NZ718495B2 - Inhalable pharmaceutical compositions comprising coenzyme Q10 - Google Patents
Inhalable pharmaceutical compositions comprising coenzyme Q10 Download PDFInfo
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- NZ718495B2 NZ718495B2 NZ718495A NZ71849512A NZ718495B2 NZ 718495 B2 NZ718495 B2 NZ 718495B2 NZ 718495 A NZ718495 A NZ 718495A NZ 71849512 A NZ71849512 A NZ 71849512A NZ 718495 B2 NZ718495 B2 NZ 718495B2
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- phospholipid
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- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 125000002640 tocopherol group Chemical group 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229940029612 triethanolamine Drugs 0.000 description 1
- VXYADVIJALMOEQ-UHFFFAOYSA-K tris(lactato)aluminium Chemical compound CC(O)C(=O)O[Al](OC(=O)C(C)O)OC(=O)C(C)O VXYADVIJALMOEQ-UHFFFAOYSA-K 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960000497 trovafloxacin Drugs 0.000 description 1
- 238000004879 turbidimetry Methods 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 229960004747 ubidecarenone Drugs 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 230000002485 urinary Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- SUHOQUVVVLNYQR-MRVPVSSYSA-N α-GPC Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N β-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 description 1
Classifications
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- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
Inhalable pharmaceutical compositions can include an aqueous dispersion of particles including a hydrophobic bioactive agent (e.g., CoQ10) suitable for continuous aerosolization. Due to their chemical composition and methods of manufacture, the pharmaceutical compositions exhibit distinctive physicochemical properties that provide advantageous aerosol transmission and output. the compositions comprises: a dispersion of liposomal particles having an average diameter between about 30 and 500 nm, each liposomal particle comprising a hydrophobic bioactive agent, a phospholipid, and an aqueous dispersion vehicle, wherein the ratio of hydrophobic bioactive agent phospholipid is between about 5:1 and about 1:5, the hydrophobic bioactive agent is between about 0.1 and 30 % w/w of the composition, the phospholipid is between about 0.1 and 30 % w/w of the composition, and the liposomal particles are dispersed within the aqueous dispersion vehicle chemical properties that provide advantageous aerosol transmission and output. the compositions comprises: a dispersion of liposomal particles having an average diameter between about 30 and 500 nm, each liposomal particle comprising a hydrophobic bioactive agent, a phospholipid, and an aqueous dispersion vehicle, wherein the ratio of hydrophobic bioactive agent phospholipid is between about 5:1 and about 1:5, the hydrophobic bioactive agent is between about 0.1 and 30 % w/w of the composition, the phospholipid is between about 0.1 and 30 % w/w of the composition, and the liposomal particles are dispersed within the aqueous dispersion vehicle
Description
INHALABLE PHARMACEUTICAL COMPOSITIONS
SING COENZYME Q10
13356464
conventional techniques for delivery of agents to the lung can be ineffective, inefficient,
and/or insufficient. For e, many known methods e aerosols that have
droplets that are two large to deliver a pharmaceutical to the lung, and/or that are too
inconsistent to reliably r a specific dose. Particle formation technologies
developed to address issues such as particle size, for example mechanical micronization
processes and solution-based phase separation processes, can have additional limitations.
Mechanical micronization methods such as milling can cause thermal and/or mechanical
degredation of the ceutical. Spray drying, another method used to micronize
drug nces, can lead to difficulty in collecting small particles.
SUMMARY OF THE INVENTION
The invention provides inhalable pharmaceutical compositions having an
aqueous dispersion of particles including a hydrophobic bioactive agent. Due to their
chemical composition and methods of manufacture, the pharmaceutical compositions
exhibit distinctive physicochemical properties that provide advantageous aerosol
transmission and output, including continuous aerosolization. Accordingly, the
invention provide improved s for the treatment of diseases, including cancer, and
itions capable of delivering bioactive agents to aid in the ent of diseases
and other conditions, ing by inhalation to the lungs.
Since a large amount of the available surface area of the lung is located in the
deep lung, drug delivery can be facilitated by aerosol delivery of particles to the
peripheral alveoli of the deep lung. In contrast, particles deposited in the upper
respiratory tract can be rapidly removed by the mucociliary escalator, subsequently
transported to the throat, and swallowed or d by coughing. The invention, in
s aspects and embodiments es for the delivery of hydrophobic bioactive
agents (e.g., including drugs that are strictly hydrophobic, lipophilic, and/or poorly water
soluble), which are generally difficult to adequately aerosolize, to the deep lung (as well
as other regions of the respiratory tract). In particular, the invention can provides for the
continuous nebulization of nanodispersions of hydrophobic drugs for therapeutic use.
Other ages of the various aspects and embodiments of the invention
e, but are not limited to, high aerosol output (e.g., as measured by total aerosol
[0007a] According to a first aspect of the invention there is provided an inhalable
ceutical ition comprising a dispersion of particles suitable for uous
aerosolization, each particle comprising: coenzyme Q10 (CoQ10); and a phospholipid
selected from dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine
(DSPC), dimyristoylphosphatidylcholine (DMPC), or a combination thereof; wherein the
ratio of CoQ10: phospholipid is between 1:1 and 4:2.5, wherein the particles are sed
within the aqueous dispersion vehicle, wherein the composition can include predominantly
liposomal arrangement, a fraction of liposomes together with other arrangements, or can be
essentially devoid of liposomes, and wherein the composition is formulated for continuous
aerosolization sufficient to deliver a therapeutic dose of the CoQ10 to the subject.
[0007b] According to a second aspect of the invention there is provided the use of an
inhalable pharmaceutical composition for the preparation of a medicament for the
treatment of a lung disease wherein said composition is formulated for administration to a
subject by: aerosolizing a dispersion of particles, thereby forming a able aerosol
comprising a plurality of droplets having a mass median namic er (MMAD)
between 1 and 5 pm, wherein each particle comprising coenzyme Q10 (CoQ10) and a
phospholipid dispersed within an aqueous dispersion vehicle, wherein the ratio of CoQ10:
phospholipid is between 1:1 and 4:2.5, n the composition can include predominantly
liposomal arrangement, a fraction of mes together with other arrangements, or can be
ially devoid of liposomes; n the phospholipid comprises
dipalmitoylphosphatidylcholine , distearoylphosphatidylcholine (DSPC),
dimyristoylphosphatidylcholine (DMPC), or a combination thereof; and wherein the
composition is formulated for continuous lization sufficient to deliver a therapeutic
dose of coenzyme Q10 to the subject.
13356464
In another aspect, the invention features, an inhalable pharmaceutical
composition comprising a dispersion of liposomal particles suitable for continuous
aerosolization. The composition includes a dispersion of liposomal particles having an
average diameter between about 30 and 500 nm, each liposomal particle comprising a
hydrophobic bioactive agent, a olipid, and an s dispersion vehicle. The
ratio of hydrophobic bioactive agentzphospholipid is between about 5:1 and about 1:5,
the hydrophobic bioactive agent is between about 0.1 and 30 % w/w of the composition,
the phospholipid is between about 0.1 and 30 % w/w of the composition, and the
liposomal particles are dispersed within the aqueous dispersion vehicle. And, upon
continuous aerosolization, the ition is capable of achieving a total emitted dose
(TED) of at least about 2,900 ug over 15 seconds.
In still another aspect, the invention features an ble ceutical
composition comprising a dispersion of liposomal particles suitable for continuous
aerosolization. The composition includes a dispersion of liposomal particles having an
average diameter between about 30 and 300 nm, each liposomal particle sing
CoQ10, dipalmitoyl phosphatidylcholine (DPPC), and an aqueous dispersion vehicle.
The ratio of CoQ10:DPPC is n about 5:1 and about 1:5, the CoQ10 is between
about 0.1 and 6 % w/w of the composition, and the liposomal particles are dispersed
within the aqueous dispersion vehicle. And, upon administration to a subject, the
composition is characterized by continuous aerosolization sufficient to e a
therapeutic dose of the hydrophobic bioactive agent to the subject (or, alternatively, the
composition can be characterized by another pharmacokinetic property such as being
capable of achieving a ive agent concentration of at least about 500 ug/g wet lung
tissue or a total emitted dose (TED) of at least about 2,900 pg over 15 seconds).
In yet another aspect, the invention es an inhalable pharmaceutical
composition comprising a dispersion of liposomal particles suitable for continuous
lization. The composition includes a dispersion of liposomal particles having an
e diameter between about 30 and 300 nm, each liposomal particle comprising
CoQ10, distearoyl phosphatidylcholine (DSPC), and an aqueous dispersion vehicle. The
ratio of DSPC is between about 5:1 and about 1:5, the CoQ10 is between about
0.1 and 6 % w/w of the ition, and the liposomal particles are dispersed within the
aqueous dispersion vehicle. And, upon administration to a subject, the composition is
characterized by continuous aerosolization ient to provide a eutic dose of the
hydrophobic bioactive agent to the subject (or, atively, the composition can be
characterized by another pharmacokinetic property such as being capable of achieving a
bioactive agent concentration of at least about 500 ug/g wet lung tissue or a total d
dose (TED) of at least about 2,900 pg over 15 seconds).
In still yet another aspect, the invention features an inhalable pharmaceutical
composition comprising a dispersion of liposomal particles suitable for continuous
aerosolization. The composition includes a dispersion of liposomal particles having an
average diameter between about 30 and 300 nm, each liposomal le sing
CleO, dimyristoyl atidylcholine (DMPC), and an aqueous dispersion vehicle.
The ratio of CoQ10zDMPC is between about 5:1 and about 1:5, the CleO is between
about 0.1 and 6 % w/w of the composition, and the liposomal particles are dispersed
within the aqueous dispersion vehicle. And, upon administration to a subject, the
composition is characterized by continuous aerosolization sufficient to provide a
therapeutic dose of the hydrophobic bioactive agent to the subject (or, alternatively, the
composition can be characterized by another pharmacokinetic property such as being
capable of achieving a bioactive agent concentration of at least about 500 ug/g wet lung
tissue or a total emitted dose (TED) of at least about 2,900 pg over 15 s).
In still another aspect, the invention features a method for ing an
inhalable pharmaceutical composition. The method es the steps of: (i) hydrating
a phospholipid, thereby forming a hydrated phospholipid; (ii) mixing the hydrated
phospholipid, a hydrophobic bioactive agent, and an aqueous dispersion e, thereby
producing a mixture; and (iii) homogenizing the mixture, thereby ing a dispersion
of liposomal particles comprising the phospholipid and hydrophobic bioactive agent
dispersed within the aqueous dispersion vehicle and having an average diameter n
about 30 and 500. The ratio of hydrophobic bioactive phospholipid is between
about 5:1 and about 1:5 the hydrophobic bioactive agent is between about 0.1 and 30 %
w/w of the composition, and the phospholipid is between about 0.1 and 30 % w/w of the
composition. And, upon administration to a subject, the composition is characterized by
continuous aerosolization sufficient to provide a therapeutic dose of the hydrophobic
bioactive agent to the subject (or, atively, the composition can be characterized by
another pharmacokinetic property such as being capable of achieving a bioactive agent
concentration of at least about 500 ug/g wet lung tissue or a total emitted dose (TED) of
at least about 2,900 ug over 15 seconds).
In yet another aspect, the invention features a method for administering an
inhalable pharmaceutical composition. The method includes the steps of: (i)
aerosolizing a dispersion of liposomal particles, thereby forming a respirable aerosol
comprising a ity of ts having a mass median aerodynamic diameter
(MMAD) between about 1 and 5 pm, and (ii) ring a therapeutically effective
amount of the hydrophobic bioactive agent to a lung of a subject in need of treatment.
The dispersion of liposomal les has an average diameter n about 30 and 500
nm, each liposomal particle sing a hydrophobic bioactive agent and a
phospholipid dispersed within an aqueous dispersion e. The ratio of hydrophobic
bioactive agentzphospholipid is between about 5:1 and about 1:5, the hydrophobic
bioactive agent is between about 0.1 and 30 % wiw of the composition, and the
phospholipid is between about 0.1 and 30 % w/w of the composition. And, upon
administration to a subject, the composition is characterized by continuous
aerosolization sufficient to provide a therapeutic dose of the hydrophobic bioactive agent
to the subject (or, alternatively, the composition can be characterized by another
pharmacokinetic property such as being e of achieving a bioactive agent
concentration of at least about 500 ug/g wet lung tissue or a total emitted dose (TED) of
at least about 2,900 ug over 15 seconds).
In still yet another aspect, the invention features an inhalable pharmaceutical
composition prepared by a process including the steps of: (i) hydrating a phospholipid,
thereby forming a hydrated olipid; (ii) mixing the hydrated phospholipid, a
hydrophobic bioactive agent, and an aqueous dispersion vehicle, thereby ing a
mixture; and homogenizing the mixture, thereby producing a dispersion of liposomal
particles comprising the phospholipid and hydrophobic bioactive agent sed within
the aqueous dispersion vehicle and having an average diameter between about 30 and
500, where the ratio of hobic bioactive phospholipid is between about 5:1
and about 1:5, the hydrophobic bioactive agent is between about 0.1 and 30 % w/w of
the composition, and the phospholipid is between about 0.1 and 30 % w/w of the
composition. And, upon administration to a subject, the composition is characterized by
continuous aerosolization ient to provide a therapeutic dose of the hydrophobic
ive agent to the subject (or, atively, the composition can be characterized by
another pharmacokinetic property such as being capable of achieving a bioactive agent
concentration of at least about 500 pg/g wet lung tissue or a total emitted dose (TED) of
at least about 2,900 ug over 15 seconds).
In still another aspect, the invention features a method for adapting a laser
diffraction particle size system for continuously measuring a continuous aerosol. The
method includes the steps of: (i) providing a laser diffraction le size system
comprising a nebulizer reservoir, membrane, laser beam, lens, and air suction source; (ii)
positioning the nebulizer reservoir with the membrane above the upper edge of the laser
beam and at a distance between the lens and the center of an aerosol cloud chamber; and
(iii) positioning the air suction source beneath the laser beam. The adapted system
avoids fogging of the lens by continuously exhausting the aerosol cloud chamber while
continuously measuring ission of the aerosol during continuous aerosolization.
In yet r aspect, the ion es a laser diffraction particle size
system for continuously measuring a continuous aerosol. The system includes (i) a
nebulizer reservoir positioned with a membrane above an upper edge of a laser beam
and at a distance between a lens and the center of an l cloud r; and (ii) an
air suction source positioned beneath the laser beam. The system avoids fogging of the
lens by continuously exhausting the aerosol cloud while continuously measuring
transmission of the aerosol during continuous aerosolization.
In still yet another , the invention features a method for uously
measuring a continuous aerosol. The method es the steps of: (i) providing a
continuous aerosol to a laser diffraction particle size system, the system comprising a
nebulizer reservoir positioned with a membrane above an upper edge of a laser beam
and at a distance n a lens and the center of an aerosol cloud chamber, and an air
suction source positioned beneath the laser beam, and (ii) continuously measuring
transmission of the aerosol while the system avoids fogging of the lens by continuously
exhausting the aerosol cloud chamber.
In still yet another aspect, the invention es a method for manufacturing
and ing the average t transmission (APT) of an inhalable pharmaceutical
composition. The method includes the steps of: (i) hydrating a phospholipid, thereby
forming a ed olipid; (ii) mixing the ed olipid, a hydrophobic
bioactive agent, and an aqueous dispersion vehicle, thereby producing a mixture; (iii)
homogenizing the mixture, thereby producing a dispersion of liposomal particles
comprising the phospholipid and hydrophobic bioactive agent dispersed within the
aqueous dispersion vehicle and having an average diameter between about 30 and 500,
wherein the ratio of hobic bioactive agentzphospholipid is between about 5:1 and
about 1:5, the hydrophobic bioactive agent is between about 0.1 and 30 % w/w of the
composition, and the phospholipid is between about 0.1 and 30 % w/w of the
composition; (iv) aerosolizing the dispersion of liposomal particles, thereby forming a
respirable aerosol comprising a plurality of droplets, each droplet comprising a
dispersion of liposomal particles and having a mass median aerodynamic diameter
(MMAD) between about 1 and 5 pm; (v) providing the respirable aerosol to a laser
diffraction particle size system, the system comprising a nebulizer reservoir positioned
with a membrane above an upper edge of a laser beam and at a distance between a lens
and the center of an aerosol cloud chamber, and an air suction source positioned beneath
the laser beam; and (vi) continuously measuring transmission of l with the laser
diffraction particle size system, thereby determining if the composition is characterized
by a predetermined APT value.
In different embodiments, any of the above aspects can be combined with
any one or more or the features below, as well as any one or more of the features in the
detailed ption and examples.
In various embodiments, the aqueous dispersion vehicle comprises water or
an aqueous salt solution. The aqueous dispersion vehicle can be a buffer such as
phosphate buffered saline.
In some embodiments, the dispersion of liposomal particles is in the form of
a continuous able l sing a plurality of aqueous droplets containing a
dispersion of liposomal particles and having a mass median aerodynamic diameter
(MMAD) between about 1 and 5 pm.
In certain embodiments, the composition is characterized by an APT between
about 50 and 100 % over at least 15 minutes of continuous aerosolization. The
composition can be characterized by an APT between about 50 and 100 %, between
about 60 and 100 %, between about 70 and 100 %, between about 80 and 100 %,
between about 90 and 100 %, between about 50 and 95 %, between about 60 and 95 %,
between about 70 and 95 %, between about 80 and 95 %, between about 90 and 95 %,
between about 50 and 90 %, between about 60 and 90 %, between about 70 and 90 %,
between about 80 and 90 %, less than about 50 %, less than about 55 %, less than about
65 %, less than about 70 %, less than about 75 %, less than about 80 %, less than about
85 %, less than about 90 %, less than about 95 %, less than about 100 %, or any sub-
range or value therebetween. The uous aerosolization can have a duration of
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13,14, 15, 20, 25, 30, 35, 40, 50, or 60 minutes.
The plurality of droplets can have a MMAD between about 1 and 5 um over at least 15
minutes of continuous aerosolization.
In s embodiments, the composition is characterized by an APT
between about 50 and 100 % and after at least seven days of storage. The liposomal
particles have an average diameter between about 30 and 500 nm after at least seven
days of storage. Storage can be at ambient conditions or other controlled conditions
(e. g., in a refrigerator).
In some ments, the composition can be characterized by one or more
physicochemical property. The composition can have a flow index of about 0.4, 0.5, 0.6,
0.7, 0.8, 0.9, 1.0, 1.1, 1.2, or 1.3. The composition can have a viscosity of about 0.1,
0.15, 0.2, 1, 100, or 110 cP. The composition can have a zeta ial of about 2.5, 1.5,
-2.5, -10, -50, -55, or -60 mV. The composition can have a surface tension of about 25,
, 35, 40, 45, or 50 mN/m. The composition can have a yield stress of about 11, 12, 13,
14, 15, 16, 17, or 18 mPa. The sion of liposomal les can have an average
diameter between about 30 and 100 nm, 50 and 150 nm, 30 and 300 nm, 100 and 400
nm, or 200 and 300 nm. The composition can have a polydispersivity index (PDI) of
about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, or 0.7. The ition can have a TAO of at least
about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 %. The composition can have
a TED of at least about 3,600, 3,900, 4,300, or 4,600 ug over 15 seconds (e. g., as
measured by DUSA, see Example 2). The composition can be characterized by non-
Newtonian fluid behavior
In various embodiments, the plurality of droplets can have a mass median
aerodynamic diameter (MMAD) of about 1, 2, 3, 4, or 5 pm. The plurality of droplets
can have a geometric standard deviation (GSD) of less than about 2.5, 2.4, 2.3, 2.2, 2.1,
2.0,1.9, 1.8, 1.7,1.6, 1.5, 1.4,1.3, 1.2,1.1, 1.0, 0.9, 0.8, 0.7, 0.6, or 0.5.
In some embodiment, the hydrophobic bioactive agent includes one or more
analgesics, anti-inflammatory agents, anthelmintics, rrhythmic agents, anti-
bacterial agents, anti-viral agents, oagulants, anti—depressants, anti-diabetics, anti-
epileptics, anti-fungal agents, out agents, anti-hypertensive agents, anti-malarials,
anti-migraine , anti—muscarinic agents, anti—neoplastic agents, erectile dysfunction
improvement agents, immunosuppressants, anti—protozoa] agents, hyroid ,
anxiolytic agents, sedatives, hypnotics, neuroleptics, B-Blockers, cardiac inotropic
agents, corticosteroids, diuretics, anti—parkinsonian , gastro-intestinal agents,
histamine receptor antagonists, keratolytics, lipid ting agents, anti-anginal agents,
cox-2 inhibitors, leucotriene inhibitors, macrolides, muscle relaxants, nutritional agents,
opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-
osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence
agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids,
non-essential fatty acids, and combinations f. The hobic bioactive agent
can include one or more hydrophobic anti-inflammatory d, NSAID agent,
antibacterial agent, antifungal agent, chemotherapeutic agent, vasoldilator, or a
combination thereof.
In certain embodiments, the hydrophobic bioactive agent includes one or
more of acutretin, albendazole, albuterol, aminogluthemide, amiodarone, amlodipine,
amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen,
beclomethsone, benezepril, atate, betamethasone, bicalutanide, budesonide,
bupropion, busulphan, butenafine, calcifediol, calciprotiene, calcitriol, camptothecan,
candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivistatin, cetrizine,
chlorpheniramine, cholecalciferol, azol, cimetidine, cinnarizine, ciprofloxacin,
ide, clarithromycin, clemastine, clomiphene, clomipramine, rogel, codeine,
coenzyme Q10, cyclobenzaprine, cyclosporine, danazol, dantrolene,
dexchlopheniramine, diclofenac, dicoumarol, digoxin, dihydroepiandrosterone,
dihydroergotamine, dihydrotachysterol, dirithromycin, donepezil, efavirenz, eposartan,
ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine,
fenofibrate, fentanyl, fexofenadine, eride, flucanazole, flurbiprofen, fluvastatin,
nytion, frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide,
glipizide, glyburide, glymepride, griseofulvin, halofantrine, ibuprofen, irbesartan,
ecan, isosorbide dinitrate, isotreinoin, nazole, ivermectin, ketoconazole,
ketorolac, lamotrigine, lanosprazole, leflunomide, lisinopril, loperamide, loratadine,
lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mefepristone,
mefloquine, megesterol e, methadone, methoxsalen, metronidazole, miconazole,
midazolam, ol, minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine,
naratiptan, nelfinavir, nifedipine, nilsolidipine, nilutanide, urantoin, nizatidine,
omeprazole, oprevelkin, osteradiol, oxaprozin, paclitaxel, lcitol, paroxetine,
pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone,
pseudoephedrine, pyridostigmine, rabeprazole, raloxifene, refocoxib, inide,
rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosigiltazone, saquinavir,
sertraline, sibutramine, sildenafil citrate, simvastatin, mus, spironolactone,
sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, tin, tazarotene, artan,
teniposide, terbinafine, terzosin, tetrahydrocannabinol, tiagabine, ticlidopine, tirofibran,
dine, mate, topotecan, fene, tramadol, tretinoin, troglitazone,
trovafloxacin, valsartan, venlafaxine, vertoporfin, vigabatrin, vitamin A, vitamin D,
vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, and
combinations thereof.
In various embodiments, the hydrophobic ive agent also includes an
additive selected from the group consisting of deoxyglucoses, deoxyglucose salts,
dihydroxy acetone, succinates, pyruvates, citrates, fumarates, malates, malonates,
lactates, glutarates, and combinations thereof. The additive can be yglucose, 2-
deoxyglucose phosphate, 6—deoxyglucose, 6-deoxyglucose phosphate, dihydroxy
acetone, and combinations thereof.
In some embodiments, the hydrophobic bioactive agent includes CoQ10.
The CleO can substituted by an additive at the 1 position, the 4 position, or
combinations thereof.
In certain ments, the hydrophobic bioactive agent is about 4 % w/w or
less of the composition. The hydrophobic bioactive agent can be about 6, 5, 4, 3, 2, or
1 % w/w or less of the composition.
In various embodiments, the phospholipid includes one or more of lecithin,
lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol,
phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,
osphatidylethanolamine, osphatidylglycerol, lysophosphatidic acid,
lysophosphatidylsen'ne, PEG—phosphatidylethanolamine, PVP-
phosphatidylethanolamine, and combinations f. The phospholipid can include
DPPC, DSPC, DMPC, or a combination thereof. The olipid can be a
substantially pure phospholipid. The phospholipid can be about 3 % W/W or less of the
ition.
In some ments, the ratio of hydrophobic bioactive agent:phospholipid
is about 1: 1, 4:3, or 4:2.5. The ratio of hydrophobic bioactive agent:phospholipid can be
about 5:1, 4:1, 3:1, 2:1, 1:1, 1:2,1:3,1:4, 1:5, or any value therebetween.
In certain ments, the phospholipid is in combination with one or more
absorbents, antifoaming agents, iers, alkalizers, buffers, antimicrobial agents,
antioxidants, binders, solubilizing agents, solvents, viscosity modifiers, humectants,
thickening , and combinations thereof. Alternatively, the composition can consist
essentially of the hydrophobic bioactive agent, phospholipid, and aqueous dispersion
vehicle.
In various ments, the composition includes sodium chloride in an
amount less than about 1.0% w/v of the composition. The composition can include a
salt in an amount making the composition essentially isosmotic with the human lung.
In some embodiments, the dispersion is suspension, nano-suspension,
emulsion, or microemulsion.
[003 8] In certain embodiments, the method also includes aerosolizing the dispersion
of liposomal particles, thereby forming a respirable aerosol comprising a plurality of
droplets, each droplet comprising a dispersion of mal particles and having a mass
median aerodynamic diameter (MMAD) between about 1 and 5 pm.
In various embodiments, mixing includes high shear mixing for up to about 5
minutes at about 10,000 to 20,000 rpm and at about 50 to 65 OC. Mixing can last for up
to about 1, 2, 3, 4, or 5 s. Mixing can be at about , 11,000, 12,000, 13,000,
14,000, 15,000, 16,000, 17,000, 18,000, 19,000, or 20,000 rpm. Mixing can take place
at about 50, 55, 60, or 65 0C. Temperature can vary depending upon the melting point of
the hydrophobic bioactive agent used.
In some embodiments, homogenizing includes microfluidization.
Homoginization can include ultrasonic nization. Homogenizing can include
high pressure homogenization for about 1—50 passes at about 30,000 psi and at about 50
to 65 0C. Homoginization can be for about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or
50 . The pressure can be about 25,000, 26,000, 27,000, 28,000, 29,000, 30,000,
31,000, 32,000, 33,000, 34,000, or 35,000 psi. The temperature can be about 50, 55, 60,
or 65 0C. Temperature can vary depending upon the melting point of the hydrophobic
bioactive agent used.
In certain embodiments, aerosolization includes vibrating mesh nebulization.
Any suitable method for continuous nebulization can be adapted for use with the present
invention.
In various embodiments, delivery achieves a mass fraction deposited of at
least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,15, or 20 %.
In some embodiments, delivery achieves local delivery to the lung
substantially without systemic ry.
In certain ments, delivery achieves an elevated amount of the
hydrophobic bioactive agent in the lung for at least 48 hours after administration.
In various embodiments, upon uous aerosolization, the composition is
e of achieving a bioactive agent concentration of at least about 900, 800, 700, 600,
500, 400, 300, 200, or 100 ug/g wet lung tissue. It will be understood that the archived
wet lung tissue concentration will be effected by the subject, method of administration,
and ation, among other things. Therefore, in various embodiments, the bioactive
agent concentration can be a therapeutically adequate or therapeutically desirable
amount of the particular bioactive agent being used.
In some embodiments, delivering a therapeutically effective amount of the
hydrophobic bioactive agent comprises metering a dose of the bioactive agent.
In certain embodiments, the subject has cancer. The cancer can be lung
cancer. More generally, the subject can have any one or more afflictions affecting the
respiratory tract including, but not limited to, one or more of asthma, allergies, c
obstructive pulmonary disease, chronic bronchitis, acute bronchitis, emphysema, cystic
fibrosis, pneumonia, tuberculosis, pulmonary edema, acute respiratory distress syndrome,
pneumoconiosis, interstitial lung disease, pulmonary edema, pulmonary embolism,
pulmonary ension, pleural effusion, pneumothorax, mesothelioma, ophic
lateral sclerosis, myasthenia gravis, and lung disease.
In various embodiments, the composition does not include an opsonization
r (e. g., an opsonization r that interferes with aerosolization). For example,
the composition can ically exclude a polyoxyethylene polyoxypropylene block
polymer such as a Poloxamer (e.g., poloxymer 188), Pluronic, Lutrol, and Superonic. In
another example, the composition can specifically exclude polyethylene glycol (PEG) of
various chain lengths, polysaccharides, other PEG-containing copolymers, poloxamines,
and the like. Alternatively, ations in accordance with the invention can include
one or more opsonization enhancers in an amount that does not substantially interfere
with aerosolizlation, for example, if the amount opsonization er imparts an
otherwise ble property on the ation. In one ment, the composition
includes a polyoxypropylene-poloxyethylene block polymer at 0.001-5% by weight of
the total composition.
The present ion is bed in further detail by the figures and
es below, which are used only for illustration purposes and are not limiting.
DESCRIPTION OF THE DRAWINGS
shows a schematic diagram of aerosolization of drug dispersions
using a vibrating mesh nebulizer. shows a schematic of several manufacturing
processes.
shows an X—Ray diffraction pattern of bulk powdered CoQ10.
shows a differential scanning calorimetry thermogram of bulk
powdered CoQ10.
shows a Scanning Electron Microscopy (SEM) picture of bulk
powdered CoQ10.
shows particle size distributions of CoQ10 dispersions prepared using
different manufacturing processes.
shows particle size distributions, ed by Laser Diffraction (LD),
of aqueous dispersions of CoQ10 following preparation in the microfluidizer and after 7
days (Formulation A, Table 1).
shows Z—average and PdI values of aqueous dispersions of CoQ10
following preparation in the microfluidizer and after 7 days (Formulation A, Table 1).
Statistical differences were not found for drug particle size distribution characteristics
(Z-average and PdI) neither in formulations prepared with different number of
microfluidization passes and analysed ing preparation nor when the same
formulations were compared at days 0 and 7.
shows hydrodynamic diameters and polydispersity of s
dispersions of CoQ10 (Formulation B, Table 1) following ation in the
microfluidizer using lecithin (top) or DPPC m). (*P S 0.05 when compared to 10
passes; §Not statistically different when compared to the in dispersion prepared
with same number of microfluidization passes).
shows a Malvern Spraytec® coupled with inhalation cell.
shows a schematic diagram of Malvern Spraytec® with inhalation cell in ntal
position. shows a schematic diagram of the “open bench” method discussed in
connection with the Examples below (distances: between membrane and upper edge of
laser beam: 25 mm; n lens and center of aerosol cloud: 25 mm; air suction
beneath laser beam: 10 cm).
shows transmittograms of lecithin dispersions of CoQ10
(Formulation C, Table 1). Results are expressed as means (n = 3) of percentage
transmission relative to nebulization of CoQ10 dispersions for 15 minutes. The slope
values from the linear regression analysis of the curves are evaluated as ement of
steadiness in aerosol production.
shows the slope of transmittograms (top) and Total Aerosol Output
(TAO — bottom) for nebulization of lecithin sions of CoQ10 (Formulation C,
Table 1) during 15 minute nebulization events. (*P S 0.05 compared to other
formulations).
shows a le size distributions analyses of aqueous dispersions of
CoQ10 (Formulation C, Table 1) following preparation in the microfluidizer using laser
diffraction (left) and dynamic light ring (right). (*P S 0.05 compared to
formulations analysed following preparation; §P S 0.05 compared to other formulations
at day 7).
shows Zeta potential and surface tension values related to
formulations of CoQ10 processed at different number of microfluidization passes
(Formulation C, Table 1). Columns and error bars represent means and standard ,
respectively (n = 10 for zeta potential and n = 5 for surface tension). The temperature
during e tension measurement was 25 0C. (*P S 0.05 when compared to 10 passes,
§Not tically different).
shows elements of the Herschel-Bulldey model for aqueous
dispersions of CoQ10 processed at different number of microfluidization passes
(Formulation C, Table 1). No statistical differences were found.
shows a schematic diagram of Dose Uniformity Sampling Apparatus
(DUSA) for Dry Powder rs (DPIs) adapted for nebulizers.
shows a particle size distributions from laser diffraction technique of
aqueous dispersions of CoQ10 following 50 passes in the microfluidizer. Results are
expressed as means i standard deviations (n = 3). Some standard deviations are too
small to be visible on the .
shows Z-average and PdI values of aqueous dispersions of CoQ10
following 50 passes in the microfluidizer. Results are sed as means 1 standard
deviations (n = 3). Some standard ions are too small to be visible on the graph (n
= 3). §Not statistically different.
shows Zeta potential of CleO sions. Results are expressed as
means i standard deviation (n = 3). *P < 0.05 when compared to synthetic
phospholipids.
shows surface tension of CleO dispersions. Results are expressed
as means 4; standard error (11 2 5). The ature values during measurement were 25
0C, 25 °C, 19 0C and 17 0C, respectively. §Not statistically different.
shows elements of the Herschel-Bulldey model for aqueous
dispersions of CleO, expressed as means 1 standard deviations (n = 3). Yield stress of
DSPC formulation is not presented because it follows Power Law model. Some
rd deviations are too small to be visible on the graph. *P < 0.05. §Not
statistically different.
shows an example schematic of a l flow curve of aqueous
dispersions.
shows gical behavior of CleO dispersions. Graphs presented
in different scales are expressed as means i standard deviations (n = 3).
shows transmittograms of saline (control) and lecithin, DMPC,
DPPC and DSPC dispersions of CleO. Results are expressed as means (n = 3) of
percentage transmission relative to nebulization of CleO dispersions for 15 minutes.
The slope values from the linear regression analysis of the curves are evaluated as
measurement of steadiness in aerosol production.
shows slope of ittograms (top) and Total Aerosol Output,
TAO (bottom), expressed as means 1 standard ions (n = 3) relative to nebulization
of CleO dispersions for 15 minutes. §Not statistically different.
shows TED from NGI (top) and from DUSA for DPI adapted for
nebulizers (bottom) of dispersions of CleO. s are expressed as means i standard
deviations (n = 3) of total drug deposited within a 15 second period at initial and final
phases of a ute nebulization event. TED: Total d Dose; DUSA: Dose
Uniformity Sampling Unit; DPI: Dry Powder Inhaler. *P < 0.05 when compared to
synthetic phospholipids. [P < 0.05 within nebulization event. §Not statistically
different compared to each other. iNot statistically different compared to other
synthetic phospholipids.
shows in vitro deposition es of lecithin, DMPC, DPPC and
DSPC dispersions of CoQ10 at a flow rate of 15 L/min using an Aeroneb Pro®
zer. Results are expressed as means 1 standard deviations (n = 3) of the
percentage of total drug deposited within a 15-second period at initial and final phases of
a 15-minute nebulization event.
shows in vitro tion profiles of lecithin, DMPC, DPPC and
DSPC dispersions of CoQ10 at a flow rate of 15 L/min using an Aeroneb Pro®
nebulizer. Results are expressed as means 1 standard deviations (n = 3) of the drug
amount deposited within a 15-second period at initial and final phases of a 15-minute
nebulization event.
shows the aerodynamic properties of lecithin, DMPC, DPPC and
DSPC dispersions of CoQ10 at a flow rate of 15 Limin using an Aeroneb Pro®
nebulizer. Results are expressed as means i standard deviations (n = 3) of MMAD or
GSD within a 15-second period at l and final phases of a 15-minute zation
event. >“P < 0.05 within nebulization event. §P < 0.05 when compared to each other.
A shows the TED NGI and TED DUSA values for the d
formulations. B shows estimated total dose (FPDet) and fraction (FPF) of
aerosolized fine particles from lecithin, DMPC, DPPC and DSPC dispersions of CoQ10
at a flow rate of 15 L/min using an Aeroneb Pro® nebulizer. Results are expressed as
means i standard ions (n = 3) related to a 15-second period at initial and final
phases of a 15-minute zation event. *P < 0.05 when compared to synthetic
phospholipids. TP < 0.05 within nebulization event. §Not statistically different
compared to each other. 1P < 0.05 when compared to each other.
shows average Dv(50) of CoQ10 dispersions aerosolized using
Aeroneb Pro® nebulizer for 15 minutes (11 = 3).
shows an example nose-only dosing apparatus used to aerosolize
CoQ10 to mice. Six mice are individually restrained in a tube, exposing their noses to
the chamber. The zer is positioned between the chamber and the fan that will
provide sufficient airflow to fill the chamber with the drug aerosol. The tubing system is
open to avoid drug recirculation.
shows estimated drug concentration-time profiles of CleO inside
the nose-only inhalation chamber.
shows cumulative estimated doses of CleO from synthetic
olipid formulations lized to mice into a nose—only inhalation chamber
during 15 minutes.
shows mean lung concentrations normalized to wet lung tissue of
CleO from synthetic phospholipid dispersions following aerosolization to mice into a
nose-only tion chamber during 15 minutes. Error bars indicate standard deviation
(n = 6).
shows mean lung trations normalized to animal body weight
of CleO from synthetic phospholipid dispersions following aerosolization to mice into
a nose-only inhalation chamber during 15 minutes. Error bars indicate standard
deviation (n = 6).
shows deposition of CleO in the nasal cavity of mice 0.5 and 1
hour post 15-minute nebulizer dosing. s are expressed as means i standard
deviations (n = 6). >“P < 0.05 when compared to control group. TP < 0.05 when
compared within the same group.
shows transmittograms of aerosolization of DMPC-stabilized
dispersions with different trations of CleO.
shows transmittograms of aerosolization of DMPC- and DSPC—
stabilized dispersions, as compared to an intravenous formulation that includes a
particular opsonisation reducer. FIGS. 39-41 show further charachterization of the
formulations studied in connection with . Other features and ages of the
invention will be apparent from the following detailed description, examples, and claims.
ED DESCRIPTION OF THE INVENTION
As discussed above, the invention provides inhalable pharmaceutical
compositions having an aqueous dispersion of particles including a hydrophobic
ive agent. Due to their chemical ition and methods of manufacture, the
pharmaceutical compositions exhibit distinctive physicochemical properties that provide
advantageous aerosol transmission and , including stable and continuous
aerosolization.
CoQ10 was used as an exemplary hydrophobic bioactive agent. Coenzyme
Q10, also known as CoQ10, ubiquinone or ubidecarenone, occurs naturally in the body.
CoQ10 participates in electron transport and proton transfer in mitochondrial respiration.
Therefore, altering the levels of this antioxidant may have an impact on biological
activities such as aging, neurodegenerative and cardiovascular diseases, and cancer.
CleO is a poorly-water soluble compound presented as a yellow or orange
crystalline powder. The highest plasma concentration of CleO reported in the
literature is 10.7 umol/L (approximately 9 ugimL), which was ed by
administration of a solubilized oral formulations (e.g., commercially available y
supplement or “nutraceutical”). heless, the maximum tolerated dose (MTD) has
yet to be determined. The present invention provides formulations of CleO for
pulmonary delivery with advantageous pharmacokinetic profiles that will e the
pharmacodynamic responses for treating respiratory system malignancies. By delivering
a high amount of drug to the disease site, a lower dose can be used (as compared to
intravenous or oral stration).
The following description provides further detail regarding the inventive
compositions (including the hydrophobic bioactive , olipids, aqueous
dispersion vehicles, and other components), methods of manufacture (including mixing,
homogenization, and aerosolization), and methods of ent (including
pharmacokinetics, pharmacodynamics, and indications). Finally, the detailed
description provides rative examples of the invention, including Example 1:
Development and Characterization of Phospholipid-Stabilized Submicron Aqueous
Dispersions of CoQ10 Adapted for Continuous Nebulization; Example 2: Prediction of
In Vitro Aerosolization Profiles Based on gical Behaviors of Aqueous
Dispersions of CleO; Example 3: Pulmonary tion and Systemic Distribution in
Mice of Inhalable Formulations of CleO; Example 4: Low Concentration Range
Determination of Hydrophobic Drugs Using HPLC; Example 5: Determination of
Suitable Hydrophobic Drug Concentrations in Phospholipid Nanodispersions Suitable
for uous Nebulization; and Example 6: Measuring Inflamatory Reponse to
Pulmonary Administration of Dispersions of Phospholipid Encapsulated Hydrophobic
Bioactive Agents.
COMPOSITIONS
In various embodiments, inhalable pharmaceutical compositions according to
the invention include aqueous dispersion of particles suitable for continuous
aerosolization. The particles each include a hydrophobic bioactive agent and a
phospholipid, and are dispersed within an aqueous dispersion vehicle. In some
ments, the particles are liposomal particles, or include a fraction of mal
particles. In some embodiments, the composition can consist essentially of the
hydrophobic bioactive agent, phospholipid, and aqueous dispersion vehicle. However,
other embodiments including one or more onal components are possible. Various
components for inclusion in the inventive compositions are discussed, in turn, below.
Hydrophobic Bioactive Agents
In various embodiments, one or more hydrophobic ive agents (also
known as lipophilic bioactive agents) can be prepared in inhalable pharmaceutical
compositions. Hydrophobic ive agents are relatively insoluble in water. For
example, a hydrophobic bioactive agent can have a lity in water of less than about
1 part of bioactive agent in about 1000 parts of water.
Suitable lipophilic bioactive agents can include, but are not limited to,
analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-
bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-
epileptics, ungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials,
anti-migraine agents, anti-muscarinic , anti-neoplastic agents, erectile dysfunction
improvement agents, immunosuppressants, rotozoa] agents, anti-thyroid agents,
anxiolytic , sedatives, hypnotics, neuroleptics, B—Blockers, cardiac inotropic
agents, osteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents,
histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents,
cox-2 inhibitors, leucotriene tors, macrolides, muscle relaxants, ional agents,
opioid analgesics, se inhibitors, sex hormones, stimulants, muscle nts, antiosteoporosis
, anti-obesity agents, cognition enhancers, anti-urinary incontinence
agents, nutritional oils, anti—benign prostate hypertrophy , essential fatty acids,
non-essential fatty acids, combinations thereof, and the like.
Non-limiting examples of suitable hobic active agents include, but are
not limited to, acutretin, albendazole, albuterol, aminogluthemide, amiodarone,
amlodipine, amphetamine, ericin B, statin, atovaquone, azithromycin,
baclofen, beclomethsone, benezepril, benzonatate, betamethasone, bicalutanide,
budesonide, bupropion, busulphan, butenafine, calcifediol, calciprotiene, calcitriol,
camptothecan, artan, cin, carbamezepine, carotenes, celecoxib, cerivistatin,
cetrizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine,
ciprofloxacin, cisapn'de, clarithromycin, clemastine, clomiphene, clomipramine,
clopidrogel, codeine, coenzyme Q10, cyclobenzaprine, cyclosporine, danazol,
dantrolene, dexchlopheniramine, diclofenac, dicoumarol, n, dihydro
epiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, donepezil,
efaVirenz, eposartan, ergocalciferol, ergotamine, essential fatty acid s, etodolac,
etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, flucanazole,
flurbiprofen, fluvastatin, fosphenytion, frovatriptan, furazolidone, gabapentin,
gemfibrozil, glibenclamide, glipizide, glyburide, glymcpride, griseofulVin, ntrine,
fen, rtan, irinotecan, isosorbide dinitrate, inoin, nazole,
ivermectin, ketoconazole, lac, lamotrigine, lanosprazole, leflunomide, lisinopril,
loperamide, loratadine, lovastatin, L—thryroxine, , lycopene, medroxyprogesterone,
mefepristone, mefloquine, megesterol acetate, methadone, methoxsalen, metronidazole,
miconazole, midazolam, miglitol, minoxidil, mitoxantrone, montelukast, nabumetone,
nalbuphine, naratiptan, nelfinavir, nifedipine, nilsolidipine, nilutanide, nitrofurantoin,
nizatidine, omeprazole, oprevelkin, osteradiol, oxaprozin, paclitaxel, lcitol,
paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol,
progesterone, pseudoephedrine, pyridostigmine, rabeprazole, fene, refocoxib,
repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosigiltazone,
saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus,
spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, osin, targretin,
tazarotene, telmisartan, teniposide, terbinafine, in, tetrahydrocannabinol, tiagabine,
ticlidopine, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin,
troglitazone, trovatloxacin, valsartan, axine, vertoporfin, Vigabatrin, Vitamin A,
vitamin D, vitamin E, vitamin K, ukast, zileuton, zolmitriptan, zolpidem, zopiclone,
combinations thereof, and the like. Salts, isomers and/or other derivatives of the above-
listed bioactive agents can also be used, as well as combinations thereof.
In various embodiments, CoQ10 can be the hydrophobic ive agent (e.g.,
alone, or in ation with one or more additional bioactive agents). CoQ10,
sometimes referred to herein as CleO or ubidccarenone, is a popular nutritional
supplement and can be found in capsule form in nutritional stores, health food stores,
pharmacies, and the like as a vitamin-like supplement that is hypothesized to help
protect the immune system through the antioxidant properties of ubiquinol, the reduced
form of CleO (ubiquinone). As used herein, CleO can also include tives
f, including, for example, ubiquinol. Similarly CleO can also include ues
of none and ubiquinol, and precursor compounds as well and ations
thereof.
In s embodiments, the lipophilic bioactive agent, such as coenzyme
Q10, can be combined with other bioactive agents or compounds for administration in
vivo. Likewise, any ive agent can be ed with additional additives and/or
excipients. The other bioactive agents, additives, and/or excipients can be hydrophobic
or hilic.
Combinations of bioactive agents can be utilized in accordance with the
present disclosure for the treatment of cancers including, but not limited to, lung cancer.
For example, a lipophilic bioactive agent, such as CleO, can be combined with
deoxyglucoses, including 2-deoxyglucose and/or 2-deoxyglucose salts, 6-deoxyglucose
and/or 6-deoxyglucose salts, as a mixture or blend and administered to a patient in viva.
Suitable salts can include phosphates, lactates, pyruvates, hydroxybutyrates,
ations thereof, and the like. In some embodiments the salt can be a phosphate
such as 2-deoxyglucose phosphate, 6-deoxyglucose phosphate, combinations thereof,
and the like. In other embodiments, the quinone or quinol ring of ubiquinone or
ubiquinol can be substituted at the 1 on, the 4 position, or both, by the
deoxyglucose or salts thereof, such as 2-deoxyglucose or 6-deoxyglucose or salts thereof,
including 2-deoxyglucose phosphate or 6-deoxyglucose phosphate, with the substituted
ubiquinone or ubiquinol then administered to a patient.
] rly, dihydroxy acetone can be combined with CoQ10 as a mixture or
blend and administered to a patient in vivo. In such embodiments, the quinone or quinol
ring of ubiquinone or nol can be substituted at the 1 position, the 4 position, or
both, with the dihydroxy acetone, with the substituted ubiquinone or ubiquinol then
administered to a patient. In other embodiments, compounds which can be administered
with the lipophilic bioactive agent, such as coenzyme Q10, include succinates, pyruvates,
es, fumarates, malates, malonates, lactates, glutarates, combinations thereof, and
the like, with specific examples including, but not limited to, sodium succinate,
potassium ate, combinations thereof, and the like.
Phospholipids
In s embodiments, the bioactive agent is sed within a liposome
and/or otherwise stabilized together with a phospholipid. Liposomes can be formed
from one or more liposome-forming compounds such as phospholipids. Similarly, the
bioactive agent and olipid can form other physical arrangement such as mixtures
and dispersions. Compositions in accordance with the invention can include
predominantly liposomal arrangement, a fraction of liposomes together with other
arrangements, or can be essentially devoid of liposomes. gh various compounds
and combinations thereof, are possible, the final composition must ultimately exhibit the
distinctive physicochemical properties of the invention, which provide advantageous
aerosol transmission and output, pharmacokinetics, and/or pharmacodynamics.
Suitable phospholipids and/or phospholipid derivatives/analogs for forming
liposomes include, but are not limited to, in, lysolecithin, phosphatidylcholine (e.g.
itoyl phosphatidylcholine (DPPC) or dimyristoyl phosphatidylcholine (DMPC),
phosphatidylethanolamine, atidylinositol, phosphatidylglycerol, phosphatidic
acid, phosphatidylserine, lysophosphatidylcholine, osphatidylethanolamine,
lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-
phosphatidylethanolamine, PVP-phosphatidylethanolamine, combinations thereof, and
the like.
In one ment, the phospholipid is a lecithin. Lecithin can be derived
from egg or soybean. Such lecithins include those commercially available as
PHOSPHOLIPON® 8SG, PHOSPHOLIPON® 90G, and PHOSPHOLIPON® 90H (the
fully hydrogenated version of PHOSPHOLIPON® 90G) from an Lecithin
Company, Oxford, CT (part of Lipo Chemicals, Inc. — the Lipo phospholipid catalog
lists other potentially suitable phospholipids, for example those suitable for parenteral
use). Other suitable lecithins include LECINOL S-10® in ble, for example,
from Nikko Chemicals, NOF ), Lipo Chemicals, Inc., and Genzyme Corporation,
as well as other commercial suppliers. Alternatively, in some embodiments it can be
advantageious to select one or more phospholipids that are less hilic than lecithin.
olipids can be ed to confer a negative surface charge to the
ing liposome vesicles, which can reduce processing time and process energy, and
which can aid in the ion of stable liposomes and aerosolization. For example, a
high phosphatidylcholine content lecithin (e.g., dipalmitoyl atidylcholine or
dimyristoyl phosphatidylcholine) can be utilized to form a liposome. An example high
phosphatidylcholine lecithin is PHOSPHOLIPON® 85G, which contains a minimum of
85% of alinoleic acid based-phosphatidylcholine. This lecithin is easy to use and is able
to produce submicron liposomes at low process temperatures (from about 20 0C to about
55 0C) without the addition of any other special additives. PHOSPHOLIPON® 85G
contains, in addition to phosphatidylcholine, approximately 5-7% phosphatidic acid.
Aqueous Dispersion Vehicles
] An aqueous medium, for example water, is required in order to form an
aqueous dispersion ing to the present invention. Example aqueous dispersion
vehicles include water, saline (e.g., iso—osmotic saline, a saline solution that will make
the final formulation iso-osmotic with a subject’s lung), and aqueous buffers (e. g.,
phosphate buffered saline). Other suitable aqueous dispersion vehicles can include other
aqueous solutions that are compatible with the desired chemical ition,
manufacturing method, andi'or medical use.
Additional components
Pharmaceutical compositions in accordance with the invention can include
one or more additional components in addition to the one or more bioactive agent, one
or more phospholipid, and one or more aqueous dispersion e. Additional
components can be used, for example, to enhance formulation of the liposomes
possessing a lipophilic bioactive agent, to improve overall rheological and processing
properties of the liposomes, and to insure microbiological integrity of the resulting
liposomal trate during storage. Such ents include, without limitation,
absorbents, antifoaming agents, acidifiers, alkalizers, s, antimicrobial ,
antioxidants (for example ascorbates, tocopherols, butylated hydroxytoluene (BHT),
polyphenols, phytic acid), binders, biological additives, chelating agents (for example,
disodium ethylenediamine tetra acetic acid (EDTA), odium EDTA, sodium
metasilicate, and the like), rants, external analgesics (for example aspirin,
nonsteroidal nflammatories and the like), steroidal anti-inflammatory drugs (such
as hydrocortisone and the like), preservatives (for example imidazolidinyl urea,
diazolidinyl urea, phenoxycthanol, methylparaben, ethylparaben, propylparaben, and the
like), reducing agents, solubilizing agents, solvents, viscosity modifiers, humectants,
thickening agents, tants, fillers, stabilizers, polymers, protease inhibitors,
antioxidants, tion enhancers, and combinations thereof. Such additional
components can be t in an amount from about 0.001% by weight to about 10% by
weight of the dispersion.
The excipients and adjuvants that can be used in the present disclosure, while
potentially having some activity in their own right, for example, as antioxidants,
generally include compounds that enhance the efficiency and/or efficacy of the active
agents. It is also possible to have more than one ent, adjuvant, or even active
agents in a given respirable aggregate.
Excipients can be selected and added either before or after the drug or
bioactive age particles are formed, in order to enable the drug or ive age particles
to be homogeneously admixed for appropriate administration. Excipients can include
those items described above as suitable for formation of liposomes. Other suitable
excipients include polymers, absorption enhancers, solubility enhancing agents,
dissolution rate enhancing agents, stability enhancing agents, bioadhesive agents,
controlled release agents, flow aids and processing aids. In some embodiments, suitable
excipients include cellulose , acrylic acid polymers, bile salts, and combinations
thereof. Other suitable excipients include those described in detail in the Handbook of
Pharmaceutical Excipients, published jointly by the American Pharmaceutical
Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press,
1986, relevant portions of which are incorporated by reference herein. Such excipients
are commercially available andior can be prepared by techniques within the purview of
those skilled in the art,
Excipients can also be chosen alone or in ation to modify the intended
on of the effective ingredients by ing flow, or bioavailability, or to l
or delay the release of the active agent. Specific non-limiting examples of excipients
include: SPAN 80, TWEEN 80, BRIJ 35, BRIJ 98, ICS, SUCROESTER 7,
SUCROESTER II, STER 15, sodium lauryl sulfate, oleic acid, laureth-9,
laureth-8, lauric acid, vitamin E, TPGS, GELUCIRE 50/13, RE 53/1 0,
LABRAFIL, dipalmitoyl phosphadityl choline, glycolic acid and salts, deoxycholic acid
and salts, sodium fusidate, cyclodextrins, polyethylene glycols, labrasol, polyvinyl
alcohols, polyvinyl pyrrolidones, tyloxapol, cellulose derivatives, polyethoxylated castor
oil derivatives, combinations thereof, and the like.
Examples of suitable humectants include, but are not limited to, polyols and
polyol derivatives, including glycerol, diglycerol, triglycerol, ethylene glycol, propylene
glycol, butylene glycol, pentylene glycol (sometimes referred to herein as 1,2-pentane
diol), isopreneglycol (1,4-pentane diol), 1,5-pentane diol, hexylene glycol, erythritol,
1,2,6-hexanetriol, hylene glycols (“PEG”) such as PEG-4, PEG-6, PEG-7, PEG-8,
PEG-9, PEG-IO, PEG-12, PEG-14, PEG-I 6, PEG-18, PEG-20, and combinations
thereof, sugars and sugar derivatives (including, inter alia, fructose, glucose, maltose,
maltitol, ol, inositol, ol, sorbityl silanediol, sucrose, trehalose, xylose,
xylitol, glucuronic acid and salts f), ethoxylated sorbitol (Sorbeth-6, Sorbeth-20,
Sorbeth-30, Sorbeth-40), ations thereof, and the like. In other ments,
glycols such as butylene glycol, 1,2—pentane diol, glycerin, 1,5-pentane diol,
combinations thereof, and the like, can be utilized as a humectant. Where utilized, any
of the above humectants, including combinations thereof, can be present in amounts
from about 0.1 % by weight to about 20% by weight of the second dispersion, in
embodiments from about 1% by weight to about 5% by weight of the second dispersion.
In some embodiments, a preservative such as phenoxycthanol and a
humectant such as propylene glycol can both be included in the formulation. The
ene glycol can provide humectant activity and assist in the preservation of the
concentrate when ed with phenoxyethanol. The phenoxyethanol and propylene
glycol mix can be water soluble and non-volatile. This embodiment is in contrast with
the use of ethanol for preservation, which is often utilized by ers of liposomal
dispersions. Where present, such preservatives can be present in amounts from about
0.01% by weight to about 3% by weight of the ation.
] Certain embodiments can include a dispersion stabilizing agent. Example
dispersion stabilizing agents include Polyethoxylated (a/k/a pegylated) castor oil
(Cremophor® EL), Polyethoxylated hydrogenated castor oil phor® RH 40),
Tocopherol polyethylene glycol succinate (Pegylated vitamin E, Vitamin E TPGS),
Polysorbates (Tweens®), Sorbitan fatty acid esters (Spans®), Bile acids and bile-acid
salts and DMPC.
Certain embodiments can exclude zation reducers (e.g., opsonization
reducers that can interfere with aerosolization). For example, the composition can
specifically exclude a polyoxyethylene polyoxypropylene block r such as a
Poloxamer (e.g., poloxymer 188), Pluronic, Lutrol, and Superonic. In another example,
the ition can specifically exclude polyethylene glycol (PEG) of various chain
lengths, polysaccharides, other ntaining copolymers, poloxamines, and the like.
Alternatively, formulations in accordance with the invention can include one or more
opsonization enhancers in an amount or kind (e.g., suitable HLB) that does not
substantially interfere with aerosolizlation, for example, if the amount opsonization
enhancer imparts an otherwise desirable property on the formulation. In one
embodiment, the composition includes a polyoxypropylene-poloxyethylene block
polymer at 5% by weight of the total composition. In another ment, the
formulation includes a relatively small amount of one or more hydrophilic polymers, to
e stability and increase TAO while maintaining effective and uous
aerosolization.
Formulations can include pulmonary surfactants and/or mucolytic agents.
Suitable pulmonary surfactants include, but are not limited to, pulmonary surfactant
preparations having the function of natural ary surfactant. These can include
both natural and synthetic pulmonary surfactants. In various embodiments,
compositions which contain olipids andfor pulmonary surfactant proteins can be
utilized.
ary phospholipids that can be used as pulmonary tants include
dipalmitoylphosphatidylcholine (DPPC), palmitoyloleylphosphatidylglycerol (POPG)
and/or phosphatidylglycerol (PG). Other suitable phospholipids include mixtures of
various phospholipids, for example, mixtures of itoylphosphatidyicholine (DPPC)
and palmitoyloleylphosphatidylglycerol (POPG) at a ratio of from about 7 to about 3 to
from about 3 to about 7.
Commercial products that can be used as pulmonary surfactants include
CUROSURF® (INN: PORACTANT ALFA) (Serono, Pharma GmbH,
Unterschleipheim), a natural surfactant from homogenized porcine lungs;
TA® (INN: BERACTANT) (Abbott GmbH, Wiesbaden), extract of bovine
lungs; ALVEOFACT® (INN: BOVACTANT) (Boehringer Ingelheim), t of
bovine lungs; EXOSURF® (INN: COLFOSCERIL PALMITATE) SmithKline),
a synthetic phospholipid containing excipients; SURFACTEN® (INN: SURFACTANT-
TA) (Mitsubishi Pharma Corporation), a pulmonary surfactant extracted from bovine
lungs; INFASURF® (INN: CALFACTANT) (Forest Pharmaceuticals), a surfactant
extracted from calf lungs; ALEC® (INN: PUMACTANT) nnia Pharmaceuticals),
an artificial surfactant of DPPC and PO; and BLES® (BLES Biochemical Inc.), a bovine
lipid extract surfactant.
] Suitable pulmonary tant ns include both proteins obtained from
natural sources, such as pulmonary lavage or extraction from amniotic fluid, and
proteins prepared by genetic engineering or chemical synthesis. Pulmonary surfactant
proteins designated by SP-B (Surfactant Protein-B) and SP-C (Surfactant Protein-C) and
their ed derivatives, including recombinant forms of the proteins, can be utilized
in some embodiments.
Suitable mucolytic agents e, but are not limited to, guaifenesin,
iodinated glycerol, glyceryl olate, terpin hydrate, ammonium chloride, N-
acetylcysteine, bromhexine, ambroxol, iodide, their pharmaceutically acceptable salts,
and combinations f.
In some embodiments, the amount of preservatives utilized in a composition
of the present disclosure including a lipophilic bioactive agent in liposomes can also be
reduced by the ion of additional additives. For example, the amount of
preservatives can be reduced in a composition of the present disclosure by the addition
of multifunctional diols including, but not limited to, 1,2-pentane diol, l,4-pentane diol,
hexylene glycol, propylene glycol, 1,3—butylene glycol, ol or diglycerol,
combinations thereof, and the like, and by lowering the water activity, Aw, via the
addition of humectants described above and through the addition of the soluble
ients. Other examples include soluble ingredients such as pH adjusting and
buffering agents, tonicity adjusting , wetting agents and the like, for example,
sodium acetate, sodium chloride, potassium chloride, m chloride, sorbitan
monolaurate, triethanolamine oleate, and the like. Other buffers that can be added
include sodium hydroxide, potassium hydroxide, ammonium hydroxide,
hanolamine, nolamine, triethanolamine, diisopropanolamine,
aminomethylpropanol, tromethamine, tetrahydroxypropyl ethylenediamine, citric acid,
acetic acid, lactic acid, and salts of lactic acid including sodium lactate, potassium
lactate, lithium lactate, calcium lactate, magnesium e, barium lactate, aluminum
lactate, zinc lactate, sodium citrate, sodium acetate, silver lactate, copper lactate, iron
lactate, manganese lactate, ammonium lactate, combinations thereof, and the like.
In some ments, solubilization of a lipophilic bioactive agent such as
CoQ10 in a material that has both lipophilic and hydrophilic properties can assist in
liposome formulation by forming water-dispersible CleO for encapsulation by a high
atidylcholine lecithin, such as PHOSPHOLIPON® 85G.
Suitable lizing agents for the lipophilic bioactive agent include, for
example, polyoxyalkylene dextrans, fatty acid esters of saccharose, fatty l ethers
of oligoglucosides (e.g., the akylpolyglucosides such as TRITONTM), fatty acid esters of
glycerol (elgl, glycerol istearate or glycerol monolaurate), and polyoxyethylene
type compounds (e.g., yethylene, polyethylene glycol, polyethylene oxide,
SOLUTOLTM CREOMOPHORTM, OLTM, CARBOWAXTM, POLYOXYLTM).
Suitable solubilizers also include polyethoxylated fatty acid esters of sorbitan (e. g.,
Polysorbates, such as TWEENTM, SPANTM, including Polysorbate 20 and Polysorbate
80), fatty acid esters of poly(ethylene oxide) (e.g., polyoxyethylene stearates), fatty
alcohol ethers of poly(ethylene oxide) (e.g., polyoxyethylated lauryl ether,
polyoxyethylene 20 oleyl ether (BRIJ 98)), alkylphenol ethers of poly(ethylene oxide)
(e. g., polyethoxylated octylphenol), polyoxyethylene-polyoxypropylene block
copolymers (also known as poloxamers, such as “PLURONICS”, including IC
F-127, a poloxamer 407 stabilizer), and lated fats and oils (e. g., ethoxylated castor
oil, or polyoxyethylated castor oil, also known as polyethylene glycol—glyceryl
inoleate), as well as combinations thereof.
In some embodiments, suitable solubilizing agents include rbates, e.g.
those sold under the brand name TWEENTM. Examples of such Polysorbates include
Polysorbate 80 (TWEENTM 80), Polysorbate 20 (TWEENTM 20), Polysorbate 60
(TWEENTM 60), Polysorbate 65 (TWEENTM 65), rbate 85 (TWEENTM 85), and
the like, and ations including these materials with other similar surfactants,
including ARLACEL® surfactants, as long as the HLB (Hydrophile-Lipophile Balance)
of the surfactant and surfactant mixture favors the formation of an O/W type on
system.
In some embodiments the active agent(s) can be in solution with one or more
organic solvents, or a combination thereof. The organic solvents can be water miscible
or water ible. Suitable organic solvents include, but are not limited to, ethanol,
methanol, tetrahydrofuran, acetonitrile, acetone, tert-butyl alcohol, dimethyl sulfoxide,
N,N-dimethyl formamide, diethyl ether, methylene chloride, ethyl acetate, isopropyl
acetate, butyl acetate, propyl acetate, toluene, hexane, heptane, pentane, 1,3-dioxolane,
isopropanol, n-propanol, propionaldehyde, combinations thereof, and the like.
S OF MANUFACTURE
Methods for preparing inhalable ceutical compositions in accordance
with the invention include (i) hydrating a olipid, y forming a hydrated
phospholipid; (ii) mixing the hydrated phospholipid, a hydrophobic bioactive agent, and
an aqueous dispersion vehicle, thereby producing a mixture; and (iii) homogenizing the
mixture, thereby ing a dispersion of liposomal les comprising the
phospholipid and hydrophobic bioactive agent sed within the aqueous dispersion
vehicle and having an average diameter between about 30 and 500 nm. The ratio of
hydrophobic bioactive agent2phospholipid is between about 5:1 and about 1:5, the
hydrophobic bioactive agent is between about 0.1 and 30 % w/w of the composition, and
the olipid is between about 0.1 and 30 % w/w of the composition. As a result of
the specific formulation and method of manufacture, the composition is characterized by
advantageous properties, for example, an average percent transmission (APT) between
about 50 and 100 % upon continuous aerosolization. Alternatively, the ition can
be characterized by other pharmacokinetic properties, such as that, upon continuous
aerosolization, the composition is capable of achieving a bioactive agent concentration
of at least about 500 ug/g wet lung tissue or a total emitted dose (TED) of at least about
2,900 ug over 15 seconds.
Although specific embodiments are discussed herein, the sions and
aerosols of the invention can be produced using various techniques within the purview
of those skilled in the art. Such methods include fast freezing methods, precipitation
s, emulsion methods and high pressure nization methods, for example, as
described in , the entire ts of which are hereby orated
herein by reference. Aqueous dispersions according to the present invention can be
prepared using any suitable method (e.g., microfluidization) such as those described in
U.S. patent applications U.S. 61/313,605, U.S. 61/313,632, U.S. 61/385,194 and U.S.
61/3 85,107, the entire contents of each of which are hereby orated herein by
reference.
] Prior to mixing and homogenization, it can be helpful to use a solubilizer
and/or heating, to help solubilize the lipophilic bioactive agent. The temperature of
heating and time of heating can depend upon the specific lipophilic bioactive agent, the
intrinsic thermal stability of the bioactive agent, and lizer utilized. For example,
in some embodiments the lipophilic bioactive agent and solubilizer can be heated to a
temperature of from about 40 °C to about 65° C, or from about 50° C to about 60° C, or
from about 50° C to about 55° C, for a period of time from about 1 minute to about 60
minutes, or about 15 minutes to about 45 minutes, or about 20 minutes to about 30
minutes. The weight ratio of lipophilic bioactive agent to solubilizer may be about 1:1,
in embodiments from about 1:1 to about 4:2, in other embodiments from about 1:2 to
about 3 :2.
For example, a solubilizer such as Polysorbate 80 can be capable of
dissolving a lipophilic ive agent, in embodiments CleO, at high levels, with the
lipophilic bioactive agent completely soluble in the solubilizer at a ratio of from about
1:2 to about 3:2, when heated to a temperature of from about 50 0C to about 55 0C, a
ature which exceeds the melting point of CleO (which is from about 47 0C to
about 48 0C).
As noted above, the amount of solubilizer added to a lipophilic bioactive
agent can depend upon the solubilizer, the lipophilic bioactive agent, and the
phospholipids utilized to form the liposomes. In some embodiments, the solubilizer can
be present in an amount from about 0.2% to 12% by weight, or about 1.5 % to 6.5% by
weight.
The solution of lipophilic bioactive agent and solubilizer can then be
combined with a phospholipid (e.g., to form liposomes) which are in turn formed into a
dispersion with an aqueous dispersion vehicle. To prepare the dispersion, the
phospholipids and aqueous dispersion e can be mixed together and heated, to
approximately 50 0C to 60 0C, e.g., 55 0C, for between about 1-24 hours or for between
about 1-8 hours, e. g., about 1 hour.
] Suitable fast freezing methods for forming aerosolized particles e those
referred to herein as spray freezing into liquid (SFL), as bed in US. Patent No.
6,862,890, the entire disclosure of which is incorporated by reference herein, and ultra-
rapid ng (URF), as described in US. Patent Application Publication No.
2004/0137070, the entire disclosure of which is incorporated by reference herein. In
some embodiments, a suitable SFL method can include mixing an active agent with a
solution agent, and ng the effective ingredient-solution agent mixture through an
insulating nozzle located at, or below, the level of a cryogenic liquid, so that the spray
generates frozen particles. In some embodiments, a suitable URF method can include
contacting a solution including an active agent and at least one ble organic solvent
with a cold surface so as to freeze the solution, and ng the organic solvent.
Suitable precipitation methods for forming aerosolized particles include those
referred to herein as evaporative precipitation into aqueous solution (EPAS), as
described in U. S. Patent No. 6,756,062, the entire disclosure of which is incorporated
by reference herein, and controlled precipitation (CP), as described in US. Patent
Application ation No. 2003/0049323, the entire disclosure of which is
incorporated by reference herein. In some embodiments, a suitable EPAS method can
include dissolving a drug or other active agent in at least one organic solvent to form a
drug/organic mixture, spraying the drug/organic mixture into an aqueous solution, while
concurrently evaporating the organic solvent in the presence of the aqueous solution to
form an aqueous dispersion of the drug particles. In some embodiments, a suitable CP
method can include recirculating an anti-solvent through a mixing zone, dissolving a
drug or other active agent in a solvent to form a solution, adding the solution to the
mixing zone to form a particle slurry in the olvent, and recirculating at least a
n of the particle slurry back through the mixing zone.
] Suitable emulsion methods for forming aerosolized particles include those
referred to herein as HIPE (high internal phase emulsions), as bed in US. Patent
Nos. 021 and 5,688,842, the entire disclosures of each of which are incorporated
by reference herein. In some embodiments, a suitable HIPE method can include
continuously merging into a disperser, in the presence of an emulsifying and stabilizing
amount of a surfactant, a continuous phase liquid stream having a flow rate RJ, and a
disperse phase liquid stream having a flow rate R2, and mixing the merged streams with
a ient amount of shear with R2:Rl sufficiently constant, to form a high internal
phase ratio on without phase inversion or stepwise distribution of an internal
phase into an external phase.
Suitable high pressure homogenization methods for forming aerosolized
particles include those using homogenizer and microfluidizer, for e, as described
in US. patent applications U.S. 61f313,605, US. ,632, US. 61/385,194 and US.
61/3 85,107.
The above methods can produce particles and aerosolized les that are
crystalline or amorphous in logy. Advantageously, none of these s
require mechanical milling or other similar unit operations that can cause thermal
degradation of the active agent.
One or more of the formulations components (e.g., the hydrophobic bioactive
agent, phospholipid, and/or aqueous dispersion vehicle) can be nized by mixing
at high shear to form a liposomal concentrate utilizing homogenizers, , blenders
and similar apparatus within the purview of those skilled in the art. In some
embodiments, commercially available nizers including an Ultra-Turrax TP 18/10
Homogenizer or similar types of stator/rotor homogenizers made by Gifford-Wood,
Frain, 1m and others as well as multi-stage homogenizers, colloid mills, sonolators or
other types of homogenizers can be used to produce ron liposomal dispersions of
the lipophilic bioactive agent. The stator/rotor type homogenizers bed above have
an operational range of from about 100 rpm to about 15,000 rpm and can be supplied
with a range of low shear, standard shear, and high shear head s.
Homogenization can be carried out by mixing the two phases at suitable
speeds of, for example, from about 5,000 rpm to about 15,000 rpm, in some
embodiments about 5,000, 7,500, 10,000, 12,500, or 15,000 rpm or and value or range
therebetween. The shear rate of the homogenizer can also be increased or decreased
independent of the speed of the homogenizing shaft by increasing or decreasing the size
of the processing screen surrounding the homogenizer head.
In some embodiments, liposomes can be produced with both a standard
fication screen and a high shear screen supplied for the Silverson L4RT
nizer. Mixing can occur for a suitable period of time of less than about 90
minutes, in embodiments from about 2 s to about 60 minutes, in embodiments
from about 5 minutes to about 45 minutes. In one embodiment, mixing may occur for
up to almost 5 minutes. The resulting liposomes can have a particle size of from about
nm to about 500 nm, 50 nm to about 200 nm, from about 50 nm to about 150 nm,
from about 50 nm to about 100 nm, from about 50 nm to about 75 nm, from about 75 nm
to about 100 nm, from about 100 nm to about 150 nm.
In embodiments, the components being mixed can be heated to a temperature
n about 45 °C to about 65 °C, in embodiments from about 50 0C to about 55 OC,
and mixed with high shear homogenization at speeds and for periods of time described
above to form submicron liposomes of CleO. Where the lipophilic bioactive agent is
CleO, the processing temperature for the CleO phase, the water/phospholipid phase,
and the ed phases should not exceed about 65 °C in order to avoid oxidative
degradation of the CleO. However, processing the mixture at a temperature from
about 50 °C to about 60 °C can be desirable to obtain a desired viscosity of the
concentrate of from about 5,000 GP to about 100,000 cP, in embodiments from about
,000 CF to about 40,000 cP at from about 35 0C to about 45 0C. In some embodiments,
processing for extended periods, e.g., for up to about 60 minutes at the speeds noted
above within this ature range, should not adversely impact the integrity of the
resulting liposomes.
The particle size of the lipophilic bioactive agent dispersion can be reduced
by utilizing mechanical devices, such as, e.g., milling, application of ultrasonic energy,
forming colloidal-sized droplets in a spray system, or by shearing the particles in a liquid
flowing at high ty in a restricted e. Significant energy can be required to
cleave bulk particles. The smaller particles increase the acial area of the active
agent. In some embodiments, surfactants are used to reduce the acial energy,
thereby stabilizing the dispersion. The particle size ines the total interfacial area
and, thus, the interfacial energy that must be accommodated to achieve a stable system.
As the particle size decreases, increasing energy is required to e the particle, and
since the total surface area increases, the tant must accommodate a greater
interfacial energy.
In a red embodiment, the particle size of the bioactive agent dispersion
is reduced by using a Microfluidizer. In some embodiments, in ng the dispersion
particle size, it can be desirable for the CleO mixture to pass through several cycles in
a Microfluidizer to obtain the desired particle size. For example, a phospholipid
dispersion of a bioactive agent (e.g., CoQ10) of the invention can be passed through at
least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 or more cycles in a Microfluidizer.
Preferably, the phospholipid dispersion of a bioactive agent (e. g., CleO) is passed
through a sufficient number of cycles in a Microfluidizer to obtain a preferred particle
size, e.g., a particle size suitable for asal delivery, e.g., via a nebulizer.
le Microfluidizers for use with the invention include, for example, the
M110P which is available through Microfluidics, Inc. (MFI). The M110P has a 75-um
passage and a F12Y interaction chamber. In sing M3, the Microfluidizer has an
inlet pressure of 25,000 psi. Numerous other Microfluidizers are commonly known in
the art and are contemplated as being suitable for use in the methods of the invention.
Microfluidizers using in the invention can have an inlet pressure of at least about 20,000
psi, at least about 25,000 psi, and preferably at least about 30,000 psi.
In the examples provided herein, after a minimum of 10 cycles through
M110P Microfluidizer with an F12Y interaction chamber with 75-um passages, les
of less than 160 nm mean diameter were produced with lecithin and particles of about
110 nm were produced with DPPC. One of ordinary skill in the art will understand that
the ve amounts of the liophilic bioactive agent (e.g., CoQ10), phospholipids (e.g.,
lecithin, DPPC or DMPC) and aqueous dispersion vehicle can be adjusted based upon
desired ties such as the desired eutic use, aerosolization, pharmacokinetics,
and/or pharmacodynamics. In the es provided herein, the Microfluidizer
operated at a pressure of about 30,000 PSI, although other pressures can be used in other
embodiments.
lization
Methods in accordance with the invention can include aerosolizing the
dispersion of liposomal particles, thereby forming a respirable aerosol comprising a
plurality of droplets, each t comprising a dispersion of liposomal particles and
having a mass median aerodynamic diameter (MMAD) between about 1 and 5 pm.
Though, in some embodiments, particles can have diameters less than 1 um and/or
greater than 5 pm.
Figure 1A shows a schematic of pulmonary delivery of an aqueous liposomal
dispersion of a hydrophobic bioactive agent in accordance with the invention. The bulk
drug is formulated into a phospholipid-stabilized aqueous dispersion with small (drug)
particle size that is aerosolized using the vibrating-mesh nebulizer into droplets
containing small drug particles. For definition purposes, cle” is referring the
internal phase of the aqueous dispersion and “droplet” is referring the result of becoming
aerosol generated. In various ments, each droplet contains a certain number of
drug particles. Figure 1B shows three different tested manufacturing processes for
obtaining an s dispersion with a small drug particle size. For the purposes of , a phospholipid dispersion containing 6% w/w of lecithin in water was added to the
molten CleO (1% w/w) at 55 CC. The formulation was then sed as follows (1)
High Shear Mixing (U1tra-Turrax® TP 18/10 Homogenizer with 8 mm rotor blade, IKA-
Werke, Staufen, y): 100 mL of formulation was d at 300 rpm and high
shear mixed at 10-12 thousands rpm for 45 s; (2) Microfluidization (M-110Y
High Pressure tic Microfluidizer®, Microfluidics, Newton, MA USA): This
process works by having two jet streams in te directions. Each pass represents one
chance that the drug particles have to collide against each other during this process,
breaking apart and becoming smaller. The formulation was predispersed using probe
sonication for 2 minutes, ed by 30 passes at approximately 13 Kpsi; or (3)
Ultrasonication (Omni Sonic Ruptor-250® Ultrasonic Homogenizer with 5/32" (3.9mm)
Micro-Tip Probe, Omni International, Kennesaw, GA, USA): at 125W for 60 minutes.
A comparison of the results of these different manufacturing methodologies are shown
in Figure 5 and discussed in further detail below.
Production and delivery of aerosols in accordance with the t invention
can be achieved through any suitable delivery means for continuous nebulization or
aqueous liposomal dispersions, including nebulizers. The most suitable delivery means
will depend upon the active agent to be delivered to the lung, the other components of
the formulation, the desired effective amount for that active agent, and characteristics
ic to a given patient. Given the present disclosure, the details of selecting and
operating such devices are within the purview of those d in the art.
In various embodiments, aerosols in accordance with the invention can be
delivered by an ultrasonic wave nebulizer, a jet nebulizer, a soft mist inhaler, an
ultrasonic ing mesh zer or other nebulizer utilizing vibrating mesh
technology. For e, suitable ultrasonic wave nebulizers include Omron NE-U17
available from Omron Corporation of Japan and Beurer Nebulizer IH30 available from
Beurer GmbH of Germany. Suitable jet nebulizers include, for example, wer
available from A&H Products, Inc. of Oklahoma. Suitable soft mist nebulizers include,
for e, Respimat Soft Mist available from nger Ingelheim GmbH of
Germany. Suitable vibrating mesh nebulizers include, for example, Pari eFlow available
from Pari Pharma GmbH of Germany, Respironics i-Neb available from onics Inc.
of Pittsburg, Pennsylvania, Omron MicroAir available from Omron Corporation of
Japan, Beurer Nebulizer IH50 available from Beurer GmbH of Germany, and Aerogen
Aeroneb available from Aerogen Ltd. of Ireland. With respect to the present invention,
a nebulizer is selected for tion therapy over pressurized Metered Dose Inhalers
(pMDIs) and Dry Powder Inhalers (DPIS) by virtue of their capability of delivering high
amounts of drugs via passive breathing. Therefore, patients with impaired pulmonary
function (e. g. lung cancer patients) are not expected to experience difficulty during
administration of the drug.
While the t disclosure has discussed tion formulations in some
detail, ing on the ic conditions being treated, the lipophilic bioactive agents,
described above can also be formulated and administered by other ic and/or local
routes. For example, aerosols can be red selectively to one or more regions of the
respiratory tract, mouth, trachea, lungs, nose, mucosa, sinuses, or a combination thereof.
Delivery can achieve one or more of topical, local, or systemic delivery, or a
combination thereof. atively, aerosols can also be used for non-inhalation
delivery. Compositions of the t invention can also be administered in vitro to a
cell (for example, to induce apoptosis in a cancer cell in an in vitro culture or for
scientific, clinical, or pre-clinical experimentation) by simply adding the composition to
the fluid in which the cell is contained.
METHODS OF ENT
Compositions of the present disclosure can be utilized to administer
lipophilic bioactive agents for the treatment of any disease or condition which may
benefit from the application of the lipophilic bioactive agent, including those disclosed
in International Publication No. , the entire disclosure of which is
incorporated by reference herein.
Method for administering an inhalable pharmaceutical composition in
accordance with the present invention can include the steps of: (i) aerosolizing a
dispersion of liposomal particles, y forming a respirable aerosol comprising a
plurality of droplets having a mass median aerodynamic diameter (MMAD) between
about 1 and 5 um and (ii) delivering a eutically effective amount of the
hydrophobic bioactive agent to a lung of a subject in need of treatment. Further, the
dispersion of liposomal particles has an average diameter between about 30 and 500 nm,
each liposomal particle comprising a hydrophobic bioactive agent and a phospholipid
dispersed within an aqueous dispersion vehicle. Furthermore, the ratio of hobic
bioactive agentzphospholipid is n about 5:1 and about 1:5, the hydrophobic
bioactive agent is between about 0.1 and 30 % wfw of the composition, and the
phospholipid is between about 0.1 and 30 % w/w of the composition.
As a result of the specific formulation and method of manufacture, the
composition is characterized by advantageous properties, for example, an average
t transmission (APT) between about 50 and 100 % upon continuous aerosolization.
Alternatively, the composition can be characterized by other pharmacokinetic ties,
such as that, upon continuous aerosolization, the composition is capable of achieving a
bioactive agent concentration of at least about 600 ug/g wet lung tissue or a total emitted
dose (TED) of at least about 2,900 ug over 15 seconds.
] Other pharmacokinetic properties can include mass fraction deposited,
amount of drug and/or formulation delivered to the target, and residence time at the
. In some embodiments, the invention can be used to deposit a mass fraction of at
least about 1, 5, 10, 15, or 20 %. The invention can also be used to facilitate delivery of
over 0.25 pg/g of an active agent to the deep lung. In certain embodiments delivery to
the lung can be of at least about 1, 5, 10, 15, 20, 25, 30, 50, 100, 200, 300, 400, or 500
ug/g of bioactive agent in lung tissue. Furthermore, the formulations can remain in the
lungs (e. g., “residence time”) for a period of at least about 2, 4, 6, 8, 10, 12, 24, or 48
hours.
The terms “pharmaceutically effective amount” and “therapeutically effective
amount” as used herein include a quantity or a concentration of a bioactive agent or drug
that produces a desired pharmacological or therapeutic effect when administered to an
animal subject, including a human. The amount of active agent or drug that includes a
pharmaceutically ive amount or a therapeutically ive amount can vary
according to factors such as the type of drug utilized, the potency of the particular drug,
the route of administration of the formulation, the system used to ster the
formulation, combinations thereof, and the like.
] The terms “treatment” or “treating” herein include any treatment of a disease
in a mammal, ing: (i) preventing the disease, that is, causing the clinical symptoms
of the disease not to develop; (ii) inhibiting the disease, that is, arresting the
development of clinical ms; and/or (iii) relieving the disease, that is, causing
regression of the clinical symptoms.
In some embodiments, compositions of the present disclosure can be utilized
in the treatment of cancer. As used herein, “cancer” refers to all types of cancer or
neoplasm or malignant tumors found in mammals, including, but not d to:
leukemias, lymphomas, mas, carcinomas and sarcomas. As used herein, the terms
“cancer,3, 6‘neoplasm,” and “tumor,” are used interchangeably and in either the singular
or plural form, refer to cells that have undergone a malignant transformation that makes
them pathological to the host organism.
Primary cancer cells (that is, cells obtained from near the site of malignant
transformation) can be readily distinguished from non-cancerous cells by well-
ished techniques, including histological examination. The definition of a cancer
cell, as used herein, includes not only a primary cancer cell, but any cell derived from a
cancer cell ancestor. This es metastasized cancer cells, and in vitro cultures and
cell lines derived from cancer cells.
When referring to a type of cancer that normally manifests as a solid tumor, a
“clinically detectable” tumor is one that is able on the basis of tumor mass, e. g., by
procedures such as CAT scan, MR imaging, X—ray, ultrasound or ion, and/or
which is detectable because of the expression of one or more cancer-specific antigens in
a sample obtainable from a t.
Examples of cancers include cancer of the brain, breast, pancreas, cervix,
colon, head and neck, , lung, non-small cell lung, melanoma, mesothelioma,
ovary, sarcoma, h, uterus and Medulloblastoma.
] The term “sarcoma” generally refers to a tumor which is made up of a
substance like the embryonic connective tissue and is generally composed of closely
packed cells embedded in a fibrillar or homogeneous substance. Examples of sarcomas
which can be treated with compositions including aerosolized particles of the present
disclosure, and optionally a potentiator and/or chemotherapeutic agent include, but not
limited to, a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma,
myxosarcoma, osteosarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma,
ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorine carcinoma,
embryonal sarcoma, Wilms’ tumor sarcoma, endometrial sarcoma, stromal sarcoma,
Ewing’s sarcoma, fascial sarcoma, fibroblastic a, giant cell sarcoma, granulocytic
sarcoma, Hodgkin’s sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma,
immunoblastic sarcoma of B cells, ma, immunoblastic sarcoma of T-cells,
Jensen’s sarcoma, Kaposi’s sarcoma, Kupffer cell sarcoma, angiosarcoma,
leukosarcoma, ant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic
sarcoma, Rous a, serocystic a, synovial sarcoma, and telangiectatic
sarcoma,
The term “melanoma” includes a tumor arising from the melanocytic system
of the skin and other organs. Melanomas which can be treated with compositions
including aerosolized les of the present disclosure include, but are not limited to,
acral-lentiginous melanoma, otic melanoma, benign juvenile I melanoma,
Cloudman’s melanoma, 891 melanoma, g-Passey melanoma, juvenile melanoma,
lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual
melanoma, and superficial ing melanoma.
The term “carcinoma” refers to a malignant new growth made up of
epithelial cells tending to rate the surrounding tissues and give rise to metastases.
Carcinomas which can be treated with compositions including aerosolized particles of
the disclosure include, but are not limited to, acinar oma, acinous carcinoma,
adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma
of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma,
carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma,
bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma,
cerebriform oma, cholangiocellular carcinoma, chorionic carcinoma, colloid
carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en
cuirasse, carcinoma cutaneum, rical carcinoma, cylindrical cell carcinoma, duct
carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid
carcinoma, oma epitheliale adenoides, tic carcinoma, carcinoma ex ulcere,
carcinoma fibrosum, gelatiniform oma, gelatinous carcinoma, giant cell carcinoma,
carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix
carcinoma, hematoid carcinoma, hepatocellular carcinoma, e cell carcinoma,
e carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma
in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher’s carcinoma,
tzky-cell carcinoma, large—cell carcinoma, ular carcinoma, carcinoma
lenticulare, lipomatous carcinoma, lyrnphoepithelial carcinoma, carcinoma are,
medullary carcinoma, melanotic carcinoma, carcinoma moue, mucinous carcinoma,
carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid oma,
carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal
carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary
oma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma,
pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma
sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, Signet-
ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solenoid carcinoma,
idal cell carcinoma, e cell oma, carcinoma spongiosum, squamous
oma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum,
oma telangiectodes, transitional cell carcinoma, oma tuberosum, us
carcinoma, verrucous carcinoma, and the like.
Additional cancers which can be treated with compositions including
lized particles of the present sure include, for example, Hodgkin’s Disease,
Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, breast cancer, n
cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary
macroglobulinemia, small-cell lung tumors, primary brain tumors, h cancer,
colon cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary; bladder
cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer,
neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia,
cervical cancer, endometrial cancer, adrenal cortical cancer, and prostate cancer.
Although various cancers have been discussed in detail, the compositions and
methods of the invention are applicable to other respiratory, oral, nasal, sinus, and
pulmonary pathologies ing, but not limited to, asthma, allergies, chronic
obstructive pulmonary disease, chronic bronchitis, acute bronchitis, emphysema, cystic
fibrosis, pneumonia, tuberculosis, pulmonary edema, acute respiratory distress syndrome,
pneumoconiosis, interstitial lung e, pulmonary edema, ary embolism,
pulmonary hypertension, pleural effusion, pneumothorax, elioma, amyotrophic
lateral sclerosis, myasthenia , and lung disease.
EXAMPLES
The following Examples are ed to be illustrative only and are not
intended to limit the scope of the invention.
] Example 1: Development and Characterization of Phospholipid-
Stabilized Submicron Aqueous Dispersions of CoQ10 Adapted for Continuous
Nebulization
This example provides methods for developing suitable formulations for
pulmonary delivery of hydrophobic drugs using CoQ10 as a case study. Excipients (e.g.,
olipids) and an aerosolization device (e.g., Aeroneb Pro® vibrating-mesh
nebulizer) were selected after an initial study (data not shown). Initial characterization
of the bulk drug using X-ray diffraction (XRD), Differential ng Calorimetry
(DSC), Laser Diffractometry (LD) and Scanning Electron Microscopy (SEM) was
performed. High shear mixing, high pressure homogenization or ultrasonication was
then evaluated as feasible manufacturing ses to obtain small particle size
dispersions of CoQ10. Following selection of an appropriate process, parameters
affecting drug particle size were studied. Using LD and gravimetrical analysis,
nebulization was evaluated to assess the performance of the drug-excipients-device
combination. CoQ10 powder studied was crystalline with a melting point imately
at 51 0C with a particle size of 30 pm. 'Iherefore, particle downsizing was deemed
necessary for pulmonary delivery. Microfluidization was found to be a suitable method
to prepare ron drug particles in aqueous dispersions. The number of passes and
type of phospholipids (lecithin or Dipalmitoyl Phosphatidylcholine — DPPC) used
affected final drug particle size of the dispersions. Nebulization performance of lecithin-
stabilized CoQ10 dispersions varied according to number of passes in the microfluidizer.
Furthermore, the gy of these dispersions appeared to play a role in the aerosol
generation from the active ing mesh nebulizer used. In conclusion, aqueous
dispersions of CoQ10 were adequately produced using a microfluidizer with
characteristics that were le for pulmonary ry with a nebulizer.
als and Methods
Materials: Coenzyme Q10 was supplied by Asahi Kasei Corp. (Tokyo,
Japan). Lecithin (granular, NF) was purchased from Spectrum Chemical Mfg. Corp.
(Gardena, CA, USA). Genzyme Pharmaceuticals (Liestal, Switzerland) provided 1,2-
dipalmitoyl-sn-glycero-3phosphocholine (DPPC). Sodium chloride (crystalline,
ied ACS) was acquired from Fisher Chemical (Fisher Scientific, Fair lawn, NJ,
USA) and the deionized water was obtained from a central reverse
osmosis/demineralizer system commonly found in research tories. The dispersant
1,3-propanediol (98%) was purchased from Sigma—Aldrich (St. Louis, MO, USA).
Ethanol 200 proof USP was purchased from Decon Laboratories (King of Prussia, PA,
USA).
Bulk Characterization of Cle0
] X-ray diffraction (XRD): Testing was performed using a Philips Model
1710 X-ray diffractometer ps Electronic Instruments Inc., Mahwah, NJ, USA) with
primary monochromated ion (CuKal, )L = 6 A) emitting at an accelerating
voltage of 40 kV and 30 mA. The CleO powder was placed into a stage and the sample
was scanned for diffraction patterns from 50 to 50° at 0.050 intervals of 20 angles, with
dwell time of 3 seconds.
Difi‘erential Scanning Calorimetry (DSC): DSC testing was performed
using a 2920 Modulated DSC (TA Instruments, New Castle, DE, USA) and analyzed
using TA Universal is 2000 Software. Powder of CleO was weighed (10.5 mg)
into aluminum pan (kit 02190041, Perkin-Elmer Instruments, Norwalk, CT, USA) and
crimped. At a heating rate of 10 °C/min, the thermal behavior of the sample was
analyzed from 10 to 120 0C.
Laser Difi‘raction (LB): Bulk CleO powder was dispersed in 20% (V/V)
1,3-propanediol in deionized water for is of particle size distribution. This
dispersed sample was then added to a small cell tus in a Malvem sizer S®
instrument (Malvern Instruments, Worcestershire, UK) equipped with a 300 mm lens
until 5-10% ation was attained. The al phase and dispersant refractive
indexes were 1.45 and 1.33, respectively.
Scanning Electron Microscopy (SEM): Analysis of physical appearance
and estimation of particle size of bulk CleO were performed using an SEM. An
aluminum stage with adhesive carbon tape held the powder sample. Coating was carried
out in a rotary-planetary-tilt stage with platinum-iridium using a Cressington Sputter
Coater 208 HR (Cressington Scientific Instruments, Watford, England) under argon
atmosphere. The SEM pictures were captured using EM® graphical user
interface software in a Carl Zeiss Supra® 40VP Scanning on Microscope (Carl
Zeiss AG, Oberkochen, Germany) operated at a working distance of 19 mm and at 5 kV
of Electron High Tension (EHT).
Development of a cturing Methodology
Three different manufacturing processes were tested in the present example
in order to obtain an aqueous dispersion CleO with a small drug le size. Similar
methods can be d to further optimize CoQ10 formulations and to provide
formulations for other hydrophobic drugs. A phospholipid dispersion containing 6%
w/w of lecithin (as the example phospholipid) in water was added to the molten CleO
(1% w/w) at 55 OC. The phospholipid concentration was above the critical micellar
concentration (e. g., for lecithin, depending on the source and processing method, CMC
varies from 1.3 to 5.5 mg/mL). The formulation was then processed as follows.
High Shear Mixing: One hundred iters of ation was stirred at
300 rpm and high shear mixed at 10,000—12,000 rpm for 45 minutes using an Ultra-
Turrax® TP 18/10 Homogenizer with 8 mm rotor blade erke, Staufen,
Germany).
High Pressure Homogenization: High pressure homogenization was
achieved using a microfluidization process. Each pass represents an opportunity for the
drug particles to collide against each other, thereby breaking apart and becoming
smaller. The formulation was persed using probe sonication for 2 minutes,
followed by 30 passes at approximately 30,000 psi using an M-110Y High Pressure
Pneumatic Microfluidizer® (Microfluidics, Newton, MA USA).
onication: The formulation was ultrasonicated at 125 W for 60
minutes using an Omni Sonic Ruptor—250® Ultrasonic Homogenizer with 5/32 inch (3.9
mm) with a tip probe (Omni International, Kennesaw, GA, USA).
Formulation Development
After ion of the manufacturing process, formulations were prepared
with high pressure homogenization to determine the effect of the selected parameters
and type of phospholipid on the le size distribution of the drug dispersion. During
preliminary studies, it was observed that the high solute concentration of formulations
containing 6% w/w of lecithin did not produce aerosol from the Aeroneb Pro® vibrating-
mesh micropump nebulizer. Further preliminary studies also showed that formulations
containing a reduced concentration of in (1% w/w, at 1:1 drug-to-lipid ratio) have
ted sufficient stability for evaluation of nebulization performance following
preparation. Therefore, reduction of phospholipid concentration was necessary while
aneously keeping the concentration of CleO constant at an adequate drug-to-
lipid ratio.
Following hydration, a phospholipid dispersion containing 1% w/w of
phospholipid (lecithin or DPPC) in water was added to the molten CleO (1% w/w) at
55 CC. The formulation was then predispersed using high shear mixing (Ultra-Turrax®
TP 18/10 Homogenizer with 8 mm rotor blade, IKA—Werke, Staufen, Germany) for up
to 5 minutes at 20,000 rpm. Subsequently, the formulation was passed through an M-
110P Bench-top luidizer® (Microfluidics, Newton, MA USA) up to 100 times at
approximately 30,000 psi while maintaining the temperature between 50 and 60 0C.
In testing the effects that the type of phospholipid and number of passes have
on particle size distribution of the formulations, phospholipid dispersions were hydrated
for approximately 1 hour without stirring (Table 1, Formulations A and B).
Formulations were then passed through a microfluidizer 10, 20, 30, 40 and 50 times
when comparing ent phospholipids; 20, 50, 70 and 100 times when evaluating the
effect from number of passes. For nebulization performance tests, the olipid
dispersions were hydrated overnight with stirring and 0.9% w/v of sodium chloride was
added to the final ation (Table 1, Formulation C).
] The le size distributions of the formulations were then analyzed using
Laser Diffraction (LD) and/or Dynamic Light Scattering (DLS). The surface tension,
zeta potential and rheology were also evaluated. For nebulization performance, l
output was performed using LD and gravimetrical analysis.
Characterization of ations
Particle Size Distribution: Particle size distribution testing of the dispersed
formulations was performed with LD using a wet sample dispersion unit stirring at 1,000
rpm coupled to a Malvem Spraytec® m Instruments, Worcestershire, UK)
equipped with a 300 mm lens. The dispersed ations were added to distilled water
(dispersant) until approximately 5% laser obscuration was ed. The internal phase
and dispersant refractive indexes were set as 1.45 and 1.33, respectively. A timed
ement was performed for 45 seconds with 1 second ng s (a total of
45 measurements). Results are presented as Dv(X) and span, where X is the cumulative
percentile of particles under the referred size (e.g. Dv(50) corresponds to the median
volume of the les). Span is a measurement of particle size distribution calculated
as [Dv(90) — Dv(10)]/Dv(50)]. A higher span indicates a more polydisperse particle size
distribution.
In addition, the nanoparticle hydrodynamic diameter of the dispersed
formulations was characterized with DLS using a Malvern Zetasizer Nano S® (Malvern
Instruments, Worcestershire, UK) at 25 OC and pre—equilibrated for 2 minutes. The
intercept of the correlation function was between 0.5 and 1.0. The dispersion was
diluted with distilled water.
Surface Tension: Surface n testing was performed using a
TA.XT.plus Texture Analyzer (Texture Technologies, Scarsdale, NY, USA) from the
maximum pull on a disk as described in the previous chapter. Briefly, the container and
glass disk probe were thoroughly degreased, cleaned with ethanol and d to dry.
The probe was attached to the texture analyzer arm, and lowered until the bottom surface
of the probe contacted the surface of the liquid formulation contained in the reservoir.
The temperature of the liquid was measured and ed. At the start of testing, the
probe was raised from the surface of the liquid at a constant speed (0.05 mm/s) for 10
mm, while the texture analyzer registered at 5 points per second the force exerted as a
on of either time or distance. Using the maximum (detachment) force the surface
tension was calculated using Equation 1 below:
x/k = 0.0408687 + 6.20312*(x"2fv) — 0.0240752 (xA2/v)"2 (Equation 1)
Where x is probe radius, v is volume and k is the us coefficient. The y
values used to ate surface n were assumed to be the same as the density of
water at the measurement temperature.
Zeta Potential: Electrophoretic light scattering was used to perform zeta
potential g with a ZetaPlus Zeta Potential Analyzer (Brookhaven Instruments
Corp., Holtsville, NY, USA). The samples were analyzed at a constant temperature of
OC and constant al) pH. Samples were diluted with distilled water to
conductance values of 300 to 550 uS. Each sample was subjected to 10 runs each, with
a 5 second interval between measurements.
Rheology: Rheological behavior of the dispersed ations were tested
using a AR-G2 rheometer (TA Instruments, New Castle, DE, USA) equipped with a
cone-and-plate geometry (cone diameter: 40 mm; truncation: 54 um). Zero-gap and
rotational mapping, respectively, were performed prior to testing. All measurements
were executed with fresh sample dispersion at a constant ature of 25 °C with no
pre-shear. Excess sample around the edge of the probe was trimmed and water added to
the solvent trap compartment. The s were measured at steady state flow step over
a range of shear rates (300 to 10 8'1) decreasing logarithmically (10 points per decade).
The upper limit of shear rate was determined by hydrodynamic limitations (high probe
speed will cause the liquid sample to spill away from the measurement zone). The
sample period was 10 seconds and considered in equilibrium after 2 consecutive
analyses within 5% nce, not exceeding a maximum point time of 2 minutes. The
results were evaluated using Rheology Advantage Data Analysis software (TA
Instruments, New Castle, DE, USA).
Nebulization Performance: Based on previous experience, the performance
of vibrating-mesh nebulizers can be affected by mesh clogging, resulting in variable
l emission (e.g., intermittent mist), since this formulation is a dispersed system.
To e the nebulization performance of these formulations, we evaluate the changes
in transmission over time from LD technique measurements. The nebulization
performance of the dispersions was evaluated using the “open bench” method with a
Malvern ec® instrument rn Instruments, Worcestershire, UK) equipped
with 300 mm lens. The nebulizer reservoir was positioned with the ne at 25 mm
above the upper edge of the laser beam and a distance of 25 mm between the lens and
the center of the aerosol cloud. Air suction was positioned 10 cm h the laser
beam. The device and air suction apparatus positions were maintained still throughout
the whole measurement period. The internal phase and dispersant refractive indexes
were 1.33 (water) and 1.00 (air), respectively. Formulation (10 mL) was added to the
nebulizer reservoir. At the start of nebulization, aerosol characteristics were
uously measured every second for 15 minutes. The slope of the transmission-time
curves (transmittograms) were considered when comparing the different phospholipid
formulations.
In addition, the Total Aerosol Output (TAO) was gravimetrically measured
for each of the formulations studied. Before aerosolization, the nebulizer was weighed
after each formulation was sed into the reservoir. The remaining formulation in
the nebulizer reservoir was re-weighed after undergoing 15 minutes of nebulization.
The difference in weight before and after nebulization results in the calculated TAO.
The weight of the nebulizer mouthpiece was not considered during the measurements.
antly, neither ittogram nor TAO provide information regarding
drug output from the nebulizer. Information is d solely to total mass output
(droplets emitted over time). In the aerosolization of these dispersions, droplets not
containing drug particles (empty droplets) are potentially generated. However, our
purpose with this test is to investigate the capability of a nebulizer such as the b
Pro® zer to continuously and steadily aerosolize the aqueous dispersions of
Coenzyme Q10 over time. Intermittent mist can be identified in the transmittograms
while TAO elucidates the magnitude of total mass being aerosolized. Saline solution
(12 mL of 0.9% w/v NaCl in water) was used as the control.
tical Analysis: The data is expressed as mean i standard deviation
with the exception of surface tension and zeta potential results, which were expressed as
mean i standard error. For rheology studies, standard errors were provided by the
software used to analyze the best fit of the results to the rheological models. Samples
were analyzed at least in cate and evaluated for statistical differences with One-
Way ANOVA for significance when p < 0.05 using NCSS/PASS software Dawson
edition. Post hoc isons were performed to identify statistically significant
differences among groups using Kramer method. A paired t-test was performed
to analyze statistical differences (p < 0.05) within the same ation for stability of
drug le size over time and to analyze the effect of different phospholipids
processed at the same uidization conditions.
Results and Discussion
This example demonstrates the feasibility of the development of a suitable
formulation of hydrophobic drugs (e.g., CoQ10) for pulmonary ry. In particular,
the example demonstrates how to different physicochemical properties of drug
sions can influence the zation performance. The example also demonstrates
how, transmission data from LD and gravimetrical analysis of nebulizer output can be
used to te steady lization as a function of time.
The XRD pattern of bulk CoQ10 shows two high intensity peaks (20) at
approximately 18.65 and 2280, ting the crystalline structure of CoQ10 (Figure 2).
An endothermic peak at approximately 51 °C in the DSC thermogram indicates the low
melting point of this compound (Figure 3). The CoQ10 drug particles are unsuitable for
pulmonary delivery as bulk material, with Dv(50) of 29.87 pm and span value of 2.051.
The magnitude of the particle ions were also confirmed by SEM pictures (Figure
4). The first approach to reduce particle size was performed with ball milling for 18
hours, which was unsuccessful e the CoQ10 turned into a cluster of drug mass.
This visual observation was confirmed by an increased particle size (Dv(50) = 29.87
pm, span = 2.282). Due to the low melting point of CoQ10, heat generated during the
process and mechanical impact may have both contributed to this outcome. Similar
results were found when bulk powder was cryomilled (data not shown).
Therefore, an alternative ch to engineering CoQ10 les for
pulmonary delivery was required. High shear mixing, high pressure homogenization
and ultrasonication were tested. The results shown in Figure 5 indicate that formulations
prepared using shear force presented drug particles in dispersion with nearly a bimodal
distribution, confirmed by a higher span value and Dv(50) around 1 pm (Table 2). Both
microfluidization and ultrasonication presented a monodisperse, unimodal distribution
with a Dv(50) value in the submicron range, so each method is capable of preparing a
formulation with small drug le size, to varying degrees and with varying size
distributions.
After selecting a process, Formulation A was processed to ine the
influence relating the number of passes in the microfluidizer to drug particle size
stability (Table 1). The LD results show that, following preparation, all formulations
presented particle size distribution in the submicron range (Figure 6). After 7 days, the
ations presented larger particles, as compared to the size immediately after
preparation, regardless of the number of passes. The DLS results indicate that
increasing the number of passes above 50 does not appear to provide smaller
hydrodynamic diameters or more monodisperse systems (Figure 7). A trough in particle
size as function of number of passes has been previously ed and attributed to a
secondary particle growth due to fusion or Ostwald ripening during ed
homogenization. Nevertheless, no statistical difference was found for drug particle sizes
between days 0 and 7 for any dual preparation with any different number of
passes.
Reduction in number of passes and evaluation of different phospholipids
were investigated using Formulation B (Table 1). DLS analysis shows that drug le
size decrease for increased number of microfluidization passes (e. g., up to 50 passes) for
both lecithin and DPPC sions of CleO (Figure 8). The DPPC ation
ted smaller particle sizes than the lecithin dispersions of CleO at the same
microfluidization conditions (e.g. number of discrete passes), with Z-averages in the
ranges of 50-120 nm and 120-170 nm, respectively. Although the DPPC colloidal
dispersion presented smaller PdI values than lecithin-stabilized ations, both
presented high polydispersity (PdI > 0.2). This result indicates that no more than 50
passes are needed to obtain formulations with small particle sizes; the final colloidal
system will depend on the phospholipid utilized.
After it was shown that small drug particle sion of CleO can be
prepared, ability to steadily nebulize these formulations was studied, along with the
physicochemical properties influencing nebulization performance. Intermittent mist,
which is undesirable, can occur when vibrating-mesh nebulizers generate aerosols from
suspended dosage forms. Therefore, formulations were ted for a lack of
intermittent mist, indicating aerosolization continuity throughout the nebulization event.
In this example, a n Spraytec® was used to analyze transmission as a
function of time, to select dispersed formulations that uously aerosolize in an
Aeroneb Pro® nebulizer. Alternative method for evaluating changes in nebulized droplet
concentration over time are described in General Chapter <l601> of the United States
Pharmacopoeia (USP) on the characterization of nebulizer products.
Prior to setting up the Malvern ec® with the “open bench” method,
numerous attempts were made to perform tests using the Malvem-provide inhalation cell
accessory (Figure 9). In this system, a laser beam is projected from the left side of the
instrument towards a detector positioned at the right side. The laser beam crosses the
inhalation cell d to the Spraytec®. A nebulizer is positioned in front of the
inhalation cell and a vacuum line is connected at the back of the cell. An air sheath
e by tubes in the middle of the cell helps direct aerosol droplets from the nebulizer
towards the vacuum . To evaluate nebulizer output, this setup was arranged with
the inhalation cell in the horizontal on (90° angle) to measure aerosol generation as
close as possible to the vibrating-mesh. The suction airflow rate was set to 30 L/min and
the sheath airflow rate was set to 15 L/min (30 — 15 L/min = 15 L/min) to obtain a final
airflow rate of 15 L/min. This airflow rate was selected to match that required to
analyze nebulizer formulations in the Next Generation Impactor (NGI) for comparison
reasons.
An experimental artifact due to an inefficient air sheath in the Malvern
Spraytec® was observed, causing the aerosol cloud to invade the detector lens
tment, g continuously increasing ation and consequently reducing
transmission. During ion of the inhalation cell a 0.45 pm HEPA membrane filter
was positioned in-line with the vacuum source, to avoid damage to the vacuum source
and to prevent exposure to the operator. However, the formulation lly d
the filter pores, which created back pressure that overcomes the air sheath and directs the
droplets towards the detection lens chamber. After the inhalation cell windows fog,
transmission values do not return to 100% and inaccurate data provides the appearance
of uninterrupted nebulizer operation. Therefore, a feasible measurement using this setup
was not possible. Without wishing to be bound by any particular theory, it is believed
that this was due to the fact that the amount of aerosol produced during each utes
zation event was enormous compared to pMDI and DPI devices, which the
inhalation cell was primarily designed for. Therefore, while such known accessories are
useful in characterizing aerosol generation from those other devices, they were not
useful for continuous nebulizers according to the present invention.
To me this artifact, an “open bench” method was developed. The
position of the nebulizer reservoir was selected to avoid vignetting (wide angle scattered
light misses the detector field) while also avoiding recirculating droplets by oning
the air suction source properly for a continuous exhaustion of the generated droplets.
The transmittograms presented in Figure 10 show a nebulization event of 15 minutes for
Formulation C (Table 1). At the end of this on the transmission values go back up
to 100% for all formulations, ting that the measurement was properly performed
with no fogging of the or lens. The three formulations presented a steady
nebulization for the initial 5 minutes. After this time point, the transmission related to
the formulation of the 10 pass runs were increased at a different rate than formulations
of the 30 and 50 pass runs. To evaluate the nebulization performance of these
formulations, the transmittogram was fitted to a linear regression in order to e the
slopes of the rate curves. By comparing their slopes, the stability of nebulization can be
determined.
The slope values and TAO of Formulation C (Table 1) with different
numbers of passes in the microfluidizer are presented in Figure 11. A lower slope value
for formulations that were run at 10 passes was observed, as ed to 30 and 50
passes. This observation agrees with the relative TAO . These data indicate that
Formulation C (processed with 10 passes in the microfluidizer) presented steadier
nebulization over time than the same formulations prepared with increased processing.
Next, the physicochemical properties of Formulation C prepared with 10, 30
and 50 passes were d to identify how processing influences nebulization
performance. By analyzing hydrodynamic size in the dispersions (Figure 12), it was we
observed from LD s that the particle size appeared to be increasing slightly over
time with most les remaining in the nanometer range. When comparing
formulations analyzed at day 0 for LD and DLS, we conclude that LD is not a suitable
technique for the same reasons described above, based on the Fraunhofer theory. The
DLS results show that all formulations presented a Z—average of imately 260 nm.
After 7 days, Dv(50) is still below range of measurement for LD technique whereas Z-
average did not vary significantly for the 30 and 50 passes. From the particle size
distribution results we can conclude that the formulations with the higher number of
passes were stable for about 1 week. PdI was between 0.2 and 0.3 following ation
and showed some level of polydispersity after 7 days.
The results indicate that a greater hydrodynamic diameter was formed for
these lecithin dispersions (approximately 260 nm) than was formed with the previous
formulation analyzed (Formulation B: 0 nm). These differences can be
explained, at least in part, by the ence in electrolyte concentrations of the
formulations. Addition of 0.9% wfv of sodium chloride to ation C serves two
purposes: to provide normal physiological osmolarity and to reduce ility in
aerosol generation from this active vibrating-mesh nebulizer. Solutions with such low
ionic concentrations, have a reduced variability factor, increased aerosol output, and
smaller droplet sizes. Without wishing to be bound by any ular , low
electrolyte content is believed to help to overcome drop detachment resistance from the
vibrating-mesh due to an improved electrical conductivity that suppresses the high
electrostatic charge of water, which in turn favors aerosol generation.
However, the addition of sodium chloride can also cause colloid ility,
according to the Derjaguin-Landau-Verwey—Overbeek (DLVO) theory of interactions of
electrolytes on olipid surfaces. In this case, a nonspecific adsorption based solely
on electrostatic forces (no chemical interactions) can be caused by monovalent cations
(e.g., Na+). A decrease in zeta potential caused by such cations can increase the
flocculation rate (e.g., as analyzed by turbidimetry). The addition of the aforementioned
salt following microfluidization was observed to change the dispersion color from dark
orange to bright yellow. Despite extensive discussion concerning the mechanism of this
colloid stability, current theories in colloid science are unable to fully explain this
phenomenon. Drug particle size distribution of the aqueous dispersion alone does not
appear to control nebulization performance because these dispersions had similar
diameters (following preparation), but ent aerosolization behavior.
Increasing the number of microfluidization passes increases both the e
n and the zeta potential (statistically icant when comparing formulations
processed with 10 or 50 passes, see Figure 13). It has been hypothesized that a higher
number of passes aids encapsulation. However, the role of e tension in aerosol
generation from active vibrating-mesh zers is not well understood. The present
example did not identify a correlation between the Formulation C zeta potential and
surface tension that correlates the different number of microfluidizer passes and
respective nebulization performance.
The rheology of the dispersions was d by plotting the shear stress as a
function of shear rate. The Herschel-Bulkley model, Equation 2, best represented the
behavior of these three formulations:
* 32% (Equation 2)
a = 0y + 1c
Where cr is shear stress, 0y is yield stress, 1c is consistency index or viscosity, 3) is shear
rate and n is flow index (n = 1: Newtonian fluid; n < 1: shear-thinning; n > 1: shear-
ning). Standard errors are 32.74 i 3.58, 31.62 i 2.04, 35.92 i 3.57 for dispersions
of CoQ10 prepared with 10, 30 and 50 microfluidization passes, respectively. The three
elements of the el-Bulkley model are presented in Figure 14. Although the
values of each element are not statistically different by this metric, the similarity
between the rheology results and the results of nebulization performance is evident.
Formulations of 30 and 50 passes presented a similar rheological behavior and
nebulization mance, which were different from formulations of 10 passes.
Interestingly, all formulations presented thickening or (n > 1).
Characteristics like size, size distribution, shape, charge, and the interactions between
particles and the surrounding fluid play significant roles in the rheological behavior of
these systems. Therefore, it is not surprising that the gical behavior of the
formulations influence nebulization performance, which is a function of the interaction
of all the physicochemical teristics.
The invention provide the first known study igating the capability of
ing-mesh zers to steadily nebulize dispersions in which fluid rheology is
analyzed as opposed to ming simpler kinematic viscosity measurements (e.g., the
viscosity of the dispersion media per se, without considering the interactions between
the dispersed particles with the surrounding fluid).
Example 2: Prediction of In Vitro Aerosolization Profiles Based on
Rheological Behaviors of Aqueous Dispersions of CoQ10
Aerosolization of dispersed formulations can generate droplets containing
variable drug concentration due to the heterogeneous nature of the dosage form.
Therefore, it can be important to characterize formulations for in vitro drug deposition,
which can be performed with cascade impactors. Laser diffractometry (LD) can also be
used for this purpose, but LD’s usefulness is generally limited to solution dosage forms.
The nonhomogeneity of dispersions create droplets with heterogeneous concentrations
of drug particles, rendering LD unsuitable. The United States Pharmacopoeia (USP)
recommends the Next Generation Impactor (NGI) be used for this testing.
Human alveolar surfactant includes about 90% phospholipids and 10%
neutral lipids. Among the phospholipids, phosphatidylcholine (PC) is predominant
(76%), with DPPC being the main ent (81% of PC) and dimyristoyl
phosphatidylcholine (DMPC) and distearoyl phosphatidylcholine (DSPC) each
comprising 3% of PCs. DPPC and DSPC are also present in the mixture of
phospholipids that comprise the excipient soybean in, but their concentration varies
widely depending on the lecithin source and extraction method.
The t example provides methods and data for selecting phospholipids
formulations in accordance with the invention. The present e also provides, more
particularly, methods and data for using tic phospholipids to prepare formulations
of CoQ10 having improved nebulization performance, and which have the potential to
deliver a desirable Fine Particle Dose (FPD) of CoQ10. The e studied three
synthetic phospholipids: DMPC, DPPC, and DSPC, which have 14, 16 and 18 carbons
in their saturated fatty acid chains and molecular weights of 678, 734, and 790 g/mol,
respectively.
In addition to the tests described in tion with Example 1, the synthetic
phospholipid formulations were r characterized for in vitro drug deposition using
NGI and Total Emitted Dose (TED) using both NGI and a Dose Uniformity ng
Apparatus (DUSA) for Dry Powder Inhalers (DPIs) adapted for nebulizers. The results
were analyzed in conjunction with the nebulization performance tests for continuous
aerosolization and for identifying the physicochemical properties governing the
mechanism of aerosol generation of dispersed systems of CoQ10 from the micropump
nebulizer. The s of Example 1 were also further validated by demonstrating that
the rheology of the dispersions plays a role in the hydrodynamics of aerosol tion
using active vibrating-mesh nebulizer.
Materials and Methods
Materials: CoQ10 was supplied by Asahi Kasei Corp. (Tokyo, Japan).
Lecithin (granular, NF) was purchased from Spectrum Chemical Mfg. Corp. (Gardena,
CA, USA). Genzyme Pharmaceuticals (Liestal, Switzerland) provided myristoyl-
sn-glycero-3phosphocholine , l,2—dipalmitoyl—sn-glycerophosphocholine
(DPPC), and l,2-distearoyl-sn-glycerophosphocholine (DSPC). DMPC was also
purchased from Lipoid GmbH (Ludswighafen, Germany). Sodium chloride alline,
certified ACS) was acquired from Fisher Chemical (Fisher Scientific, Fair lawn, NJ,
USA) and the deionized water was obtained from a central reverse
osmosis/demineralizer system. Hexane and l 200 proof were purchased from
Sigma-Aldrich (St. Louis, MO, USA) and ol from Fisher Chemical (Fisher
Scientific, Fair lawn, NJ, USA), all of which were from HPLC grade. The external filter
for NGI testing (glass fiber, GC50, 75 mm) and the filter for DUSA (glass fiber, AP40,
47 mm) testing were purchased from Advantec MFS Inc. (Dublin, CA, USA) and from
Millipore (Billerica, MA, USA), respectively. Syringes (1 mL) and syringe filters
(hyperclean, 17 mm, 0.45 um, PTFE) were obtained from Becton Dickinson (Franklin
Lakes, NJ, USA) and Thermo Scientific (Bellefonte, PA, USA), respectively.
] Formulation: Formulations (100 mL) were prepared using hot high pressure
homogenization to determine the effect of the type of phospholipid on the aerosolization
profile — nebulization performance and in vitro drug deposition of particles for
pulmonary delivery. 2.5% w/w was ed as the maximum phospholipid
concentration. During preliminary studies (see Example 5), it was found that the
maximum nominal drug loading that could be achieved for CleO with formulations not
ting intermittent mist within a 15-minute nebulization event using the Aeroneb
Pro® nebulizer was 4% w/w. Therefore, formulations with synthetic phospholipids
were prepared at a drug-to-lipid ratio of 4:2.5.
] Following overnight ion while stirring, a phospholipid dispersion
containing 2.5% w/w of olipid (DMPC, DPPC, or DSPC) in water was added to
the molten CleO (4% w/w) at 55 °C. The formulation was then predispersed using
high shear mixing with an U1tra-Turrax® TP 18/10 Homogenizer with 8 mm rotor blade
(IKA-Werke GmbH, n, Germany) for 5 minutes at 20,000 rpm. Subsequently,
each formulation was passed 50 times through an M-l lOP Bench-top Microfluidizer®
(Microfluidics, Newton, MA, USA) at approximately 30,000 psi while maintaining a
temperature between 55 and 65 OC. Following microfluidization, 0.9% w/v of sodium
chloride was added to the final formulation for reasons outlined in the previous example.
The particle size distributions of the formulations were then analyzed using
Laser ction (LD) and/or Dynamic Light Scattering (DLS). The surface tension,
zeta potential and rheology were also evaluated. For nebulization performance, aerosol
output generated from an Aeroneb Pro® nebulizer (Aerogen, Galway, Ireland) was
analyzed using LD and gravimetrical analysis. In vitro drug tion was evaluated
using a NGI while the TED was analyzed from both the NGI results and from
measurement using a Dose Uniformity Sampling Apparatus (DUSA). In on to the
characterization and zation performance presented in Example 1, the in vitro drug
deposition of lecithin dispersion of CleO (drug—to—lipid ratio: 1:1) passed 50 times
h the Microfluidizer® was prepared and analyzed. This was evaluated against the
synthetic phospholipid formulations (DMPC, DPPC, or DSPC dispersions of CoQ10).
Details of the preparation, characterization and evaluation of nebulization performance
of the lecithin dispersion are presented in Example 1. Testing was performed
immediately following ation, except for stability of drug particle size in the
dispersions in which the samples were tested 7 days after preparation.
Characterization
] Particle Size Distribution: Particle size distribution testing of the dispersed
formulations was performed with LD using a wet sample sion unit stirring at 1,000
rpm coupled to a Malvem Spraytec® (Malvem Instruments, Worcestershire, UK)
equipped with a 300 mm lens. The dispersed formulations were added to distilled water
(dispersant) until approximately 5% obscuration was attained. The internal phase and
dispersant refractive indexes were 1.45 and 1.33, respectively. A timed measurement
was performed for 45 s with 1 second sampling periods (a total of 45 data
acquisition periods). Results are presented as DV(X) and span, where X is the
cumulative percentile of particles under the referred size (e. g. DV(50) corresponds to the
median volume of the particles). Span is the ement of particle size distribution
calculated as ) — Dv(10)]va(50)]. A higher span indicates a more sperse
particle size distribution.
The nanoparticle ynamic er of the dispersed formulations was
also characterized with DLS using a Malvern Zetasizer Nano ZS® (Malvern
Instruments, Worcestershire, UK) at 25 °C and pre-equilibrated for 2 minutes. The
intercept of the correlation function was between 0.5 and 1.0. Distilled water was used
for dilution of the dispersions where needed.
Surface n: Surface tension testing was performed using a
TA.XT.plus Texture Analyzer (Texture Technologies, Scarsdale, NY, USA). The
container and glass disk probe were thoroughly sed, cleaned with ethanol and
allowed to dry. The probe was attached to the texture analyzer arm, and lowered until
the bottom surface of the probe contacted the surface of the liquid formulation contained
in the reservoir. The temperature of the liquid was measured and recorded. At the start
of testing, the probe was raised from the surface of the liquid at a nt speed (0.05
mm/s) for 10 mm, while the texture analyzer registered at 5 points per second the force
exerted as a on of either time or distance. Using the maximum (detachment) force
the surface tension was calculated using Equation 3 below:
X / k = 0.0408687 + 6.20312 * (XA2/V) — 0.0240752 * (XA2/V)’\2 (Equation 3)
Where X is probe radius, V is volume and k is the us coefficient. The density
values used to calculate surface n were assumed to be the same as the density of
water at the measurement ature.
Zeta Potential: Electrophoretic light scattering was used to perform zeta
potential testing with a Malvern Zetasizer Nano ZS® (Malvern ments,
Worcestershire, UK). The samples were analyzed at a constant temperature of 25 OC
and constant (neutral) pH. Samples were diluted with distilled water, obtaining
conductivity values ranging from 400 to 1400 pS/cm. Each sample was analyzed in
triplicate and subjected to 10 to 100 runs each measurement, with automatic
optimization of attenuation and voltage selection.
Rheology: Rheological behavior of the dispersed formulations were tested
using a AR-G2 ter (TA Instruments, New Castle, DE, USA) equipped with a
nd-plate geometry (cone diameter: 40 mm; truncation: 54 um). Zero-gap and
rotational mapping were performed prior to testing. All measurements were executed
with fresh sample dispersion at a nt temperature of 25 0C with no pre-shear.
Excess sample around the edge of the probe was trimmed and water was added to the
solvent trap compartment. The samples were measured at the steady state flow step over
a range of shear rates (from 1000 to as low as 0.01 s‘l) decreasing logarithmically (5
points per decade). The lower and upper limits of shear rate were determined,
respectively, by the instrument sensitivity and hydrodynamic tions (high probe
speed will cause the liquid sample to spill away from the ement zone) for each
formulation. The sample period was 20 seconds and considered in equilibrium after 2
consecutive analyses within 5% tolerance, not exceeding a maximum measurement time
of 2 minutes. The results were evaluated using Rheology Advantage Data is
software (TA Instruments, New Castle, DE, USA).
Nebulization Performance: The performance of vibrating-mesh nebulizers
with dispersion formulations can be affected by mesh clogging, resulting in variable
aerosol emission (e.g., intermittent mist). To analyze the nebulization performance of
the synthetic phospholipid formulations, the changes in transmission over time were
evaluated from LD technique measurements. The nebulization performance of the
dispersions was evaluated using the “open bench” method with a Malvem Spraytec®
(Malvem Instruments, Worcestershire, UK) ed with 300 mm lens. The nebulizer
reservoir was positioned with the ing mesh located 25 mm above the upper edge of
the laser beam at a distance of 25 mm between the lens and the center of the aerosol
cloud. Air suction was positioned 10 cm beneath the laser beam. The device and air
suction apparatus positions were not disturbed throughout the entire ement
period. The al phase and dispersant refractive indexes were 1.33 (water) and 1.00
(air), tively. Formulation (10 mL) was added to the nebulizer reservoir. At the
start of nebulization, aerosol characteristics were continuously measured every second
for 15 minutes. The slope of the transmission-time curves (transmittograms) were
ered when ing the different phospholipid formulations.
[0023 6] In addition, the Total Aerosol Output (TAO) was gravimetrically measured
for each of the formulations studied. Before aerosolization, the nebulizer was weighed
after each formulation was dispensed into the reservoir. The remaining formulation in
the nebulizer reservoir was re—weighed after undergoing 15 minutes of nebulization.
The difference in weight before and after nebulization results in the calculated TAO.
The weight of the zer mouthpiece was not considered during the measurements.
] Importantly, neither transmittogram nor TAO alone provide complete
information regarding drug output from the nebulizer. Information is limited solely to
total mass output (droplets emitted over time). In the aerosolization of these dispersions,
droplets not containing drug particles (empty droplets) are potentially generated.
ittent mist can be identified in the transmittograms while TAO elucidates the
magnitude of total mass being aerosolized. Saline solution (12 mL of 0.9% w/v NaCl in
water) was used as the control.
In vitro Aerodynamic Deposition: To evaluate in vitro aerosol deposition,
within a 15-minute zation event, the first and last 15 seconds (herein called initial
and final sections or phases) of aerosol generation were collected using NGI or DUSA
for DPI (both from Copley Scientific, Nottingham, UK). This design helps in
ining whether the slope in transmission, previously observed for lecithin
formulations and related to TAO (Chapter 4, n 4.3), translates into similar drug
mass output.
To measure the aerodynamic properties of the formulations, the NGI was set
up with airflow of 15 L/min and the drug collected from the induction port, the seven
stages of the cascade impactor, the micro-orifice collector (MOC) and the external filter
was analyzed using High Performance Liquid Chromatography (HPLC). The sum of the
masses in each of the ned tments of the NGI hardware setup provides the
TED measured from the NGI. The mass deposited in each stage is also used to
determine the deposition pattern and to ate the Mass Median Aerodynamic
Diameter (MMAD) as described in the General Chapter <601> of the USP. This
parameter is the equivalent droplet size in which half (50%) of the droplets are smaller
and the other half are larger than the specified cutoff diameter, based on the drug amount
deposited in different stages of the NGI. The Geometric Standard Deviation (GSD) can
be used to indicate the droplet size distribution around the MMAD. The FPD was
ated from the sum of drug mass deposited on ion Stages 3 through 7, MOC
and al filter (aerodynamic cutoff diameter below 5.39 um).
Losses can occur during the NGI analysis drug collection due to deposition in
the nebulizer mouthpiece andfor inner tments between stages of the cascade
impactor. Mass balance can be performed to ascertain the extent of such losses. During
preliminary studies, it was ed that a 15-minute aerosol generation from
dispersions prepared with synthetic phospholipids caused high amounts of ation
to accumulate in the nebulizer mouthpiece. TED was evaluated from an adapted DUSA
to confirm that acceptable mass recovery was being achieved during the analysis (Figure
). During DUSA testing, the l was deposited directly onto a glass fiber filter,
positioned on one end of the DUSA, which was connected to a vacuum pump. The
nebulizer mouthpiece was positioned on the opposite end, and directly connected to the
DUSA using a silicone adapter. TED was determined from the drug amount collected in
the glass fiber filter and from the internal walls of the DUSA, which was analyzed using
HPLC generated data following a timed nebulization.
To further e the dose, FPD results were extrapolated from 15-second
measurements to calculate an estimated total delivered drug (estimated total FPD or
FPDet) within a l5-minute period in accordance with Equation 4:
._ . $530
_ —FP.~.‘3;-._.“",
“Pa, = E93 (""93 :+th;T
“‘1 3 (Equation 4)
Where i is an integer number enting ond intervals (time duration of NGI and
TED analyses). The j value is the subsequent integer number smaller than i, and n is the
number of l5-second fractions within a 15-minute zation period (n = 60). Fine
Particle Dose (FPDr) was also calculated based upon FPDet.
HPLC Analysis of COQ10: This method was adapted from the previously
developed method presented in Example 4. A Waters HPLC and column system
(Waters Co., Milford, MA, USA) connected to a UV ion utilized a 1525 binary
pump, a 717 autosampler, a 2487 dual 2» absorbance detector, set at 275 nm, and a
Symmetry® RP-C8 column (3.9 x 150 mm, 5 pm) connected to Symmetry® C8 guard
column (3.9 x 20 mm, 5 um). A methanol:hexane mobile phase at 97:3 (v/v) and was
eluted at a flow rate of 1.0 mL/min. Stock solution of CleO was initially dissolved in
hexanezethanol at a ratio of 2:1 (v/v) and then diluted with the mobile phase to obtain the
desired concentrations. The ity range was ined by injecting 50 uL of
samples at a controlled temperature of 40 °C. Chromatogram peaks were acquired
within run time of 9 minutes and the peak areas were used to ine curve linearity.
All samples were collected from NGI and DUSA testing with ethanol, with
the exception of drug collection from the NGI plates (Stages 1 through 7 and MOC) for
analysis of lecithin sions. Due to the low solubility of the formulation in ethanol,
a mixture of hexanezethanol 2:1 Viv was utilized. The samples collected in glass fiber
filters (external filter in NGI and filter from DUSA) were vortexed for 30 seconds prior
to filtering with 0.45 mm syringe filters. Mobile phase was used for sample dilution.
tical Analysis: The data is expressed as mean 1 standard deviation
with the exception of surface tension, which was expressed as mean 1 standard error.
For gy studies, standard errors were provided by the re used to analyze the
best fit of the results to the rheological models. Samples were analyzed at least in
triplicate and evaluated for statistical differences with One-Way ANOVA for
significance when p < 0.05 using ASS software Dawson edition. Post hoc
comparisons were performed to identify statistically significant differences among
groups using Tukey-Kramer . A paired t—test was performed to analyze statistical
differences (p < 0.05) within the same nebulization event for different formulations and
to compare TED methods.
Results and Discussion
Synthetic phospholipids (DMPC, DPPC, and DSPC) were used to prepare
CleO formulations and compared the results with in formulation analyzed in
Example 1. Because CleO delivery is achieved via a dispersion, lization can
generate droplets containing differing s of drug. Therefore, the aerodynamic
properties of the formulation were analyzed using a cascade impactor, based on the drug
amount deposited in each stage of the NGI apparatus. Furthermore, TED was analyzed
based on drug collected in a filter delivered directly from the nebulizer mouthpiece.
Nebulization mance combined with the aerodynamic properties of the dispersion
can provide a basis for the comparison of the inhalable potential of the formulations.
These characteristics also for the identification of physicochemical properties favoring
effective drug emission of drug dispersions from a nebulizer.
The hydrodynamic size in the sions (Figure 16 and Table 3) show that
the lecithin formulation drug particle size was predominantly in the submicron range.
tic phospholipid formulations ted some larger particles, though analysis of
Dv(X) and span does not present tical differences among formulations (excepting
the Dv(10) of DMPC and DSPC dispersions). Further analysis of drug le size
distribution using DLS shows that lecithin dispersions presented larger nanoparticles
with a higher polydispersity than the synthetic phospholipid formulations (Figure 17).
Among synthetic phospholipids, the DSPC dispersion presented the largest drug
nanoparticles while the DMPC ation presented the most monodisperse profile.
Following sing, the synthetic phospholipids presented some microparticles,
although the tion of particles in the nanometric scale was primarily smaller than
drug particles that were produced from lecithin dispersions of CleO.
The zeta potential of lecithin dispersion was significantly higher than that of
the synthetic phospholipid dispersions (Figure 18). Without wishing to be bound by any
particular theory, the mixture of different phospholipids at various concentrations
depending on the source and extraction method for lecithin can lead to variable zeta
potential values. The zeta potential values of synthetic phospholipids can be attributed
to the presence of sodium chloride in the ations e ses in ionic
strength at neutral pH can increase the zeta ial of negatively charged
phospholipids like DMPC, DPPC, and DSPC.
Increasing the number of microfluidizer passes can cause a decrease in
surface tension (e. g., possibly due to a more efficient encapsulation). For the synthetic
phospholipid compositions, an increase in surface tension was observed which tracked
the se in the number of s in the acyl chains of the phospholipid. The
formulations were designed to have the same amount of DMPC, DPPC, and DSPC at
2.5% w/w. However, the molecular weight vary slightly due to the different number of
carbons in each respective acyl chain. Accordingly, the molar concentrations of the
phospholipids in the dispersions were 36.9, 34.1 and 31.6 mM, respectively. The
structure of phospholipids in water dispersions depended directly on the number of
olipid molecules. ore, without wishing to be bound by any particular
theory, it is believed that the number of phospholipid molecules available in “solution”
to cause a decrease in surface tension at a constant temperature can explain the
differences in surface tension. It is noteworthy that the surface tension of the CleO
sion prepared with lecithin, which is a mixture of phospholipids, falls between the
values of DMPC and DSPC (Figure 19).
Particle characteristics such as size, size distribution, shape, charge,
deformability, and the interactions between particles and the surrounding fluid can play
a role in the rheological behavior of dispersed systems. To evaluate the rheology of the
sions, shear stress was plotted as a function of shear rate and the results were fit to
the best rheological model. The Herschel—Bulkley model (See Equation 2 and
corresponding text above) best represented most of the formulations.
The Power Law model is similar to Herschel-Bulldey, except that it does not
present yield stress value. Standard errors are 35.92 i 3.57, 9.83 i 0.17, 10.27 i 0.35,
21.15 i 8.17 for lecithin, DMPC, DPPC and DSPC dispersions, tively. The three
elements of the Herschel-Bulkley model are presented in Figure 20. DSPC dispersion of
CleO was governed by Power Law and therefore did not present yield stress.
Interestingly, the yield es of the formulations are shown to be statistically ent
but no trend was identified. DSPC ation had a icantly higher Non-
Newtonian viscosity than the other analyzed samples, possibly due to its evident shear-
thinning behavior (n < 1). Interestingly, the flow index results indicated that DPPC,
DMPC, and lecithin sions respectively presented increasing shear-thickening
behavior (n > 1).
] The rheology was further analyzed by holding shear rate and ity as the
ndent and dependent variables, respectively, in order to fit the results to the
general flow curve of aqueous dispersions (Figure 21). Graphical representations are
presented in Figure 22, which clearly shows the accentuated DSPC formulation shear-
thinning event. Relevant equations related to these models are shown in Table 4. By
g these curves to the rheological models, it was found that the ations
presented different behavior (Table 5). Standard errors are 93.49 i 8.60, 43.27 i 10.55,
41.34 i 8.57, 16.00 i 4.74 for lecithin, DMPC, DPPC and DSPC dispersions,
respectively.
The lecithin formulation of CleO fits to the Sisko model, indicating that the
investigated shear rate range falls within the mid-to-high shear-rate range related to the
general flow curve of dispersions. This is confirmed by the small characteristic time
seen in Table 5 and the curve shape at higher shear rates shown in Figure 22. This result
also confirms the shear-thickening behavior presented from the evaluation of the
Herschel-Bulkley model (Figure 20). Of the formulations studied, only the lecithin
dispersion presented thixotropic behavior. This indicates a time-dependent change
following interruption of shear stress (e.g., shear-thinning event) during structure
recovery from the shear-thickening behavior presented by this dispersion in the shear
rate range studied. Therefore, the synthetic phospholipid formulations promptly r
to their initial state at cessation of shear stress.
The DMPC and DPPC dispersions followed the Cross model, thus both zero-
rate and infinite-rate viscosities are presented. However, the formulations’ characteristic
times differ greatly, with the lowest value shown for the DMPC formulation. This
indicates that, similarly to lecithin dispersion, the DMPC formulation falls towards the
upper range of shear rate related to the general flow curve of dispersions (Table 5),
explaining the second Newtonian plateau (3.66 cP) being greater than the first
Newtonian zone (1.13 cP). Therefore, the rheological behavior of the DMPC dispersion
is closer to the Sisko than the Cross model. For this reason, both lecithin and DMPC
dispersions present rate index (or Cross rate constant) values above unity, reflecting the
absence of the power law region in the shear rate range igated. When the viscosity
within this specific range is riately extending from the first to the second
Newtonian zone, 1 — m is close to the rate index n. The shear-thickening behavior is
evident from the curve shape at higher shear rates (Figure 22). The larger characteristic
time of the DPPC formulation indicates that the curve falls more towards the lower
range of shear rates and therefore supports the te-rate ity being smaller than
the zero-rate viscosity. The Cross rate constant is close to unity, which tes a
degree of shear-thinning or in the power law region. Observation of the curve
shape of DPPC dispersion in Figure 22 supports these findings and the relatively low
degree of shear-thickening or presented in the Herschel—Bulkley model (Figure
). This relatively low degree of shear-thickening behavior, when compared to lecithin
and DMPC formulations, can be attributed to ences in rheology at higher shear
rates.
The gical behavior of the DSPC followed the Williamson model. The
statistically significant higher characteristic time in ction with the flow curve
shape of this dispersion indicate that the shear rate range investigated falls within the
low-mid shear rate range of the l flow curve of dispersions (Figure 22). The rate
index value reflects the shear—thinning behavior at the power law region (Table 5).
[0025 6] As discussed in connection with Example 1, it can be important to investigate
the capability of ing-mesh nebulizers to continuously and steadily aerosolize
dispersions, with concomitant analysis of fluid rheology as opposed to simpler kinematic
viscosity measurements. Previous works have focused on the viscosity of the dispersion
media per se, regardless of the interactions between the dispersed particles within the
surrounding fluid. Because high ncy mechanical stress of the nebulizer is directly
transferred to the formulation, analysis of rheology parameters at higher shear rates may
better ate to what is actually occurring in the vicinity of the Vibrating ne.
Some standard error values obtained from fitting the results to rheological
models can be considered relatively high. Without g to be bound by any
particular theory, it is believed that these values can be attributed to a limited shear rate
range studied using the experimental design of the present examples. Although further
and/or additional experiments could be conducted to lower standard error, the
understanding of formulation reaction to the stress applied nevertheless es
valuable information about what can be ed from the active membrane nebulization
of such dispersions.
In order to compare the nebulization performance of the ations, a
Malvern Spraytec® was set up with the open bench method described in Example 1.
The transmittograms presented in Figure 23 show nebulization events with a 15 minute
duration. At the end of this duration, the transmission values returns to 100%, indicating
that the ements were performed properly and without detector lens fogging. To
evaluate the nebulization performance of these formulations, the transmittograms were
fitted to a linear regression to analyze the slopes of the . The steadiness of a given
nebulization event can be inferred from the slope. The slopes and the TAO results are
presented in Figure 24. Aerosolization of the control (i.e., ) was steadiest over
time, as indicated by the slope of essentially zero and the highest TAO. The lecithin
formulation exhibited steady nebulization for the initial 5 minutes (300 seconds),
followed by an increase in transmission. The DMPC sion exhibited a ission
profile with a n opposite to lecithin. At the start of nebulization, a slight slope was
observed up to about 8 minutes (480 seconds), followed by steady nebulization. DPPC
and DSPC sions presented a very shallow slope throughout zation.
The lecithin dispersion exhibited the highest slope and a low TAO (that was
not statistically different from the DMPC formulation). Although the DPPC and DSPC
formulations presented similar slopes (e.g., not statistically different), the TAO from
DSPC showed a higher mass output than that the TAO from DPPC, despite both
formulations being steadily nebulized. These results show the importance of analyzing
the slope of the transmittograms in conjunction with the mass output (or TAO). The
DSPC ation presented the best s among the s dispersions of CleO,
exhibiting a low slope value and the highest TAO among the phospholipid dispersions.
To summarize, the order of increasing nebulization performance in the studied
ations was: Lecithin < DMPC < DPPC < DSPC.
These findings can be evaluated concomitantly with the respective
rheological behavior of the formulations at higher shear rates. Upon ation of the
curves (Figure 22), at high shear rates lecithin and DMPC dispersions present the
characteristic shear-thickening behavior following the second Newtonian plateau, which
is confirmed by their low respective characteristic times. The occurrence of shear-
thickening following the shear-thinning event can be attributed to an arrangement
instability ing the two-dimensional layering of the fluid. Being above a critical
shear stress can causes random arrangement of the dispersed les, ing in an
increase in viscosity. The random arrangement can limit steady nebulization
performance, as shown by these two formulations. On the other hand, the high
characteristic times and shear-thinning behavior at the power law region presented by
DSPC, and to a lesser extent DPPC, dispersions at high shear rates can explain their
relatively superior nebulization performance. These results suggest that a high
characteristic time corresponding to a shear-thinning behavior at high shear rates may
favor the nebulization performance, while shear-thickening (low characteristic time)
may have the opposite effect. Therefore, these results suggest that the rheological
or at high shear rates can be ly related to the nebulization performance of
the dispersions.
However, these data suggest that mass output may not be correlated (e. g.,
directly correlated) to drug emission in the case of the zation of the dispersions
described herein. Therefore, in order to measure drug aerosolization and to gain
understanding of the aerodynamic properties of the formulations, the in vitro deposition
of the olipid formulations of CleO was analyzed using NGI and adapted
DUSA. is of drug deposition at initial and final time fractions of the 15-minute
zation period allowed for an evaluation of this data in ction with the
nebulization performance.
The TED of lecithin, DMPC, DPPC and DSPC formulations are presented in
Figure 25. The lecithin dispersion of CleO presented a statistically icant
decrease in drug aerosolization comparing initial and final phases of nebulization period,
following both NGI and DUSA analysis. This difference in amount of drug emitted at
the beginning and at the end of the nebulization confirms that the slope (25.99 x 10'3 i
2.80 x 10'3 %/s) observed in the results from nebulization performance using LD is not
only related to decreased mass output, but also to the amount of drug being aerosolized.
Overall, the lecithin sion also presented a significantly smaller TED both at the
initial and final phases when compared to the synthetic phospholipid formulations.
No statistical difference was found within the same nebulization event for the
dispersions prepared with synthetic olipids under NGI analysis. However, the
DMPC dispersion ted a smaller TED within the same nebulization event using the
DUSA methodology. r, the TED/DUSA results can be more relevant to the
present analysis because the droplets containing the drug are directly deposited in a filter
whereas the TED/NGI results have potential losses associated with the NGI apparatus.
Regardless of the potential , a satisfactory mass balance was achieved because no
statistical difference was identified in comparing the two methods’ determination of
TED. The slope (16.06 x 10‘3 i 2.88 x 10‘3 %/s) from nebulization performance testing
of DMPC dispersion is in agreement with the difference in drug amount being
aerosolized within the 15-minute nebulization period. DPPC and DSPC dispersions of
CleO aerosolized in approximately equal. These results show that these formulations
both exhibit steady nebulization (e.g., as fied in the relatively small linear
regression slope ).
namic properties that can affect pulmonary drug delivery are shown
in Figures 26 and 27. The lecithin formulation exhibited a higher droplet size, as related
to drug mass fraction deposited, at the initial stage of nebulization than at the final stage
(Figure 26). The DMPC formulation, to a lesser extent, exhibited a similar pattern to the
lecithin formulation. The DPPC and DSPC formulations had a more balanced droplet
size throughout the 15 minute nebulization event. With respect to the drug amount
deposited (as opposed to drug fraction), Figure 27 shows that the overall deposition of
lecithin ation was low both at the initial and final phases (e. g., when compared to
the other formulations). This result is in agreement with the TED results. Among the
three synthetic phospholipids studied, the DMPC formulation presented the lowest
deposition, which is in agreement with the TAO and TED results. The DPPC and DSPC
formulations had high drug s deposited and maintained consistent aerodynamic
properties throughout the 15 minute nebulization event.
To r compare the aerodynamic ties of the aerosolized
dispersions, the MMADs and GSDs are presented in Figure 28. The MMAD and GSD
values are initially similar for all four formulations. However, by the completion of the
nebulization event, the values were different. This behavior indicates that the size of the
emitted droplets containing drug nanoparticles is phospholipid dependent. ably,
the changes in transmittogram slope observed within the same nebulization event for
lecithin and DMPC dispersions (Figure 24) are ed not only in the amount of drug
being aerosolized (TED results, Figure 25), but also on the aerodynamic properties
shown in their in vitro NGI deposition profiles (Figures 26 and 27). As the nebulization
progresses, the droplets aerosolized became r and fewer.
A further understanding of the nebulization output’s potential for lung
deposition can be obtained by analyzing fine particles (e. g., aerodynamic sizes below
.39 pm). Figure 29A shows the TED NGI and TED DUSA values for the studied
ations. The TED NGI data ts that only the lecithin ation ted a
significant difference in drug amount aerosolized when comparing the initial and final
phases within a 15-minutes nebulization. The TED DUSA values show that the lecithin
and DMPC formulations exhibited a difference in drug amount aerosolized when
comparing the initial and final phases within a 15-minutes nebulization. The TED
DUSA results can be considered more meaningful e droplets containing the drug
are directly deposited in a filter for measurement, whereas the TED NGI results can have
losses throughout the NGI equipment aerosol passageways. Figure 29B shows the
FPDet and FPF values for the d formulations. The FPF increased over time for all
of the dispersions aerosolized with the Aeroneb Pro® nebulizer under the present
experimental conditions, confirming that droplet sizes decreases during the course of
nebulization. The FPD of the lecithin formulation changes drastically during
nebulization. The MMAD values of aerosolized DMPC dispersions decreases during
nebulization, while FPD does not statistically change. The DPPC formulation exhibited
steady zation performance and, consequently, consistent TED values hout
nebulization. Although the MMAD values are not statistically different, the FPD results
show that the DPPC ation exhibit a higher amount of aerosolized drug by the end
of zation. A similar behavior was observed for the DSPC formulation, but the
results was not statistical significant (P = 0.08) based on this example alone.
Figure 30 shows that the geometric sizes of the droplets containing CoQ10
particles also decrease over time, especially in the lecithin and DMPC formulations.
Aerosols of the DPPC and DSPC formulations exhibited a relatively tent (e. g.,
similar to the saline control) droplet size during the 15 minute nebulization.
pancies in namic and geometric sizes can be attributed to the different
experimental setups (see discussion in Example 1).
Table 6 show the unprecedentedly high doses with the potential to reach the
lungs (based on FPD) exhibited by the present invention, with the DPPC and DSPC
formulations presenting the highest . These doses are approximately 10 to 40
times greater than itraconazole spersions previously aerosolized using the same
type of nebulizer (vibrating-mesh device, data not shown) and as much as 280 times
greater than us aerosolization of budesonide suspension (Pulmicort Respule®,
AstraZeneca, UK) using a Sidestream® PortaNeb® jet nebulizer (Medic-Aid Ltd, UK).
Of perhaps lent importance, the present invention allows for verifying the quality
and quantity of nebulization (e.g., bolus vs. steady aerosol during nebulization event).
In some cases refinements can be necessary for effective drug loading. For
example, water evaporation can occur during hot high pressure homogenization.
Similarly, the small volume of formulation prepared (e. g., 100 mL) can result in drug
loss through deposition on the manufacturing equipment.
Finally, the observed changes in nebulization mance during
nebulization events have been shown to correspond to differences in aerodynamic
properties between the different formulations. Nevertheless, the rheological behavior of
these formulations was shown to be compatible with active vibrating—mesh nebulizer for
continuously nebulizing phospholipid-stabilized nanodispersions of hydrophobic
bioactive agents. The concentration of the s elements of the dispersion (e.g.,
hydrophobic bioactive agent) has a significant role in determining the critical shear rate
at which the shear thickening event post-second Newtonian u . Thus,
knowledge of a dispersion’s rheology can be used to identify a maximum drug loading
while still maintaining a d nebulization performance. Nebulizer aerosol generation
occurs through application of a stress (e.g., air jet stream, ultrasonic force, vibrating-
mesh) into or onto the bulk liquid formulation. Therefore, the methodology provided
herein, including the combination of rheological studies of dispersions and analysis of
nebulization performance using LD ques, provides for the formulation
pment of hydrophobic drugs continuous nebulizer based inhalation therapy.
Example 3: Pulmonary Deposition and Systemic Distribution in Mice of
Inhalable Formulations of Cle0
Example 3 presents an evaluation of in viva ic distribution, lung, and
nasal depositions in mice following pulmonary delivery of CleO formulations
prepared with synthetic phospholipids. Three tic phospholipids were selected to
stabilize these dispersions based upon the experimental results presented above and
because of the phospholipids physiological ence in the lungs: DMPC, DPPC, and
DSPC. Lecithin was not selected as a results of its low in vitro deposition. The dosing
apparatus includes a nose-only inhalation r ing aerosol generated by an
Aeroneb Pro® vibrating-mesh nebulizer. The results showed the achievement of a high
and sustained dose of CleO to the mice’s lungs, which varied from 1.8 to 3.0% of the
theoretical exposure.
Materials and s
Materials: CleO was supplied by Asahi Kasei Corp. (Tokyo, Japan).
e ceuticals (Liestal, Switzerland) provided l,2-dimyristoyl-sn-glycero
phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycerophosphocholine , and
stearoyl-sn-glycerophosphocholine (DSPC). DMPC was also obtained from
Lipoid GmbH (Ludswighafen, Germany). Sodium chloride (crystalline, certified ACS)
was acquired from Fisher Chemical (Fisher Scientific, Fair lawn, NJ, USA) and the
deionized water was obtained from a central reverse osmosis/demineralizer .
Mouse restraint tubes (item C), anterior nose inserts (item E2TE-N) and
posterior holders (item E2TA-N) were purchased from Battelle Toxicology Northwest
(Richland, WA, USA). A fan (12V, 0.10A, model OD4020-12HB) was purchased from
Knight Electronics (Dallas, TX, USA). HPLC grade hexane and ethanol 200 proof were
purchased from Sigma-Aldrich (St. Louis, MO, USA). Syringes (1 mL) and needles
(gauges 21G1 and 23G1) were obtained from Becton Dickinson (Franklin Lakes, NJ,
USA). Heparinized tubes (1.3 mL ubes Lithium Heparin (LH) with screw cap
closure, product no. 3.105) were purchased from Sarstedt AG & Co. (Numbrecht,
Germany). Microcentrifuge tubes (1.5 mL, clear, DNase free, BL3152) were
obtained from Bio-Link Scientific, LLC (Wimberley, TX, USA).
Formulation: Formulations were prepared using high pressure
homogenization as described in Example 2. To summarize, following overnight
ion while ng, a phospholipid sion containing 2.5% w/w of
phospholipids (DMPC, DPPC, or DSPC) in water was added to the molten CoQ10 (4%
w/w) at 55 OC. The formulation was predispersed, using an Ultra-Turrax® TP 18/10
Homogenizer with 8 mm rotor blade, by high shear mixing (IKA-Werke, Staufen,
Germany) for 5 minutes at 20,000 rpm. The formulation was then passed 50 times
through a M-110P “Plug-and-Play” Bench-top Microfluidizer® (Microfluidics, Newton,
MA USA) at approximately 30,000 psi while maintaining a temperature between 55 and
65 OC. Following microfluidization, 0.9% W/V of sodium chloride was added to the final
formulation. A ation for the l group was similarly prepared using DPPC in
absence of drug (CleO was not added).
Pulmonary Delivery to Mice: Animals were caged in groups of 4 and
maintained on a normal rodent chow diet with free access to water. A nose-only
chamber apparatus capable of dosing six mice at a time was assembled as shown in
Figure 31. Prior to dosing, CD—1® IGS ICR mice (Charles River Laboratories
International, Inc., Wilmington, MA, USA) were individually acclimatized for
approximately 10 minutes per day for 3 days into restraint tubes, restricted by an anterior
nose insert and a posterior holder. The dosing apparatus was placed inside a fume hood
to collect escaping aerosol containing drug. To avoid ce from the airflow
provided by the fume hood, an erlenmeyer container was placed at the end of the tubing
system as a buffer. The airflow rate was set to 1 L/min to ensure proper drug
lization into the nose-only chamber (internal : 230 mL; diameter: 3.8 cm;
length: 20.3 cm) using an Aeroneb Pro® vibrating-mesh nebulizer (Aerogen, Galway,
Ireland). Following preparation, all formulations (saline control, DMPC, DPPC, and
DSPC) were closed for 15 minutes to mice weighing from 23 to 33 g each, at time of
dosing. Each single-dose studied group consisted of -six male s. At each
time point (0.5, l, 3, 8, 24, and 48 hours after the end of the aerosolization event) six
animals randomly selected from different dosing events of the same formulation were
sacrificed by narcosis with carbon dioxide. As part of the collection process, blood was
withdrawn by cardiac puncture, lungs were ted, and a nasal wash was performed.
The s were extracted for analysis with liquid chromatography coupled with
tandem mass spectrometry (LC/MS/MS).
Estimated Dose: To estimate the dose to which mice were d during
this study, it was assumed that the nose—only chamber gradually fills with the aerosol
ning CleO. Therefore, the drug concentration ly increases until it s
a plateau. At steady-state, it is also assumed that the rate of drug entering the chamber is
equal to the rate of drug leaving the chamber (dC/dt=0). Therefore, Equation 5 can be
used to measure the drug concentration inside the chamber at any given time:
C = FPDr/F * (I — e"- )L t) (Equation 5)
Where C is the drug concentration, FPDr is the rate of delivery of the Fine
Particle Dose (the amount of particles with aerodynamic cutoff diameter below 5.39 pm
per minute) as determined in the previous chapter, F is the airflow rate, 9» is the chamber
air-change rate and t is any given time within the nebulization period. The chamber air-
change rate, R, can be determined based on the airflow rate and on the chamber al
volume, V, based upon Equation 6:
k = F/V (Equation 6)
Based on these assumptions, the following Equation 7 describes the
estimated dose delivered to mice:
ESi’fE-FR-fiifmi Bose = RH~
. 7:
-" :93“ s t g _;_.,~
‘ v» {t «3:- {;.E E.» — I];,
.‘F I" ' ' I
) (Equation 7)
Where RMV is the species—specific Rate Minute Volume and t’ is the
duration of the nebulization event. The estimated dose as calculated above can then be
normalized by the animal body weight, W (g). RMV is calculated in accordance with
Equation 8:
RMV = 4.19 * WA0.66 (Equation 8)
Analysis of COQ10 Levels in Lung , Blood Plasma, and Nasal
Cavity: For each experiment, CleO levels were determined after liquid extraction
using liquid chromatography d with tandem mass spectrometry (LC-MS/MS).
The methods were validated in the drug concentration range of 0.1 to 600 ug/mL. The
general sample preparation protocols for lung , blood plasma, and nasal cavity
analysis are described below.
Following harvesting of the mice lungs, the tissue was weighed (wet weight),
frozen in dry ice, and transferred to a -80 °C refrigerator for storage until to analysis.
After samples were thawed for analysis, lung tissue (50 i 1.5 mg) was weighed
subsequently homogenized with Dulbecco’s Phosphate Buffer Saline .
Homogenate (100 uL) and al standard were added to isopropanol (IPA) and
vortexed. Following centrifugation, the atant (100 uL) was added to another tube
containing IPA. The sample was vortexed again and transferred for LC-MS/MS
analysis.
Following cardiac puncture, approximately 1 mL of mice blood was collected
in heparinized tubes and kept in ice bath until centrifugation for 10 minutes at 7000 g.
The atant was then transferred to 1.5 mL microcentrifuge tubes and kept
erated at -80 0C until analysis (see lung tissue procedure described above).
] A solvent wash was performed to evaluate the amount of drug deposited into
the nasal cavity. The murine nasal cavity was directly accessed from the posterior
portion of the hard palate by inserting a needle into the nasopharynx and g the
nasal fossa with hexanezethanol 2:1 (v/v). The solvent was collected in a scintillation
vial from the anterior (frontal) portion of the nose and subsequently allowed to dry at
room temperature. The sample was then re—suspended and injected into LC-MS/MS for
quantification of CleO.
Statistical Analysis: Samples were tested for normality using the Shapiro
Wilk test (p < 0.05) and outliers were excluded from data analysis. Pharmacokinetic
parameters were determined using Microsoft Office Excel 2007 software nd,
WA) with the add-in program PKSolver. Statistical analysis was performed using
NCSS/PASS software Dawson edition. At each time point, lung tissue samples were
analyzed for statistical differences among ent groups with y ANOVA for
significance (p < 0.05). The same analysis was performed for nasal wash samples, with
onal post hoc multiple ison tests performed to identify statistically
significant differences between treated and control groups using Dunnett’s method (p <
0.05). A paired t—test was performed to analyze statistical differences (p < 0.05) within
the same treatment group for changes in drug deposition in the nasal cavity over time.
Results and Discussion
A nebulizer was used to te aerosol for dosing mice for 15 minutes with
control, DMPC, DPPC, and DSPC formulations. The dose delivered to the lungs was
estimated based on the FPDr , as determined during the in vitro characterization
of drug deposition using the Next Generation Impactor (NGI) bed in Example 2.
Figure 32 shows the calculated drug tration-time profile within the
dosing chamber. A plateau is reached at 3.0 minutes. The concentration at steady-state
(CSS) is equal to FPDr since the airflow rate during this experiment was 1 L/min (Table
7). The chamber air-change rate was 4.35 min]. The estimated doses delivered to mice
of aerosolized DMPC, DPPC, and DSPC dispersions of CleO for 15 minutes increases
in this respective order (Figure 33). When normalized to the body weight of animals,
similar estimated doses were delivered to mice receiving either DPPC or DSPC
formulations. These doses of CleO were found to be greater than when the mice were
dosed with the DMPC formulation.
The drug concentration in plasma was below the quantitative level (0.1
ug/mL) for all studied groups at every time point. The baseline tration of CleO
in mice blood plasma is approximately 0.1 umoliL (86 ng/mL). In the lungs, the drug
concentration was also below the quantitative level for the control group at every time
point investigated. However, Figure 34 shows that CleO stays in the lungs at
relatively high trations for up to 48 hours. The mechanism by which CleO
could be absorbed through the lung epithelium is unknown. Without g to be
bound by any particular theory, it is believed that, despite the lipophilicity of CleO,
e diffusion is only part of a more complex absorption process involving an
onal active and facilitated transport phenomena. It is le that the relatively
small amount of lungs to systemic translocation is, at least in part, part due to this low
permeability. In addition, the dispersions are formulated in the nano-size range, which
are known (e.g., with respect particles below 0.2-0.5 um) to be stealth to alveolar
macrophages. In addition to size, other physicochemical properties of the drug can
influence the translocation of nanoparticles across the air-blood barrier, for example:
particle material, in viva solubility, and binding affinity to cell membranes (e. g. through
surface charge and structure). The presence of olipids in these ations may
have also caused a greater lung peripheral distribution of the drug rticles.
The translocation of insoluble nanoparticles across the air-blood barrier is
known to be minimal compared to the long term clearance from the alveoli up to the
mucociliary escalator and into the GI tract, which can take weeks. A significant
spreading of drug towards the lung periphery due to the presence of phospholipids in the
formulations investigated in this study is a possible contributing factor explaining why
the nce of CleO from the lungs was not detected after 48 hours and similarly
why the drug levels in the plasma were below the quantitative limit. rmore,
because drug clearance from the lungs was not significant in the studied time period, the
elimination constants and half-lives could not be determined for the nebulized
formulations.
Other pharmacokinetic parameters are presented in Table 8. The lung
deposition profiles of aqueous dispersions of CleO using different phospholipids
presented relatively similar results. The Cmax ranged from 604.0 to 791.3 ug/g of wet
lung tissue, and was ed 1 hour (tmax) post dosing for all treated groups. These
values translate to approximately 4.0 to 5.0 mgfkg of mouse body weight and correspond
to 1.8 to 3.0% of the theoretical exposure dose (Figure 35). The AUCO-48 results were
surprisingly different; with the DMPC formulation of CleO presenting the highest
value less of whether the st estimated dose that the mice were exposed to
was ted. Although DPPC and DSPC dispersions of CleO presented high
estimated dose, their Cmax and AUCO-48 values varied . No statistical
differences were found in drug concentration at the same time point among the treated
groups (Figures 34 and 35).
The drug deposition in the nasal cavity was lower than that which was
measured in the lungs (Figure 36), not exceeding an average of 1.7 mg/kg of mouse
body weight among the treated . Only the DPPC group demonstrated a
statistically significant decreasing trend for the first two time points investigated. A
small amount of CleO was observed in the control group, possibly from an
endogenous source. Finally, all mice were alive and presenting healthy signs 48 hours
after the end the nebulization event. This demonstrates the safety of delivering high
amounts of exogenous CleO to the lungs.
In Example 2, unprecedentedly high doses with potential to reach the lungs
based on FPDet results were predicted, with DPPC and DSPC formulations presenting
the highest values. These doses are approximately 10 to 40 times greater than
itraconazole spersions previously aerosolized using the same type of zer
(vibrating-mesh device) and as much as 280 times greater than previous aerosolization
of a budesonide suspension (Pulmicort Respule®, AstraZeneca, UK) using a
Sidestream® PortaNeb® jet nebulizer (Medic-Aid Ltd., UK). This Example verified
that the high doses translated into an improved drug deposition in the lungs. Cmax
values of CleO were as much as ld and 165-fold higher than previous studies
using the same nebulizer to deliver dispersions of cyclosporine A and itraconazole,
respectively (data not shown). These data present a significant improvement in delivery
of high amounts of hydrophobic drug ly to the lungs. The in vitro methods of the
ion for designing and ing formulations with optimized potential to r
high drug amounts to the lungs were essential in achieving these results.
Example 4: Low Concentration Range Determination of Hydrophobic
Drugs Using HPLC
Preclinical and clinical studies require the determination of small amounts of
compounds (e.g., hydrophobic drugs such as CleO) in different biological fluids and
tissues. Currently, there are many analytical methods of HPLC with ultraviolet (UV)
detectors available. However, for high sensitivity analysis, more sophisticated and
complex s are required, for example: HPLC followed by chemical reactions,
HPLC with electrochemical detectors (ECD) and liquid chromatography-triple
quadrupole (tandem) mass spectrometry (LC — MS/MS). Among the parameters for
validation of HPLC methods are accuracy, precision, range, linearity and limits of
detection (LOD) and quantification (LOQ). Signal-to-noise (S/N) ratio is a quick and
simple method to determine LOD and LOQ, which are essential when analyzing low
concentration of drugs.
Methods: A Waters HPLC and column system including a 1525 binary
pump, a 717 autosampler, a 2487 dual 7» absorbance or, set at 275 nm, and a
Symmetry RP-C8 column 5 um (3.9 x 150 mm) connected to Symmetry C8 guard
column 5 pm (3.9 X 20 mm) was ed. The mobile phase (MP) includes
Methanol:Hexane at 97:3 (v/v). Stock solution of pure CleO was initially dissolved in
Hexane:Ethanol (diluent) at a ratio of 2:1 (v/v) and subsequently diluted with the mobile
phase to obtain the desired concentration. Limit of Detection (LOD), Limit of
Quantification (LOQ) and linearity (3-interday curves) were determined by injecting 50
uL samples at a controlled temperature of 30 OC. Chromatogram peaks were acquired
within run time of 11 minutes at a flow rate of 1.0 mL/min. Area and height of peaks
were used to determine curve linearity. LOD and LOQ were defined by signal-to-noise
(S/N) ratio calculations according to method from the European Pharmacopoeia, with
minimum acceptable values of 3 and 10, respectively. Concentration points were 10, 25,
37.5 and 50 ng/mL (n = 6).
For mobile phase ation, solvents were filtered prior to use through 0.45
pm nylon membrane filters and sparged for 10 minutes with helium gas. For
preparation of stock and working standard solutions (500 ug/mL), 12.5 mg of CleO
was accurately d in a 25 mL amber volumetric flask and ved in -
l (2:1 v/v). Subsequently, this stock standard solution was diluted with MP to 10
ug/mL. To avoid light degradation of the API, standard solutions were kept in amber
containers during drug lation. Working standard solutions were prepared by
transferring le aliquots of stock on to arent tubes and diluted to final
concentration with MP. Finally, the working standard solutions were transferred to
polypropylene conical containers and placed them in amber HPLC vials for analyses.
Results: The retention time (RT) of CoQ10 was determined as
approximately 8 minutes and injection of blank sample (diluent) shown not to interfere
in peak determination at 275 nm. Temperature control was ed to be essential to
obtain symmetric peaks at lower concentrations. LOD and LOQ were defined as 10
ng/mL (n = 6; S/N ratio = 6.0; SD = 0.6; RSD = 10.5%) and 25 ng/mL (n = 6; S/N ratio
= 12.6; SD = 1.3; RSD = 10.1%); respectively. The curve ities were obtained
using height or area of the chromatogram peaks in the range of 25 to 2500 ng/mL with r2
2 0.9999 (n=3 for each concentration).
] sion: The method can be used as an ative to more x and
expensive methods for analysis of CoQ10 in small concentrations. The ease of sample
preparation and small retention time allows for a quick analysis. The possibility of using
either the area or the height of chromatogram peaks gives more flexibility to adapt this
method to different applications. Further studies on tion of CoQ10 from
biological materials, stability, and internal standard selection are needed to define the
role of this method. This study provides an alternative and suitably stable method to
determine CoQ10 at very low concentrations using an economically viable RP-HPLC
system.
Example 5: Determination of Suitable Hydrophobic Drug
Concentrations in Phospholipid Nanodispersions Suitable for Continuous
Nebulization.
In developing hydrophobic drug formulations for continuous nebulization, it
can be useful to establish a maximum nominal drug loadings to phospholipid-stabilized
dispersions that will sustain continuous vibrating—mesh nebulization. This is because,
for example, vibrating-mesh nebulizer can exhibit problems such as variable
aerosolization due to clogging of mesh pores that can be mitigated by appropriate
formulation.
Methods: Formulations were prepared based upon the general methods
sed in connection with Examples 1 and 2. For this study, specific sions
were prepared with 50 uidization te passes using 2.5% w/w of dimyristoyl
phosphatidylcholine (DMPC) and 7.5%, 7.0%, 6.0%, 5.0%, or 4.0% w/w of COQ10.
The sions were then aerosolized within 24 hour using an b Pro® nebulizer
for 15 minute lization event. The aerosolization profile was monitored via
analysis of Total Aerosol Output (TAO) and using laser diffraction with a Malvem
Spraytec® coupled with an inhalation cell as described above.
Results and Discussion: The nebulization performances of the DMPC-
stabilized formulations are presented in Figure 37. As the hydrophobic drug
concentration decreases, the aerosolization becomes more continuous. The TAO values
for decreasing drug concentrations are, respectively, 1.25 g (12.4%), 1.62 g (16.1%) and
2.15 g (21.4%)0 The TAO results are in agreement with the analysis of nebulization
performance from laser diffraction, with increasing values as the drug concentrations
se. The transmission values do not return to 100% at the end of nebulization, due
to an experimental artifact. Although a formulation containing 5% w/w of CleO was
prepared, the analysis using laser diffraction could not be performed appropriately due to
this artifact. Based on visual observation, it was determined that this drug concentration
was not suitable for continuous aerosolization of the CleO dispersion because of
generation of intermittent mist during nebulization. For the 4.0% w/w CoQ10
formulation, this intermittence was only observed at the end phase of nebulization,
therefore being chosen as a suitable l drug concentration.
] Conclusion: The nominal concentration of 4% w/w of CleO was
determined to be the appropriate drug loading for continuous lization with the
Aeroneb Pro® nebulizer as established using DMPC at 2.5% w/w to stabilize the
dispersions. Nominal concentrations can vary depending upon the ic hydrophobic
drug used, as well as other components of the formulation such as the phospholipid.
Example 6: Measuring atory Reponse to Pulmonary
Administration of Dispersions of Phospholipid Encapsulated Hydrophobic
Bioactive Agents
The inflammatory response to the administration of hydrophobic bioactive
agents (e.g., as discussed in connection with Example 1-3 above) was measured.
Surgery is performed on iced mice to expose the pleural cavity and a at the
throat. A small incision is cut into the trachea and a cannula possessing about a 23
gauge needle with a sheath of plastic tubing (about 0.037 inch outside er (OD)
and about 0.025 inch ID) is inserted through the incision to the base of the trachea and
clamped to seal the opening. An aliquot (about 0.75 mL) of phosphate buffered saline is
led through the cannula into the lungs and d to wash the ial and
alveolar surfaces. This process is repeated for a total of three washes. The ate
buffered saline containing cells is placed into centrifuge vials and centrifuged at about
3000 rpm (MiniSpin Plus, Eppendorf International, Hamburg, DE). The supernatant is
removed leaving the collected cells in the pellet. The supernatant from the BAL
(Bronchoalveolar Lavage) is analyzed by enzyme-linked immunosorbent assay (ELISA)
for IL—12 elevation (n=2 per sample tested). Administering CleO is not associated
with a rise in IL-l2 levels and does not cause lung inflammation.
Example 7: Comparison of nebulization performance n aqueous
dispersions of COQ10 and an intravenous ation.
In order to more fully understand the effect of the inclusion and amount
certain pharmaceutical ation components on nebulization performance, the
continuous lization of several aqueous dispersions of COQ10 and an intravenous
formulation were studied. The results of this example are summarized in Figure 38,
which shows ittograms of aerosolization of DMPC- and DSPC-stabilized
dispersions, as compared to an intravenous formulation that includes a particular
opsonisation reducer. Additional data is presented in Figures 39-41.
Tested formulations studied included (i) a saline control (0.9% w/w NaCl in
water); (ii) Lecithin (50 passes, as presented in Example 1); (iii) CQDPPC06 -
formulation containing DPPC (4:2.5); (iv) CQDSPCOl — formulation containing DSPC
(4:2.5); (v) CQDMPC05 - formulation containing DMPC (4:2.5); (vi) CQDMPC06 -
formulation containing DMPC (3:2.5); (vii) IV Cytotech - an intravenous formulation
provided by Cytotech Labs for is of nebulization performance, including
COQ102DMPC2Poloxamer 188 (4:3: 1.5). Formulations iii-vi were prepared by the
method presented in e 2. Formulation viii was prepared in accordance with the
method presented in International Publication Number .
, presented a slope close to zero and a high TAO, which indicates
successful delivery of the solution using the nebulizer. Dispersion formulations
prepared with DMPC (excepting the IV formulation), despite drug concentration
differences, presented similar results both for slope and TAO, whereas in (50
) presented the highest slope and a comparatively a low TAO. The importance of
analyzing both TAO and slope are illustrated by these figures. Although formulations
CQDPPC06 and OI presented similar slopes, the TAO from CQDSPC01 was
higher than CQDPPC06, showing a higher output despite both being steady zed.
On the other hand, although the IV formulation presented some nebulization, the aerosol
output was the lowest among all formulations. Therefore, for all practical purposes, the
IV formulation failed to continuously nebulize in that it could not be reasonably used for
delivering a therapeutic dose of the bioactive agent. Formulation CQDSP01 presented
the arguably best results among the aqueous dispersions of API 31510. The order of
nebulization performance observed was (high to low): DSPC, DPPC, DMPC, lecithin,
and IV ch.
Figure 40 shows an analysis of drug particles dispersed in the formulations
studied in connection with Example 7. Lecithin, DMPC, and DSPC present
predominantly submicron sizes, although only in presented a low span.
Nevertheless, the lecithin formulation nanoparticles are relatively large (e. g., ~ 260 nm)
and sperse (PdI > 0.2). The on of micron-size particles is t in the
DSPC ation. The IV formulation presented a monodisperse distribution of ~ 60
nm particles. The DMPC and DPPC formulations t a mixture of small and large
drug particles.
Figure 41 shows another analysis of drug particles dispersed in the
formulations studied in tion with Example "i. The surface charge of drug
particles in dispersion was relatively low for the DMPC, DPPC, and DSPC formulations,
as reflected by their zeta potential values. The lecithin formulation had the largest zeta
potential, despite the lowest phospholipid concentration. The surface tension of the
formulations increase with increasing hydrophobicity of synthetic phospholipids
(increase in the number of carbons in lipid chain of phospholipids): DMPC < DPPC <
DSPC. Interestingly, the e tension of lecithin, a mixture of phospholipids, falls
within the DMPC and DSPC values. However, the mole fractions of the synthetic
phospholipids are different because the formulations were prepared by weight (DMPC
was the t and DSPC was the lowest).
Without g to be bound by any particular theory, it is believed that the
ion of poloxamer in the IV formulation was the predominant factor in the IV
formulations weak nebulization performance. However, the differences in nebulization
can also be ially attributed to other s including, but not limited to, the
inclusion of PBS rather than saline in the IV formulation, ionic concentration and charge
of the formulation (e. g., due to different aqueous dispersion agents and/or the presence
of the opsonization reducer), and/or differences in the manufacturing method.
EQUIVALENTS
The specification should be understood as disclosing and encompassing all
possible permutations and combinations of the described aspects, embodiments, and
examples unless the context indicates otherwise. One of ordinary skill in the art will
appreciate that the invention can be practiced by other than the summarized and
described aspect, embodiments, and examples, which are presented for purposes of
illustration, and that the invention is limited only by the following claims.
Recitation of ranges of values herein is merely intended to serve as a
shorthand method of ing dually to each separate value g within the
range. Unless otherwise indicated, each individual value is incorporated into the
specification as if it were individually d. Each of the documents cited herein
(including all patents, patent applications, scientific publications, manufacturer's
specifications, and instructions), are hereby orated by reference in their entirety.
Those skilled in the art will recognize, or be able to ascertain using no more
than routine experimentation, many equivalents to the specific embodiments of the
invention bed herein. Such equivalents are intended to be encompassed by the
following claims.
Claims (37)
1. An inhalable pharmaceutical composition comprising a dispersion of particles suitable for continuous aerosolization, each particle sing: coenzyme Q10 ); and a olipid selected from dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), or a combination thereof; wherein the ratio of CoQ10: phospholipid is between 1:1 and 4:2.5, wherein the particles are dispersed within the aqueous dispersion vehicle, wherein the composition can e predominantly liposomal arrangement, a fraction of liposomes together with other ements, or can be ially devoid of liposomes, and wherein the composition is formulated for continuous aerosolization sufficient to deliver a therapeutic dose of the CoQ10 to the subject.
2. The inhalable pharmaceutical composition of claim 1, wherein the CoQ10 is comprised within a liposome and/or otherwise stabilized together with a phospholipid.
3. The inhalable ceutical composition of claim 1, wherein the CoQ10 is between 6% and 0.1 % w/w of the composition.
4. The inhalable pharmaceutical composition of claim 1, wherein the phospholipid is 3% w/w or less of the composition.
5. The inhalable pharmaceutical composition of claim 1, wherein the aqueous dispersion e comprises water or an aqueous salt solution.
6. The inhalable pharmaceutical composition of claim 1, wherein the dispersion of particles is in the form of a uous respirable l comprising a plurality of aqueous droplets containing a dispersion of particles and having a mass median aerodynamic diameter (MMAD) between 1 and 5µm. 13354311 (13815900_1):DPS
7. The inhalable pharmaceutical composition of claim 1, wherein the composition is terized by an average percent transmission (APT) between 50 and 100 % over at least 15 minutes of continuous aerosolization.
8. The inhalable pharmaceutical composition of claim 1, wherein the dispersion of particles is in the form of a continuous respirable l comprising a plurality of droplets having a MMAD between 1 and 5µm over at least 15 minutes of continuous aerosolization.
9. The inhalable pharmaceutical composition of claim 1, wherein the composition is characterized by an APT between 50 and 100 % after at least seven days of storage.
10. The ble pharmaceutical composition of claim 1, wherein the composition is characterized by an APT between 50 and 100 %.
11. The inhalable pharmaceutical composition of claim 1, n the particles have an average diameter between 30 and 500 nm after at least seven days of storage.
12. The inhalable pharmaceutical composition of claim 1, wherein the composition is characterized by non-Newtonian fluid behavior.
13. The inhalable pharmaceutical composition of claim 1, wherein the ition has a flow index (n) of 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, or 1.3.
14. The inhalable pharmaceutical composition of claim 1, wherein the composition has a viscosity (i) of 0.1, 0.15, 0.2, 1, 100, or 110 cP.
15. The inhalable pharmaceutical composition of claim 1, wherein the composition has a zeta potential of 2.5, 1.5, -2.5, -10, -50, -55, or -60 mV.
16. The inhalable ceutical ition of claim 1, wherein the composition has a surface tension of 25, 30, 35, 40, 45, or 50 mN/m.
17. The inhalable pharmaceutical composition of claim 1, n the ition has a yield stress (a) of 11, 12, 13, 14, 15, 16, 17, or 18 mPa. 13815900
18. The inhalable pharmaceutical composition of claim 1, wherein the dispersion of particles have an average diameter between 30 and 500 nm.
19. The inhalable pharmaceutical composition of claim 1, wherein the dispersion of particles have an average diameter between 30 and 300 nm.
20. The inhalable pharmaceutical composition of claim 1, wherein the sion of particles have an average diameter between 30 and 100 nm.
21. The inhalable ceutical composition of claim 1, wherein the composition has a polydispersivity index or (PDI) of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, or 0.7.
22. The inhalable ceutical composition of claim 1, wherein the composition does not comprise an opsonization r.
23. The inhalable pharmaceutical composition of claim 1, wherein the composition has a total aerosol output (TAO) of at least 40%.
24. The inhalable pharmaceutical composition of claim 6, wherein the MMAD is 1, 2, 3, 4, or 5 µm.
25. The inhalable pharmaceutical composition of claim 6, wherein the plurality of droplets have a geometric standard ion (GSD) of less than 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1.
26. The inhalable pharmaceutical composition of claim 1, further comprising a salt in an amount making the composition essentially isosmotic with the human lung.
27. The inhalable ceutical composition of claim 1, wherein the dispersion is a suspension, nano-suspension, emulsion, or microemulsion.
28. The inhalable pharmaceutical ition of claim 1, further sing a polyoxypropylene-poloxyethylene block polymer at 0.001-5% by weight of the total composition. 13815900
29. The inhalable ceutical ition of claim 1, wherein, upon continuous aerosoloization, the composition is capable of achieving a bioactive agent concentration of at least 500 μg/g wet lung tissue.
30. The inhalable pharmaceutical ition of claim 1, wherein, upon continuous aerosolization, the composition is capable of achieving a total emitted dose (TED) of at least 2,900 μg over 15 seconds.
31. The inhalable pharmaceutical composition of claim 30, wherein the total emitted dose (TED) is at least 3,600 μg, 3,900 μg, 4,300 μg, or 4,600 μg over 15 s.
32. The inhalable pharmaceutical ition of claim 1, wherein the continuous aerosolization has a duration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 50 or 60 minutes.
33. The use of an inhalable pharmaceutical composition for the preparation of a ment for the treatment of a lung disease wherein said composition is formulated for administration to a subject by: aerosolizing a dispersion of particles, thereby forming a respirable aerosol comprising a plurality of droplets having a mass median aerodynamic diameter (MMAD) between 1 and 5 pm, wherein each particle comprising coenzyme Q10 (CoQ10) and a phospholipid dispersed within an aqueous dispersion vehicle, wherein the ratio of CoQ10:phospholipid is between 1:1 and 4:2.5, wherein the ition can e predominantly liposomal arrangement, a fraction of liposomes together with other arrangements, or can be essentially devoid of liposomes; wherein the phospholipid comprises itoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), or a combination thereof; and 13815900 wherein the composition is formulated for continuous aerosolization sufficient to deliver a therapeutic dose of coenzyme Q10 to the subject.
34. The use of claim 33, wherein the CoQ10 is comprised within a liposome and/or otherwise stabilized together with a phospholipid.
35. The use of claim 33, wherein the subject has lung cancer.
36. The use of claim 33, wherein the subject has one or more of asthma, allergies, chronic obstructive pulmonary disease, chronic bronchitis, acute itis, emphysema, cystic fibrosis, pneumonia, tuberculosis, ary edema, acute respiratory distress syndrome, pneumoconiosis, interstitial lung disease, pulmonary edema, pulmonary embolism, pulmonary ension, pleural effusion, pneumothorax, mesothelioma, ophic lateral sis, and myasthenia gravis.
37. The use of claim 33, n the dispersion of particles has an average diameter between 30 and 500 nm.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201161498505P | 2011-06-17 | 2011-06-17 | |
US61/498,505 | 2011-06-17 | ||
NZ619041A NZ619041B2 (en) | 2011-06-17 | 2012-06-18 | Inhalable Coenzyme Q10 formulations and methods of use thereof |
Publications (2)
Publication Number | Publication Date |
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NZ718495A NZ718495A (en) | 2017-12-22 |
NZ718495B2 true NZ718495B2 (en) | 2018-03-23 |
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