NZ618002B2 - Dry powder vancomycin compositions and associated methods - Google Patents
Dry powder vancomycin compositions and associated methods Download PDFInfo
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- NZ618002B2 NZ618002B2 NZ618002A NZ61800212A NZ618002B2 NZ 618002 B2 NZ618002 B2 NZ 618002B2 NZ 618002 A NZ618002 A NZ 618002A NZ 61800212 A NZ61800212 A NZ 61800212A NZ 618002 B2 NZ618002 B2 NZ 618002B2
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- vancomycin
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- 239000002105 nanoparticle Substances 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229950003551 ramoplanin Drugs 0.000 description 1
- 108010076689 ramoplanin Proteins 0.000 description 1
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- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
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- 229960001608 teicoplanin Drugs 0.000 description 1
- 229960005240 telavancin Drugs 0.000 description 1
- 108010089019 telavancin Proteins 0.000 description 1
- ONUMZHGUFYIKPM-MXNFEBESSA-N telavancin Chemical compound O1[C@@H](C)[C@@H](O)[C@](NCCNCCCCCCCCCC)(C)C[C@@H]1O[C@H]1[C@H](OC=2C3=CC=4[C@H](C(N[C@H]5C(=O)N[C@H](C(N[C@@H](C6=CC(O)=C(CNCP(O)(O)=O)C(O)=C6C=6C(O)=CC=C5C=6)C(O)=O)=O)[C@H](O)C5=CC=C(C(=C5)Cl)O3)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](NC(=O)[C@@H](CC(C)C)NC)[C@H](O)C3=CC=C(C(=C3)Cl)OC=2C=4)O[C@H](CO)[C@@H](O)[C@@H]1O ONUMZHGUFYIKPM-MXNFEBESSA-N 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
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- HABDXNKVAIZXKJ-XTTLPDOESA-N vancocin sulfate Chemical compound OS(O)(=O)=O.O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 HABDXNKVAIZXKJ-XTTLPDOESA-N 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
Dry powder vancomycin compositions and methods for administering and preparing such compositions. The compositions of the disclosure comprise vancomycin or a pharmaceutically acceptable salt thereof, and a hydrophobic amino acid, wherein the hydrophobic amino acid is present in an amount less than 50% by weight of the composition, and wherein the composition is a substantially amorphous dry powder. A composition of the present disclosure may be administered to a subject via pulmonary administration in an amount effective to treat and/or prevent a bacterial infection in the subject. Administration of an effective amount of a composition of the present disclosure may be particularly useful in treating a gram-positive bacterial infection in a subject suffering from pneumonia, cystic fibrosis, bronchiectasis, or other chronic lung disease with a bacterial infection of the subject's airway and/or lung. The compositions may further comprise a hydrophobic amino acid which may be selected from the group consisting of: tryptophan, tyrosine, leucine, trileucine, and phenylalanine. The compositions may further comprise a carbohydrate bulking agent carbohydrate bulking agent which may be selected from the group consisting of: lactose, mannitol, trehalose, raffinose, and a maltodextrin. 0% by weight of the composition, and wherein the composition is a substantially amorphous dry powder. A composition of the present disclosure may be administered to a subject via pulmonary administration in an amount effective to treat and/or prevent a bacterial infection in the subject. Administration of an effective amount of a composition of the present disclosure may be particularly useful in treating a gram-positive bacterial infection in a subject suffering from pneumonia, cystic fibrosis, bronchiectasis, or other chronic lung disease with a bacterial infection of the subject's airway and/or lung. The compositions may further comprise a hydrophobic amino acid which may be selected from the group consisting of: tryptophan, tyrosine, leucine, trileucine, and phenylalanine. The compositions may further comprise a carbohydrate bulking agent carbohydrate bulking agent which may be selected from the group consisting of: lactose, mannitol, trehalose, raffinose, and a maltodextrin.
Description
[Stamp] ggg
#23h Z1 Wz R-l Zkdp1q P88 Yi Jl C
[Stamp] ggg
#23h Z1 Wz R-l Zkdp1q P88 Yi Jl C
DRY POWDER VANCOMYCIN COMPOSITIONS AND ASSOCIATED S
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to US. . App. Ser. No. 61/487,971 filed May 19,
2011 which is incorporated herein by reference.
OUND
Vancomycin is a glycopeptide antibiotic used in the prophylaxis and treatment of
infections caused by Gram-positive bacteria. ycin is the international nonproprietary
name (INN) corresponding to the compound with the following formula:
It has been proposed that vancomycin acts by inhibiting proper cell wall synthesis in
Gram-positive bacteria. More cally, it is believed that vancomycin prevents incorporation
of N-acetylmuramic acid (NAM) and N—acetylglucosamine (NAG) glycan subunits into the
peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls.
The binding of ycin to the terminal D-alanyl-D-alanine moieties of the NAM/NAG-
peptides prevents their oration into the peptidoglycan matrix.
ycin has been administered intravenously for systemic therapy, as well as orally
in the treatment of pseudomembranous colitis. Vancomycin has also been used off—label in a
nebulized aerosol form for the treatment of various infections of the upper and lower respiratory
tract. However, the use of an approved drug in an off—label manner may put a patient at risk as
the safety and efficacy have not been studied and/or the appropriate dose may not be given.
Furthermore, delivery by nebulization can take up to 20 minutes, which is a significant burden to
patients. Currently, there are no known commercially available dry powder inhalable
forms of vancomycin.
SUMMARY
The present disclosure generally relates to dry powder compositions and methods
for administering and preparing such compositions.
In one embodiment, the present disclosure provides a ition comprising
vancomycin or a pharmaceutically able salt thereof, wherein the ition is a dry
powder.
In an embodiment, the present disclosure provides a composition sing
ycin or a pharmaceutically acceptable salt thereof, and a hydrophobic amino acid,
wherein the hydrophobic amino acid is present in an amount less than 50% by weight of
the composition, and wherein the composition is a substantially amorphous dry powder.
In an embodiment, the t disclosure es use of a composition comprising
vancomycin or a pharmaceutically acceptable salt thereof, and a hydrophobic amino acid,
n the hydrophobic amino acid is present in an amount less than 50% by weight of
the composition, and n the composition is a substantially amorphous dry powder, for
the manufacture of a medicament for pulmonary administration to a subject for the
treatment of a pulmonary or airway condition.
In another embodiment, the present disclosure also provides a method comprising
administering a dry powder composition comprising vancomycin or a pharmaceutically
acceptable salt thereof to a subject via ary administration.
In yet another embodiment, the present disclosure provides a method comprising
spray drying an aqueous composition comprising vancomycin or a pharmaceutically
acceptable salt thereof and a hydrophobic amino acid so as to form a dry powder
composition.
The features and advantages of the present invention will be apparent to those
skilled in the art. While numerous changes may be made by those skilled in the art, such
changes are within the spirit of the invention.
DRAWINGS
Some specific e embodiments of the disclosure may be understood by
referring, in part, to the following description and the accompanying drawings.
Figure 1 is a graph ing the aerodynamic particle size distribution of a dry
powder vancomycin composition (Lot SA010) as measured using the Andersen Cascade
Impactor and Monodose RS0l Model 7 inhaler.
(9674493_1):GGG
Figure 2 is a graph depicting the effect of leucine content on the ry efficiency
of dry powder vancomycin compositions (Lots SA002, SA006, SA007, SA008 and
SA009) as measured using the fast screening impactor and Monodose RS0l Model 7
inhaler. Emitted dose (%) is the amount of drug in the dry powder that exits the inhaler as a
tage of the initial amount of drug in the dry powder present in the capsule. Fine
particle fraction (%) is the amount of drug in the dry powder having an aerodynamic size
less than 5 μm as a percentage of the emitted dose. Delivery efficiency (%) is the amount
of drug in the dry powder having an aerodynamic diameter less than 5 μm as a percentage
of the initial amount of drug in the capsule.
Figure 3 is an image of lab-scale dry powder ycin particles (Lot SA010)
obtained using a scanning electron microscope.
(9674493_1):GGG
Figure 4 is a graph depicting the aerodynamic particle size distribution of a dry powder
vancomycin ition (Lot SAOlO) stored at 25°C and 60% relative humidity (RH) for a
period up to 6 months as measured using the en e Impactor and se RSOl
Model 7 inhaler.
Figure 5 is a graph depicting the emitted dose content uniformity under 3 different
stability conditions for a period up to 6 months of 10 consecutive actuations through a Monodose
RSOl Model 7 inhaler ed to FDA draft guidance specification limits of i- 20% (Lot
SAOlO).
Figure 6 is a graph depicting the aerodynamic particle size distribution of a dry powder
vancomycin composition of the present disclosure (Lot G-ll-26—l) as measured from three
Monodose RSOl Model 7 inhalers tested at 100 L/min for 2.4 3 (equivalent to 4 L) using a Next
Generation Impactor.
Figure 7 is a graph depicting the emitted dose content uniformity across ten Monodose
RSOl Model 7 inhalers tested at 100 L/min for 2.4 5 (equivalent to 4 L) for lot G—l 11. The i
20% and i 25% represent the FDA draft guidance limits.
Figure 8 is a graph depicting the effect of trehalose concentration on the chemical
stability of a dry powder vancomycin composition of the present disclosure at 50°C for 4 weeks.
Figure 9 is a graph depicting a comparison of two lots of dry powder vancomycin
itions containing 10% leucine. One contains no API or process modifications (Lot
SAOIO) and the other has a more pure API , was processed under nitrogen, precautions
were taken to t from light and the water content in the powder composition was lower (Lot
26—1).
Figure 10 is an image of pilot-scale dry powder vancomycin particles (Lot
19SA01.HQ00005) obtained using a scanning electron microscope.
Figure 11 is a graph depicting plasma concentrations as a function of time (semi~log)
after a single dose administration of a ycin dry powder composition (Lot G-l 11) or
intravenous administration of vancomycin (inhaled vancomycin dose 16 mg, ; inhaled
vancomycin dose 32 mg, triangle; inhaled ycin dose 80 mg, square; Intravenous infusion
250 mg over 60 min, circle with line).
While the present disclosure is susceptible to various modifications and alternative forms,
specific example embodiments have been shown in the figures and are herein described in more
detail. It should be understood, however, that the description of specific example embodiments is
not intended to limit the invention to the particular forms disclosed, but on the contrary, this
disclosure is to cover all modifications and lents as illustrated, in part, by the appended
claims.
DESCRIPTION
The present disclosure generally relates to dry powder ycin compositions and
methods for administering and preparing such compositions. In some embodiments, a
composition of the present disclosure may be administered to a subject via pulmonary
administration in an amount effective to treat and/or prevent a bacterial infection in the t.
Administration of an effective amount of a composition of the present disclosure may be
particularly useful in treating a gram-positive bacterial infection in a subject suffering from
pneumonia, cystic fibrosis, bronchiectasis, or other chronic lung disease with a bacterial
infection of the subject’s airway and/or lung.
In one embodiment, a composition of the present disclosure is a dry powder comprising
vancomycin or a pharmaceutically acceptable salt thereof. As used herein, the term vancomycin
es analogues and derivatives of vancomycin. As used herein, the term “dry” means that the
composition has a moisture content such that the particles are readily dispersible in an inhalation
device to form an aerosol. In some embodiments, this moisture t may be below about 10%
by weight water, below about 7% by weight water, below about 5% by weight water or below
about 3% by weight water. Furthermore, as used herein, the term “powder” means a ition
that consists of finely dispersed solid particles that are capable of being readily dispersed in an
inhalation device and subsequently inhaled by a subject so that the particles reach the lungs to
permit ation into the upper and lower airways. Thus, the powder is said to be “respirable.”
In some embodiments, a dry powder composition of the t disclosure may have a tap
density r than about 0.4 g/cm3, greater than about 0.45 g/cm3 or greater than about 0.5
g/cm3. While vancomycin may be predominately used in the descriptions ned in this
disclosure, it should be understood that the present disclosure may be practiced with any other
glycopeptide antibiotics (eg. vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, and
decaplanin), and derivatives and analogues thereof, among other things, to treat certain gram
positive infections.
In certain specific embodiments, a dry powder composition of the present disclosure
comprises vancomycin, or a pharmaceutically acceptable salt thereof, present in an amount of
about 90% by weight of the composition, the powder having a tap density of greater than about
0.4 g/cm3, and r ses leucine in an amount of about 10% by weight of the
composition.
In some embodiments, a dry powder composition of the present disclosure may comprise
particles having an average particle size of less than or equal to about 10 microns (pm) in
diameter as defined by the mass median aerodynamic diameter (MMAD) red using
cascade ion). In some embodiments, at least 95% of the particles have a MMAD of less
than about 10 pm. In some embodiments, the diameter may be less than or equal to about 7 pm.
In other embodiments, the diameter may be less than or equal to about 5 pm. In certain specific
embodiments, the diameter may be between about 0.5 pm and about 5 pm in diameter,
particularly about 1 pm to about 3 um. Dry powder compositions of the present disclosure
comprising particles having an average le size of less than or equal to about 10 mm in
er may be ularly useful for delivery Via an oral tion device.
In other embodiments, a dry powder composition of the present disclosure may comprise
particles having an e particle size of greater than or equal to about 10 pm in er as
defined by MMAD (measured using cascade impaction). In some embodiments, at least 95% of
the particles have a MMAD of greater than about 10 mm. In certain specific embodiments, the
particle size may be between about 10 um and about 50 pm in diameter, particularly about 20
pm to about 40 um. Dry powder compositions of the present disclosure comprising les
having an average particle size of greater than or equal to about 10 um in diameter may be
particularly useful for nasal delivery.
In some embodiments, the particles may be hollow. In some embodiments, the particles
2O may be porous. In some embodiments, the particles may have a spheroidal shape distribution,
which may be relatively uniform. In some embodiments, the vancomycin potency as measured
by microbial activity is effectively unchanged when compared to the unformulated drug (i.e.
within 5% of the drug).
Vancomycin or a pharmaceutically acceptable salt f suitable for use in the present
sure is generally available through various commercial vendors. es of suitable
pharmaceutically acceptable salts of vancomycin include, but are not limited to, vancomycin
hydrochloride, vancomycin sulfate, etc.
In some ments, in addition to vancomycin or a ceutically acceptable salt
thereof, a composition of the present sure may further comprise one or more additives. One
example of a suitable additive includes a hydrophobic amino acid. Such hydrophobic amino
acids may include, but are not limited to, tryptophan, tyrosine, leucine, trileucine and
phenylalanine. In some embodiments, it may be desirable to include a hydrophobic amino acid in
a composition of the present disclosure so as to improve the physical stability and/or
dispersibility of the composition, e the chemical stability of vancomycin or a
pharrnaceutically acceptable salt thereof, and/or to alter the taste of the composition by masking
the bitter taste of vancomycin and its salts, and/or to alter the rate the ition is absorbed
into the systemic circulation from the lung (e.g., increase or slow the rate). While not wishing to
be bound to any particular theory, it is currently believed that the hydrophobic amino acid
additive remains on the surface of the particles and protects them from moisture and light,
thereby increasing the stability of the formulation.
Another example of a suitable additive includes a carbohydrate bulking agent. Such
ydrate bulking agents may include, but are not limited to, lactose, mannitol, ose,
se, and maltodextrins. In some embodiments, it may be desirable to include a
carbohydrate bulking agent in a composition of the present disclosure so as to improve the
physical stability of the composition. Furthermore, in some embodiments, the carbohydrate
bulking agent may also improve the al stability of vancomycin or a aceutically
acceptable salt thereof. Other additives known to those of ordinary skill in the art may also be
included.
Generally, ves suitable for use in the compositions of the present disclosure may be
included in an amount of about 50% or less by weight of the composition, 30% or less by weight
of the ition, or 10% or less by weight of the composition. In other embodiments,
ves suitable for use in the compositions of the present disclosure may be included in an
amount of from about 10% to about 30% by weight of the composition. In other embodiments,
additives le for use in the itions of the present disclosure may be included in an
amount of from about 10% to about 20% by weight ofthe composition.
The compositions of the present disclosure may further comprise pharrnaceutically
acceptable auxiliary substances or nts, including, without limitation, pH adjusting and
buffering agents and/or tonicity adjusting agents, such as, for example, sodium acetate, sodium
lactate, sodium chloride, potassium chloride, calcium chloride, etc. Leucine has the dual benefit
of also modifying the pH. Similarly, the compositions of the present disclosure may contain
pharrnaceutically acceptable carriers and excipients including microspheres, microcapsules,
nanoparticles or the like.
In certain embodiments, the dry powder ition may be reconstituted and the
ing reconstituted powder may have a pH greater than 3.0, preferably greater than 3.5 and
most preferably greater than 4.0.
As previously mentioned, administration of an effective amount of a dry powder
ycin composition may be particularly useful in alleviating symptoms and/or treating
subjects suffering from conditions including, but not limited to pneumonia and cystic fibrosis
with gram-positive bacterial infections, and/or colonization of the airways and/or lung
parenchyma by bacteria or other pathogens susceptible to vancomycin or its derivatives. Other
conditions may include, but are not d to, bronchitis, bronchiectasis, diffuse
panbronchiolitis, bronchiolitis, bronchiolitis obliterans, bronchiolitis obliterans organizing
pneMonia , pneumonia of any cause, including but not d to community ed
pneumonia, nosocomial nia and ventilator associated pneumonia (VAP). es of
gram—positive bacterial infections may include, but are not limited to, bacterial infections by
Streptococcus pneumoniae, and Staphylococcus aureus, including methicillin-resistant
Staphylococcus aureus.
As will be ized by one of ordinary skill in the art, the effective amount needed to
treat a particular condition or disease state will depend on the pathogen, individual, the
condition, length of treatment, the regularity of treatment, the type of vancomycin used, and
other factors, but can be readily determined by one of ordinary skill. The patient can e a
desired dosage by inhaling an appropriate amount of the composition.
A dry powder composition of the present disclosure may be delivered to a subject by any
means so long as the solid particles of the dry powder composition are capable of being inhaled
by a subject so that the particles reach the lungs to permit penetration into the upper and lower
airways. In n embodiments, a dry powder composition of the present disclosure may be
red to a subject by placing the dry powder within a suitable dosage receptacle in a
sufficient amount. Suitable dosage receptacles include those used in reservoir devices (e.g.,
devices that contain more than one dose in which the device itself meters the dose) or factory-
metered dose s (e.g., devices in which each dose is contained in either a single unit or
le . In one example, a suitable oir device may have a dosage receptacle that fits
within a le inhalation device to allow for the aerosolization of the dry powder composition
by dispersion into a gas stream to form an aerosol and then delivering the aerosol so produced
from a mouthpiece attached for subsequent tion by a subject in need of treatment. Such a
dosage receptacle includes any ner enclosing the composition known in the art such as
gelatin, hydroxypropyl methyl cellulose or plastic capsules with a removable portion or body
that can be cut or pierced that allows dispersal of the dry powder composition (e.g., via a gas
stream directed into the container and via centrifugal force). Such containers are exemplified by
those shown in US. Pat. No. 4,227,522 issued Oct. 14, 1980; US. Pat. No. 4,192,309 issued
Mar. 11, 1980; and US. Pat. No. 4,105,027 issued Aug. 8, 1978. Suitable containers also include
those used in conjunction with GlaxoSmithKline’s Ventolin Rotahaler brand powder inhaler or
Fisons’ Spinhaler brand powder inhaler. Another suitable unit—dose container which provides a
superior moisture barrier is formed from an aluminum foil plastic laminate. The powder
composition is filled by weight or by volume into the depression in the formable foil and
hermetically sealed with a covering foil—plastic laminate. Such a container for use with a powder
inhalation device is described in US. Pat. No. 4,778,054 and is used with GlaxoSmithKline’s
ler (US. Pat. Nos. 432; 4,811,731; and 5,035,237). All of these references are
incorporated herein by reference. In other ments, a dry powder composition of the present
disclosure may be red to a subject via a tracheal tube.
In some embodiments, compositions of the present disclosure may be prepared by spray
drying an aqueous mixture of vancomycin or a salt thereof and a pharmaceutically acceptable
carrier under conditions sufficient to provide a respirable dry powder composition. In some
ments, the dry powder composition is substantially amorphous.
lly speaking, spray drying is a process in which a homogeneous aqueous mixture
of vancomycin or a salt thereof and the carrier is introduced via a nozzle (e. g., a two fluid
nozzle), spinning disc or an equivalent device into a hot gas stream to atomize the solution
thereby g fine droplets which subsequently mix into a hot gas stream. The aqueous
mixture may be a on, suspension, slurry, or the like, but should be homogeneous to ensure
uniform distribution of the components in the mixture and ultimately the powdered composition.
Preferably the aqueous mixture is a solution. In some embodiments, the s mixture may
have a solids content of at least 1% by weight water. In other embodiments, the aqueous mixture
may have a solids content of at least 2% by weight water. In other embodiments, the aqueous
mixture may have a solids content of at least 4% by weight water. The solvent, generally water,
rapidly evaporates from the droplets producing a fine dry powder having particles 1 to 5 pm in
diameter.
In some embodiments, the spray drying is done under conditions that result in a
substantially amorphous powder of homogeneous tution having a particle size that is
respirable, a low re content and characteristics that allow for ready aerosolization. In some
embodiments, the particle size of the resulting powder is such that more than about 95% of the
mass is in particles having a diameter of about 10 pm or less.
For the spraying process, such spraying s as rotary ation, pressure
atomization and id atomization can be used. Examples of suitable devices are disclosed in
US. Patent No. 6,372,258, the contents of which are hereby incorporated by reference.
Alternatively, dry powder compositions may be prepared by other processes such as
lyophilization and jet milling as disclosed in W0 91/ 16038, the disclosure of which is hereby
incorporated by reference.
A number of formulation and processing strategies may be useful to improve,
among
other things, the storage and stability properties of the dry powder vancomycin compositions of
the present disclosure. In certain embodiments, the vancomycin used may be chosen to be of a
higher purity. In other embodiments, steps may be taken to avoid oxidation of vancomycin. For
example, processing and packaging of the ition may be performed under nitrogen.
Similarly, in some embodiments the processing and packaging may be performed to minimize
exposure to direct light. Such steps may reduce light-mediated degradation of vancomycin. In
some embodiments, steps may be taken to reduce the amount of moisture in the composition.
Such steps may be useful to avoid hydrolysis, deamidation, and oxidation of vancomycin. As
mentioned above, a carbohydrate bulking agent may be added to the composition, which also
may improve al stability.
Furthermore, while the dry powder vancomycin compositions of the present disclosure
have many ageous properties, in certain ments, one particularly advantageous
property is that the compositions may have a pharrnacokinetic profile that is favorable for
antibacterial efficacy of a time dependent bactericidal antibiotic, such as vancomycin, in that it
may provide a prolonged high concentration of vancomycin in the lung, and y increase the
time during which the m inhibitory concentrations of target pathogens are exceeded.
For example, in certain embodiments, upon administration of a dry powder vancomycin
composition to a subject, the median amount of time necessary for the blood plasma levels of a
subject to reach their m tration of vancomycin (Tmax) may be greater than or equal
to about 30 minutes, greater than or equal to about one hour, or less than or equal to about six
hours. In some embodiments, Tmax may be n about one hour and three hours. Similarly, in
certain embodiments, the median amount of time necessary for blood plasma levels of a t
to decrease to one half of the total maximum tration of vancomycin (t1 r2) may be greater
than six hours. In some embodiments, 121/2 may be about eight hours.
In n embodiments, upon administration of a dry powder vancomycin composition to
a subject, the mean maximum blood plasma concentration of vancomycin (Cmax) may be within
the range of about 50% to about 150% of about 14 x 620 ng/mL, wherein n represents a factor to
be multiplied and may be a value from 0.01 to 10 and when n =1 the dose is 80 mg.
In one particular embodiment, wherein the vancomycin or the pharmaceutically
acceptable salt f is present in an amount of about 80 mg, the dry powder composition may
provide a mean maximum blood plasma concentration of vancomycin within the range of about
50% to about 150% of about 620 ng/mL, a mean AUC0-24h value within the range of about 50%
to about 150% of about 6,250 nghr/mL, and a median Tmax value within the range of about 0.75
1010
hours to 3 hours, as ed following a single pulmonary administration. As would be
recognized by one of skill in the art, for dry powder compositions containing lower or higher
concentrations of ycin than 80 mg, the above ranges may be adjusted directly
proportionally by the dose. Accordingly, in certain embodiments the present disclosure also
provides compositions wherein the vancomycin or the pharmaceutically acceptable salt thereof is
present in the dry powder composition in an amount of about 11 x 80 mg and wherein the dry
powder composition provides: a mean maximum blood plasma concentration of vancomycin
(Cmax) Within the range of about 50% to about 150% of about 11 x 620 ng/mL; an mean AUC0-24h
value within the range of about 50% to about 150% of about n x 6,250 nghr/mL; and a median
Tmax value in the range of about 0.5 hours to about 6 hours, wherein the maximum blood plasma
concentration of vancomycin, the 4h value, and the Tmax value are measured following a
single pulmonary stration of the dry powder composition; wherein n represents a factor to
be multiplied and may be a value from 0.01 to 10.
In some embodiments, the dry powder vancomycin compositions of the present
disclosure may provide a delivery efficiency of 40% or more. In other embodiments, the dry
powder vancomycin compositions of the t disclosure may provide a delivery efficiency of
60% or more. Delivery efficiency (%) is the amount of the dry powder having an namic
diameter less than 5 um as a percentage of the initial amount of dry powder in the capsule.
Delivery efficiency is the emitted dose (%) (i.e., the amount of the dry powder that exits the
inhaler as a percentage of the initial amount of the dry powder present in the capsule) multiplied
by the fine particle fraction (%) (i.e., respirable amount or the amount of the dry powder having a
mass median namic diameter (MMAD) of 5 pm or less as a percentage of the emitted
dose).
In some embodiments, the dry powder ycin itions of the present
disclosure may provide an absolute bioavailability of 40% or more. Absolute bioavailability is
calculated as AUCO-inf of vancomycin after the ycin composition administration divided
by AUCO-inf of vancomycin after enous administration and adjusted for dose.
To facilitate a better understanding of the present invention, the following examples of
certain aspects of some embodiments are given. In no way should the following examples be
read to limit, or define, the entire scope of the invention.
Dry powder vancomycin compositions were produced on a Buchi lab scale spray dryer at
high yield (75—95%) and at two different batch sizes (1 g and 20 g) with no loss in purity. These
powders exhibited very high delivery efficiencies and consistency across lots.
1111
The full aerodynamic le size distribution for the 20 g batch is depicted in Figure 1
showing that the vast majority of the particle size distribution is less than 5 um and that a
significant proportion (approx. 59%) is within the ultra-fine particle fraction (3 pm) predictive of
deep lung delivery.
Initial studies have shown that the emitted dose content uniformity of vancomycin
powders easily meet the FDA’s draft guidance specifications for aerosol dose content uniformity.
This has been one of the greatest challenges facing the pulmonary drug ry ry in the
last 10 years. The specifications state that no more than 1 out of 10 actuations should be outside
i 20% ofthe label claim with no actuation outside i 25% ofthe label claim.
In some embodiments, the delivery efficiency of dry powder vancomycin compositions
may be improved through the addition of small amounts of e (Figure 2). The addition of
leucine to vancomycin powders significantly reduces the water content of the powder and the
mass median aerodynamic diameter. In addition, the addition of leucine results in powders with
more physiologically acceptable pH values. See Table 1 below for the effect of leucine
concentration on powder water content, particle size and reconstituted pH.
TABLE 1
Attribute API 5% Leucine 10% Leucine 20% Leucine
(Lot SA008) (Lot SA006) (Lot SA007)
Water content by Karl r (%) n/a 7.9 6.4 5.8
MMAD by AeroSizer (urn) n/a 1.82 1.71 1.57
Reconstituted pH 3.0 4.0 4.2 4.4
Protocol for making one example of a dry powder vancomycin ition
Solution Preparation
An example batch formula is included in Table 2. The target mass of e is weighed
into a beaker. The required mass of de-ionized water is added and mixed using a magnetic stir
bar. Vancomycin hloride is then added and the solution is stirred for 1.0—1.5 hours until
visibly ciear. The feedstock solution is ed immediately before being spray dried. The
solution tration is approximately 4% w/w total dissolved solids.
1212
TABLE 2
Batch formula for a nominal 90% vancomycin HCl, 10% leucine formulation (Lot SAOlO)
Ingredient Mass (g)
Vancomycin hydrochloride l7.l
Leucine 1.9
Water 475.2
Processing Procedure
A benchtop spray drying system (Buchi model 191) with high efficiency cyclone is used
to generate and t the . For 19 g batch sizes, the powder is more conveniently
recovered from the process stream across 4 cyclone powder collection events. The equilibrium
drying condition is established using de-ionized water. When stable operation is ed, the
nozzle input is switched to feedstock solution. The solution is fed to the dryer until a quarter of
the solution has been utilized and then the nozzle is switched back to water for approximately 5
minutes to clear the system. The dryer is then shutdown momentarily to allow for collector
change-out, restarted immediately and lined—out on water prior to resuming feed solution.
The filled collector is rapidly capped on removal to minimize exposure to room humidity.
Each collector is then transferred into individual glass sample Vials within a low ty dry
glove box and the complete set of vials packaged into an aluminum pouch with desiccant and
heat—sealed.
Figure 3 s a scanning electron microscope (SEM) image of a ycin—leucine
powder formulation from Lot SAOl 0.
Stability of dry powder ycin compositions
Results from a 6-month stability study conducted on Lot SAOlO show that the l
particle size distribution does not change with time (Figure 4). Similarly, the emitted dose does
not change and remains within FDA draft guidance limits of i 20% of the mean (Figure 5). The
chemical stability from this initial study predicted a composition that would require refrigerated
storage.
1313
EXAMPLE 2
As previously mentioned, in some embodiments, dry powder vancomycin compositions
of the present disclosure may be prepared using spray drying methods. Such methods have
proven to be very efficient and exhibit ent batch to batch consistency.
Table 3 below shows yield, primary le size and water content data for batch sizes
ranging from 25 g to 100 g, which were prepared using spray drying methods. X10, X50 and X90
are the mass diameter of particles to which 10%, 50% and 90% of the distribution is smaller,
tively. ND = Not determined.
Additionally, the full namic particle size distribution for Lot G—l 11 is included
in Figure 6 and shows that the vast majority of the particle size distribution is less than 5 pm
(85%) and that a significant proportion (approx. 70%) is within the ultra—fine le fraction
(< 3 um) predictive of deep lung delivery.
TABLE 3
Lot # Lot Size Yield X10 X50 X90 Water
0;) PM (um) (um) (um) t
G—11-18 25 86 0.51 1.20 2.55 5.77
G19 25 89 0.54 1.25 2.49 5.10
D-11—039 50 86 0.47 1.33 2.53 3.99
D040 100 92 0.46 1.34 2.47 3.78
D041 50 ND 0.47 1.31 2.46 4.10
D-ll-042 50 90 0.48 1.31 2.47 3.97
D—11-043 100 ND 0.49 1.32 2.50 3.72
D-l 1,-044 75 92 0.52 1.42 3.61 3.90
D045 75 91 0.49 1.33 2.87 4.34
D—12—001 50 87 0.44 1.24 2.59 4.39
D002 50 84 0.42 1.25 2.59 4.81
D003 50 87 0.44 1.26 2.55 4.35
D004 75 88 0.46 1.27 2.57 4.55
D006 25 91 0.45 1.28 2.63 4.70
Figure 7 shows that the emitted dose content uniformity for Lot G-l 1—26-1 meets the
FDA’s draft guidance specifications for aerosol dose content uniformity (i.e., no more than 1 out
1414
of 10 actuations should be outside i 20% of the label claim with no actuation outside i 25% of
the label .
Stability
A summary ofthe 6-month stability study for Lot G—111 is included in Table 4.
TABLE 4
Attribute Specification Months
0 1 3 6
Appearance White powder Pass Pass Pass Pass
Assay (mg) 13.3 — 18.0 15.9 15.8 15.9 15.3
Purity (%) > 85.0 95.6 95.5 95.8 95.5
Emitted Dose (mg) 9.1 — 13.6 12.0 11.9 12.2 11.9
Fine Particle Dose (mg) 6.3 — 11.7 8.9 8.9 9.2 9.1
Water Content (%) 3.0 — 8.0 4.5 4.6 4.1 4.1
EXAMPLE 3
A carbohydrate g agent was ed in a vancomycin-leucine formulation. The
chemical stability of this formulation was studied at 50°C for 4 weeks. Figure 8 shows that the
addition of a carbohydrate g agent (e. g., trehalose) can improve the chemical stability of
dry-powder vancomycin compositions of the present disclosure.
Two lots of a vancomycin composition containing 10 % leucine were compared. One of
the lots contained no process modifications (Lot SA010) and the other, was processed under
nitrogen, protected from light, and protected from moisture (Lot G—111). As shown in
Figure 9, these modifications significantly ed the degradation of vancomycin. Indeed,
extrapolation of the data suggests the composition to be room temperature stable for at least 2
years.
EXAMPLE 4
The powder production process has been successfully scaled-up from lab to pilot—scale
equipment. The process can produce up to 1,000 g of powder per day at high yield (75%) and
with no loss in purity.
Figure 10 s a SEM image of particles from a 1,000 g lot (Lot 19SA01.HQ00005)
ctured on a Niro Mobile Minor “2000” spray dryer.
Table 5 below shows powder testing data from two scaled—up lots. Table 6 shows the
corresponding final product test results for Lot 19SA01.HQ00002.
1515
TABLE 5
Lot # Lot Size Yield X10 X50 X90 Water
(g) (%) (um) (um) (#1111) Content
19SA01.HQ00002 l 000 75 0.49 1.83 3.92 4.7
19SA01.HQ00005 1 000 75 0.90 1.81 3.52 5.4
TABLE 6
Attribute Specification Results
Appearance White powder Pass
Assay (mg) 13.3 — 18.0 16.5
Purity (%) > 85.0 96.0
Emitted Dose (mg) 9.1 — 13.6 12.4
Fine Particle Dose (mg) 6.3 — 11.7 8.0
Water Content (%) 3.0 — 8.0 4.7
EXAMPLE 5
Following a single administration of a dry powder vancomycin composition (Lot G-l 1-
062-1) in eighteen healthy volunteers, a slow absorption phase followed by an elimination phase
were observed. The main pharmacokinetic parameters after single dose administration of the
inhaled vancomycin composition and enous vancomycin are shown in Table 7. The
corresponding mean plasma concentration curves over 24 h are shown in Figure 11. AUCM
refers to the area under the plasma concentration-time curve to the last measurable time point (24
h) ated by the linear trapezoidal rule. AUCO_jnf refers to the area under the concentration-
time curve to infinity. Cmax refers to the maximum blood plasma concentration of vancomycin,
and Tmax refers to the amount of time ary to reach maximum blood plasma levels of
vancomycin, and tm refers to the elimination half—life associated with the al slope (Ken) 0f
the semilogarithmic drug tration-time curve, calculated as 0.693/Ke].
Table 7
t1/2 Tmax Cmax AUC(0—t) AUC(0-inl)
1616
Inhaled vancomycin
16 mg Mean 8.45 2.08 108.8 6 1,461.4
SD 2.02 0.80 33.2 237.7 257.2
32 mg Mean 8.65 1.83 231.5 2,379.8 3,051.1
SD 0.53 0.61 89.6 975.4 959.1
80 mg Mean 8.04 1.33 617.8 6,257.9 7,135.7
SD 1.30 0.41 230.0 1506.9 1,457.9
IV vancomycin
250 mg Mean 7.23 0.92 10,028.3 41,027.8 44,356.3
SD 1.13 0.20 1767.7 0 3,623.4
The median TmX value was more than one hour with all doses, suggesting a slow
absorption of ycin from the lungs. There was a slight trend towards a shorter Tmax with
increasing doses (16 mg: 2 h (range 1—3 h); 32 mg: 1.5 h (range l-3 h); 80 mg: 1.25 h (range 1—
2 h). The observed Tmax values were considerably higher than ed based on previously
published results with inhaled antibiotic powder (TOBI Podhaler prescribing information, Tmax
of l h with all tested doses ranging from 28 mg to 112 mg). The CmX of vancomycin was very
closely dose proportional between 16 mg and 80 mg (R > 0.95). Likewise, very good dose
linearity was observed in the AUC values between the different inhaled vancomycin doses (R >
0.95). The absolute ilability of vancomycin after the stration of the vancomycin
composition, based on the results from those subjects within each cohort who received both the
vancomycin composition and IV infusion, was on average 49% d: 8% (calculated as AUC0_;M~ of
ycin after the vancomycin composition administration divided by AUCO_inf of
vancomycin after intravenous administration and adjusted for dose).
The m; with the different vancomycin dose levels was very tent, imately
8 h, and longer than the tug observed following intravenous on. The apparent prolongation
of 11/2 further suggests prolonged pulmonary absorption that continued to feed vancomycin into
the systemic circulation during the elimination phase of the concentration curve.
This pharmacokinetic profile is very favorable for antibacterial efficacy of a time
dependent (and concentration-independent at concentrations exceeding approximately 1 ug/ml)
bactericidal antibiotic, such as vancomycin, in that it provides a more prolonged high
1717
concentration of vancomycin in the lung, and thereby increases the time during which the
minimum inhibitory concentrations of target pathogens are exceeded.
ore, the present invention is well adapted to attain the ends and advantages
mentioned as well as those that are inherent therein. The ular embodiments disclosed above
are illustrative only, as the present invention may be modified and practiced in different but
lent manners apparent to those skilled in the art having the benefit of the teachings herein.
Furthermore, no limitations are intended to the details of construction or design herein shown,
other than as described in the claims below. It is therefore evident that the particular illustrative
embodiments disclosed above may be altered or modified and all such variations are considered
within the scope and spirit of the present invention. While compositions and methods are
described in terms of “comprising,97 6‘containing,” or “including” various components or steps,
the compositions and methods can also “consist essentially of” or “consist of” the various
components and steps. All numbers and ranges disclosed above may vary by some amount.
Whenever a numerical range with a lower limit and an upper limit is disclosed, any number and
any included range falling within the range is specifically disclosed. In particular, every range of
values (of the form, “from about a to about b,” or, lently, “from approximately a to b,” or,
lently, “from approximately a—b”) disclosed herein is to be understood to set forth every
number and range encompassed within the broader range of values. Also, the terms in the claims
have their plain, ry meaning unless otherwise explicitly and clearly defined by the
ee. Moreover, the indefinite es “a” or “an,” as used in the claims, are defined herein to
mean one or more than one of the t that it introduces. If there is any conflict in the usages
of a word or term in this specification and one or more patent or other documents that may be
incorporated herein by reference, the definitions that are consistent with this specification should
be adopted.
Claims (27)
1. A composition comprising vancomycin or a pharmaceutically acceptable salt thereof, and a hydrophobic amino acid, wherein the hydrophobic amino acid is present in an amount less than 50% by weight of the composition, and wherein the composition is a ntially amorphous dry powder.
2. The composition of claim 1, wherein the pharmaceutically acceptable salt comprises vancomycin hydrochloride.
3. The composition of claim 1, wherein the hydrophobic amino acid is selected from the group consisting of: tryptophan, tyrosine, leucine, cine, and phenylalanine.
4. The composition of claim 1, wherein the hydrophobic amino acid is leucine.
5. The composition of claim 1, wherein the hydrophobic amino acid is t in an amount less than 30% by weight of the composition.
6. The ition of claim 1, wherein the hydrophobic amino acid is present in an amount of about 10% to about 20% by weight of the composition.
7. The composition of claim 1, further comprising a carbohydrate bulking agent.
8. The ition of claim 7, wherein the carbohydrate bulking agent is selected from the group consisting of: lactose, mannitol, trehalose, ose, and a maltodextrin.
9. The composition of claim 7, wherein the ydrate bulking agent is trehalose.
10. The composition of claim 1, n the dry powder comprises particles having a mass median aerodynamic diameter of less than or equal to about 10 µm.
11. The composition of claim 1, wherein the dry powder comprises particles having a mass median aerodynamic diameter of greater than or equal to about 10 µm.
12. The composition of claim 10, wherein at least 95% of the particles have a mass median aerodynamic diameter of less than about 10 µm. (9674343_1):GGG [Stamp] ggg #23h Z1 Wz R-l Zkdp1q P88 Yi Jl C [Stamp] ggg #23h Z1 Wz R-l Zkdp1q P88 Yi Jl C [Stamp] ggg #23h Z1 Wz R-l Zkdp1q P88 Yi Jl C [Stamp] ggg #23h Z1 Wz R-l Zkdp1q P88 Yi Jl C
13. The composition of claim 1, wherein the dry powder comprises particles having a mass median aerodynamic diameter greater than or equal to about 1 µm and less than or equal to 5 µm.
14. The composition of claim 1, wherein the dry powder is encapsulated in a capsule.
15. The composition of claim 14, wherein the e comprises hydroxypropyl methylcellulose.
16. The composition of claim 1, wherein the dry powder has a moisture content below about 10% by weight water.
17. The composition of claim 1, n the dry powder has a moisture content below about 7% by weight water.
18. The composition of claim 1, wherein the dry powder is substantially ous.
19. The composition of claim 1, wherein the pH of reconstituted powder is greater than 3.0, greater than 3.5, or greater than 4.0.
20. The ition of claim 1, wherein the dry powder has a tap density of greater than about 0.4 g/cm3.
21. The composition of claim 1, wherein: the dry powder has a tap density of greater than about 0.4 g/cm3; wherein ycin or the ceutically acceptable salt thereof is present in an amount of about 90% by weight of the composition; and wherein the hydrophobic amino acid is leucine in an amount of about 10% by weight of the composition.
22. The composition of claim 21, wherein the composition provides a median Tmax value between one and three hours.
23. The composition of claim 21, wherein the composition provides a median Tmax value greater than or equal to one hour. (9674343_1):GGG Page 19 SPRUSON & FERGUSON [Stamp] ggg #23h Z1 Wz R-l Zkdp1q P88 Yi Jl C [Stamp] ggg #23h Z1 Wz R-l Zkdp1q P88 Yi Jl C [Stamp] ggg #23h Z1 Wz R-l Zkdp1q P88 Yi Jl C ] ggg #23h Z1 Wz R-l Zkdp1q P88 Yi Jl C
24. The composition of claim 21, wherein the composition provides a median Tmax value greater than or equal to 30 minutes.
25. The composition of claim 21, wherein the composition provides a median Tmax value less than or equal to 6 hours.
26. The composition of claim 21, wherein the composition provides a mean maximum blood plasma concentration of vancomycin (Cmax) within the range of about 50% to about 150% of about n x 620 ng/mL, wherein n is a value from 0.01 to 10 and n is 1 when the dose of vancomycin is 80 mg.
27. The ition of claim 21, wherein the composition provides a median t
Priority Applications (1)
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NZ704819A NZ704819B2 (en) | 2011-05-19 | 2012-05-21 | Dry powder vancomycin compositions and associated methods |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201161487971P | 2011-05-19 | 2011-05-19 | |
US61/487,971 | 2011-05-19 | ||
PCT/US2012/038775 WO2012159103A1 (en) | 2011-05-19 | 2012-05-21 | Dry powder vancomycin compositions and associated methods |
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NZ618002B2 true NZ618002B2 (en) | 2015-06-30 |
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