, entitled "High Efficient
Delivery of a Large Therapeutic Mass Aerosol," application Ser. No.
09/591,307, filed Jun. 9, 2000, Attorney Docket No. 2685.2001-000,
which is incorporated herein by reference in its entirety. In
another embodiment of the invention, at least 50% 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
a further embodiment, at least 5 milligrams and preferably at least
10 milligrams of a medicament is delivered by administering, in a
single breath, to a subject's respiratory tract particles enclosed
in the receptacle. Amounts as high as 15, 20, 25, 30, 35, 40 and 50
milligrams can be delivered.
[0086] The present invention will be further understood by
reference to the following non-limiting examples.
EXEMPLIFICATIONS
[0087] Some of the methods and materials employed in the following
examples are described in U.S. application Ser. No. 09/211,940,
filed Dec. 15, 1998, in U.S. application Ser. No. 08/739,308, filed
Oct. 29, 1996, now U.S. Pat. No. 5,874,064, in U.S. application
Ser. No. 08/655,570, filed May 24, 1996, in U.S. application Ser.
No. 09/194,068, filed May 23, 1997, in PCT/US97/08895 application
filed May 23, 1997, in U.S. application Ser. No. 08/971,791, filed
Nov. 17, 1997, in U.S. application Ser. No. 08/784,421, filed Jan.
16, 1997, now U.S. Pat. No. 5,855,913 and in U.S. application Ser.
No. 09/337,245, filed on Jun. 22, 1999, all of which are
incorporated herein by reference in their entirety.
Materials
[0088] Leucine was obtained from Spectrum Chemical Company. DPPC
was obtained from Avanti Polar Lipids (Alabaster, Ala.).
Spray Drying
[0089] A Mobile Minor spray-drier from Niro was used. The gas
employed was dehumidified air. The gas temperature ranged from
about 80 to about 150.degree. C. The atomizer speed ranged from
about 15,000 to about 50,000 RPM. The gas rate was 70 to 92 kg/hour
and the liquid feed rate ranged from about 50 to about 100
ml/minute.
Geometric Size Distribution Analysis
[0090] Size distributions were determined using a Coulter
Multisizer II. Approximately 5-10 mg of powder was added to 50 mL
isoton II solution until the coincidence of particles was between 5
and 8%. Greater than 500,000 particles were counted for each batch
of spheres.
Aerodynamic Size Distribution Analysis
[0091] Aerodynamic size distribution was determined using an
Aerosizer/Aerodisperser (Amherst Process Instruments, Amherst,
Mass.). Approximately 2 mg powder was introduced into the
Aerodisperser and the Aerodynamic size was determined by time of
flight measurements.
EXAMPLE 1
[0092] A mixture including 40 weight % of an amino acid and 60
weight % DPPC was formed in a 70/30 vol/vol ethanol-water
co-solvent and spray-dried. The results are shown in Table 1.
[0093] Table 1 shows median geometric and aerodynamic diameters for
particles including several amino acids, their hydrophobicity and
estimated tap density. Tap density was estimated using the equation
discussed above.
TABLE-US-00001 TABLE 1 Est. tap Amino acid hydrophobicity MMGD MMAD
density Leucine 0.943 7.9 3.0 0.11 Isoleucine 0.943 8.1 2.7 0.14
Phenylalanine 0.501 7.9 3.8 0.23 Glutamine 0.251 6.5 4.4 0.45
Glutamate 0.043 5.1 4.1 0.64
EXAMPLE 2
[0094] Mixtures including 60 weight % DPPC with varying ratios of
leucine and lactose were formed in a 70/30 vol/vol ethanol-water
cosolvent and spray-dried. The mixtures included: (A) 60:40
DPPC:leucine, (B) 60:20:20 DPPC:leucine:lactose and (C) 60:40
DPPC:lactose. The spray-drying operating conditions were held
constant for each of the runs (these included an inlet temperature
of 100.degree. C., an atomizer spin rate of 20,000 RPM, a fluid
feed rate of 65 ml/min and a dewpoint in the range of -15 to
-20.degree. C.). The results are shown in Table 2. In summary, the
replacement of leucine with increasing amounts of lactose led to a
reduction in yield and particle geometric size, and an increase in
particle MMAD and density. Increasing amounts of lactose also
appeared to lead to an increase in the tendency of the particles to
agglomerate.
TABLE-US-00002 TABLE 2 MMGD MMAD Est. Tap. Density Formulations
yield (%) (.mu.m) (.mu.m) g/cm.sup.3 A 27 8.04 2.97 0.14 B 26 6.54
3.67 0.31 C 1 4.70 3.85 0.67
EXAMPLE 3
[0095] Particles containing albuterol sulfate were prepared in the
following manner. A mixture including 76% DSPC, 20% leucine and 4%
albuterol sulfate was formed in a 70/30 (v/v) ethanol/water
co-solvent and spray dried. The mass median geometric diameter of
the resulting particles was 8.2 .mu.m and the mass median
aerodynamic diameter was 2.8 .mu.m.
EXAMPLE 4
[0096] Particles including 4% albuterol sulfate, 60% DPPC and 36%
leucine, alanine or glycine were formed as described above. A
comparison of the characteristics of each set of particles is shown
in Table 3. For each formulation the table shows the amino acid
employed, the mass median aerodynamic diameter (MMAD), the
volumetric median geometric diameter (VMGD), and the density
calculated using the equation d.sub.aer=d.sub.g* .rho.. The data
show that all three amino acids were useful in forming particles
suitable for pulmonary delivery. Leucine and alanine formulations
appeared best suited for delivery which is preferentially to the
deep lung while glycine formulations appeared more suitable for
delivery that is preferential to the central and upper airways.
TABLE-US-00003 TABLE 3 Amino acid MMAD VMGD Calculated Density
Formulations (36% w/w) (.mu.m) (.mu.m) g/cm.sup.3 A leucine 2.38
10.28 0.054 B alanine 3.17 11.48 0.076 C glycine 5.35 13.09
0.167
[0097] 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.
* * * * *