U.S. patent application number 17/140752 was filed with the patent office on 2021-05-06 for methods of identifying potential components for targeted drug delivery compositions.
The applicant listed for this patent is Warsaw Orthopedic, Inc.. Invention is credited to Roger E. Harrington, Victor Kelley, Josee Roy.
Application Number | 20210132023 17/140752 |
Document ID | / |
Family ID | 1000005331540 |
Filed Date | 2021-05-06 |
United States Patent
Application |
20210132023 |
Kind Code |
A1 |
Roy; Josee ; et al. |
May 6, 2021 |
METHODS OF IDENTIFYING POTENTIAL COMPONENTS FOR TARGETED DRUG
DELIVERY COMPOSITIONS
Abstract
Methods of preparing compositions for preferential distribution
of active agents to injury sites are provided. The compositions may
comprise a polymer with hydrophilic properties and one or more
active agents, such as compounds comprising hydrophilic metal ions.
Because the delivery ligand and the active agent are specifically
selected so the interactions between them are mainly of an ionic
nature. Methods of identifying suitable components for such
compositions are also disclosed.
Inventors: |
Roy; Josee; (Memphis,
TN) ; Kelley; Victor; (Cordova, TN) ;
Harrington; Roger E.; (Collierville, TN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Warsaw Orthopedic, Inc. |
Warsaw |
IN |
US |
|
|
Family ID: |
1000005331540 |
Appl. No.: |
17/140752 |
Filed: |
January 4, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14621004 |
Feb 12, 2015 |
10883976 |
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17140752 |
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12731822 |
Mar 25, 2010 |
8956667 |
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14621004 |
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61163565 |
Mar 26, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 33/15 20130101;
A61K 47/60 20170801; A61K 33/06 20130101 |
International
Class: |
G01N 33/15 20060101
G01N033/15; A61K 47/60 20060101 A61K047/60; A61K 33/06 20060101
A61K033/06 |
Claims
1. A method of preparing compositions for preferential distribution
of active agents, the method comprises: preparing a solution
comprising a delivery ligand comprising polyethylene glycol and one
or more active agents comprising a magnesium salt; subjecting the
solution to one or more conditions to induce separation of phases
in the solution; and isolating a phase comprising delivery
ligand-active agent complexes.
2. The method of claim 1, wherein the isolated phase has a
concentration of delivery ligand-active agent complexes above a
threshold concentration.
3. The method of claim 1, wherein the delivery ligand and the at
least one active agent are selected so the interaction between them
is mainly of an ionic nature.
4. The method of claim 1, wherein the solution comprises between
about 10% and about 60% weight per volume of the delivery
ligand.
5. The method of claim 1, wherein the polyethylene glycol has a
molecular weight of about 200 Da to about 24,000 Da.
6. The method of claim 1, wherein the magnesium salt is magnesium
chloride.
7. The method of claim 1, wherein the concentration of the active
agent in the solution is about 0.8%.
8. The method of claim 1, wherein the magnesium salt is magnesium
sulfate.
9. The method of claim 1, wherein the solution comprises between
about 30 and about 40% of the delivery ligand.
10. A method of identifying potential components for compositions
for preferential distribution of active agents, the method
comprises: preparing a solution comprising a delivery ligand
comprising polyethylene glycol and one or more active agents
comprising a magnesium salt; subjecting the solution to one or more
conditions to induce separation of phases in the solution; and
determining whether one or more phases comprise delivery
ligand-active agent complexes.
11. The method of claim 10, wherein one or more phases have a
concentration of delivery ligand-active agent complexes above a
threshold concentration.
12. The method of claim 10, wherein the delivery ligand and the at
least one active agent are selected so the interaction between them
is mainly of an ionic nature.
13. The method of claim 10, wherein the solution comprises between
about 10% and about 60% weight per volume of the delivery
ligand.
14. The method of claim 10, wherein the polyethylene glycol has a
molecular weight of about 200 Da to about 24,000 Da.
15. The method of claim 10, wherein the magnesium salt is magnesium
chloride.
16. The method of claim 10, wherein the concentration of the active
agent in the solution is about 0.8%.
17. The method of claim 10, wherein the magnesium salt is magnesium
sulfate.
18. The method of claim 10, wherein the solution comprises between
about 30 and about 40% of the delivery ligand.
Description
FIELD OF THE INVENTION
[0001] This invention relates to methods of identifying
compositions for targeted drug delivery.
BACKGROUND OF THE INVENTION
[0002] Targeted delivery of therapeutic agents to specific organs
is a highly challenging, exponentially developing area of
experimental and translational biomedicine. In traditional drug
delivery systems, after the patient is administered a therapeutic
agent, the agent is distributed throughout the patients' body via
the systemic blood circulation. Because only a small amount of the
therapeutic agent can reach the organ on which it needs to act, a
high initial dose of the therapeutic agent needs to be administered
to the patient. Administering a high dose of therapeutic agent to a
patient is likely to increase the systemic concentration of the
therapeutic agent, which may have an adverse effect on the
patient's healthy organs. If targeted delivery is successful, it
would result in a significant reduction in drug toxicity, reduction
of the drug dose, and increased treatment efficacy.
[0003] Accordingly, there is a need in the art for compositions
that enable targeted delivery of therapeutic agents to specific
organs and for methods of preparing such compositions.
SUMMARY OF THE INVENTION
[0004] In one aspect of the invention, methods of identifying
potential components for compositions for preferential distribution
of active agents to injury sites are provided. Such methods
comprise preparing a solution comprising a delivery ligand and one
or more active agents, subjecting the solution to one or more
conditions to induce separation of phases in the solution, and
determining whether one or more phases comprise delivery
ligand-active agent complexes, which may be above a threshold
concentration.
[0005] In another aspect of the invention, methods of preparing
compositions for preferential distribution of active agents to
injury sites are provided. Such methods comprise preparing a
solution comprising a delivery ligand and one or more active
agents; subjecting the solution to one or more conditions to induce
separation of phases in the solution, and isolating a phase
comprising delivery ligand-active agent complexes, which may be
above a threshold concentration.
[0006] The delivery ligands may comprise a polymer with hydrophilic
properties, while the active agent can comprise a metal ion with
hydrophilic properties. Such metal ions are capable of forming
complexes with the delivery ligand by forming ionic bonds through
electrostatic attraction to certain heteroatoms of the ligand, for
example, N, O and S atoms. The type of ionic bond can vary
including electron sharing between one or more metal molecules and
one or more subunits present on one or more ligand molecules. The
metal counterion may also participate in the formation of the
complex with the delivery ligand.
[0007] Additional features and advantages of various embodiments
will be set forth in part in the description that follows, and in
part will be apparent from the description, or may be learned by
practice of various embodiments. The objectives and other
advantages of various embodiments will be realized and attained by
means of the elements and combinations particularly pointed out in
the description and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
[0008] For the purposes of this specification and appended claims,
unless otherwise indicated, all numbers expressing quantities of
ingredients, percentages or proportions of materials, reaction
conditions, and other numerical values used in the specification
and claims, are to be understood as being modified in all instances
by the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the following specification
and attached claims are approximations that may vary depending upon
the desired properties sought to be obtained by the present
invention. At the very least, and not as an attempt to limit the
application of the doctrine of equivalents to the scope of the
claims, each numerical parameter should at least be construed in
light of the number of reported significant digits and by applying
ordinary rounding techniques.
[0009] Notwithstanding that the numerical ranges and parameters
setting forth the broad scope of the invention are approximations,
the numerical values set forth in the specific examples are
reported as precisely as possible. Any numerical value, however,
inherently contains certain errors necessarily resulting from the
standard deviation found in their respective testing measurements.
Moreover, all ranges disclosed herein are to be understood to
encompass any and all subranges subsumed therein. For example, a
range of "1 to 10" includes any and all subranges between (and
including) the minimum value of 1 and the maximum value of 10, that
is, any and all subranges having a minimum value of equal to or
greater than 1 and a maximum value of equal to or less than 10,
e.g., 5.5 to 10.
[0010] It is noted that, as used in this specification and the
appended claims, the singular forms "a," "an," and "the," include
plural referents unless expressly and unequivocally limited to one
referent.
[0011] In one aspect of the invention, methods of identifying
potential components for compositions for preferential distribution
of active agents to injury sites are provided. Such methods
comprise preparing a solution comprising a delivery ligand and one
or more active agents, subjecting the solution to one or more
conditions to induce separation of phases in the solution, and
determining whether one or more phases comprise delivery
ligand-active agent complexes, which can be above a threshold
concentration.
[0012] The term "injury site," as used herein, refers to an organ
affected by a biological condition known to cause vessels supplying
the organ to leak. Leaky blood vessels allow abnormal entrance or
escape of a fluid substance such as blood and protein rich exudate
from blood vessels. Biological conditions known to cause leaks in
the vessels include, but are not limited to, conditions that cause
swelling, such as acute and chronic inflammation; and conditions
that cause angiogenesis, such as cancer and degenerative diseases
including age-related macular degeneration and diabetic
retinopathy.
[0013] In another aspect of the invention, methods of preparing
compositions for preferential distribution of active agents to
injury sites are provided. Such methods comprise preparing a
solution comprising a delivery ligand and one or more active
agents; subjecting the solution to one or more conditions to induce
separation of phases in the solution, and isolating a phase
comprising delivery ligand-active agent complexes, which can be
above a threshold concentration.
[0014] A solution comprising a delivery ligand and one or more
active agents may be prepared by mixing a delivery ligand and one
or more active agents in a biological carrier, such as saline
solution or water. The delivery ligand and one or more active
agents are specifically selected so the interactions between them
are mainly of an ionic nature. The interactions between the
delivery ligand and the active agent may be defined as a
"chelation" like effect and is based mainly on ionic interactions
between the delivery ligand and the at least one active agent. For
example, although polyethylene glycol (PEG) as a whole is
non-ionic, the free electron pairs on the heteroatoms on the PEG
chains impart an anionic character to the polymer and can bind to a
cation, such as Mg.sup.2.
[0015] The initial solution can comprise between about 10% to 60%
of the ligand and about 0.1% to about 20% of the active agent
(percent weight per volume or g of ligand or active agent/100 ml
solution). The concentration of the delivery ligand in the instant
compositions depends on the number of chelation sites in the
delivery ligand. The delivery ligands are composed of repeating
sub-units of one or more types, some of which include chelation
sites. Delivery ligands with higher molecular weight are composed
of a higher number of sub-units, and thus they are more likely to
have more chelation sites than delivery ligands with lower
molecular weight. Accordingly, as a general rule, the concentration
of the delivery ligand with higher molecular weight in the
composition may be lower than the concentration of the delivery
ligand comprising the same sub-units and having a lower molecular
weight.
[0016] Compounds suitable for use as delivery ligands in instant
methods may meet the following criteria: 1) they are water soluble;
2) they are rapidly cleared from the intact blood vessels and
excreted; 3) they accumulate preferentially where the blood vessels
are damaged; 4) they possess hydrophilic properties; and 5) they
include chelation sites suitable for binding with cations.
[0017] As noted above, it is desirable that the delivery ligands
are rapidly excreted from the body when the blood vessels are
intact. Accordingly, suitable delivery ligands can have a half-life
less than 3 hours, less than 2 hours, or less than 1.5 hours. The
rate of excretion, or half-life, of a delivery ligand is related to
the molecular weight of the ligand, with higher molecular weight
ligands having longer half-lives. Furthermore, for the same
molecular weight, hydrophilic ligands have shorter half-lives than
more hydrophobic ligands. Hydrophilic ligands that can be excreted
mostly unchanged through urine have shorter half-life than ligands
that requires some transformation before excretion. For example,
since 24,000 DA is the cut-off for glomerular filtration, any
ligand heavier than 24,000 DA needs to be degraded to some extent
before it can be excreted, which adds to its half-life. Delivery
ligands may be selected from polymers with hydrophilic properties
having a molecular weight less than 24,000 DA.
[0018] The delivery ligand may be selected from a hydrophilic or an
amphipathic polymer. The term "hydrophilic polymer," as used
herein, means any macromolecule comprising of one or more repeating
units, which exhibit an affinity for or attraction to water
molecules, connected to each other in chained and/or branched
structures. The hydrophilic polymer may be selected from synthetic
or naturally occurring polymers.
[0019] Naturally occurring hydrophilic compound include, but are
not limited to: proteins such as collagen and derivatives thereof,
fibronectin, albumins, globulins, fibrinogen, and fibrin, with
collagen particularly preferred; carboxylated polysaccharides such
as polymannuronic acid and polygalacturonic acid; aminated
polysaccharides, particularly the glycosaminoglycans, e.g.,
hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin
sulfate, keratosulfate and heparin; methyl cellulose, sodium
carboxylmethyl cellulose and activated polysaccharides such as
dextran and starch derivatives.
[0020] Useful synthetic hydrophilic agents include, but are not
limited to: polyalkylene oxides, particularly polyethylene glycol
and poly(ethylene oxide)-poly(propylene oxide) copolymers,
including block and random copolymers; polyols such as glycerol,
polyglycerol (particularly highly branched polyglycerol),
poly(polyethylene glycol methacryalte), poly(glycerol
methacrylate), poly(glycerol acrylatete), poly(polyethylene glycol
acrylate), poly(alkyl oxazoline), phosphoryl choline polymers,
sodium and potassium polymethacrylate, sodium and potassium
polyacrylate, polymethacrylatic acid and polyacrylic acid,
propylene glycol and trimethylene glycol substituted with one or
more polyalkylene oxides, e.g., mono-, di- and tri-polyoxyethylated
glycerol, mono- and di-polyoxyethylated propylene glycol, and mono-
and di-polyoxyethylated trimethylene glycol; polyoxyethylated
sorbitol, polyoxyethylated glucose; acrylic acid polymers and
analogs and copolymers thereof, such as polyacrylic acid per se,
polymethacrylic acid, poly(hydroxyethyl-methacrylate),
poly(hydroxyethylacrylate), poly(methylalkylsulfoxide
methacrylate), poly(methylalkylsulfoxide acrylate) and copolymers
of any of the foregoing, and/or with additional acrylate species
such as aminoethyl acrylate and mono-2-(acryloxy)-ethyl succinate;
polymaleic acid; poly(acrylamides) such as polyacrylamide per se,
poly(methacrylamide), poly(dimethylacrylamide), and
poly(N-isopropyl-acrylamide); poly(olefinic alcohol)s such as
poly(vinyl alcohol); poly(N-vinyl lactams) such as poly(vinyl
pyrrolidone), poly(N-vinyl caprolactam), and copolymers thereof;
polyoxazolines, including poly(methyloxazoline) and
poly(ethyloxazoline); and polyvinylamines.
[0021] The term "amphipathic polymer," as used herein, refers to
any macromolecule which have localized quantum variations in charge
giving rise to polar substructures and non-polar substructures. The
polar substructures evidence an affinity for or attraction to other
polar molecular structures such as water molecules (hydrophilic),
while the nonpolar substructures exhibit an affinity or attraction
for nonpolar molecules such as lipids, oils, greases, fats, etc.
(lipophilic). Suitable amphipathic polymers include, but are not
limited to, poloxamer P-188, polyetherester copolymers such as
polyethylene glycol and polylbutylene terephthalate copolymers,
polyethylene glycol and polypropylencoxide copolymers, polyethylene
glycol and polypropylene glycol block copolymers.
[0022] The amphipathic polymers also include a family of
polyetheramines known as Jeffamine.RTM.. These polyetheramines
contain primary amino groups attached to the end of a polyesther
backbone, which is typically based on propylene oxide (PO),
ethylene oxide (EO), or a mixture thereof. The Jeffamine.RTM.
family includes monamines, diamines, triamines and secondary
amines. Jeffamine.RTM. may be procured from Huntsman Corporation,
headquartered in The Woodlands, Texas.
[0023] In some embodiments, the delivery ligand may comprise
polyethylene glycol (PEG). PEG of molecular weights between about
200 and 24000 DA may be used or, more preferably, between about
1000 to 6000 DA are suitable for use as delivery ligands in instant
compositions. PEGs of different molecular weights may be obtained
from, for example, Sigma-Aldrich, St. Louis, Mo., USA.
[0024] The term "active agent," as used herein, refers to a
chemical element or compound that alleviates signs or symptoms of
the biological condition affecting the targeted organ and causing
vessels to leak. In various embodiments, the chemical structure of
the delivery ligand and the active agent is selected so they can
form a complex with the delivery ligand mainly based on
interactions of ionic nature.
[0025] In some embodiments, the active agent may be selected from
metal ions or compounds that include such ions. Suitable active
agents include, but are not limited to monodentate metal ions, such
as potassium and lithium; bidentate ions, such as magnesium and
calcium; transition metal ions, such as iron, zinc and copper, as
well as more complex ions. Such metal ions are capable of forming
complexes with the delivery ligand by forming ionic bonds through
electrostatic attraction to certain heteroatoms of the delivery
ligand, for example, N, O and S atoms. The type of ionic bond can
vary including electron sharing between one or more metal molecule
and one or more subunit present on one or more polymer molecules.
The metal counterion may also participate in the formation of the
complex with the delivery ligand.
[0026] In one embodiment, the active agent comprises a magnesium
compound. Various magnesium salts may provide a source for the
magnesium ions. Suitable magnesium salts include, but are not
limited to, magnesium sulfate, magnesium carbonate, magnesium
chloride, magnesium oxide and magnesium hydroxide or any
combination thereof. The concentration of the active agent in the
instant compositions may range between about 0.1% to about 20%
weight per volume. These compounds are readily available
commercially from, for example, Sigma Aldrich, St. Louis, Mo.,
USA.
[0027] Next, the solution is subjected to one or more conditions
that induce separation of phases in the solution. Suitable
conditions that may induce separation of phases may include, but
are not limited to, heat, change in pH, mechanical forces including
agitation, time and so forth. For example, autoclaving a solution
comprising PEG and magnesium leads to formation of two liquid
phases with different densities.
[0028] Whether a phase contains the delivery ligand-active agent
complexes above a certain threshold may in some instances be
detectable by eye. Otherwise, it can be detected using analytical
methods, such as spectroscopy, microscopy, spectrometry, and so
forth. If no phase has a concentration of the delivery
ligand-active agent complexes above a certain threshold, the
solution or the phase with the highest concentration of the
delivery ligand-active agent complexes may be subjected to
additional conditions to induce further separation. Similarly,
after the phase with a concentration of delivery ligand-active
agent complexes above a certain threshold is isolated from the rest
of the solution, the rest of the solution or the phase with the
next highest concentration may be subjected to more vigorous
conditions. If the concentration of the delivery ligand-active
agent complexes does not rise to the threshold level even after
subjecting the solution to numerous conditions, it is likely that
the particular combination of the delivery ligand and active agent
used in the test is not suitable for instant compositions.
[0029] The phase with a concentration of delivery ligand-active
agent complexes above a certain threshold is isolated from the rest
of the solution. The desired phase may be isolated by filtering,
micro-filtering, centrifuging, ultra-centrifuging, settling,
decanting or a combination of these.
[0030] In addition to the delivery ligand and the active agents,
the instant compositions may include one or more pharmaceutically
acceptable carriers. The instant compositions may include
excipients such as solvents, binders, fillers, disintegrants,
lubricants, suspending agents, surfactants, viscosity increasing
agents, buffering agents, antimicrobial agents, among others. Many
different pharmaceutically acceptable carriers and excipients are
known and disclosed, for example, in Remington's Pharmaceutical
Sciences, Lippincott Williams & Wilkins; 21 edition (May 1,
2005).
[0031] In some embodiments, the instant compositions are prepared
for parenteral administration. Parenteral administration is
generally characterized by a subcutaneous, intramuscular, or
intravenous injection. Instant compositions for parenteral
administration may be prepared as liquid solutions or solid forms
suitable for solution prior to injection.
[0032] Although the invention herein has been described with
reference to particular embodiments, it is to be understood that
these embodiments are merely illustrative of the principles and
applications of the present invention. It is therefore to be
understood that numerous modifications may be made to the
illustrative embodiments and that other arrangements may be devised
without departing from the spirit and scope of the present
invention which is defined by the following claims.
* * * * *