U.S. patent application number 14/959684 was filed with the patent office on 2016-06-02 for pulmonary pharmaceutical formulations.
The applicant listed for this patent is Civitas Therapeutics, Inc.. Invention is credited to Charles D. Blizzard, Daniel LeBlanc, Michael M. Lipp, Rebecca Martin, Rachel Ryznal, Mark A. Tracy, Kevin L. Ward.
Application Number | 20160151393 14/959684 |
Document ID | / |
Family ID | 40378645 |
Filed Date | 2016-06-02 |
United States Patent
Application |
20160151393 |
Kind Code |
A1 |
Blizzard; Charles D. ; et
al. |
June 2, 2016 |
PULMONARY PHARMACEUTICAL FORMULATIONS
Abstract
The present invention provides improved pharmaceutical
formulations for pulmonary delivery having improved chemical and
physical stability of the therapeutic, prophylactic or diagnostic
agent as compared to formulations known in the art. The improved
pharmaceutical formulations of the invention for administration to
the respiratory system of a patient for the treatment of a variety
of disease conditions comprise a mass of biocompatible particles
comprising an active agent, and a hydrogenated starch hydrosylate
(HSH). The improvement over the prior art comprises the presence of
HSH in the pharmaceutical formulation. The invention further
relates to a method of treating diseases comprising administering
the pharmaceutical formulations of the present invention to the
respiratory system of a patient in need of treatment.
Inventors: |
Blizzard; Charles D.;
(Westwood, MA) ; Lipp; Michael M.; (Framingham,
MA) ; Ward; Kevin L.; (Arlington, MA) ;
Ryznal; Rachel; (North Oxford, MA) ; LeBlanc;
Daniel; (Wellesley, MA) ; Tracy; Mark A.;
(Arlington, MA) ; Martin; Rebecca; (Blacksburg,
VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Civitas Therapeutics, Inc. |
Chelsea |
MA |
US |
|
|
Family ID: |
40378645 |
Appl. No.: |
14/959684 |
Filed: |
December 4, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14084550 |
Nov 19, 2013 |
|
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14959684 |
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12195878 |
Aug 21, 2008 |
8614255 |
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14084550 |
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60957108 |
Aug 21, 2007 |
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Current U.S.
Class: |
514/11.8 ;
514/174 |
Current CPC
Class: |
A61K 9/1623 20130101;
A61K 9/1617 20130101; A61P 11/06 20180101; A61K 31/13 20130101;
A61K 9/0075 20130101; A61K 45/06 20130101; A61K 31/58 20130101;
A61K 47/36 20130101; A61K 38/29 20130101 |
International
Class: |
A61K 31/58 20060101
A61K031/58; A61K 38/29 20060101 A61K038/29; A61K 9/00 20060101
A61K009/00 |
Claims
1. A dry powder composition for administration to the respiratory
system of a patient comprising biocompatible particles wherein the
biocompatible particles comprise a therapeutic agent, or any
combination thereof; and a hydrogenated starch hydrolysate
(HSH).
2. The composition of claim 1, wherein HSH is present in the
particles in an amount from about 50% by weight to 95% by
weight.
3. The composition of claim 1, further comprising a buffering
agent.
4. The composition of claim 3, wherein the buffering agent is
sodium phosphate, sodium acetate, sodium carbonate, glycylglycine,
histidine, HEPES, arginine, TRIS, glycine or a hydroxytricarboxylic
acid or salt thereof.
5. The composition of claim 4, wherein the hydroxytricarboxylic
acid is citric acid.
6. The composition of claim 3, wherein the buffering agent is a
citrate salt.
7. The composition of claim 1, wherein the particles have a tap
density about 0.4 g/cm.sup.3 or less.
8. The composition of claim 1, wherein the particles have a fine
particle fraction of about 20% or more by weight.
9. A method for treating a disease condition in a patient
comprising the step of administering to the respiratory tract of
the patient, an effective amount of the composition of claim 1.
10. The method of claim 9, wherein the dry powder composition is
inhaled using a dry powder inhaler comprising a receptacle
containing the composition.
11. The method of claim 9, wherein the particles have a tap density
of about 0.4 g/cm.sup.3 or less.
12. The method of claim 9, wherein the particles have a fine
particle fraction of about 20% or more by weight.
13. The composition of claim 1, wherein the therapeutic-agent is
budesonide.
14. A method of treating a patient suffering from an inflammatory
disorder, comprising the step of administering by inhalation to the
respiratory tract of the patient, an effective amount of the
composition of claim 13.
15. The method of claim 14, wherein the inflammatory disorder is
asthma, allergic rhinitis, infectious rhinitis, inflammatory bowel
disease or nasal polypsis.
16. A kit for administration of a composition of claim 1,
comprising at least one receptacle, wherein said receptacle
comprises at least one unit dosage of the composition and wherein
the receptacle is suitable for use with a dry powder inhaler.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/084,550, filed Nov. 19, 2013, which is a continuation of
U.S. application Ser. No. 12/195,878, filed Aug. 21, 2008, now U.S.
Pat. No. 8,614,255, issued Dec. 24, 2013, which claims the benefit
of U.S. Provisional Application No. 60/957,108 filed on Aug. 21,
2007. The entire teachings of the above applications are
incorporated herein by reference.
TECHNICAL FIELD
[0002] The invention generally relates to pharmaceutical
formulations suitable for inhalation having improved physical and
chemical properties, and to methods for treating, preventing and
diagnosing diseases using such formulations.
BACKGROUND OF THE INVENTION
[0003] Pulmonary delivery of therapeutic, diagnostic and
prophylactic agents provides an attractive alternative to oral,
transdermal and parenteral administration. Pulmonary administration
can typically be completed without the need for medical
intervention (self-administration), the pain often associated with
injection therapy is avoided, and the amount of enzymatic and pH
mediated degradation of the bioactive agent, frequently encountered
with oral therapies, can be significantly reduced. In addition, the
lungs provide a large mucosal surface for drug absorption and there
is no first-pass liver effect of absorbed drugs. Further, it has
been shown that high bioavailability of many molecules, for
example, macromolecules, can be achieved via pulmonary delivery or
inhalation. Typically, the deep lung, or alveoli, is the primary
target of inhaled bioactive agents, particularly for agents
requiring systemic delivery.
[0004] Pharmaceutical formulations for respiratory delivery are
known to be particularly useful for the delivery of proteins and
peptides which are difficult to administer by other routes.
Proteins and peptides are known to present formulation challenges
due to a variety of reasons including their susceptibility to
destabilization by physical and chemical factors during the
formulation process and during subsequent storage. Thus,
pharmaceutical formulations suitable for delivery to the
respiratory system having improved physical and chemical stability
are desirable.
SUMMARY OF THE INVENTION
[0005] The present invention provides improved pharmaceutical
formulations for pulmonary delivery having improved chemical and
physical stability of the therapeutic, prophylactic or diagnostic
agent (also referred to herein interchangeably as "bioactive
agents," "medicaments" or "drugs") as compared to formulations
known in the art. Such improved formulations provide numerous
advantages including but not limited to, more reliable pulmonary
delivery of the drug, ease of manufacturing, and improved
storability even in environmental conditions that would normally
destabilize the drug. The improved pharmaceutical formulations of
the invention for administration to the respiratory system of a
patient for the treatment, prevention and diagnosis of a variety of
disease conditions comprise a mass of biocompatible particles
comprising an active agent and a hydrogenated starch hydrosylate
(HSH). The improvement over the prior art comprises the presence of
HSH in the formulation. The invention further relates to a method
of treating diseases comprising pulmonary administration to the
respiratory tract e.g., deep lung, central airways and/or upper
airways of a patient in need of treatment an effective amount of
the pharmaceutical formulations of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0006] The present invention is based, at least in part, on the
discovery that the chemical and physical stability of
pharmaceutical formulation administrable by inhalation is improved
by including a hydrogenated starch hydrosylate (HSH) in the
formulation. In the development of pharmaceutical formulations for
delivery to the respiratory system, the physical and chemical
stability of such formulations under a variety of storage
conditions is essential to the ultimate performance of the drug
upon administration to the respiratory system. Given that many
inhalable drugs are self-administered by the patient and thus
stored by the patient, such drug formulations are often exposed to
environmental conditions that are not ideal for long term storage
prior to self-administration by the patient. Thus it is critical
that the drug maintain physical and chemical stability under a
variety of less than ideal or adverse conditions such that when the
patient eventually administers the formulation, the integrity and
percentage of the active agent actually delivered to the patient is
maintained as compared to the drug formulation that is stored under
"ideal" storage conditions.
[0007] Various aspects of the invention are described in further
detail in the following subsections.
Compositions and Pharmaceutical Formulations
[0008] In one embodiment of the pharmaceutical formulation of the
present invention includes a therapeutic, prophylactic or
diagnostic agent, preferably, parathyroid hormone or a fragment
thereof and a hydrogenated starch hydrolysate (HSH), preferably
polyalditol, Particularly preferred are particles that include more
than about 1 weight percent (wt. %) of a therapeutic, prophylactic
or diagnostic agent, for instance, at least 1-50 weight percent of
parathyroid hormone or a fragment thereof. In one embodiment, the
particles include at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35,
40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 wt. % of
parathyroid hormone or a fragment thereof. In one preferred
embodiment the particles further comprise a buffering agent,
preferably a hydroxytricarboxylic acid or a salt thereof, such as
citrate or sodium citrate. In another preferred embodiment, the
particles comprise an amino acid, such as leucine. In other
embodiments, the presence of any combination of an HSH and/or a
buffering agent, such as a hydroxycarboxylic acid or a salt thereof
and/or a hydrophobic amino acid, as described herein, facilitates a
lower percentage of the therapeutic, prophylactic or diagnostic
agent while maintaining favorable features e.g., stability of the
drug formulation.
[0009] In a preferred embodiment of the invention, the
pharmaceutical formulations are in the form of a dry powder
suitable for inhalation. A "dry powder" or "powder" as used herein
with regard to the particles and the formulations of the invention
means that the moisture content of the mass of particles is
generally below about 10% by weight of water, more preferably below
about 5% by weight of water and preferably less that about 3% by
weight of water.
[0010] The therapeutic, prophylactic or diagnostic agents when
released in vivo, possesses the desired biological activity, for
example, therapeutic and/or prophylactic properties in vivo. The
active agents in accordance with the invention can have a variety
of biological activities, such as bone resorption-stimulating
activity, glucoregulatory or antidiabetic activity. Suitable
biologically active agents include, but are not limited to, PTH,
PTH (1-84), rhPTH-(1-84) (Allelix Biopharmaceuticals), PTH
fragments including but not limited to, rhPTH (1-34), teriparitide
(rDNA origin) recombinant parathyroid hormone (1-34) (FORTEO.TM.,
Eli Lilly & Co), hPTH (1-34), hPTH (1-31) and monocyclic hPTH
(1-31) (Andreassen et al), additional PTH fragments and analogs
thereof, for example, Ostabolin and Ostabolin-C.TM., (Zelos
Therapeutics, Waltham, Mass.) as well as other C-terminal PTH
fragments and N-terminal PTH fragments hereinafter collectively
referred to as PTH, glucagon, Glucagon-Like Peptides such as,
GLP-1, GLP-2 or other GLP analogs, derivatives or agonists of
Glucagon Like Peptides, exendins such as, exendin-3 and exendin-4,
derivatives, agonists and analogs thereof, vasoactive intestinal
peptide (VIP), immunoglobulins, antibodies, cytokines (e.g.,
lymphokines, monokines, chemokines), interleukins, macrophage
activating factors, interferons, erythropoietin, nucleases, tumor
necrosis factor, colony stimulating factors (e.g., G-CSF), insulin,
enzymes (e.g., superoxide dismutase, plasminogen activator, etc.),
tumor suppressors, blood proteins, hormones and hormone analogs and
agonists (e.g., follicle stimulating hormone, growth hormone,
adrenocorticotropic hormone, and luteinizing hormone releasing
hormone (LHRH)), vaccines (e.g., tumoral, bacterial and viral
antigens), antigens, blood coagulation factors, growth factors (NGF
and EGF), gastrin, GRH, antibacterial peptides such as defensin,
enkephalins, bradykinins, calcitonin and muteins, analogs,
truncation, deletion and substitution variants and pharmaceutically
acceptable salts of all the foregoing. Other active agents include,
but are not limited to somatostatin, testosterone, progesterone,
estradiol, nicotine, fentanyl, norethisterone, clonidine,
scopolamine, salicylate, cromolyn sodium, salmeterol, albuterol,
epinephrine, L-dopa, diazepam, trospium, iloprost, formoterol and
budesonide.
[0011] HSH is a generic term for various hydrogenated syrups which
are also known as "sugar alcohols", "polyhydric alcohols" or
"polyols". HSHs are ubiquitous dietary components. They are used as
sweeteners, viscosity agents, bodying agents, humectants,
crystallization modifiers, and rehydration aids in the food and
pharmaceutical industries.
[0012] HSHs are derived from such common food substances as
maltodextrins, glucose, syrups and maltose syrups. HSH molecules
have the chemical structure (G).sub.nS where G is glucose and S is
sorbitol, and n is an integer greater than or equal to zero.
Sorbitol (G).sub.0S is formed by the reduction of glucose, changing
the aldehyde to a hydroxyl group. Maltitol (G).sub.1S is formed by
the reduction of maltose, a dimer of glucose, and maltotriotol
(G).sub.2S is composed of two glucose units and a sorbitol moiety.
Other higher order polyols contain three or more molecules of
glucose and a sorbitol moiety. HSHs that do not contain a specific
polyol as the majority component are referred to by the general
term "hydrogenated starch hydrosylate".
[0013] HSHs are typically prepared by the hydrolysis or partial
hydrolysis of starch (such as corn, wheat or potato starch)
followed by hydrogenation of the hydrolysis product at high
temperature under pressure. Starch is a polymer of repeating
glucose units that are linked by glycosidic bonds. Hydrolysis
breaks the glycosidic bonds, yielding a heterogeneous mixture of
shorter-chain glucose monomers, oliogomers and polymers. The degree
of hydrolysis (quantified as DE, or dextrose equivalents) dictates
the fraction of glucose monomer present in the solution, which is
in turn dictated by the method of hydrolysis (acid hydrolysis, heat
or enzymatic digestion). By varying the conditions and extent of
hydrolysis, various mono-, di, oligo-, and polymeric hydrogenated
saccharides can be obtained. Complete hydrolysis would reduce all
higher-order saccharides to glucose monomers (dextrose), a
theoretical DE of 1000. Hydrogenation of high DE solution results
in a greater proportion of monomeric (sorbitol) and oligomeric
polyols in the final product. The grade of HSH is determined by the
ratios of maltitol, sorbitol and other higher-order polyols or
polysaccharides.
[0014] Polyalditol is the preferred HSH of the invention.
Polyalditol is a pharmaceutical-grade form of HSH comprising
approximately 1% sorbitol, 3.5% maltitol, and 95.5% higher order
polyols.
[0015] In one embodiment, at least one HSH is present in the
biocompatible particles of the invention in an amount of at least
5% by weight. Preferably, the HSH is present in the particles in an
amount ranging from about 50% to about 95% by weight. In a
preferred embodiment the HSH is polyalditol.
[0016] In one embodiment, a buffering agent is present in the
particles in an amount of at least 1% to about 50% by weight. In
one embodiment, the buffering agent is present in an amount ranging
from about 1% to about 25% by weight. Examples of buffering agents
which can be employed include, but are not limited to: sodium
phosphate, sodium acetate, sodium carbonate, citrate,
glycylglycine, histidine, HEPES, arginine, TRIS, glycine and sodium
citrate or mixtures thereof. In a preferred embodiment the
buffering agent is a hydroxytricarboxylic acid or a salt thereof,
such as citric acid or a citrate salt, such as sodium citrate.
[0017] The particles suitable for use in the invention can further
comprise an amino acid or salt thereof. Examples of amino acids
which can be employed include, but are not limited to: glycine,
proline, alanine, cysteine, methionine, valine, leucine, tyrosine,
isoleucine, phenylalanine and tryptophan. In a preferred embodiment
the amino acid is hydrophobic. Suitable hydrophobic amino acids,
include but are not limited to, leucine, isoleucine, alanine,
valine, phenylalanine, glycine and tryptophan. Combinations of
hydrophobic amino acids or combinations of amino acids wherein the
overall combination is hydrophobic can also be employed. In a
preferred embodiment, the amino acid is leucine.
[0018] The amino acid, preferably leucine, can be present in the
particles of the invention in an amount from about 1% to about 91
weight %. In one embodiment the amino acid, preferably leucine, can
be present in the particles in an amount ranging from about 5 to
about 60 weight percent and preferably in an amount ranging from
about 5 to about 30 weight percent. In another embodiment, the
particles comprise the amino acid, preferably leucine, in an amount
of at least 46 weight percent.
[0019] In a further embodiment, the particles can also include
other materials such as, for example, buffer salts, dextran,
polysaccharides, lactose, trehalose, cyclodextrins, proteins,
peptides, polypeptides, fatty acids, fatty acid esters, inorganic
compounds, and phosphates.
[0020] A preferred formulation of the invention comprises about 1%
to about 10% by weight of parathyroid hormone or fragment thereof,
about 65% to about 95% by weight of polyalditol, about 1% to about
25% by weight of sodium citrate. Another preferred composition
comprises about 4.7% by weight of parathyroid hormone or fragment
thereof, about 80% by weight of polyalditol, and about 15.3% by
weight of sodium citrate.
[0021] Another preferred formulation of the invention comprises
budesonide and an HSH, preferably polyalditol. Optionally, the
formulation further comprises a buffering agent, such as a
hydroxytricarboxylic acid including citric acid or a salt thereof.
The formulation can further comprise an amino acid. A particularly
preferred formulation of the invention comprises about 1% to about
10% by weight of budesonide, about 65% to about 99% by weight of
polyalditol and about 0% to about 25% by weight of sodium
citrate.
Methods of Treatment and Administration
[0022] The method of the invention includes delivering to the
pulmonary system an effective amount of a medicament such as, for
example, a therapeutic, prophylactic or diagnostic agent. As used
herein, the term "effective amount" means the amount needed of a
therapeutic, prophylactic or diagnostic agent to achieve the
desired therapeutic or diagnostic effect or efficacy, e.g, in the
case of parathyroid hormones and its analogs, to treat a condition
characterized by abnormal levels of parathyroid hormone.
[0023] In a preferred embodiment of the invention, the bioactive
agent is parathyroid hormone or a fragment thereof. Parathyroid
hormone is the most important endocrine regulator of calcium and
phosphorus concentration in extracellular fluid. This hormone is
secreted from cells of the parathyroid glands and finds its major
target cells in bone and kidney. Another hormone, parathyroid
hormone-related protein, binds to the same receptor as parathyroid
hormone and has major effects on development. Like most other
protein hormones, parathyroid hormone is synthesized as a
preprohormone. After intracellular processing, the mature hormone
is packaged within the Golgi into secretory vesicles, the secreted
into blood by exocytosis. Endogenous parathyroid hormone is
secreted as a linear protein of 84 amino acids.
[0024] Parathyroid hormone functions by stimulating at least three
processes. First, PTH mobilizes calcium from the bone. Although the
mechanisms remain obscure, a well-documented effect of parathyroid
hormone is to stimulate osteoclasts to reabsorb bone mineral,
liberating calcium into blood. Second, PTH enhances absorption of
calcium from the small intestines. Facilitating calcium absorption
from the small intestine would clearly serve to elevate blood
levels of calcium. Parathyroid hormone stimulates this process, but
indirectly by stimulating production of the active form of vitamin
D in the kidney. Vitamin D induces synthesis of a calcium-binding
protein in intestinal epithelial cells that facilitates efficient
absorption of calcium into blood. Third, PTH suppresses calcium
loss in urine. That is, in addition to stimulating fluxes of
calcium into blood from bone and intestine, parathyroid hormone
puts a brake on excretion of calcium in urine, thus conserving
calcium in blood. This effect is mediated by stimulating tubular
reabsorption of calcium. Another effect of parathyroid hormone on
the kidney is to stimulate loss of phosphate ions in urine
(Colorado State University hypertext for biomedical science
website). Thus, PTH (1) increases the calcium and phosphorus
release from bone, (2) decreases the loss of calcium; (3) increases
the loss of phosphorus in the urine; and (4) increases the
activation of 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D in
the kidneys. Secretion of PTH is regulated by the level of calcium
in the blood. Low serum calcium causes increased PTH to be
secreted, whereas increased serum calcium inhibits PTH release.
Typical normal values are 10-55 pg/ml (pg/ml=picograms per
milliliter.) Greater-than-normal levels of PTH may be associated
with (1) chronic renal failure; (2) hyperparathyroidism; (3)
malabsorption syndrome (inadequate absorption of nutrients in the
intestinal tract); (4) osteomalacia in adults; (5) rickets in
children; and (6) Vitamin D deficiency. Lower-than-normal levels
may be associated with (1) autoimmune destruction of the
parathyroid gland; (2) hypomagnesemia; (3) hypoparathyroidism; (4)
metastatic bone tumor; (5) milk-alkali syndrome (excessive calcium
ingestion); (6) sarcoidosis; and (7) vitamin D intoxication. There
is no doubt that chronic secretion or continuous infusion of
parathyroid hormone leads to decalcification of bone and loss of
bone mass. However, in certain situations, treatment with
parathyroid hormone can actually stimulate an increase in bone mass
and bone strength. It has been found that this seemingly
paradoxical effect occurs when the hormone is administered in
pulses (e.g., by once daily injection), and such treatment appears
to be an effective therapy for diseases such as osteoporosis. Thus,
PTH is useful for the treatment of subjects with abnormal levels of
parathyroid hormone.
[0025] In another preferred embodiment of the invention, the active
agent is budesonide, a glucocorticoid steroid that is used for the
treatment of a variety of inflammatory disorders, including asthma
and rhinitis. Budesonide is available in several dosage forms,
including a formulation for pulmonary delivery marketed under the
name PULMICORT.RTM. (AstraZeneca), which includes micronized
budesonide and lactose and is administered via a nebulizer. The
current invention provides inhaleable budesonide formulations that
can be administered via a dry powder inhaler and exhibit
significant stability, as shown in Example 3. The budesonide
formulations of the invention can be used to treat any inflammatory
condition, including those conditions for which budesonide is known
to be effective, including asthma, allergic or infectious rhinitis,
nasal polyps, and inflammatory bowel disease.
[0026] 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
symptoms or condition being treated. Dosages for a particular
patient 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 the therapeutic, prophylactic or diagnostic agent range
from about 0.1 milligrams (mg) to about 100 mg. In another
embodiment, at least 5 milligram of a therapeutic, prophylactic or
diagnostic agent is delivered by administering, in a single breath,
to a subject's respiratory tract the biocompatible particles
enclosed in the receptacle. Preferably at least 5 milligrams of
therapeutic, prophylactic or diagnostic agent is delivered to a
subject's respiratory tract. Amounts of drug as high as 15, 20, 25,
30, 35, 40 or 50 milligrams can be delivered.
[0027] The terms "treating", "treatment" and the like are used
herein to mean affecting a subject, tissue or cell to obtain a
desired pharmacologic and/or physiologic effect. The effect may be
prophylactic in terms of completely or partially preventing a
disease or other undesirable condition, for example, conditions
characterized by abnormal levels of parathyroid hormone as
described above.
[0028] The term "subject" or "patient" as used herein refers to any
animal having a disease or condition which requires treatment with
a pharmaceutically active agent e.g., a therapeutic, prophylactic
or diagnostic agent, in particular parathyroid hormone or a
fragment thereof. The subject may be a mammal, preferably a human,
or may be a non-human primate or non-primates such as used in
animal model testing.
[0029] The invention is also 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 therapeutic, prophylactic or diagnostic
agent. The invention also includes administering the biocompatible
particles from a receptacle having, holding, containing, storing or
enclosing a mass of particles, to a subject's respiratory
tract.
[0030] In a preferred embodiment, the receptacle is used in a dry
powder inhaler. Examples of dry powder inhalers that can be
employed in the methods of the invention include but are not
limited to the inhalers disclosed is U.S. Pat. Nos. 4,995,385 and
4,069,819, 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 known to those skilled in the
art.
[0031] In one embodiment, at least 80% of the mass of the
biocompatible particles stored in the inhaler receptacle is
delivered to a subject's respiratory system in a single,
breath-activated step. 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 a powder in an inhalation device known to those skilled in
the art.
[0032] In one embodiment, the volume of the receptacle is at least
about 0.37 cm.sup.3. In another embodiment, the volume of the
receptacle is at least about 0.48 cm.sup.3. In yet another
embodiment, are receptacles having a volume of at least about 0.67
cm.sup.3 or 0.95 cm.sup.3. In one embodiment of the invention, the
receptacle is a capsule designated with a capsule size 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, N.J.).
[0033] The receptacle encloses or stores particles, also referred
to herein as powders. The receptacle is filled with particles, as
known in the art. For example, vacuum filling or tamping
technologies may be used. Generally, filling the receptacle with
powder can be carried out by methods known in the art. In one
embodiment of the invention, the article or powder enclosed or
stored in the receptacle have a mass of at least about 0.1
milligram to at least about 20 milligrams. In one embodiment, the
powder enclosed or stored in the receptacle is present in an amount
of at least 0.1, 0.3, 0.6, 0.9, 1, 3, 5, 7, 10, 13, 15, 17, 20, 23,
25, 27, or 30 milligrams.
[0034] 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.
[0035] The invention is also 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.
[0036] 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.
[0037] The invention also features a kit comprising at least two
receptacles, each receptacle containing a different amount of dry
powder therapeutic, prophylactic or diagnostic agents, suitable for
inhalation. The powder can be, but is not limited to any such dry
powder parathyroid hormone or fragment thereof as described herein.
In addition, the invention also features a kit comprising two or
more receptacles comprising two or more unit dosages comprising
particles comprising the therapeutic, prophylactic or diagnostic
agent formulations described herein. The kits may also contain
instructions for the use of the reagents in the kits (e.g., the
receptacles containing the formulation). Through the use of such
kits, accurate dosing can be accomplished.
[0038] The kits described herein can be used to deliver a
therapeutic, prophylactic or diagnostic agent, for example,
parathyroid hormone or a fragment thereof, to a subject in need of
the therapeutic, prophylactic or diagnostic agent. When the
therapeutic, prophylactic or diagnostic agent is parathyroid
hormone, the dose administered to the subject can be altered, for
example, by a patient or by a medical provider, by increasing or
decreasing the number of receptacles (e.g., capsules) of
parathyroid hormone containing particles, thereby increasing or
decreasing the unit dosage of the parathyroid hormone. When a
patient is in need of a higher dose of parathyroid hormone than
usual, that patient can administer to himself or herself additional
receptacles, or a different combination of receptacles, so that the
dose of parathyroid hormone or a fragment thereof is increased to
the desired amount. Conversely, when a patient needs less
parathyroid hormone or a fragment thereof, the patient can
administer to himself or herself fewer receptacles, or a different
combination of receptacles, such that the dose is decreased to the
desired amount. The kits may also contain instructions for the use
of the reagents in the kits (e.g., the receptacles containing the
formulation). Through the use of such kits, accurate dosing can be
accomplished.
Administration of Biocompatible Particles
[0039] Particles of the invention are suitable for delivering a
therapeutic, prophylactic or diagnostic agent to the pulmonary
system. "Pulmonary delivery," as that term is used herein refers to
delivery to the respiratory tract. Pulmonary delivery is generally
the result of oral inhalation by the patient. The "respiratory
tract," as defined herein, 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 (e.g., terminal and respiratory). 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, namely, the alveoli, or deep lung. The
deep lung, or alveoli are typically the desired target of inhaled
therapeutic formulations for systemic drug delivery. In one
embodiment of the invention, most of the mass of particles deposit
in the deep lung or alveoli. In another embodiment of the
invention, delivery is primarily to the central airways. In other
embodiments, delivery is to the upper airways.
[0040] 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 dry powder particles having physical
characteristics characterized by a fine particle fraction (FPF),
geometric and aerodynamic dimensions and by other properties which
favor target lung deposition and are formulated to optimize release
and bioavailability profiles, as further described below. As used
herein, the term "fine particle fraction" of a collection of
particles refers to the fraction by weight, typically expressed as
weight percent, of the total powder which is present as particles
of aerodynamic diameter less than 3.3 .mu.m.
[0041] In one embodiment, the FPF of the formulations of the
invention is at least about 20%. For example, the FPF of the
formulations can be at least about 20% or 30% or 40% or 50%, or 60,
or 70%, or 80%, or 90%.
[0042] The FPF of the particles of the invention can measured in
several ways. In one method of measuring FPF, the gravimetric fine
particle fractions as a percentage of the total powder
(FPF.sub.TP<3.3 .mu.m) were obtained gravimetrically at a flow
rate of 28.3 L/min using stages 0, 2, and 3 of an Andersen Cascade
Impactor (ACI) with effective cut-off diameters of 9.0, 4.7, and
3.3 .mu.m, respectively. Filters were placed on the impaction plate
below stage 3 and on the filter stage of the ACI. A flow meter,
timing device, and vacuum pump were connected to the impactor and
the flow rate was adjusted to 28.3 L/min. The inhaler was then
actuated and powder was emitted, with a total volume of 2 L of air
drawn through the inhaler and impactor. The difference in the
filter weights before and after dose emission was used to calculate
the gravimetric fine particle fractions.
[0043] Another method of measuring the aerodynamic size
distribution is with a Next Generation Impactor (NGI). The NGI
operates on similar principles of inertial impaction as the ACI.
The NGI consists of seven stages and is calibrated at flow rates of
30, 60, and 100 LPM. In contrast to the ACI, for which the impactor
stages are stacked, the stages of the NGI are all in one plane.
Collection cups are used to collect the particles below each stage
of the NGI.
[0044] 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 ACI and NGI, but with five stages in the MSLI. Additionally,
instead of each stage consisting of a solid plate or collection
cup, each MSLI stage consists of a 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.
[0045] In one preferred embodiment, the particles 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 (e.g., 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, N.C.) or a GEOPYC.TM. 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., 10th
Supplement, 4950-4951, 1999. Features which can contribute to low
tap density include irregular surface texture and porous
structure.
[0046] 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.
[0047] The particles of the invention have a preferred size, e.g.,
a volume median geometric diameter (VMGD) of at least about 1
micron. 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 mean
diameter, mass mean 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.
A person skilled in the art can use the term "volume mean geometric
diameter" and "volume median geometric diameter" interchangeably
without regard to their statistical meaning.
[0048] 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 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 to targeted sites within the
respiratory tract.
[0049] 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.
[0050] 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).
[0051] The aerodynamic diameter, d.sub.aer, can be predicted from
the equation:
d.sub.aer=d.sub.g .rho..sub.tap
[0052] where d.sub.g is the geometric diameter, for example the
MMGD, and p is the powder density.
[0053] 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
example, 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.
[0054] 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.
[0055] 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 an aerodynamic diameter ranging from about 1 to
about 3 .mu.m are preferred for delivery to the deep lung.
[0056] 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.
[0057] 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, (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=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. is in 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., of 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] 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. Preferably, the particles are
administered as a dry powder via a dry powder inhaler.
[0060] 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, N.C.),
FLOWCAPS.RTM.. (Hovione, Loures, Portugal), INHALATOR.RTM..
(Boehringer-Ingelheim, Germany), and the AEROLIZER.RTM.. (Novartis,
Switzerland), the diskhaler (Glaxo-Wellcome, RTP, N.C.) and others,
such as known to those skilled in the art. In one embodiment, the
inhaler employed is described in U.S. Pat. No. 6,766,799, issued
Jul. 27, 2004 to Edwards, et al., and in U.S. Pat. No. 6,732,732,
issued May 11, 2004 to Edwards, et al. The entire contents of these
applications are incorporated by reference herein.
Spray Drying
[0061] The invention also is related to producing particles that
have compositions and aerodynamic properties described above. In a
preferred embodiment, the particles of the invention are produced
as a dry powder composition by spray drying. Generally,
spray-drying techniques are described, for example, by K. Masters
in "Spray Drying Handbook", John Wiley & Sons, New York, 1984.
In this method, first and second components can be prepared, one or
both of which comprises a therapeutic, prophylactic or diagnostic
agent. For example, the first component comprises an active agent,
e.g., a parathyroid hormone dissolved in the aqueous phase, and the
second component, comprising excipients e.g., hydroxytricarboxylic
acid or a salt thereof and an HSH, is dissolved in either the
aqueous or organic phase depending on solubility, where the organic
solvent is typically ethanol, or an ethanol/water mixture. The
first and second components can be combined either directly or
through a static mixer to form a combination. The combination can
be atomized to produce droplets that are dried to form dry
particles. In one aspect of this method, the atomizing step can be
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.
[0063] 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.
Preferably, the amount of organic solvent can be present in the
co-solvent in an amount ranging from about 30 to about 90% by
volume. In a more preferred embodiment, the organic solvent is
present in the co-solvent in an amount ranging from about 45 to
about 60% by volume. 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.
[0064] 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. Heated drying gas is introduced to
the spray dryer to provide energy for droplet evaporation and
particle drying. The atomizer can be a rotary atomizer. Such a
rotary atomizer may be vaneless, or may contain a plurality of
vanes. Alternatively the nozzle can be a two-fluid mixing nozzle.
Such a two-fluid mixing nozzle may be an internal mixing nozzle or
an external mixing nozzle. Alternatively the nozzle can be a
pressure nozzle or an ultrasonic nozzle. The means for transporting
the aqueous and organic components can be two or more separate
pumps, or a single pump. The apparatus can also include a geometric
particle sizer that determines a geometric size distribution of the
dry particles, and an aerodynamic particle sizer that determines an
aerodynamic diameter of the dry particles.
[0065] The aqueous solvent and the organic solvent that make up the
active agent solution are combined either directly or through a
static mixer. The active agent solution is then transferred to a
two fluid atomizer nozzle (e.g., within a spray dryer) at a flow
rate of about 5 to 75 g/min (mass) and about 6 to 80 ml/min
(volumetric). For example, the active agent solution is transferred
to the spray drier at a flow rate of 28 g/min and 30 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:
[0066] The pressure within the nozzle is from about 10 psi to 100
psi; an atomization liquid flow rate of about 13 to 67 g/min (mass)
and a liquid feed of 10 to 70 ml/min (volumetric); an atomization
gas flow rate of 10 to 100 g/min; an atomization gas to liquid
ratio from about 1:3 to 6:1; the drying medium, heated air or gas
has a feed rate of about 80 to 110 kg/hr an inlet temperature from
about 90.degree. C. to 150.degree. C.; an outlet temperature from
about 40.degree. C. to 71.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.
[0067] 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 two-fluid atomization includes the Mobile Niro spray
dryer, manufactured by Niro, Denmark. The hot gas can be, for
example, air, nitrogen, carbon dioxide or argon.
[0068] The biocompatible 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 85.degree. C.
[0069] The biocompatible 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.
[0070] The invention is further illustrated by the following
non-limiting examples.
EXAMPLES
Introduction
[0071] The inventors have previously demonstrated that maltodextrin
of various molecular weights (or dextrose equivalents) spray-dries
well in formulations using a variety of processing conditions.
Maltodextrin powders were produced that have low tapped densities
(<0.4 g/mL) and large median geometric particle sizes (>5
.mu.m), that disperse well, and demonstrate good aerodynamic
properties. Maltodextrin powders have a relatively low
hygroscopicity and are stable up to 75% RH (depending upon
molecular weight) and are additionally thermally stable at elevated
temperatures (up to 50.degree. C.). However, maltodextrin contains
carbonyl groups which can act as a reducing sugar and potentially
participate in the Maillard reaction with proteins and/or
peptides.
[0072] Polyalditol is similar in structure and properties to
maltodextrin with the exception of hydrogenation, which converts it
to a sugar alcohol, making it non-reactive with proteins and
peptides susceptible to the Maillard reaction. Based on this
information the rationale for using polyalditol is that it spray
dries similarly to maltodextrin in accordance with the invention,
resulting in powders with good physical stability and aerodynamic
properties, but is less reactive with proteins and peptides in
terms of chemical stability. This and other unexpected advantages
of the polyalditol-containing formulations of the invention are
described in the following studies.
Experimental Procedures
Materials and Methods
Materials
[0073] Teriparatide has an identical sequence to the 34 N-terminal
amino acids of human parathyroid hormone (PTH) and has the same
binding affinity for the surface receptors that mediate its
biological activity. Teriparatide is manufactured by Eli Lilly and
Company using a recombinant DNA technology. Teriparatide used in
the following experiments was obtained through Lilly. Lactose,
trehalose, citric acid, sodium citrate dihydrate, maltodextrin,
calcium chloride, calcium ascorbate, calcium hydroxide and sucrose
were purchased from Spectrum Chemical. Dipalmitoyl
phosphatidylcholine (DPPC) was obtained from Genzyme Corporation.
Dipalmitoyl phosphatidylethanolamine (DPPE), dimyristoyl
phosphatidylethanolamine (DMPE), and distearoyl phosphatidylcholine
(DSPC) were obtained from Avanti Polar Lipids. Innovatol
PD60-polyalditol was purchased from Grain Processing Corporation.
Water for Irrigation was purchased from B. Braun. Water for
Injection was manufactured at Alkermes. Ethanol was purchased from
Pharmco and Aaper Alcohol & Chemical Co. Size 2 HPMC capsules
were manufactured by Shionogi and obtained from Alkermes. Inhalers
were obtained from Alkermes. Budesonide was obtained from Spectrum
Chemicals.
Methods
Spray Drying Process
[0074] Teripearatide inhalation powders (TIP) and budesonide
inhalation powders are produced by spray drying solutions of
dissolved raw materials. The aqueous solution potentially contains
the water soluble excipient(s) and drug(s) if applicable, and the
organic solution contains the solvent, organic soluble excipients
(phospholipids), and drug(s) if applicable. The aqueous and organic
phases can be separately pumped to an ISG (interfacial surface
generator) static mixer, where they are combined. The flow rates of
the individual phases are monitored via flowmeters prior to static
mixing. Based on formulation and solubility requirements, the
in-line feed solutions can be heated to control for temperature.
The combined solution is pumped to an atomizer at the top of a
size-1 Niro spray dryer. The solution is atomized using a 2-fluid
nozzle. The nitrogen gas atomizes the liquid stream, breaking it
into small droplets as it exits the 2-fluid atomizer.
[0075] Nitrogen drying gas is heated to the target temperature and
sent into the drying chamber through a disperser surrounding the
atomizer at the top of the dryer. The atomized liquid droplet is
then dried with the drying gas under vacuum in the spray drying
chamber. The dried powder exits the bottom of the spray dryer and
is carried to the product filter housing by the drying gas, where
it is collected on a product filter bag. Following spray drying,
the filter bag is pulsed with nitrogen, and the filter housing is
air hammered. The powder falls into the collection vessel at the
bottom of the product filter housing and the collection vessel
containing the powder is removed from the system.
[0076] The bulk powder is then transferred at ambient temperature
to an RH (relative humidity) controlled glove box, scraped into an
amber jar, and stored at refrigerated conditions. All runs were
completed on a size 1 Niro spray dryer with a two-fluid atomizer
and baghouse filter for powder collection. The atomization gas rate
was maintained between 10 and 100 g/min. Nozzle back-pressure was
maintained between 10 and 100 psig, and the atomizer gas/feed rate
ratio was maintained between 0.2 and 2.0. The outlet temperature
was maintained between 50.degree. C. and 120.degree. C. The drying
gas rate was maintained between 50 and 150 kg/hr. Total liquid feed
rate for all runs was between 10 and 100 mL/min for all runs.
Volume Median Geometric Particle Size
[0077] Geometric particle size of bulk powder is determined using a
Fraunhofer laser diffraction technique. The equipment consists of a
HELOS diffractometer (Sympatec, Inc.) and a RODOS dispersion system
to control the primary and depression pressures. The dispersed
particles are drawn through a laser beam where the resulting
diffracted light pattern is collected by detectors. The diffraction
pattern is then translated into a volume-based particle size
distribution. The monitored results are the volume median geometric
diameter (VMGD).
Fine Particle Fraction (ACI-3)
[0078] The fine particle fraction of the total dose (FPF<3.3
.mu.m (% TP)) is obtained gravimetrically at a flow rate of 28.3
LPM, using a 3-stage Andersen Cascade Impactor. The screens may be
coated with a solvent, such as methanol, and placed on impaction
plates below each stage to minimize particle bounce. The effective
cut-off diameter of the stages are 9.0 .mu.m, 4.7 .mu.m, and 3.3
.mu.m. A flow meter, flow controller, and pump are connected to the
impactor and the flow rate is adjusted to target. The capsule, with
fill weight of between 2 and 20 mg, is punctured within the
inhaler, and the flow is turned on for 4.2 seconds (target 2.0 L
total volume). The filter is weighed before and after powder
emission to determine the fine particle fraction of the total dose
less than 3.3 .mu.m (% TP).
Emitted Powder (EP) Using Gravimetric Analysis
[0079] The dose emitted from the inhaler is obtained
gravimetrically at various flow rates and volumes, using an inlet
cone and filter assembly connected to a flow meter, flow
controller, and pump. The duration and rate of flow are adjusted
using the flow controller, with durations that correspond to
specific volumes of air. For each determination, the capsule is
punctured within the inhaler; the inhaler is inserted into an
adapter on the cone and filter assembly, and the flow turned on for
the required duration. The filter is removed and weighed to
determine the mass of powder emitted. Multiple determinations are
made for each set of flow conditions. An inhaler is used with flow
parameters of 28.3 LPM flow rate and 2.0 L volume, using a fill
weight of between 2 and 20 mg in size 2 HPMC capsules.
Emitted Geometric Particle Size
[0080] The emitted geometric particle size from the inhaler was
measured according to Alkermes SOP 110-00640 ver.02 that describes
the method for using the IHAv2 and the HELOS laser diffractometer
to obtain the geometric particle size distribution of the emitted
powder. XLP inhalers were used at 28.3 LPM/2.0 L volume, using a
fill weight of 6.+-.0.5 mg in size 2 HPMC capsules.
Tapped Density
[0081] The tapped density of bulk powder is determined using a
modified version of the USP <616> Bulk Density and Tapped
Density method as described in the United States Pharmacopoeia. The
modified method uses a smaller powder volume and reports the mean
tapped density in g/mL, to two significant figures.
Bulk Powder Temperature and Relative Humidity Studies
[0082] The VMGD of the TIP and budesonide formulations was assessed
using the volume median geometric particle size method following
overnight exposure of approximately 50 mg of bulk powder in opened
vials to a range of relative humidity (16, 32, 43, 57, and 75% at
ambient temperature) or elevated temperatures (37 and 50.degree.
C.) in sealed chambers. The test assessed physical stability
(powder agglomeration) to temperature and relative humidity
exposure as indicated by the change in VMGD following overnight
exposure of the powders to various relative humidities or
temperatures.
Water Content
[0083] Water content determination was made on a Brinkmann
(Metrohm) 756 Karl Fischer coulometer with a 774 oven sample
processor using standard methods. A sample weight of 50 mg was used
to allow for the lower water contents of the powders.
Chemical Purity and Drug Content
[0084] Chemical purity and drug content of the drug products were
determined by standard analytical methods as described below.
Teriparatide
[0085] PTH purity and drug content for the PTH-containing
formulations were determined using the following methods.
[0086] Related impurities analysis was performed on a Waters 2695
separations module equipped with a Waters 2487 UV detector. Column
was a Zorbax 300-SB C18, 4.6.times.150 mm, 3.5 .mu.m particle size
(Agilent P/N 863973-902). Mobile phase A was 200 mM sodium sulfate
buffer prepared by dissolving sodium sulfate in HPLC grade water
and adjusting to pH 2.3 using phosphoric acid. Mobile phase B was
acetonitrile. The gradient profile is located in Table 1.
TABLE-US-00001 TABLE 1 HPLC gradient profile for determination of
impurities in teriparatide formulations. Time A B (min.) (%) (%) 0
90 10 5 76 24 35 74 26 45 50 50
Column temperature was 40.degree. C. Samples were stored at
5.degree. C. Flow rate was 1 mL/min. Injection volume was 50 .mu.L.
Samples were prepared in HPLC grade water at a concentration of 250
.mu.g Teriparatide per milliliter of solution.
[0087] A reverse phase-HPLC method was used to measure the drug
assay/content of TIP. As with the impurities method, HPLC grade
water was used to better dissolve samples. Each sample was prepared
in triplicate. The sample of interest was added to each set of 3
assay samples 30 min before being run on the HPLC to avoid
unnecessary degradation in solution. The drug content reported
herein is expressed on a percent dry basis.
Budesonide
[0088] For budesonide, drug content and impurity levels are both
determined by reverse phase HPLC analysis using a Waters Symmetry
C4 3.5 micron, 4.6.times.150 mm column with gradient elution. The
method parameters are shown in Table 2. The gradient profile is
shown in Table 3.
TABLE-US-00002 TABLE 2 Method parameters for determination of
budesonide and impurity levels in budesonide formulations.
Injection volume 20 .mu.L Run time 22 min Column Temperature
30.degree. C. Sample Temperature 2-8.degree. C. Detection 245 nm
Sample Diluent 50% Acetonitrile
TABLE-US-00003 TABLE 3 HPLC gradient profile for determination of
budesonide and impurity levels in budesonide formulations. Flow
rate Time Water Acetonitrile (mL/min) (min) (%) (%) 1 0 90 10 3 90
10 10 30 70 18 30 70
Example 1
Spray Drying TIP Candidates to Understand the Role of Excipients in
Chemical and Physical Stability
[0089] To establish whether the reducing sugars (maltodextrin and
lactose) were contributing to the formation of impurities during
storage, the impact of formulation and spray drying process
conditions on the chemical and physical stability of various spray
dried TIP powders was explored. The experiments were designed to
study the effect of formulation and spray drying process conditions
on the chemical and physical stability of early stage spray dried
TIP powders. The key points of the study included: a broad range of
DPPC: lactose ratios; the level of sodium citrate in the
formulation, sodium phosphate compared to sodium citrate, solution
pH, and ethanol concentration. The powders were initially
characterized and stored refrigerated prior to the initiation of
the stability study. For the stability study, the powders were
equilibrated at 20% RH at ambient temperature overnight. Following
RH equilibration, the bulk powders were sealed in vials with
parafilm and packaged in foil bags. The foil bags were placed in a
controlled temperature environment at either 25.degree. C. for
testing at time zero, 2 weeks and 4 weeks or at 40.degree. C. for
testing at 1 week and 2 weeks.
[0090] The ACI-3 and total related impurity results following
storage of the various formulations, listed in Table 4 demonstrated
several points. Formulations containing either lactose or
maltodextrin generated higher levels of impurities than those
formulations without a reducing sugar excipient. The lactose
formulations produced with high ethanol 55%) and all of the
maltodextrin formulations had greater than 10% impurities following
1 week of storage at 40.degree. C.; whereas the DPPC/citrate (run
3) and polyalditol (run 15) formulations had the lowest levels of
impurities following 1 week of storage at 40.degree. C. The lactose
formulation produced with 30% ethanol had an impurity level of 4%
after 4 weeks of storage at 25.degree. C.; whereas the same
formulation produced with 70% ethanol had an impurity level of 43%.
From this data it was concluded that the presence of reducing
sugars, especially in formulations with ethanol concentrations of
55%, negatively impacted the chemical stability of teriparatide.
Additionally, the DPPC/citrate and polyalditol formulations, runs 3
and 15 respectively, were deemed chemically and physically stable
when stored at 25.degree. C. and were selected for additional
formulation screening studies.
TABLE-US-00004 TABLE 4 Impact of Formulation Excipients on Powder
Properties and Stability Initial Data ACI-3 Impurities VMGD Tapped
1 wk @ 2 wk @ 1 wk @ 2 wk @ 2 wk @ 4 wk @ Lot No. Run Formulation
(ratio) @ 1 bar Density Tzero 40.degree. C. 25.degree. C. Tzero
40.degree. C. 40.degree. C. 25.degree. C. 25.degree. C.
200-00036-122 1 DPPC/Lactose/Citrate/pTH 10.0 0.07 35 35 31 2.5
14.6 21.0 4.4 5.2 (60/20/15.5/4.5)-55% EtOH 200-00036-123 2
DPPC/Lactose/Citrate/pTH 8.2 0.19 31 27 33 2.6 17.6 23.6 4.6 5.5
(60/20/15.5/4.5)-70% EtOH 200-00036-124 3 DPPC/Citrate/pTH 8.2 0.21
24 17 29 2.1 5.4 6.7 2.1 2.7 (80/15.5/4.5)-70% EtOH 200-00036-125 4
Lactose/Citrate/pTH 6.2 0.35 23 21 n.t. 16.4 76.0 n.t. 37.1 42.7
(80/15.5/4.5)-70% EtOH 200-00036-126 5 DPPC/Lactose/Citrate/pTH 6.5
0.21 32 27 n.t. 2.2 18.2 n.t. 4.8 6.0 (70/10/15.5/4.5)-70% EtOH
200-00036-127 6 DPPC/Lactose/Citrate/pTH 6.6 0.25 28 33 n.t. 2.1
14.7 n.t. 5.7 5.0 (40/20/35.5/4.5)-70% EtOH 200-00036-128 7
DPPC/Lactose/Citrate/pTH 6.8 0.25 28 20 n.t. 2.4 17.3 n.t. 4.4 5.3
(70/20/5.5/4.5)-70% EtOH 200-00036-129 8 Lactose/Citrate/pTH 14.8
0.06 23 24 23 2.6 8.4 12.5 4.0 3.8 (80/15.5/4.5)-30% EtOH
200-00036-130 9 DPPC/Lactose/Phosphate/pTH 7.3 0.19 28 18 n.t. 2.3
19.8 n.t. 5.2 6.8 (60/20/15.5/4.5)-70% EtOH-pH 7.0 200-00036-131 10
DPPC/Lactose/Phosphate/pTH 6.3 0.25 20 7 n.t. 2.0 30.7 n.t. 4.2 5.3
(60/20/15.5/4.5)-70% EtOH-pH 5.5 200-00036-132 11
DPPC/Lactose/Phosphate/pTH 7.8 0.25 17 10 n.t. 4.4 28.4 n.t. 8.8
10.4 (60/20/15.5/4.5)-70% EtOH-pH 8.5 200-00036-133 12
DPPC/Phosphate/pTH 8.5 0.23 25 -1 n.t. 1.8 11.1 n.t. 2.5 3.2
(80/15.5/4.5)-70% EtOH 200-00036-134 13 Maltodextrin
M100/Citrate/pTH 7.4 0.12 38 34 n.t. 2.2 14.2 n.t. 5.0 6.0
(88/7.5/4.5)-45% EtOH 200-00036-135 14 Maltodextrin
M100/Citrate/pTH 14.4 0.05 26 23 n.t. 2.7 12.5 n.t. 4.9 5.9
(88/7.5/4.5)-30% EtOH 200-00036-136 15 Polyalditol PD60/Citrate/pTH
14.0 0.06 23 24 25 1.9 2.9 3.4 2.0 2.3 (80/15.5/4.5)-30% EtOH n.t.
denotes not tested
Example 2
Effect of T/RH and Bare Capsule Exposure on TIP Formulations
[0091] In this study, the effect of bare capsule exposure to
patient in-use temperature and relative humidity conditions of
25.degree. C./75% RH and 30.degree. C./75% RH was evaluated to
determine the robustness of these formulation for further
development in preparation for Phase I clinical trials. System
performance was characterized by emitted powder, Fine Particle
Fraction <3.3 .mu.m and water content with bare capsule exposure
times of 30 and 60 minutes. Those results were compared to data
obtained at standard conditions (25.degree. C./30% RH) with zero
minutes of bare capsule exposure. In brief, the dose delivery for
the following TIP formulations was assessed:
[0092] Polyalditol/Citrate/Teriparatide (80/15.5/4.5)
[0093] DPPC/Citrate/Teriparatide (80/15.5/4.5)
[0094] DPPC/CaCl.sub.2/Citrate/Teriparatide (70/10/15.5/4.5)
[0095] DPPC/Sucrose/Citrate/Teriparatide (60/20/15.5/4.5)
The dose delivery results obtained at 30.degree. C./75% RH
(representing Zone 4 conditions) for TIP formulations are shown in
Table 5. There was no effect of bare capsule exposure up to 30
minutes on the dose delivery at 30.degree. C./75% RH for the
polyalditol formulation. The effect of T/RH on the dose delivery
for the DPPC/calcium chloride formulation was greater than the
polyalditol formulation but less than the DPPC or DPPC/Sucrose
formulations. The fine particle fraction results obtained after
bare capsule exposure to the T/RH condition (30.degree. C./75% RH)
are shown in Table 6. For an exposure time of up to 30 minutes no
significant effect was noted to fine particle fraction.
TABLE-US-00005 TABLE 5 The emitted powder results obtained at
30.degree. C./75% RH for TIP formulations Emitted Exposure Powder
(% TP) Formulation Time Standard Lot No: (ratio) (min) Mean
Deviation 200- Polyalditol/ Control 82 1 00036-163
Citrate/Teriparatide 0 82 2 (80/15.5/4.5) 15 78 2 30 79 6 200-
DPPC/CaCl2/ Control 81 2 00036-187 Citrate/Teriparatide 0 63 5
(70/10/15.5/4.5) 200- DPPC/Sucrose/ Control 82 4 00036-151A
Citrate/Teriparatide 0 43 8 (60/20/15.5/4.5) 200- DPPC/Citrate/ 0
24 3 00036-181 Teriparatide 15 24 2 (80/15.5/4.5) 30 27 5
TABLE-US-00006 TABLE 6 The fine particle fraction results obtained
at 30.degree. C./75% RH for TIP formulations FINE PARTICLE Exposure
FRACTION (% TP) Formulation Time Standard Lot No: (ratio) (min)
Mean Deviation 200- Polyalditol/ 0 37 1 00071-009
Citrate/Teriparatide 15 32 4 (80/15.5/4.5) 30 30 2 60 22 5
Example 3
Preparation and Characterization of Spray-Dried
Budesonide/Polyalditol Formulations
[0096] A series of budesonide/polyalditol formulations were
prepared using the general methods described above and the process
parameters set forth in Table 7. The resulting particles were
characterized to determine the effect of certain formulation and
spray drying process conditions on the chemical and physical
stability of spray dried budesonide powders. As set forth in Table
7, these formulations varied in terms of budesonide, polyalditol,
and sodium citrate content, and process conditions, including
solvent composition.
[0097] The stability of the following formulations was assessed at
20% relative humidity and either 40.degree. C. or 25.degree. C.
[0098] Polyalditol/Budesonide/Sodium Citrate 90/5/5
[0099] Polyalditol/Budesonide/Sodium Citrate 65/5/30
[0100] Polyalditol/Budesonide 95/5.
[0101] These formulations were compared to bulk budesonide and
spray-dried budesonide. The results, presented in Table 8, show
that all of the polyalditol formulations tested were stable over
four weeks at 40.degree. C. In fact, the stability of the
budesonide in these formulations was similar to that seen for the
bulk budesonide and the spray-dried budesonide particles.
TABLE-US-00007 TABLE 7 Process parameters for the preparation of
polyalditol/budesonide formulations. Atom. Average Solvent Gas
Tapped Lot Formulation Ratio Rate Formulation Nozzle Yield FPF <
Density Number Ratio Formulation (EtOH/H.sub.2O) (g/min) Ratio
Pressure (%) 3.3 mm (g/mL) 00194-27 95/5 Polyalditol/Budesonide
35/65 30 50 35 7.1 na 0.12 00194-37 95/5 Polyalditol/Budesonide
35/65 35 50 36-45 23 0.14 00194-51 94/5/1
Polyalditol/Budesonide/Citrate 45/55 34 50 45 25 0.08 00194-52
90/5/5 Polyalditol/Budesonide/Citrate 45/55 40 50 55 37.6 25 0.10
00194-53 80/5/15 Polyalditol/Budesonide/Citrate 45/55 38 50 52 6.2
25 0.11 00194-54 65/5/30 Polyalditol/Budesonide/Citrate 45/55 45 50
62 22.9 27 0.10 00194-79 85/10/5 Polyalditol/NaCl/Budesonide 35/65
35 50 43 97.3 0.17 00194-80 75/20/5 Polyalditol/NaCl/Budesonide
35/65 35 50 44 76.7 0.16 00194-84 95/5 Polyalditol/Budesonide 20/80
28 50 33-40 85.7 0.13 00194-85 95/5 Polyalditol/Budesonide 20/80 24
50 39-136 64.0 0.05 00194-86 85/10/5 Polyalditol/Citrate/Budesonide
20/80 26 50 32-37 57.3 0.10
TABLE-US-00008 TABLE 8 Results of stability testing of budesonide
formulations. Mean Mean Mean Mean Mean Mean Mean Water Content
Purity Content Purity Content Purity Content (%) (%) (%) (%) (%)
(%) (%) 2 weeks, 2 weeks, 4 weeks, 4 weeks, Lot Number Formulation
T.sub.0 T.sub.0 T.sub.0 40.degree. C. 40.degree. C. 40.degree. C.
40.degree. C. 00194-52 Polyalditol/Budesonide/Citrate 4.93 97.38
5.86 4.96 97.09 4.97 97.04 00194-54 Polyalditol/Budesonide/Citrate
4.97 97.41 7.41 ND ND 4.94 96.3 00194-37 Polyalditol/Budesonide
5.10 98.04 5.03 5.02 98.02 5.04 97.72 VG0169 Budesonide (bulk API)
98.8 96.88 na 100.19 97 98.94 97 00197-036-2 Budesonide, spray
dried 98.43 97.22 na 96.57 94.62 93.11 93.02 00197-60 Budesonide,
spray dried 97.59 97.32 na ND ND 97.08 97.42
[0102] The patent and scientific literature referred to herein
establishes the knowledge that is available to those with skill in
the art. All United States patents and published or unpublished
United States patent applications cited herein are incorporated by
reference. All published foreign patents and patent applications
cited herein are hereby incorporated by reference. All other
published references, documents, manuscripts and scientific
literature cited herein are hereby incorporated by reference.
[0103] 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.
* * * * *